Furylated Flavonoids: Fully Biobased Building Blocks Produced by

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Furylated flavonoids: fully biobased building blocks produced by condensed tannins depolymerization Laurent Rouméas, Guillaume Billerach, Chahinez Aouf, Eric Dubreucq, and Helene Fulcrand ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b03409 • Publication Date (Web): 01 Nov 2017 Downloaded from http://pubs.acs.org on November 3, 2017

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ACS Sustainable Chemistry & Engineering

Furylated flavonoids: fully biobased building blocks produced by condensed tannins depolymerization Laurent Rouméas†‡§, Guillaume Billerach†, Chahinez Aouf†, Éric Dubreucq‡, Hélène Fulcrand†* †

‡

INRA, UMR 1083 SPO – 2 place Pierre Viala – 34060 Montpellier (FRANCE)

Montpellier-SupAgro UMR 1208 IATE – 2 place Pierre Viala – 34060 Montpellier (FRANCE) §

Université de Montpellier – place Eugène Bataillon – 34090 Montpellier (FRANCE) *E-mail: [email protected]

KEYWORDS : biomass, biobased aromatic, polyphenols, furan derivatives, hemisynthesis

ABSTRACT : An original method had been set up to produce fully bio-based phenolic building blocks from condensed tannins, largely available from agro-industrial residues or wood industry co-products. The acid-catalyzed depolymerization of condensed tannins in the presence of furan or sylvan in mild conditions (30-40 °C – 0.1 M HCl) gives the corresponding furylated flavonoids with high yields. The reaction was more efficient with sylvan than with the less nucleophilic furan. A key feature of the products is the high stability of the flavanyl to furyl C-C linkage compared to the thioether bond obtained by the classical thiolysis, which makes them promising platform molecules for further functionalization, including in alkaline conditions. The simplicity of the process makes it easy to scale-up, and the reaction can be carried out on raw

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plant materials directly. In accordance with green chemistry concepts, solvents and excess reagents can readily be recovered by distillation and recycled.

INTRODUCTION In order to reduce both the dependency of the chemical industry on oil resources and the impact of petrochemicals on the environment and human health, development of biorefining processes to produce chemical compounds from natural resources is becoming increasingly important1. Aside from specialty molecules, this includes the production of biobased platform molecules (i.e., basic chemicals that are used as a starting point for a whole range of other compounds)2. Among the numerous petroleum-derived building blocks to be substituted, aromatic compounds represent a real challenge. Indeed, they are widely used for many industrial applications due to their specific physico-chemical properties3. Numerous works have strived to convert biomass directly into “drop-in” chemicals (i.e., substituting synthetic chemicals with identical compounds from an alternative source). Examples of this are BTX (benzene, toluene, xylene) which can be obtained by catalytic conversion of ligneous materials4. Although this strategy allows the direct integration of bio-derived chemicals into already existing industrial processes, it does not solve the problem of “over-use” of traditional petrochemical compounds, such as the controversial bisphenol A5,6, phthalates7,8, or parabens9,10, which are used so widely that they now constitute contamination on a planetary level and continuous exposure for numerous living species, including humans11,12. The past decade has witnessed a growing interest in the use of natural polyphenols in the chemical industry, such as flavonoids or phenolic acids, mostly as food additives and materials13. Within the vast collection of natural polyphenols, condensed tannins (proanthocyanidins) are nevertheless the most abundant in the higher plants


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biomass after lignin14. Condensed tannins are found in high amounts in numerous and diverse natural resources, such as unused biomasses like bark, needles, and leaves15, or in agro-industrial by-products such as fruit marcs from wine and cider making, for example16. Condensed tannins are oligomers and/or polymers of polyaromatic and polyfunctional molecules classified as flavan-3-ols17. Many structures and configurations occur naturally, although proanthocyanidins are mainly (epi)catechin polymers, also called procyanidins. Contrary to lignins, condensed tannins can be easily depolymerized into monomer units18. This represents a highly interesting opportunity to obtain biobased phenolic building blocks19. Under acidic conditions, the interflavanoid bonds connecting the sub-units within the polymeric chains are cleaved according to a heterolytic process that is initiated by the protonation of the strongly activated phloroglucinolic A-ring of flavonoid sub-units (Scheme 1).


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Scheme 1. General mechanism of acid-catalyzed depolymerization of procyanidins, the most abundant type of proanthocyanidins. The extension units are released as carbocations (relatively stabilized by quinone methide resonance forms) that can react to form new bonds, thus leading to an equilibrium between polymerized and cleaved forms. Under these conditions, a redistribution of the polymers by random repolymerization thus occurs and limit the monomer yield. However, this equilibrium can be displaced in the presence of nucleophilic scavengers. In this case, the depolymerization produces the terminal flavonoid units in their constitutive forms, whereas the reaction of the nucleophiles with the carbocation intermediates results in flavonoid derivatives. It is hence possible to generate the constitutive monomers of proanthocyanidins, i.e., (epi)catechins 1, in a mixture with the flavonoid derivatives of the extension (epi)catechins units (Scheme 1)20. The depolymerization of condensed units is commonly used for structural tannin analysis. The constitutive units released by the depolymerization of proanthocyanidins can readily be identified and quantified by HPLC coupled to an UV-detector21. These analytical methods are generally considered as sufficiently efficient to provide the exact average composition of proanthocyanidins. Only two kinds of nucleophilic scavengers are usually employed to react with the carbocationic intermediates generated from tannin depolymerization: mercaptans (e.g., thioglycolic acid22, benzyl mercaptan23, thiophenol24, 2-mercaptoethanol25 or cysteamine26) and activated aromatic compounds (phloroglucinol27 or, more surprisingly, pyrogallol28 ; Scheme 1). Inspired by the analytical methods based on thiolysis (i.e., depolymerization under acidic conditions in the presence of a mercaptan), some studies have aimed at producing monomers from proanthocyanidins on a gram scale26,29–31. These works have been designed to produce flavonoid derivatives usable per se, in particular as antioxidants26,30. In other applications of


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these thioetherified flavonoids, the sulfured group is substituted by a specific group of interest29. Indeed, the extension units obtained as thioetherified derivatives are known to be unstable, especially under alkaline conditions32. At pH values higher than 8.5, the flavanyl-mercaptyl bond is readily cleaved and it becomes possible to substitute the mercaptan with another nucleophile (including flavonoids). Exploited for other purposes, this reactivity sheds light on the instability of the C-S bond of the thioetherified flavonoids under alkaline conditions. Yet, alkaline conditions are commonly used to obtain nucleophilic phenolates, which can be easily functionalized for many industrial applications, such as for the production of phenyl-alkyl-ether by the Williamson ether synthesis. Thus, to produce stable building blocks for other applications it is highly desirable to create C-C linkages instead of C-S linkages between the extension units and the nucleophilic scavengers. Phenolic compounds such as phloroglucinol and pyrogallol should not be considered as relevant nucleophiles for the depolymerizaton of tannins, since they could rather be used directly as building blocks themselves. The seeking for cheap, bio-based, stable, and good nucleophiles able to form C-C bonds with tannin subunits has highlighted furan and its derivatives as possible depolymerization reagents. Furan and sylvan (2-methylfuran) in particular are obtained by industrial catalytic decarbonylation33,34 and hydrogenative reduction35,36, respectively of the carbonyl group of furfural, a major biobased industrial product obtained directly from the acid-catalyzed dehydration of pentoses (e.g., xylose)33. The present work thus focuses on the production of furylated flavonoids by depolymerization of condensed tannins in the presence of furan or sylvan (FEMA GRAS flavoring substance n°4179), according to the concepts of sustainable chemistry. One of the main objectives was to produce fully biosourced building blocks that are sufficiently stable under alkaline conditions to


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allow for the functionalization of their phenolic hydroxyl groups, while avoiding unwanted rearrangements. The resulting building blocks can thus be used in chemistry and polymer formation37,38. Before addressing the depolymerization of tannins by furan or sylvan, this paper re-examines the instability of the thioetherified flavonoids under mild alkaline conditions. Building on that confirmation, a method of depolymerization of condensed tannins by acidolysis using furan and sylvan as innovative nucleophiles was developed in order to produce fully biosourced building blocks. To achieve this objective, the depolymerization reaction was first studied on model proanthocyanidins, and then applied to a natural condensed tannin extract. The reaction was optimized by varying the time, the concentration of tannins, and the acid catalyst. The stability of the furylated products in alkaline medium was then compared to that of thioetherified flavonoids. Lastly, preparative experiments were carried out on an industrial tannin extract and directly on a natural raw material (i.e., bark of the Douglas fir tree) to evaluate the production of the desired derivatives on a multi-gram scale.

EXPERIMENTAL SECTION Reagents and solvents. The tannin extract of white grape seeds (high quality grade) was supplied by the Union of Mediterranean Distilleries (France), and Douglas bark (from Pseudotsuga menziesii) was supplied by Alliance Forêts Bois (France), and was ground so as to achieve a particle size of 6 mm. Procyanidin B2 (≥90%) was purchased from ExtraSynthese (France). 2-mercaptoethanol (≥ 99%), sylvan (2-methylfuran, ≥ 98%), H2SO4 (95-98%), methanesulfonic acid (MsOH, ≥99.5%), NaOH (≥ 98%), and Na2CO3 (≥ 99.5%) were purchased from Sigma-Aldrich (France), furan (≥ 99%) from Acros Organics (France), p-toluenesulfonic


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acid monohydrate (TsOH.H2O, ≥ 99%), boric acid from Prolabo (VWR, France), and fuming HCl (37% aq.) from Carl Roth (France). MeOH (analytical grade), MeCN (analytical grade), Et2O (≥ 99.8%) and petroleum ether (40-60 °C) were purchased from Sigma (France), AcOEt (pure) from Carlo Erba (France), NH4Cl (≥ 99%), Na2SO4 (≥ 98.5%), and NaCl (· 99.8%) were purchased from Carl Roth (France). UPLC-MS analyses. The liquid chromatography system was an Acquity UPLC (Waters, USA) appliance equipped with a photodiode array detector. The monitoring of depolymerization products was carried out at 280 nm. The column (HSS T3, 100 × 2.1 mm, 1.8 µm) was a Nucleosil 120-3 C18 endcapped (Macherey-Nagel, Sweden). The flow rate was 0.55 mL·min-1, and the gradient conditions were as follows: solvent A (H2O-HCOOH, 99/1, v/v), solvent B (CH3CN–H2O–HCOOH, 80/19/1, v/v/v); initial 0.1% B; 0-5 min, 60% B linear; 5-7 min, 99% B linear; 7–8 min, 99% B isocratic; and 8–9 min, 0.1% B linear. The Acquity UPLC system was coupled online with an AmaZon X ESI Trap mass spectrometer (Bruker, Germany). In the source, the nebulizer pressure was 44 psi, the temperature of dry gas was set at 200 °C with a flow of 12 L min-1 and the capillary voltage was set at 4 kV. The mass spectra were acquired over a mass range of 90-1500 Th in the positive ionization mode. The speed of mass spectrum acquisition was set at 8.1 m·z-1·min-1. Chromatographic purifications. Flash-chromatographies were performed on a PF430 system (Interchim, France). The column (35 g) was a prepacked DIOL grafted silica, with a granulometry of 30 µm (Interchim, France). The flow rate was set at 20 mL·min-1. Characterization of the tannin extract (analytical mercaptolysis). Based on optimized depolymerization of tannins with 2-mercaptoethanol30, a solution of the extract was prepared at exactly 2.00 g·L-1 in MeOH. The reagent for mercaptolysis was prepared by the dissolution of 2-


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mercaptoethanol (1.0 mL) in MeOH (9.0 mL). Fuming HCl (167 µL) was then added to this solution. A microtube (1.5 mL) was loaded with 500 µL of tannin extract solution and 500 µL of the mercaptolysis reagent. The microtube was closed and heated for 2 h at 40 °C. The resulting solution was analyzed directly by UPLC-MS. Preparative production of thioetherified flavonoids. The multigram-scale preparation of thioetherified derivatives by acidolysis in the presence of mercaptoethanol, and their purification, were performed as previously described31. Furanolysis and sylvanolysis optimization General procedure. The depolymerization reagent was prepared by mixing the nucleophile (5.0 mL·of furan or sylvan) and MeOH (5.0m L) in equal volumes, and it was then acidified with fuming HCl (167 µL). A microtube (2mL) was loaded with 1.0 mL of the sample solution and 1.0 mL of the depolymerization reagent. To monitor the reaction kinetics, the resulting solution was immediately aliquoted into glass microvials (10×200 µL). The microvials were sealed with aluminum caps using PTFE septa, and then left at the desired temperature. For each time point of the kinetics analysis, one vial was analyzed directly by UPLC-MS. The standard deviation values were calculated from experiments performed in independent triplicates. Procyanidins B2 depolymerization. The sample solution was prepared as 500 mg·L-1 in MeOH. Tannin extract depolymerization. The sample solution was prepared as 2.0 g·L-1 in MeOH. Investigation of the influence of the acid catalyst. For each acid, the depolymerization solution was prepared by dissolving MsOH (130 µL), H2SO4, (56 µL) or TsOH (380 mg) in a solution of sylvan/MeOH 1/1 v/v (10 mL). A microtube was loaded with the tannin solution (500 µL) and the sylvanolysis solution (500 µL) and then left for 1 h at 30 °C.


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Preparative furanolysis of the tannin extract. The tannin extract (5.0 g) was dissolved in MeOH (375 mL) and furan (125 mL). The solution was acidified with fuming HCl (4.17 mL), and the reaction was carried out at 30 °C for 6 h. The reaction was stopped by cooling to 0 °C in an ice bath. An aqueous solution of Na2CO3 (10.6 g·L-1) was added (250 mL). MeOH and furan were evaporated under vacuum, and depolymerized products were extracted with AcOEt (3×100mL). The resulting organic layer was dried over Na2SO4, and evaporated under vacuum, giving rise to a dark brown solid (3.34 g). This residue was extracted by trituration and sonication in Et2O (3×100mL), and washed with an NH4Cl saturated aqueous solution (200 mL). The organic layer was dried over Na2SO4, resulting in a thick light brown powder (2.40 g) containing 1, 2, 5, and 6. This product (150 mg) was purified by flash-chromatography with a gradient of AcOEt/Et2O (0 to 50% v/v). Fractions of interest were combined and dried under vacuum to yield a white powder (54 mg) of 5. Preparative sylvanolysis of the tannin extract. The tannin extract (8.0 g) was dissolved in MeOH (300 mL) and sylvan (100 mL). The solution was acidified with fuming HCl (3.33 mL), and the reaction was carried out at 30 °C for 2 h. The reaction was stopped by cooling to 0 °C in an ice bath. An aqueous solution of Na2CO3 (8.48 g·L-1) was added (250 mL). MeOH and sylvan were evaporated under vacuum, and depolymerized products were extracted with AcOEt (3×100 mL). The resulting organic layer was dried over Na2SO4, and evaporated under vacuum, giving rise to a thick dark brown solid (5.7 g). This residue was extracted by trituration and sonication in Et2O (3×100 mL), and washed with an NH4Cl saturated aqueous solution (200 mL). The organic layer was dried over Na2SO4, yielding a light brown powder (3.72 g) containing 1, 2, 7, and 8. A 300 mg sample of this product was purified by flash-


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chromatography, with a gradient of AcOEt/Et2O (0 to 50% v/v). Fractions of interest were combined and evaporated under vacuum to yield a white powder (99 mg) of 7. NMR and HRMS characterization. NMR spectra acquisitions were obtained with an Avance III HD NMR spectrometer (Brucker, Germany). 1H spectra were obtained at 400MHz, and 13C at 151MHz, both at 25 °C. Samples were dissolved in d6-DMSO. Spectrum acquisitions were done on a Synapt G2-S mass spectrometer (Waters, USA) using the TOF MS ES+ mode. Samples were dissolved in MeOH. 4-(furan-2-yl)-(epi)catechin (5)

White pulverulent solid. 1H NMR δ (ppm) : 9.15 (1H, s, H10), 9.04 (1H, s, H11), 8.82 (1H, s, H3’), 8.72 (1H, s, H4’), 7.55 (d, J=1.7 Hz, H5’’), 6.81 (1H, d, J=1.7 Hz, H2’), 6.66 (1H, d, J=8.1 Hz, H5’), 6.51 (1H, dd, J=1.7/8.1 Hz, H6’), 6.34 (1H, dd, J=1.7/2.9 Hz, H4’’), 5.92 (1H, d, J=2.1 Hz, H6), 5.80 (d, J=2.9 Hz, H3’’), 5,78 (1H, d, J=2.1 Hz, H8) 5.08 (1H, d, J=4.7 Hz, H9), 4.57 (1H, bp, H2), 4.07 (1H, m, H4), 3.94 (1H, m, H3) ; 13C NMR δ (ppm) : 157.3 (C7), 157.1 (C2’’), 157.0 (C5), 155.9 (C8a), 144.7 (C4’), 144.6 (C3’), 141.4 (C5’’), 130.1 (C1’), 117.7 (C6’), 114.9 (C5’), 114.7 (C2’), 110.3 (C4’’), 106.6 (C3’’), 98.2 (C5a), 95.4 (C6), 94.0 (C8), 74.4 (C2), 68.4 (C3), 39.1 (C4). HRMS (ESI, M+H+) found 357.0974 (calculated for C19H16O7 + H : 357.0969). 4-(5-methylfuran-2-yl)-(epi)catechin (7)


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White pulverulent solid; mp 235-236 °C;

1

H NMR δ (ppm) : 9.13 (1H, s, H10), 9.03 (1H, s,

H11), 8.82 (1H, s, H3’), 8.72 (1H, s, H4’), 6.81 (1H, d, J=2.0 Hz, H2’), 6.66 (1H, d, J=8.1 Hz, H5’), 6.52 (1H, dd, J=1.9/7.9 Hz, H6’), 5.92 (1H, d, J=2.3 Hz, H3’’), 5.79 (1H, d, J=2.5 Hz, H3’’), 5.77 (1H, d, J=2.5 Hz, H8), 5.62 (d, J=2.5 Hz, H4’’), 5.05 (1H, d, J=5.0 Hz, H9), 4.61 (1H, bp, H2), 4.03 (1H, m, H4), 3.92 (1H, m, H3), 2.24 (3H, bp, H6’’) ; 13C NMR δ (ppm) : 157.3 (C7), , 157.0 (C5) 155.9 (C8a), 155.3 (C2’’), 144.7 (C4’), 144.6 (C3’), 149.8 (C5’’), 130.1 (C1’), 117.8 (C6’), 114.9 (C5’), 114.7 (C2’), 107.3 (C4’’), 106.3 (C3’’), 98.2 (C5a), 95.3(C6), 94.0 (C8), 74.3 (C2), 68.4 (C3), 39.1 (C4), 13.3 (C6’’). HRMS (ESI, M+H+) found 371.1128 (calculated for C20H18O7 + H : 371.1126) Stability of thioetherified and sylvanyled derivatives under alkaline conditions. A 100 µL sample of the phenolic monomers obtained by mercaptolysis or sylvanolysis (10 g·L-1 in MeOH) was loaded into a 1.5 mL microtube. 900 µL of sodium borate aqueous buffer (0.14 mol·L-1, pH 9.0) was then added to the sample, which was then immediately flushed with argon, stoppered, left at room temperature for 19 h, and then analyzed directly by UPLC-MS. Direct depolymerization/extraction by sylvanolysis of condensed tannins of Douglas fir bark. Douglas bark characterization: Douglas bark (100 mg) was suspended in mercaptolysis reactant (10 mL of a solution of 2-mercaptoethanol:MeOH:fuming HCl 5:5:0.083 v/v/v), and left for 2 h at 40 °C. The mixture was briefly centrifuged and the supernatant was analyzed directly by UPLC-MS. Direct sylvanolysis on Douglas fir bark: Douglas fir bark (10.0 g) was suspended in a mixture of MeOH (75 mL) and sylvan (25 mL). The mixture was acidified with fuming HCl (833 µL) and left at 30 °C under vigorous stirring. The reaction was followed by UPLC-MS. The maximum


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yield of 7 (119 µmol·g-1 of bark) was reached in 2.5 h. The mixture was cooled in an ice bath, filtered through a Büchner funnel and the residue was washed with MeOH (2×30 mL). After the addition of 100 mL of sodium carbonate (5.3 g·L-1 in water), MeOH and sylvan were evaporated under vacuum. The depolymerized products were then extracted with AcOEt (3×100 mL). The organic layer was dried over Na2SO4, giving rise to an oily dark orange solid (1.25 g) containing 1 and 7. This solid was triturated in petroleum ether (3×50 mL) to remove terpenes and lipids. The residue was suspended in Et2O (140 mL) and washed with an NH4Cl saturated aqueous solution (2×50 mL). The organic layer was then dried over Na2SO4 to yield an orange solid (920 mg).

RESULTS AND DISCUSSION Characterization of tannin extract and preparative production of thioetherified derivatives by mercaptolysis. In this work, a commercial extract of white grape seed tannins was used in order to design the new process of depolymerization. This kind of extract is produced industrially by a number of companies and commercialized for various applications. It represents a good example of readily available proanthocyandins, which are essentially composed of polymers of (epi)catechin and (epi)catechin-3-O-gallate. The characterization of this extract was done by an optimized analytical mercaptolysis developed in a prior study31. In this method, tannins were depolymerized by incubating the extract at 1.0 g·L-1 in 2-mercaptoethanol/MeOH 5% v/v with 0.1 mol·L-1 of HCl, at 40 °C for 2h before direct analysis of the reaction products by UPLC-MS (Scheme 2).


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Scheme 2. Depolymerization of grape seed tannins by mercaptolysis25,31. The depolymerization products of procyanidins were identified by MS(+), and they were quantified by UV absorption at 280 nm, which is a relatively specific absorbance wavelength for phenolic compounds. The total content was 486 ± 7 mg (1.51 ± 0.03 mmol) of constitutive flavonoids per gram of tannin extract. After combining the different stereoisomers of each compound, the analyses provided the composition of the procyanidins. The terminal unit content was 509 ± 11 µmol of 1 and 46.6 ± 2 µmol of 2 per gram of tannin extract. The extension units, observed as thioetherified derivatives 3 and 4, amounted to 824 ± 17 µmol·g-1 and 130 ± 4 µmol·g-1, respectively. The results obtained after thiolysis with 2-mercaptoethanol (i.e. mercaptolysis) will serve as indicative reference for the depolymerizable proanthocyanidin content of the tannin extract. A preparative mercaptolysis31 was also performed, in order to assess the stability of thioetherified derivatives under alkaline conditions. For this, the products were solubilized at 1.0 g·L-1 in borate buffer (pH 9.0), and left overnight at room temperature. UPLC analyses show that at pH 9.0, the thioetherified derivatives were drastically degraded, with less than 5% remaining after 19 h (UV chromatograms are available in supporting information). This may be explained by the fact that at high pH, the deprotonation of the phenolic hydroxyl groups makes the aromatic ring very electron rich, while the nucleophilic mercaptan used as an electrophilic scavenger under acidic conditions becomes a good leaving group due to its benzylic position, thereby resulting in a methylene quinone intermediate31. This electrophilic intermediate


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reacts with other deprotonated units by electrophilic aromatic substitution to produce polymers (Scheme 3).

Scheme 3. Base-catalyzed mechanism of rearrangement of thioetherified flavonoids in methylene quinone, leading so to their repolymerization and/or degradation32. Therefore, thiolysis of condensed tannins is useful for analytical purposes but the use of the thioetherified flavonoid derivatives as building blocks is restricted. When phenolic groups have to be converted into more reactive phenolates (as in the Williamson ether synthesis, KolbeSchmitt carboxylation, Reimer-Tiemann formylation etc.), the use of thioetherified flavonoids does not seem suitable.

Furanolysis and sylvanolysis Like phloroglucinol or pyrogallol, furan and sylvan are activated aromatic compounds. Thus, we have postulated that they may react with the carbocationic extension units generated by the acidolysis of condensed tannins (Scheme 1), through electrophilic aromatic substitution. The findings presented below demonstrate that the nucleophilicity of both furan and sylvan is strong enough to make them react with the released carbocation. Depolymerization by acidolysis in the presence of furan or sylvan (then referred to as “furanolysis” or “sylvanolysis”, respectively) produced “furanyled” or “sylvanyled” flavonoids along with tannin terminal units (Scheme 4).


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PROCYANIDINS (condensed tannins from grape seeds)

Furanolysis (R' = H) or sylvanolysis (R' = Me) O R'

OH HO 1

+

(H )

R' = H : furanyled flavanoids R=H:5 R = Gal : 6

O

OH

+2+

OR OH

O R'

Furylated flavanoids

R' = Me : sylvanyled flavanoids R=H:7 R = Gal : 8

Scheme 4. Depolymerization of grape seed tannins by furanolysis or sylvanolysis. Furanolysis and sylvanolysis of the procyanidin dimer B2. Firstly, in order to have a good overview of the reactions, furanolysis and sylvanolysis were performed on the simplest proanthocyanidin model, i.e., the dimeric procyanidin B2 (epicatechin-epicatechin C4-C8) in a solution of 25% v/v of furan or sylvan in acidified MeOH (HCl 0.1 mol·L-1) at 40 °C. The UPLC-MS analyses showed that in both cases, furanolysis and sylvanolysis were complete in less than 10 min (Table 1). Table 1. UPLC-MS results of the products yielded by furanolysis and sylvanolysisa of the procyanidin dimer B2 Area Relative [M+H]+ (Th) (mAU·s) area (%)

Reaction time Compound 0 min (initial) Dimer B2

579

516

100

Epicatechin 1 4-(furan-2-yl)-epicatechin 5

291 357

255 253

49.4 49.2

Epicatechin 1 4-(sylvan-2-yl)-epicatechin 7

291 371

252 257

49.0 50.0

Furanolysis 10 min (end) Sylvanolysis 10 min (end) a

UV chromatograms (280 nm) and mass spectra of dimeric procyanidin B2 at t0 and the resulting products obtained after sylvanolysis completion (10 min) are available in the supporting information. The integration of the UV peak area corresponding to the depolymerization products indicated the nearly total (>98%) recovery of the absorbance signal for dimer B2. No residual dimer was


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detected at the end of the reactions. Moreover, the peak area corresponding to the extension and the terminal units were similar. This suggests (i) that the reaction was complete and (ii) that the molar extinction coefficients of (epi)catechin derivatives are very similar as that of (epi)catechin.

Furanolysis and sylvanolysis of a tannin extract - Optimization of parameters. Different parameters have been altered in order to optimize the reaction in terms of the rate and the yield, as well as the use of solvent and reactants. The optimization experiments were carried out on the commercial tannin extract of white grape seeds. Impact of the temperature on depolymerization kinetics. Using furan or sylvan in a large excess (i.e., furan:MeOH 1:3 v/v, all other parameters remaining equal to those of analytical mercaptolysis), the maximum product concentration, observed after 10 to 30 min with furan and less than 5 min with sylvan, was similar to that obtained by mercaptolysis. At this point in time, however, a progressive degradation of the depolymerization products was observed. To reduce the extent of this degradation and to gain a better control of the reaction kinetics, the temperature was decreased to 30 °C (Figures 1).


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Figure 1. Kinetics of (a) furanolysis and (b) sylvanolysis of a tannin extract at 30°C over 8 h and 4 h, respectively.1: blue squares; 2: green triangles; 5 and 7 from furanolysis and sylvanolysis, respectively: red diamonds (their matching galloylated forms 6 and 8: brown triangles). This lower temperature also allowed furan to be used at atmospheric pressure (since the boiling point of furan is 31 °C). Furanolysis and sylvanolysis produced furanyled and sylvanyled derivatives with yields that were at least as good as those obtained by analytical mercaptolysis, i.e., a yield of 101% for the furanyled derivatives after 120 min of furanolysis, and 103% for the sylvanyled derivatives after 45 min of sylvanolysis (Table 2).


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Table 2. MS identification of depolymerization products and UPLC yields of furanolysis and sylvanolysis of the tannin extract (1.0 g·L-1)

(M+H) (Th)

Yields (µmol·g-1 of tannin extract)

Yields relative to mercaptolysis (%)

+

Monomers a

Furanolysis Terminal units

1 3

291 443

672 ± 26 44 ± 7

135 97

Extension units (furanyled derivatives)

5 6

357 509

832 ± 24 74 ± 2

103 58

Terminal units

1 3

291 443

614 ± 8 53 ± 2

123 116

Extension units (sylvanyled derivatives)

7 8

371 523

815 ± 8 106 ± 4

101 84

Sylvanolysis

a

The different stereoisomers of each monomer were combined (e.g., 1 = catechin + epicatechin). The yields of the recovered (epi)catechin 1 were even better than those of the reference values (135% and 123% for furanolysis and sylvanolysis, respectively), likely due to the lower reaction temperature. The lower yield of galloylated derivatives obtained (58% and 84% for furanolysis and sylvanolysis, respectively) is consistent with previous observations pointing out that galloylated condensed tannins are more resistant to depolymerization39. Investigation of the influence of the acid catalyst. Various acids have been tested, including H2SO4, MsOH, and TsOH, so as to avoid the use of HCl. The latter is highly corrosive (even on stainless steel), which would cause problems with industrialized processes. With the same acid normality (0.1 N in MeOH) and the same tannin concentration (1.0 g·L-1) at 30 °C, the variations between the sylvanolysis yields obtained with HCl as catalyst and those obtained with the other


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strong acids did not exceed 1.2%. The nature of the acid did not seem to influence the reaction efficiency. Nonetheless, due to its ease of use in a laboratory setting, it was decided to retain HCl as the acid catalyst for the next set of experiments. Investigation of the influence of tannin concentration. In order to carry out the reaction with the least amounts of solvent and reactant, while still maintaining good yields, the most efficient concentrations of tannins needed to be determined. Several reactions were carried out by varying tannin concentrations in a solution of 25% v/v of furan or sylvan in MeOH with 0.1 mol·L-1 of HCl, at 30 °C (Table 3). Table 3. Relative reaction yields of furanolysis and sylvanolysis of the tannin extract.

Reaction

Tannin Relative Time period to concentration yieldsa reach the maximum (g·L-1) (%) yield (min)

Furanolysis

1.0

101

90-120

Furanolysis

2.0

93

90-120

Furanolysis

3.0

87

90-240

Furanolysis

5.0

87

240-360

Furanolysis

10

66

240-360

Sylvanolysis

1.0

103

45-60

Sylvanolysis

5.0

104

45-90

Sylvanolysis

10

93

60-90

Sylvanolysis

20

95

60-90

Sylvanolysis

40

89

60-120

Sylvanolysis

80

47

90-120

a

The yields are expressed as the ratios of 5 or 7 concentration (from furanolysis or sylvanolysis, respectively) to the values from analytical mercaptolysis.


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The results clearly show that sylvan allowed a much higher concentration of tannins to be used compared with furan. For furanolysis, more than 10% of entity 5 was lost during a depolymerization carried out with a concentration over 3.0 g·L-1 of tannins, and this loss reached at least 20% above 10 g·L-1. In regard to sylvanolysis, it is possible to sustain a yield of 7 greater than 80% with more than 40 g·L-1 of tannins. This can be explained by the stronger nucleophilic power of sylvan compared to that of furan. Indeed, sylvan is more activated than furan due to the significant inductive electro-releasing effect of the methyl group by hyperconjugation. Moreover, the reaction times required to reach the maximum yields were increased by the tannin concentrations, even when the nucleophile remained in large excess. This observation evidences the competition between the reaction of furan or sylvan with cationic flavonoids, and the repolymerization of the latter. This competition could constitute a limit in terms of the use of highly concentrated reaction conditions. Preparative

production.

The

preparative

production

of

furylated

flavonoids

by

depolymerization was carried out on the industrial tannin extract. The reactions were performed with a concentration of 5.0 g·L-1 of tannins in furan:MeOH 1:3 with 0.1 mol·L-1 of HCl, at 30 °C over 6 h, and at 40 g·L-1 of tannins in sylvan:MeOH 1:3 with 0.1 mol·L-1 of HCl, at 30 °C over 2 h. Following the reaction, HCl was neutralized with a solution of Na2CO3, and the depolymerization products were isolated to a certain extent by liquid/liquid extraction. The resulting mixture was constituted of various stereoisomers of 1 and 2 and their corresponding furanyled flavonoids 5 and 6 or sylvanyled flavonoids 7 and 8, with m/m yields of 48% or 47%, respectively. In order to formally identify the new structures by NMR and HRMS, small amounts of both the furanolysis and the sylvanolysis products were purified by liquid chromatography to obtain


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pure samples of 5 and 7. NMR data confirmed the structures of the expected products. Compared to the epicatechin 1 spectra, 1H and 13C NMR spectra of furanyled and sylvanyled derivatives 5 and 7 show the introduction of the furan or the sylvan ring. Indeed, the disappearance of the signal of one 1H on the carbon C4, and the deshielding of the other one to 4.07 ppm indicate the bonding of the furan ring on this position. This was also confirmed by the HSQC 1J correlation of the carbon Cf2 and the hydrogen bonded by the carbon C4.

Stability of products in alkaline conditions. To assess the stability of the sylvanyled derivatives (and of the furanyled ones by extrapolation) under alkaline conditions, the mixture of depolymerization products obtained by sylvanolysis and isolated by liquid-liquid extraction were dissolved in an alkaline borate buffer (pH 9.0), and left overnight at room temperature. The UV chromatogram of the sample after 19 h in the borate buffer indicates that more than 98% of the sylvanyled derivative 7 remained unchanged (whereas in the same time period, 7.4% of the constitutive (epi)catechin 1 was degraded). In contrast with the instability of thioetherified flavonoids, this confirms the stability of furylated derivatives in alkaline media (UV chromatograms are available in supporting information).

Direct depolymerization/extraction by sylvanolysis of condensed tannins of Douglas fir bark. In order to design an industrial process to produce phenolic building blocks in accordance with green chemistry concepts, it is necessary to minimize the number of process steps, while maintaining productivity at a maximal level. For this, carrying out the depolymerization directly on the biomass may overcome the extraction issues resulting from the poor solubility of condensed tannins with high degree of polymerization and from their association to plant tissues


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(e.g., cell wall matrix) by weak or even covalent bonding40. The one-pot reaction was developed using Douglas fir bark, a cheap and widely available by-product of the timber industry, as a raw material. Tannin analysis of the Douglas bark sample by analytical mercaptolysis showed a potential of 129 ± 4.9 µmol (47.2 ± 2 mg) of thioetherified flavonoids per gram of Douglas bark, i.e. 4,7% of DW. Sylvanolysis was performed on 10 g of bark at a concentration of 100 g·L-1 in a depolymerization solution consisting of sylvan:MeOH:HCl (37% aq.) 25/75/0.83 (v/v/v). The maximum quantity of sylvanyled (epi)catechin (119 µmol·g-1 or 44.2 ± 2 mg·g-1 of bark) was reached in 2.5 h, corresponding to 92% of the value obtained by analytical mercaptolysis. After filtration, liquid/liquid extraction and delipidation, 920 mg of a mixture of monomeric flavonoids including taxifolin, terminal (epi)catechin units, and 398 mg of sylvanyled derivatives 7 were isolated, representing 9 and 4% respectively of DW.

CONCLUSIONS Condensed tannins can be depolymerized by acidolysis in the presence of furan or sylvan as nucleophiles to obtain furyl- or sylvanyl-(epi)catechin. In analytical conditions (performed on diluted proanthocyanidin solutions at 1.0 g·L-1), the yields are comparable to those obtained with traditional mercaptan nucleophiles. Gram-scale production of fully biosourced phenolic building blocks by tannin depolymerization can readily be carried out with a simple acid catalysis at moderate temperatures in methanol as solvent. Various kinds of acids can be used, including sulfuric acid (cheaper and less corrosive than hydrochloric acid), or sulfonic acid. Polymer supported acids can also be used when the depolymerization is carried out on soluble tannin extracts. The reaction requires significant amounts of furan or sylvan, but the unreacted excesses are readily recoverable by simple


22

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distillation, due to their low boiling point (31 °C and 63 °C for furan and sylvan, respectively). Moreover, furan and sylvan are liquids, which make them suitable for use in chemical industrial processes. In the case of furan, the main constraint in the process is the low limit of tannin concentration compatible with good yields. The one-pot depolymerization/extraction of condensed tannins in raw biomass to produce fully biobased phenolic building blocks is currently under development at pilot-scale in view of several industrial applications41,42.

Perspectives in the field of biobased materials The furylated flavonoids, stable in alkaline condition, constitute new fully biobased aromatic building blocks that can be further functionalized on the phenolic hydroxyl groups (examples given on Scheme 5). In this respect, we developed and patented42 the production of epoxy prepolymers or polyamine hardener from the building blocks presented herein. Furthermore, the presence of the furan ring offers additional possible functionalizations, via Friedel-Craft or Diels-Alder reaction for instance. Hence, the polyphenol-furan building blocks display bi-functional moieties.


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Scheme 5. Possible functionalizations of furylated flavonoid derivatives for the curing of thermosetting biobased resins:

a

phenolic resins,

b

polyepoxy,

c

polyesters,

d

vinylesters,

e

polyurethane, fpolyamide, gpolycarbonates, hradical polymerized resins.

ASSOCIATED CONTENT Supporting Information. NMR spectra 1H, 13C, HSQC-DEPT & HMBC, and HRMS spectra of compounds 5 and 7, MS spectra and UPLC-UV chromatograms of dimeric proanthocyanidin B2 and its products from sylvanolysis, as well as UPLC-UV chromatograms of the products of tannins depolymerization by mercaptolysis and sylvanolysis are available free of charge (PDF). AUTHOR INFORMATION Corresponding Author


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*E-mail: [email protected] ORCID: 0000-0002-6035-1457 Funding Sources The authors are grateful to Region Languedoc-Roussillon and to the University of Montpellier for the funding of the PhD salary, which enabled to carry out the present research work. Notes The authors declare no competing financial interest. REFERENCES (1) Goldstein, I. S. Potential for Converting Wood into Plastics: Chemicals from wood may regain importance as the cost of petroleum continues to rise. Science 1975, 189 (4206), 847–852. (2) Dodds, D. R.; Gross, R. A. Chemicals from Biomass. Science 2007, 318 (5854), 1250– 1251. (3) Franck, H.-G.; Stadelhofer, J. W. Industrial Aromatic Chemistry: Raw Materials · Processes · Products; Springer Science & Business Media, 2012. (4) Elfadly, A. M.; Zeid, I. F.; Yehia, F. Z.; Rabie, A. M.; Aboualala, M. M.; Park, S.-E. Highly selective BTX from catalytic fast pyrolysis of lignin over supported mesoporous silica. Int. J. Biol. Macromol. 2016, 91, 278–293. (5) Morrissey, R. E.; George, J. D.; Price, C. J.; Tyl, R. W.; Marr, M. C.; Kimmel, C. A. The developmental toxicity of bisphenol A in rats and mice. Fundam. Appl. Toxicol. Off. J. Soc. Toxicol. 1987, 8 (4), 571–582. (6) Beronius, A.; Rudén, C.; Håkansson, H.; Hanberg, A. Risk to all or none? A comparative analysis of controversies in the health risk assessment of Bisphenol A. Reprod. Toxicol. 2010, 29 (2), 132–146. (7) Schettler, T. Human exposure to phthalates via consumer products. Int. J. Androl. 2006, 29 (1), 134–139. (8) Heudorf, U.; Mersch-Sundermann, V.; Angerer, J. Phthalates: Toxicology and exposure. Int. J. Hyg. Environ. Health 2007, 210 (5), 623–634. (9) Golden, R.; Gandy, J.; Vollmer, G. A review of the endocrine activity of parabens and implications for potential risks to human health. Crit. Rev. Toxicol. 2005, 35 (5), 435–458. (10) Darbre, P. D.; Harvey, P. W. Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks. J. Appl. Toxicol. 2008, 28 (5), 561–578. (11) Groff, T. Bisphenol A: invisible pollution. Curr. Opin. Pediatr. 2010, 22 (4), 524–529. (12) F. Botta, V. Dulio. Résultats de le l'étude prospective 2012 sur les contaminants émergents dans les eaux de surface continentales de la métropole et des DOM. Rapport final, DRC-13136939-12927A, 2014.


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SYNOPSIS. The depolymerization of condensed tannins (proanthocyanidins) by mild acidolysis with furan derivatives gives new fully biobased phenolic building-blocks.


28

Furylated Flavonoids: Fully Biobased Building Blocks Produced by

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