Diaryl Ether Compound and Manufacturing Method from Lignin

The invention relates to a diaiyl ether compound and a method for the manufacture of the diaiyl ether compound from lignin.

BACKGROUND

Lignin is an amorphous polymer that comprises aromatic repeat units. Lignin contains the following repeat units and may contain other repeat units

R = H or OMe

Lignin is a sustainable source of aromatic compounds and is available in abundant quantities as a waste product from the pulp and paper and bioethanol industries (see e.g. Ragauskas A. J., Beckham G. T., Biddy M. J., Chandra R., Chen F., Davis M. F., Davison B. H., Dixon R. A., Gilna P., Keller M., Langan P., Naskar A. K., Saddler J. N., Tschaplinski T., J., Tuskan G., A., Wyman C., E., Science 2014, 344, 1246843; Rinaldi R., Jastrzebski R., Clough M. T., Ralph J., Kennema M.; Bruijnincx P. C. A., Weckhuysen B. M., Angew. Chem. Int. Ed. 2016, 55, 8164-8215; Sun Z., Fridrich B., de Santi A., Elangovan S., Barta K., Chem. Rev. 2018, 118, 614-678; Schutyser W., Renders T., Van den Bosch S., Koelewijn S. F., Beckham G. T., Seis B. F., Chem. Soc. Rev. 2018, 47, 852-908; Questell- Santiago Y. M., Galkin M. V., Barta K., Luterbacher J. S., Nat. Rev. Chem. 2020, 4, 311- 330; Abu-Omar M. M., Barta K., Beckham G. T., Luterbacher J. S., Ralph J., Rinaldi R., Roman-Leshkov Y., Samec J. S. M., Seis B. F., Wang F., Energy Environ. Sci. 2021, 14,

262-292J. Nonetheless, lignin is under-exploited as a renewable chemical feedstock due to the limited number of efficient and selective downstream processing strategies available.

Various methods have been extensively studied for the conversion of lignin into aromatic products that can broadly be classified as catalytic oxidative degradation, catalytic reductive degradation and acid/base-catalyzed degradation. Catalytic oxidative degradation has a number of advantages compared to other catalytic fractionation methods including hydrogenolysis (a reductive process], and acid/base- catalyzed degradation (see e.g. Questell-Santiago Y. M., Galkin M. V., Barta K., Luterbacher J. S., Nat. Rev. Chem. 2020, 4, 311-330; Behling R., Valange S., Chatel G., Green Chem. 2016, 18, 1839-1854; Yang C., Maldonado S., Stephenson C. R. J., ACS Catal. 2021, 11, 10104-10114], Catalytic oxidative degradation advantageously takes place under mild and environmentally benign conditions, which contrasts with hydrogenolysis that uses noble metal catalysts, high reaction temperatures and pressures, or the use of corrosive acid/base-catalyzed degradation reagents. In addition, catalytic oxidative degradation has the potential to retain key functionality in the products that could be relevant in subsequent synthetic steps (see e.g. Cai Z., Long ]., Li Y., Ye L., Yin B., France L. ]., Dong ]., Zheng L., He H., Liu S., Tsang S. C. E., Li X., Chem 2019, 5, 2365-2377; Luo H„ Weeda E. P„ Alherech M„ Anson C. W„ Karlen S. D„ Cui Y„ Foster C. E., Stahl S. S.,J. Am. Chem. Soc. 2021, 143, 15462-15470; Subbotina E., Rukkijakan T., Marquez-Medina M. D., Yu X., Johnsson M., Samec J. S. M., Nat. Chem. 2021, 13, 1118-1125],

Although catalytic oxidative methods with the ability to cleave the C-C bonds of the alkyl side chains or even produce aromatic monomer products have been proposed, many are limited by poor selectivity and consequently low product yields (see e.g. Sedai B., Baker R. T., Adv. Synth. Catal. 2014, 356, 3563-3574; Wang M., Lu J., Li L., Li H., Liu H., Wang F.,/. Catal. 2017, 348, 160-167; Schutyser W., Kruger J. S., Robinson A. M., Katahira R., Brandner D. G., Cleveland N. S., Mittal A., Peterson D. ]., Meilan R., Roman-Leshkov Y., Beckham G. T., Green Chem. 2018, 20, 3828-3844; Liu M., Zhang Z., Shen X., Liu H., Zhang P., Chen B., Han B., Chem. Commun. 2019, 55, 925-928; Liu M., Zhang Z., Song J., Liu S., Liu H., Han B., Angew. Chem. Int. Ed. 2019, 58, 17393-17398; Liu J., Qiu X., Huang X., Luo X., Zhang C., Wei J., Pan J., Liang Y., Zhu Y, Qin Q., Song S., Jiao N„ Nat. Chem. 2019, 11, 71-77; Liu M„ Zhang Z„ Yan J„ Liu S„ Liu H„ Liu Z„ Wang W„ He Z„ Han B„ Chem 2020, 6, 3288-3296; Luo H„ Wang L. Shang S. Li G„ Lv Y„ Gao S„ Dai W„ Angew. Chem. Int. Ed. 2020, 59, 19268-19274; Zhou H„ Li Z„ Xu S.-M., Lu L„ Xu M., Ji K., Ge R., Yan Y., Ma L., Kong X., Zheng L., Duan H., Angew. Chem. Int. Ed. 2021, 60, 8976-8982; Cui T„ Ma L„ Wang S„ Ye C„ Liang X., Zhang Z„ Meng G„ Zheng L„ Hu H.- S„ Zhang J„ Duan H„ Wang D„ Li Y.J. Am. Chem. Soc. 2021, 143, 9429-9439; Ma L„ Zhou H., Kong X., Li Z., Duan H., ACS Sustain. Chem. Eng. 2021, 9, 1932-1940; Shi S.-H., Liang Y„ Jiao N„ Chem. Rev. 2021, 121, 485-505.).

The critical issue that must be solved to overcome the aforementioned limitations is that the phenolic hydroxy group is unstable under oxidative conditions (see e.g.

Rahimi A., Ulbrich A., Coon J. J., Stahl S. S., Nature 2014, 515, 249-252), leading to side reactions including repolymerization and ring opening reactions, which generates complex polymers, oligomers, and non-aromatic side products (see e.g. Esguerra K. V. N., Fall Y., Petitjean L., Lumb J.-P., J. Am. Chem. Soc. 2014, 136, 7662-7668; Niederer K. A., Gilmartin P. H„ Kozlowski M. C„ ACS Catal. 2020, 10, 14615-14623; Xu W„ Huang Z„ Ji X., Lumb J.-P., ACS Catal. 2019, 9, 3800-3810; Neuhaus W. C„ Kozlowski M. C„ Angew. Chem. Int. Ed. 2020, 59, 7842-7847.). Hence, aromatic products are isolated in yields of < 5% in certain direct oxidative degradation reactions.

Proceeding from the prior art elucidated hereinabove, it is an object of the invention to provide a method for the transformation of lignin into aromatic compounds in good yields. The aromatic compounds can then be used as starting material for aromatic products. Another object of the invention was to provide a diary! ether compound that can be manufactured from renewable resources.

Other and more specific objects will in part be apparent and will in part appear hereinafter. SUMMARY OF THE INVENTION

Some or all of these objects are achieved according to the invention by the compound according to claim 1, the method according to claim 6, and the use according to claim 14.

Further advantageous embodiments of the invention are specified in the dependent claims and are elucidated in detail herein below.

It was surpriginsly found that with the present invention, the drawbacks frequently encountered in the methods known in the prior art could be at least partially overcome. In particular, it was found that the present invention provides an efficient route to extract the aromatic monomers from lignin affording functionalized diaryl ethers. Moreover, the invention can overcome the limitations of oxidative methods described in the prior art and can afford high-value specialty chemicals in good yields. Further, side reactions typically encountered in oxidative depolymerization reactions of lignin may be suppressed with the present invention.

Without wishing to be bound by scientific theory, it is believed that in the method according to the invention, the hydroxyl groups in the repeat units of lignin depicted above are oxidized followed by cleavage of the bond thereinbetween (the bond between the oi-carbon and the 0-carbon, relative to the aromatic ring). This is followed by further bond cleavage to yield the free phenolic oxygen that subsequently reacts with the aryl boronic compound having the structure (II) (see below).

DESCRIPTION OF PREFERRED EMBODIMENTS

Compound according to the reaction

The invention provides for a compound having the structure (I) 5 ^{wherein R1 is H or –OMe, R2 is –CHO, –CO2H, C1-C4-alkoxycarbonyl, or C3-C6-cycloalkoxycarbonyl,} R ³ , R ⁴ , and R ⁵ are independently of each other H, halogen, halogenated C1-C4-alkyl, C5- _{C10-aryl, in particular phenyl, nitro, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, or C3-C6- cycloalkoxycarbonyl.} ^{In the compound having the structure (I), R2 is preferably–CHO, –CO2H, or –CO2Me, more preferably –CHO or –CO2H, most preferred –CO2H. These compounds are valuable intermediates for other compounds.} _{In the compound having the structure (I), the substituents R} ³ _{, R} ⁴ _{, and R} ⁵ _{are preferably independently of each other H, F, Cl, Br, perfluorinated C1-C4-alkyl, preferably –CF3, –NO2, –OMe, or –CO2Me. The aforementioned substituents provide access to a range of intermediates that may be relevant for example for pharmaceutical compounds.} According to an embodiment, R ³ is as defined herein and R ⁴ and R ⁵ are H. ^{In the compound having the structure (I), the substituents R3, R4, and R5 may be freely} _{positioned on the aromatic ring, wherein only one substituent may be present per carbon atom in the aromatic ring. Preferably, R3 is in para position.} - 6 - ^{According to a preferred embodiment, the compound according to the invention has} _{the structure (Ia):} R ^{1 2} ( ^{Ia), wherein R1, R2, and R3 are as defined herein. Preferably, the compound has the structure (Ia), wherein R1 is H or –OMe,} _{R2 is –CHO or –CO2H, and R3 is H, F, Cl, Br,–CF3, –NO2, –OMe, or –CO2Me, preferably wherein R3 is in para position.} ^{According to another embodiment, R3 is halogen, halogenated C1-C4-alkyl, C5-C10-aryl, in particular phenyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, or C3-C6-cycloalkoxycarbonyl, and R3 is in para position, and wherein R4 and R5 are H.} _{According to yet another preferred embodiment, the compound according to the invention has the structure (Ib):} 2 ( ^{Ib), wherein R1 is H or –OMe, R2 is –CHO, –CO2H, C1-C4-alkoxycarbonyl, or C3-C6-cycloalkoxycarbonyl, preferably –CHO or –CO2H, and} _{R3 is halogen, halogenated C1-C4-alkyl, C5-C10-aryl, in particular phenyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, or C3-C6-cycloalkoxycarbonyl.} According to a preferred embodiment, the compound according to the invention has one of the following structures: - 9 - H OMe O M , M O . Method according to the invention ^{The invention also provides for a method for the manufacture of a diaryl ether} _{compound described herein, wherein lignin is reacted with an aryl boronic compound having the structure (II)} ( ^{II), wherein R3, R4, and R5 are as defined herein above, R6 and R7 are independently of each other H, C1-C4-alkyl, or R6 and R7 together with} _{the oxygen atoms and the boron atom form a 5- or 6-membered ring optionally substituted with 1 to 4 C1-C3-alkyl substituents.} - 10 - ^{Thus, the invention in particular provides for a method for the manufacture of a diaryl} _{ether compound having the structure (I)} R ^{1 2} wherein lignin is reacted with an aryl boronic compound having the structure (II) 6 ^{7 , wherein R1, R2, R3, R4, and R5 are as defined herein above, R6 and R7 are independently of each other H, C1-C4-alkyl, or R6 and R7 together with the oxygen atoms and the boron atom form a 5- or 6-membered ring optionally substituted with 1 to 4 C1-C3-alkyl substituents.} _{According to an embodiment, R6 and R7 are H, or R6 and R7 form together with the oxygen atoms and the boron atom a pinakolboryl residue or a neopentylglycolboryl residue. Hence, in the aryl boronic compound having the structure (II), R6 and R7 may preferably be H or the aryl boronic compound may have the structure (IIa) or (IIb)}

The lignin used in the method according to the invention may be from different sources. Preferably the lignin comes from grass and/or wood, in particular softwood and/or hardwood. Examples for wood are beech wood, poplar wood, pine wood, and oak wood. Advantageously, the lignin may be beech lignin, poplar lignin, pine lignin, and/or oak lignin. Preferably, lignin contains the following repeat units

R = H or OMe

Lignin preferably contains p-0-4 linkages. In the repeat units depicted above, a p-0-4 linkage is present from the carbon atom in p-position from the aryl ring to the oxygen atom of an adjacent repeat unit, depicted as a dashed bond (oxygen atom of the adjacent repeat unit not shown]. The amount of p-0-4 linkages in lignin can be determined for example using NMR spectroscopy, in particular using HSQC NMR spectroscopy. The amount of P-0-4 linkages in lignin refers to the molar amount of P- 0-4 linkages in lignin.

In the method according to the invention, beech lignin is preferably employed.

According to an embodiment, the lignin is extracted from grass or wood. Extraction of the lignin may be accomplished by mixing the grass or wood with an organic solvent, for example tetrahydrofuran or dioxane, and an aqueous acidic solution, preferably in an extraction vessel. The mixture may be heated to 90 to 130°C, preferably to 100 to 120°C. The heating may be conducted for 0.5 to 2 hours. The reaction mixture may then be filtered and washed with dioxane and concentrated to obtain a concentrated mixture. The concentrated mixture may then be dissolved in acetone and water (v/v 9:1] and the solution may be precipitated in water. The precipitate may be collected and dried to yield crude lignin. The crude lignin may be dissolved in acetone and methanol (v/v 9:1] and precipitated in diethyl ether, filtered and dried under vacuum to yield lignin.

In the method according to the invention, the lignin is preferably reacted with the aryl boronic compound having the structure (II) in the presence of a transition metal salt. Various transition metal salts may be used in the method according to the invention. Preferably the transition metal salt is a copper salt, a palladium salt, or a ruthenium salt, even more preferably a copper salt. Examples for suitable copper salts are copper oxide, copper sulfate, copper(I] chloride, copper(ll] chloride, copper nitrate, Cu(BF4]2, copper acetate, copper perchlorate, copper(ll) bis(2-ethylhexanoate], copper(ll] 2- thiophenecarboxylate, copper(ll) 2-pyrazinecarboxylate, copper bis(acetylacetonate), and copper triflate, preferably copper sulfate, copper(I] chloride, copper(II] chloride, copper nitrate, Cu(BF4]2, copper acetate, copper perchlorate, copper(II) bis(2- ethylhexanoate], copper(ll) 2-thiophenecarboxylate, copper(ll] 2- pyrazinecarboxylate, copper bis(acetylacetonate), and copper triflate, more preferably copper(l) chloride, copper(ll] chloride, copper nitrate, Cu(BF4]2, copper acetate, copper perchlorate, copper(ll) bis(2-ethylhexanoate], copper(Il) 2- thiophenecarboxylate, copper(II) 2-pyrazinecarboxylate, and copper triflate, even more preferably copper(l] chloride, copper nitrate, and copper triflate. Most preferably, the lignin is reacted with the aryl boronic compound having the structure (11] in the presence of copper triflate.

The transition metal salt is advantageously present in the method according to the invention in an amount of at least 1 mol%, preferably at least 5 mol%, more preferably at least 10 mol%, based on the total amount of p-0-4 linkages in the lignin. The upper limit for the amount of transition metal salt in the method according to the invention is preferably 50 mol% or less, more preferably 40 mol% or less, based on the total amount of P-O-4 linkages in the lignin. According to an embodiment of the invention, the transition metal salt is present in an amount of 5 to 40 mol%, preferably 5 to 35 mol%, more preferably 10 to 35 mol%, based on the total amount of p-0-4 linkages in the lignin.

According to an embodiment of the invention, the lignin is reacted with the aiyl boronic compound having the structure (II ) in the presence of a ligand. Different ligands can be used. Advantageously, the ligand is a nitrogen-containing or a phosphorous-containing aromatic or non-aromatic organic compound, in particular monodentate or bidentate aliphatic or aromatic nitrogen-donor-ligands or monodentate or bidentate aliphatic or aromatic phosphorous-donor-ligands, such as a Ci-Cio-alkylamine, a C2-Cio-alkylenediamine, a pyridine compound, a biphenyl compound or a phenanthroline compound in each case optionally substituted with one to four Ci-C4-alkyl substituents, one to four Ci-C4-alkoxy substituents, one to four phenyl substituents, one to four hydroxyl groups, one to four oligoethylene glycol groups, or one to four halogen atoms, in particular chlorine atoms, or such as a tri-(Ci- C4-alkyl]phosphine, a bis-[di-(Ci-C4-alkyl)] phosphine bridged by an Ci-C4-alkylene bridge or a tri-fCe-Cio-aryfJphosphine or a bis-[di-(C6-Cio-aryl)]phosphine bridged by an Ci-C4-alkylene bridge. Preferably, the lignin is reacted with the aryl boronic compound having the structure (II) in the presence of a nitrogen-containing aromatic ligand, more preferably a nitrogen-containing aromatic ligand selected from the group consisting of

(L-l), (L-1I), (L-I1I),

(L-1V), and (L-V), even more preferably a nitrogen-containing aromatic ligand selected from the group consisting of

Most preferably, the lignin is reacted with the aryl boronic compound having the structure (II) in the presence ll) as ligand.

The ligand, in particular the nitrogen-containing aromatic ligand, is advantageously present in the method according to the invention in an amount of at least 1 mol%, preferably at least 5 mol%, more preferably at least 10 mol%, based on the total amount of P-0-4 linkages in the lignin. The upper limit for the amount of the ligand, in particular the nitrogen-containing aromatic ligand, in the method according to the invention is preferably 50 mol% or less, more preferably 40 mol% or less, based on the total amount of P-O-4 linkages in the lignin. According to an embodiment of the invention, the ligand, in particular the nitrogen-containing aromatic ligand, is present in an amount of 5 to 40 mol%, preferably 5 to 35 mol%, more preferably 10 to 35 mol%, based on the total amount of 0-0-4 linkages in the lignin.

In the method according to the invention, the lignin is preferably reacted with the aryl boronic compound having the structure (II) under oxidizing conditions. Oxidizing conditions can be achieved in various ways. Preferably, the lignin is reacted in the presence of an oxidizing agent such as peroxides, permanganates, chrome-based oxidizing agents, BrOs-, CIO’, air, or oxygen. Most preferred, the lignin is reacted in the presence of oxygen. Oxygen is preferably used at a pressure of 0.5 to 10 atmospheres, more preferably 0.5 to 8 atmospheres, most preferred 1 to 5 atmospheres.

According to a preferred embodiment, the lignin is reacted with the aryl boronic compound having the structure (II) in the presence of a transition metal salt, in particular as described herein, and a nitrogen-containing aromatic ligand, in particular as described herein, preferably under oxidizing conditions, in particular as described herein.

In the method according to the invention, the lignin is preferably reacted with the aryl boronic compound having the structure (II) in the presence of a base. The base may be an organic base or an inorganic base, preferably an inorganic base. Examples of suitable inorganic bases are alkaline metal hydroxides or alkaline metal carbonates or alkaline earth metal hydroxides or alkaline earth metal carbonates, preferably alkaline metal carbonates or hydroxides, more preferably NaOH, KOH, Na2CO3, K2CO3, and/or CS2CO3, most preferred K2CO3.

If a base is used, the base may be present in various amounts. Preferably, the lignin is reacted with the aiyl boronic compound having the structure (II) in the presence of a base in the amount of 1.0 to 10.0 equivalents, preferably from 2.0 to 8.0 equivalents, more preferably 2.0 to 6.0 equivalents, most preferred from 3.0 to 5.0 equivalents, based on the total amount of p-O-4 linkages in the lignin. According to another preferred embodiment, the lignin is reacted with the aryl boronic compound having the structure (II ) in the presence of a transition metal salt, in particular as described herein, a base, in particular as described herein, and a nitrogen-containing aromatic ligand, in particular as described herein, preferably under oxidizing conditions, in particular as described herein.

For reacting the lignin with the aryl boronic compound having the structure (II ) in the method according to the invention, a solvent is advantageously used. Various solvents can be used in the method according to the invention. The solvent is advantageously an organic solvent, preferably a dipolar aprotic organic solvent or water. More preferably, the lignin is reacted with the aryl boronic compound having the structure (II) in the presence of a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, water, methanol, dioxane, dichloromethane, and mixtures thereof, even more preferably in the presence of a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, water, and mixtures thereof, most preferred in the presence of a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, N- methylpyrrolidone, dimethylsulfoxide, acetonitrile, and mixtures thereof. According to a preferred embodiment, the solvent is dimethylsulfoxide. These solvents provide sufficient solubility for the compounds in the reaction.

In the method according to the invention, the lignin is preferably reacted with the aryl boronic compound having the structure (II) for a duration of 1 to 12 hours, more preferably 1 to 10 hours, even more preferably 2 to 9 hours, most preferably 4 to 8 hours.

The method according to the invention can be conducted at various temperatures. Advantageously, the lignin is reacted with the aryl boronic compound having the structure (II) at a temperature from 80 to 200°C, preferably from 100 to 180°C, more preferably from 120 to 160°C, most preferably from 130 to 150°C. At these temperatures, the reaction proceeds sufficiently fast while the compounds are not degraded.

In the method according to the invention, the aryl boronic compound having the structure (II) may be used in different amounts. Advantageously, the aryl boronic compound having the structure (11) is employed in an amount of 1.0 to 3.0 equivalents, preferably 1.0 to 2.5 equivalents, more preferably 1.0 to 2.0 equivalents, based on the total amount of p-O-4 linkages in the lignin, in the method according to the invention. With the aryl boronic compound in these amounts, a high conversion of the lignin is achieved while the amount of chemical waste is still limited.

With the method according to the invention, different diaryl ether compounds having the structure (1) may be obtained as described above. For example, with the method according to the invention, R ² in the diaryl ether compound may be -CHO or -COzH.

The method according to the invention may include further steps. For example, the method according to the invention may contain an esterification step, for example methylation, butylation or benzylation. An esterification step, in particular a methylation, is preferably conducted at 10 to 100 °C, more preferably from 15 to 50°C. An esterification step, in particular a methylation, is preferably conducted for 8 to 16 hours, more preferably for 10 to 14 hours.

The method according to the invention may also contain a work-up step. In particular, after reacting the lignin with the aryl boronic compound having the structure (II), the resulting mixture may be treated with ethyl acetate and a saturated ammonium chloride solution to obtain an extract of the organic products. The extract of the organic products may be filtered over silica gel to remove inorganic compounds as well as any ligands employed.

The invention also relates to the use of an aiyl boronic compound having the structure CH) in the conversion of lignin to a diaryl ether compound, wherein R ³ , R ⁴ , R ⁵ , R ^s , R ⁷ are as defined herein.

The diaryl ether compound according to the use of the invention may in particular be a diaryl ether compound having the structure (I) a diaryl ether compound having the structure (la): [la), or a diaryl ether compound having the structure (lb):

[lb), wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are as defined herein above.

Fig. la to 1c shows HSQC NMR spectra of mixtures of trioxane and l-(3,4- dimethoxyphenyl)-2-(2-methoxyphenoxy)propane-l,3-diol at different concentrations including a coarse peak assignment and the integrals of the respective peaks,

Fig. 2 shows an HSQC NMR spectrum of isolated beech wood lignin before the reaction. The insert table summaries the occurrence values of bonding motifs and potential linkages of lignin (mmol per 1 g lignin). Trioxane was used as an internal standard to calculate the content of the corresponding structures. For this spectrum, 54.6 mg beech lignin and 4.5 mg trioxane was dissolved in 0.5 mL DMSO-de. Also shown are the typical structural elements in beech lignin and the assignments of particular protons of these structures in the HSQC NMR spectrum.

Fig- 3 'H NMR spectrum i Fig. 4 ¹³ C NMR spectrum i

Fig. 5 *H NMR spectrum i Fig. 6 ¹³ C NMR spectrum i

Fig. 7 ¹ H NMR spectrum i

Fig. 8 ¹³ C NMR spectrum i

Fig. 9 ¹ H NMR spectrum i i3C NMR spectrum i

Fig. 10 iH NMR spectrum i

Fig. 11 13C NMR spectrum Fig. 12 iH NMR spectrum i

Fig- 13

13C NMR spectrum i

Fig. 14 iH NMR spectrum i

Fig. 15 Fig. 16 ¹³ C NMR spectrum i

Fig. 17 ■H NMR spectrum i Fig. 18 ¹³ C NMR spectrum i

Fig. 19 •H NMR spectrum i

Fig. 20 ¹³ C NMR spectrum i

Fig. 21 !!! NMR spectrum i Fig. 22 ¹³ C NMR spectrum i

Fig. 23 'H NMR spectrum i Fig. 24 ¹³ C NMR spectrum i

Fig. 25 !H NMR spectrum i

Fig. 26 ¹³ C NMR spectrum i

Fig. 27 gas chromatogram of the reaction mixture to yield the main product methyl 4-(4-chlorophenoxy]-3,5-dimethoxybenzoate from beech lignin.

EXAMPLES Materials and methods

Materials

Commercially available Cu salt catalysts were purchased from Alfa Aesar and cocatalysts (ligands) were purchased from Strem Chemicals. Bases, boronic acids, and other reagents were obtained from Sigma-Aldrich. Solvents were purchased from Acros Organics. Compressed air and oxygen were purchased from Carbagas.

Lignin extraction

Wood sawdust (< 0.5 mm) was dried at 80 °C for 24 h prior to lignin extraction. Wood sawdust (50 g), dioxane (360 mL), and HC1 aqueous solution (40 mL, 2 mol/L) were added to a flask and protected under N2. The mixture was heated to reflux for 1 h (~110 ^Q C). The mixture was filtered, washed with dioxane and concentrated to afford a brown liquid-gel (-100 mL). The liquid-gel was dissolved in a mixture of acetone and H2O (v/v = 9:1, 250 mL). Crude lignin was obtained by the precipitation of the solution in H2O (2 L) and dried using a lyophilizer. Crude lignin was dissolved in the mixture of acetone and methanol (v/v = 9:1, 200 mL, if not fully dissolved, further methanol was added). The lignin was regenerated by precipitation in diethyl ether (2 L), filtered and dried under vacuum.

Exemplary reaction to prepare diaiyl ether compounds from lignin

Beech lignin (40 mg, content of p-0-4 linkages is 0.245 mmol/g lignin), 4- chlorophenylboronic acid (1.5 equiv.), Cu(OTf)2 (30 mol%), bathophenanthroline (Bphen, 30 mol%), K2CO3 (4 equiv.), biphenyl (as internal standard for gas chromatography, 2 equiv.), and DMSO (2 mL) were added into an autoclave. The reactor was heated to 140 °C for 6 h. After cooling to room temperature, the crude product was methylated in a second step by addition of K2CO3 (3 equiv.) and Mel (10 equiv.) followed by stirring for 12 h. After the reaction, ethyl acetate (EA, 3 mL) and a saturated NH4CI (5 mL) aqueous solution were added to the mixture to extract the organic products. The aqueous solution was extracted with EA (3x3 mL). For qualitative and quantitative analysis of the products, the combined organic phase was filtered over silica gel to remove the inorganic salts and ligand. Further purification was achieved using thin layer chromatography with hexane: ethyl acetate (0 to 10%) to yield methyl 4-(4-chlorophenoxy)-3,5-dimethoxybenzoate as a white powder or crystal (1.9 mg, 60% isolated yield). A gas chromatogram of the reaction mixture is shown in Figure 27, wherein the assignment of the main species is also shown in Figure 27.

According to the exemplary method described above, several syntheses as compiled in Table 1 were performed using different copper salts, ligands, bases, and solvents, and the yields as reported in Table 1 were obtained in these syntheses.

Step 1 Copper salt,

With the reaction above, a mixture of the diaryl ethers with methyl 4-(4-chlorophenoxy)-3,5-dimethoxybenzoate being the major product ’H and ¹³ C NMR spectra of these compounds are shown in Figures 3 to 10. The combined yields of these diaryl ether products are reported in Table 1 as the yield of all diary! ether products.

Table 1: Syntheses performed and respective yields

Explanations to Table 1: ^a - yield of methyl 4-(4-chlorophenoxy)-3,5- dimethoxybenzoate obtained in %, determined by GC (see below), based on the amount of p-0-4 linkages in the lignin (see below); ^b - yield of all diaryl ether products obtained in %, determined by GC (see below) based on the amount of p-0-4 linkages in the lignin (see below).

Table 2: Structures and abbreviations of the ligands listed in Table 1. According to the exemplary method above, several syntheses as compiled in Table 3 were performed using different amounts of Cu(OTf)2, of the bathophenanthroline ligand, of the amount of potassium carbonate base, of the atmosphere, of the reaction time, and of the reaction temperature, and the yields as reported in Table 3 were obtained.

Using the reaction, a mixture of the diaryl ethers with methyl 4-(4-chlorophenoxy)-3,5-dimethoxybenzoate being the major product.

The combined yields of these diaryl ether products are reported in Table 3 as the yield of all diaiyl ether products.

Table 3: Syntheses performed and respective yields

Explanations to Table 3: ^a - amount of catalyst in mol%, based on the amount of p-0-4 linkages in the lignin (see below]; ^b - amount of ligand in mol%, based on the amount of p-0-4 linkages in the lignin (see below]; ^c - amount of K2CO3 base in equivalents, based on the amount of p-0-4 linkages in the lignin (see below]; ^d - atmosphere employed; ^e - reaction duration in hours; ^f - reaction temperature in °C; 8 - yield in % of methyl 4-(4-chlorophenoxy]-3,5-dimethoxybenzoate and in brackets the yield of all diaryl ether compounds of this reaction, in each case determined by GC and based on the amount of p-0-4 linkages in the lignin (see below]. According to the exemplary method above, several syntheses were performed using different aryl boronic acid compounds: wherein the respective residues R ^z are listed in Table 4. The reaction conditions employed were as follows: (Step 1) Beech lignin (40 mg], boronic acid or borate ester (1.5 equiv.), Cu(OTf)2 (30 mol%), Bphen (30 mol%), K2CO3 (4 equiv.), biphenyl (0.02 mmol), DMSO (2 mL), O ₂ (3 atm), 140 °C, 6 h. (Step 2) K2CO3 (3 equiv.), Mel (10 equiv.), 25 °C, 12 h.

Table 4: Compounds synthesized with respective yields.

Explanations to Table 4: ^a - Residue R ^z in the synthetic scheme above; ^b - Yield of the major diaryl ether product as depicted in the synthetic scheme, determined by GC (see below); ^c - Figure containing ¹ H NMR spectrum of the major diaryl ether product (see synthetic scheme above) in CDCh; ^d - Figure containing ¹³ C NMR spectrum of the major diaryl ether product (see synthetic scheme above) in CDCh.

Analytical Methods

Qualitative and quantitative analysis of the crude products was performed by gas chromatography (GC) (Agilent 7890B, equipped with mass detector (Agilent 7000C) equipped with a hydrogen flame-ionization detector (FID) and HP-5 nonpolar column. Helium was used as the carrier gas. The GC yield was determined based on internal standard curves (biphenyl) and areas of integrated peak area.

■H and ¹³ C NMR spectra were recorded on a Bruker Avance 111 HD 400 instrument equipped with a 5 mm BBFO probe. DMSO-de or CDCh were used as solvent. Short- range ¹³ C- ¹ H correlation NMR spectra (HSQC) were recorded on a 500 MHz spectrometer (Bruker AVANCENEO-500). HSQC spectra ofthe original reaction mixture were recorded in DMSO-de, used as the reaction solvent. The reaction mixture was dried with 4A molecular sieve and centrifuged to remove inorganic salts.

Quantitative methods

Determination of the concentration of p-0-4 linkages was conducted using HSQC NMR spectroscopy with trioxane as an internal standard.

Briefly, beech lignin was extracted with dioxane from beech wood sawdust, leaving carbohydrates as solid residues (see also Lancefield, C. S.; Ojo, 0. S.; Tran, F.; Westwood, N. J., Isolation of Functionalized Phenolic Monomers through Selective Oxidation and C- 0 Bond Cleavage of the p-0-4 Linkages in Lignin. Angew. Chem. Int. Ed. 2015, 54, 258- 262.). In the lignin polymer, the aromatic rings are connected by serval types of alkyl side chain. The different connections of the aromatic rings can be identified by short- range ¹³ C- ¹ H correlation (HSQC) NMR spectroscopy. For example, the beech lignin structure comprises syringyl and guaiacyl aromatic rings, together with their main alkyl side chains, p-0-4 (A) and p-p (B) linkages, which are clearly identified by HSQC NMR spectroscopy.

Determination of the concentration of p-O-4 linkages by quantitative ¹³ C NMR spectroscopy would be hindered by overlapping signals from other alkyl linkages including the p~p and a-0-4 linkages. ² ’ ³ Thus, HSQC NMR spectroscopy was employed to determine the concentration of the p-0-4 linkages using trioxane as an internal standard (chemical shift of trioxane: <5H/5C: 5.1/93.4 ppm). Here, the integrals of HSQC NMR signals of different functional groups are linearly related to their amounts (Sette M„ Lange H„ Crestini C„ QUANTITATIVE HSQC ANALYSES OF LIGNIN: A PRACTICAL COMPARISON. Comput. Struct. Biotechnol. J. 2013, 6, e201303016; Heikkinen, S.; Toikka, M. M.; Karhunen, P. T.; Kilpelainen, I. A., Quantitative 2D HSQC (Q-HSQC) via Suppression of J-Dependence of Polarization Transfer in NMR Spectroscopy: Application to Wood Lignin./. Am. Chem. Soc. 2003, 125, 4362-4367). Using the model compound l-(3,4-dimethoxyphenyl)-2-(2-methoxyphenoxy)propane- 1,3 -diol having the structure (i)

CO, the molar correlation coefficient between the amount of p-0-4 linkages and the integral of the peak in the HSQC NMR spectrum was determined. In the structure (i) above, the a-, P-, and y-positions are labelled. Sections of the HSQC NMR spectra of the model compound l-(3,4-dimethoxyphenyf)-2-(2-methoxyphenoxy}propane-l,3-diol together with trioxane at different known concentrations and molar ratios are shown in Figures la to lc.

For the determination of the molar correlation factor /p-o-4 for the amount of p-0-4 linkages, the integral of the peak Act atba/bc: 4.9/72.3 ppm (the integral being referred to as Sp-0-4) and the integral of the trioxane peak at <5H/5C: 5.1/93.4 ppm (the integral being referred to as Strioxane) in the HSQC NMR spectra in Figures la to lc were used. In Figure la, 19.2 mg l-(3,4-dimethoxyphenyf)-2-(2-methoxyphenoxy)propane-l,3-diol and 5.1 mg trioxane in 0.5 mL DMSO-de were used. In Figure lb, 10.9 mg l-(3,4- dimethoxyphenyl)-2-(2-methoxyphenoxy]propane-l,3-diol and 5.0 mg trioxane in 0.5 mL DMSO-de were used. In Figure lc, 7.4 mg l-(3,4-dimethoxyphenyf)-2-(2- methoxyphenoxy)propane-l,3-diol and 6.9 mg trioxane in 0.5 mL DMSO-de were used.

In the three HSQC NMR spectra of Figure la to lc, the integrals Sp-0-4 and Strioxane were determined, with the value of Strioxane being adjusted to 100. For each of the HSQC NMR spectra in Figure la to lc, the ratio (6*Sp-o-4/Strioxane) was calculated and plotted against the ratio Mi/Mt, wherein Mi is the molar amount of l-(3,4-dimethoxyphenyl)-2-(2- methoxyphenoxy)propane-l,3-diol and Mt is the molar amount of trioxane employed in the solutions for the respective HSQC NMR spectrum. The factor 6 in the ratio of the integrals is due to the different amounts of protons giving rise to the peaks for Aa and trioxane. Linear regression analysis of the resulting points in the graph and additionally the origin (0;0) of the graph was performed to reveal a straight line through these points and through the origin of the graph. This is also further described in Sette M., Lange H„ Crestini C„ QUANTITATIVE HSQC ANALYSES OF LIGNIN: A PRACTICAL COMPARISON. Comput. Struct. Biotechnol. J. 2013, 6, e201303016 and in Heikkinen, S.; Toikka, M. M.; Karhunen, P. T.; Kilpelainen, I. A., Quantitative 2D HSQC [Q-HSQC] via Suppression of J-Dependence of Polarization Transfer in NMR Spectroscopy: Application to Wood Lignin./. Am. Chem. Soc. 2003, 125, 4362-4367. The slope factor of this straight line amounted to 2.9613 and was used as the molar correlation factor/p-o-

4.

With the molar correlation factor from the model compound as determined above, the molar amount of p-0-4 linkages per gram of extracted beech lignin [see above] was determined as follows. 54.6 mg of the extracted beech lignin and 4.5 mg of trioxane were dissolved in 0.5 mL DMSO-de, and an HSQC NMR spectrum was recorded. A section of the HSQC NMR spectrum of extracted beech lignin is shown in Figure 2 along with the structure of the repeat units found in beech lignin and the corresponding peak assignment in the HSQC NMR spectrum. The peak of the p-0-4 linkages in the HSQC NMR spectrum is denoted A _a in Figure 2, as above. In the HSQC NMR spectrumbereich liegen, the integral Sp-o-4 of the peak A« and the integral Strioxane of the trioxane peak were determined, with the value of Strioxane being adjusted to 100, resulting in a value of 13.2 for the integral Sp-o-4. The molar amount of p-0-4 linkages per gram in the extracted beech lignin was then calculated as follows:

The molar amount of trioxane [ntrioxane] was calculated by dividing the mass of trioxane (mtrioxane) by the molecular weight of trioxane (Mw(trioxane)): The molar amount of p-0-4 linkages (M p-0-4) in the analyzed beech lignin sample (54.6 mg) was calculated using the integrals Sp-0-4 and Strioxane (see above, also for the factor 6) as well as the molar correlation factor/p-0-4 and the molar amount of trioxane as:

Then, the molar amount of p-0-4 linkages (Mp-0-4) in beech lignin per gram was calculated using the mass of the lignin sample (54.6 mg) as:

According to this method, the amounts of other alkyl side linkages in lignin and the amounts of p-0-4 linkages in different kinds of lignin sources may also be quantified.

The yield (%) of ether products is based on the amount of the (3—0—4 linkages in the lignin as follows: nether was determined by GC based on internal standard curves and areas of integrated peak area. n ether! mol of ether products