Facile production of levulinate from muconic acid

Abstract

The present disclosure is directed to a process for preparation of a compound of Formula (I), where R is as described herein. This process includes providing a compound of Formula (II), or a salt thereof, where (VI) is as described herein; and converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (I). The present disclosure is also directed to a process for preparation of a compound of Formula (III)-(V): (III), (IV), and / or (V), where R1, R2, R3, and (VI) are as described herein.

Description

FACILE PRODUCTION OF LEVULINATE FROM MUCONIC ACID

[0001] This application claims the priority benefit of U.S. Provisional Patent Application Serial No. 63 / 562,921, filed March 8, 2024, which is hereby incorporated by reference in its entirety.

[0002] This invention was made with government support under EFMA2132200 awarded by National Science Foundation. The government has certain rights in the invention.FIELD

[0003] The present disclosure relates to a method to produce levulinate from muconic acid.BACKGROUND

[0004] In 2021, petroleum -based products accounted for 90% of transportation fuel in the USA (U.S. Energy Information Administration, U.S. Energy Facts Explained, www.eia.gov / energyexplained / us-energy-facts / ). In spite of widely acknowledged environmental risks from carbon emissions and resource depletion, this dependency is expected to escalate due to the growing number of vehicles. Renewable energy resources like biofuels are increasingly relevant, but currently contribute merely 6% to the U.S. transportation sector (U.S. Energy Information Administration, U.S. Energy Facts Explained, www.eia.gov / energyexplained / us-energy-facts / ). Given the urgency of climate change and increasing energy demands, it is imperative to leverage biomass not only as a fuel source but also for the production of high-value chemicals. For example, levulinic acid (LA), identified as a top 10 value-added platform chemical (Bozell et al., “Technology Development for the Production of Biobased Products From Biorefinery Carbohydrates — the US Department of Energy’s “Top 10” Revisited,” Green Chemistry 12:539-554 (2010)), can be synthesized from the cellulose and hemicellulose fractions of biomass (Ahmad et al., “Catalytic and Mechanistic Insights Into the Production of Ethyl Levulinate From Biorenewable Feedstocks,” Green Chemistry 18:4804- 4823 (2016)). LA can be converted into y-valerolactone (GVL), a precursor for transportation fuels like oligomeric butene and 5-nonanone (Serrano-Ruiz et al., “Conversion of Cellulose to Hydrocarbon Fuels by Progressive Removal of Oxygen,” Applied Catalysis B: Environmental 100: 184-189 (2010); Braden et al., “Production of Liquid Hydrocarbonfuels by CatalyticConversion of Biomass-Derived Levulinic Acid,” Green Chemistry 13: 1755-1765 (2011); Sen et al., “Production of Butene Oligomers as Transportation Fuels Using Butene for Esterification ofLevulinic Acid From Lignocellulosic Biomass: Process Synthesis and Technoeconomic Evaluation,” Green Chemistry 14:3289-3294 (2012)). Its versatility extends to applications as a solvent, monomer feedstock, and plasticizer among others (Xuan et al., “Levulinic Acid as a Versatile Building Block for Plasticizer Design,” ACS Sustainable Chemistry & Engineering 7: 12552-12562 (2019); Amarasekara et al., “Renewable Polymers: Synthesis and Characterization of Poly(levulinic Acid-Pentaerythritol),” Journal of Polymer Science Part A: Polymer Chemistry 56:955-958 (2018); Melro et al., “Levulinic Acid: A Novel Sustainable Solvent for Lignin Dissolution,” International Journal of Biological Macromolecules 164:3454- 3461 (2020); Valsange et al., “Biobased Aliphatic Polyesters From a Spirocyclic Dicarboxylate Monomer Derived From Levulinic Acid,” Green Chemistry 23:5706-5723 (2021)). Moreover, LA esters, such as ethyl levulinate (EL), offer advantages in biofuels and diesel blending, boasting a higher octane number of 107.5 compared to other esters (Christensen et al., “Properties and Performance of Levulinate Esters as Diesel Blend Components,” Energy & Fuels 25:5422-5428 (2011)). LA has also shown promise as a precursor for bio-jet fuel, highlighting its potential for higher-value applications (Juarez et al., “Self-Condensation of Levulinic Acid Into Bio-Jet Fuel Precursors Over Acid Zeolites: Elucidating the Role of Nature, Strength and Density of Acid Sites,” Applied Catalysis A: General 631 : 118480 (2022)).

[0005] LA can be derived from both hexose (cellulose) and pentose (hemicellulose) sugars (Pyo et al., “Clean Production of Levulinic Acid from Fructose and Glucose in Salt Water by Heterogeneous Catalytic Dehydration,” ACS Omega 5: 14275-14282 (2020)), with the pentose route being more atom -efficient (Ahmad et al., “Catalytic and Mechanistic Insights Into the Production of Ethyl Levulinate From Biorenewable Feedstocks,” Green Chemistry 18:4804- 4823 (2016); Russo et al., “Mesoporous Carbon-Silica Solid Acid Catalysts for Producing Useful Bio-Products Within the Sugar-Platform of Biorefineries,” Green Chemistry 16:4292- 4305 (2014)). Typically, pentose sugars are converted to furfural, hydrogenated to furfuryl alcohol (FAL), and then hydrolyzed to LA (Mellmer et al., “Selective Production of Levulinic Acid from Furfuryl Alcohol in THF Solvent Systems over H-ZSM-5,” ACS Catalysis 5:3354- 3359 (2015); Vargas-Hernandez et al., “Furfuryl Alcohol From Furfural Hydrogenation Over Copper Supported on SBA-15 Silica Catalysts,” Journal of Molecular Catalysis A: Chemical 383 : 106-113 (2014)) (Figure 1). Although multiple mechanisms for LA synthesis from FAL exist (Ahmad et al., “Catalytic and Mechanistic Insights Into the Production of Ethyl Levulinate From Biorenewable Feedstocks,” Green Chemistry 18:4804-4823 (2016)), Gonzalez Maldonado et al., “Experimental and Theoretical Studies of the Acid-Catalyzed Conversion ofFurfuryl Alcohol to Levulinic Acid in Aqueous Solution,” Energy & Environmental Science 5:6981-6989 (2012) identified ethoxymethyl furan (EMF) and triethoxy pentan-2-one (TEP) as key intermediates. One pathway yielded diethyl ether (DEE), while another did not (Gonzalez Maldonado et al., “Experimental and Theoretical Studies of the Acid-Catalyzed Conversion of Furfuryl Alcohol to Levulinic Acid in Aqueous Solution,” Energy & Environmental Science 5:6981-6989 (2012)). Lu et al., “Design of Organosulfonic Acid Functionalized Organosilica Hollow Nanospheres for Efficient Conversion of Furfural Alcohol to Ethyl Levulinate,” Green Chemistry 17: 1767-1778 (2015) emphasized 1,4-ethanol addition to EMF as the major route for EL production, excluding DEE formation. Zhu et al., “Graphene Oxide: An Efficient Acid Catalyst for Alcoholysis and Esterification Reactions,” ChemCatChem 6:3080-3083 (2014) and Zhu et al., “One-Pot Conversion of Furfural to Alkyl Levulinate Over Bifunctional Au- H4SiWi204o / Zr02 Without External H2,” Green Chemistry 18:5667-5675 (2016) however, reported pathways involving both EMF and TEP. Consequently, the scientific community remains uncertain about the roles of EMF and TEP, and a definitive pathway for LA and EL synthesis from FAL has yet to be confirmed.

[0006] While polysaccharides like cellulose serve as feedstocks for various industries, their availability can be limited due to competing uses in food production. In contrast, lignin, a waste byproduct from industries such as paper and forestry, presents an abundant alternative. Unlike cellulose, untreated lignin resists natural degradation for millions of years. Consequently, lignin offers a more sustainable resource for developing new pathways for LA synthesis. Previous studies have demonstrated the capability to produce valuable chemicals like muconic acid (MA) from lignin (Chen et al., “Bioconversion of Lignin-Derived Feedstocks to Muconic Acid by Whole-Cell Biocatalysis,” ACS Food Science & Technology 1 :382-387 (2021)).

[0007] The lignin-MA pathway for LA synthesis emerges as a cheaper and less energy demanding alternative when contrasted with the hemicellulose-FAL route. FAL is commonly produced industrially by hydrogenation of furfural using expensive catalysts like Pt and Pd (Chen et al., “Highly Selective Hydrogenation of Furfural to Furfuryl Alcohol Over Pt Nanoparticles Supported on g-CLN4 Nanosheets Catalysts in Water,” Scientific Reports 6:28558 (2016)), making it both energy- and material -intensive. In contrast, MA production through enzymatic oxidation of catechol avoids the use of such expensive catalysts and hydrogen (Khalil et al., “Muconic Acid Isomers as Platform Chemicals and Monomers in the Biobased Economy,” Green Chemistry 22: 1517-1541 (2020); Coupe et al., “Sustainable Oxidative Cleavage of Catechols for the Synthesis of Muconic Acid and Muconolactones Including Lignin Upgrading,”Green Chemistry 22:6204-6211 (2020); Kohlstedt et al., “From Lignin to Nylon: Cascaded Chemical and Biochemical Conversion Using Metabolically Engineered Pseudomonas Putida,” Metabolic Engineering 47 :279-293 (2018); Mizuno et al., “Microbial Production of cis, cis- Muconic Acid From Benzoic Acid,” Applied Microbiology and Biotechnology 28:20-25 (1988)), and has demonstrated high selectivity for MA. For example, Becker et al., “Metabolic Engineering of Corynebacterium Glutamicum for the Production of cis, cz.s-Muconic Acid From Lignin,” Microbial Cell Factories 17: 1-14 (2018) reported 100% yield of cz.s.cz.s-muconic acid (ccMA) with titers reaching 85 g / 1 using a Corynebacterium glutamicum strain. Further, guaiacol, one of the most abundant lignin monomers following softwood lignin depolymerization, has been converted to catechol in a single step using the Pseudomonas putida KT2440 strain (Almqvist et al., “Muconic Acid Production Using Engineered Pseudomonas putida KT2440 and a Guaiacol-Rich Fraction Derived from Kraft Lignin,” ACS Sustainable Chemistry & Engineering 9:8097-8106 (2021)), indicating the strong potential for large-scale MA production from waste lignin.

[0008] MA serves as a versatile chemical platform, offering a green pathway to a host of commodity chemicals, including adipic acid (Vardon et al., “cz.s.cz.s-Muconic Acid: Separation and Catalysis to Bio-Adipic Acid for Nylon-6, 6 Polymerization,” Green Chemistry 18:3397- 3413 (2016); Vardon et al., “Adipic Acid Production From Lignin,” Energy & Environmental Science 8:617-628 (2015)), terephthalic acid (Lu et al., “Production of Diethyl Terephthalate from Biomass-Derived Muconic Acid,” Angewandte Chemie 128:257-261 (2016)), 8- caprolactam (Beerthuis et al., “Catalytic Routes Towards Acrylic Acid, Adipic Acid and 8- Caprolactam Starting From Biorenewables,” Green Chemistry 17: 1341-1361 (2015); U.S. Patent No. 9,073,867 to Coudray et al.), and 1,6-hexam ethylene diamine (WO 2015 / 086819 to Muller et al.). These chemicals are essential for the synthesis of industrially relevant polyamides and polyesters such as nylon-6, 6, nylon-6, and polyethylene terephthalate. Beyond these traditional chemicals, the use of MA also enables the production of novel monomers like cyclohex- 1-ene- dicarboxylic acid (CH1DA) (Carraher et al., “Solvent-Driven Isomerization of cz.s.cz.s- Muconic Acid for the Production of Specialty and Performance-Advantaged Cyclic Biobased Monomers,” Green Chemistry, 2020, 22:6444-6454). For instance, Carter et al., “Bioenabled Platform to Access Polyamides with Built-In Target Properties,” Journal of the American Chemical Society 144:9548-9553 (2022) synthesized novel comonomers from trazz .trazz -muconic acid ( / / MA) through Diels-Alder cycloaddition, enabling tunability in nylon-6, 6 copolymers for properties like hydrophobicity and flame retardancy. Composites incorporating CH1DA showed a 70%reduction in water absorption and increased char formation, demonstrating flame retardancy (Carter et al., “Bioenabled Platform to Access Polyamides with Built-In Target Properties,” Journal of the American Chemical Society 144:9548-9553 (2022)). Rorrer et al., “Renewable Unsaturated Polyesters from Muconic Acid,” ACS Sustainable Chemistry & Engineering 4:6867-6876 (2016) showcased the applicability of ccMA in succinate-based polyesters, which were then converted to fiberglass panels with shear moduli of 30 GPa, comparable to commercial alternatives. Another study highlighted the potential of poly(dialkyl muconates) as a replacement for acrylic rubbers, given their glass transition temperature of -60°C (Quintens et al., “Muconic Acid Esters as Bio-Based Acrylate Mimics,” Polymer Chemistry 10:5555-5563 (2019)). While the applicability of MA in the production of various polymers is well- established, its potential in biofuels remains unexplored.

[0009] The present disclosure is directed to overcoming these and other deficiencies in the art.SUMMARY

[0010] One aspect of the present disclosure relates to a process for preparation of a compound of Formula (I):where R is H or Ci-6 alkyl. This process includes: providing a compound of Formula (II):salt thereof, where A* represents a bond of unspecified stereochemistry; and converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (I).

[0011] Another aspect of the present disclosure relates to a process for preparation of a compound of Formula (III):whererepresents a bond of unspecified stereochemistry;R1is Ci -6 alkyl; andR2is Ci-6 alkyl.This process includes: providing a compound of Formula (II):salt thereof; and converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (III).

[0012] Another aspect of the present disclosure relates to a process for preparation of a compound of Formula (IV) or Formula (V):whereR3is H or Ci-6 alkyl.This process includes: providing a compound of Formula (II):salt thereof, whererepresents a bond of unspecified stereochemistry; and converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (IV) or Formula (V).

[0013] The applications of muconic acid (MA), a bio-privileged molecule, were extended to the biofuel industry by achieving a 100% selective conversion to levulinic acid (LA) under solvent-free conditions. Although several routes for LA synthesis exist in the literature, the exact mechanism remains undetermined. The most probable acidic pathway for synthesizing LA from MA was identified using nuclear magnetic resonance (NMR) analysis combined with density functional theory (DFT) calculations. Results demonstrated that ethanol and water concentrations critically impact the selectivity for LA and ethyl levulinate (EL). A suite of NMR techniques, including1H-NMR,13C-NMR, and 2-D correlation methods such as heteronuclearsingle quantum coherence spectroscopy (HSQC) and homonuclear correlation spectroscopy (HCOSY), were employed in conjunction with gas chromatography-mass spectrometry (GCMS) analysis and DFT calculations to elucidate the intermediates involved in LA synthesis. Kinetic studies revealed rate constants for the consumption of MA and the formation of LA, with activation energies calculated to be 16.1 kJ / mol and 158.18 kJ / mol, respectively.

[0014] The present disclosure describes a novel pathway for the highly selective formation of LA and EL from MA. The reaction conditions are notably mild, proceeding in bulk with 100% selectivity for LA under ambient pressure and the potential for scale-up to 100% MA concentration. This breakthrough paves the way for new applications of MA, particularly in the field of biofuels. The work not only establishes LA as a viable end product originating from lignin, but also offers valuable insights into the chemistry of MA as an emerging platform biochemical. By utilizing DFT calculations and identifying intermediate species, the present disclosure provides essential guidance for optimizing MA process conditions to achieve high selectivity and yield for target chemicals.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure l is a schematic showing lignin- and cellulose-based pathways to levulinic acid (LA) and levulinates.

[0016] Figure 2 is a schematic showing family of acid catalyzed reactions of cis,cis- muconic acid.

[0017] Figure 3 shows 'H-NMR of levulinic acid synthesized at 80°C for 16 hours in chloroform without ethanol and water.

[0018] Figure 4 shows gas chromatography-mass spectrometry (GCMS) spectra of levulinic acid. Reaction conditions: LA was synthesized in the absence of ethanol and water at 80°C for 16 hours in the presence of 30.5 wt.% sulfuric acid.

[0019] Figure 5 is a schematic showing proposed reaction pathway for levulinic acid synthesis. Intermediates named tautomer, 1-3, 3-hydroxyhex-3-ene, and keto adipic acid are short-lived and highly unstable.

[0020] Figure 6 is a graph showing trends of muconolactone (Mlac) conversion over increasing temperature with respect to levulinic acid (LA) / ethyl levulinate (EL) formation. Abbreviations: cz.s.cz.s-muconic acid (ccMA), cis, / zzzzz.s-muconic acid (ctMA), and dilactone (Dilac).

[0021] Figure 7 is a graph showing effect of time on MLac formation. Reaction conditions: chloroform, ethanol, water, and sulfuric acid were used for MLac synthesis at 80 °C.

[0022] Figure 8 shows1H-NMR (600 MHz, CDCh) of the intermediates formed under deuterated reaction conditions at 75 °C for 3 hours.

[0023] Figure 9 shows13C-NMR (600 MHz, CDCI3) of the intermediates formed under deuterated reaction conditions at 90 °C for 2 hours.

[0024] Figure 10 shows HSQC NMR for the intermediates. Reaction conditions: deuterated chloroform and deuterated sulfuric acid were used for LA synthesis at 75°C for 16 hours.

[0025] Figure 11 shows GCMS spectra of tautomer.

[0026] Figure 12 shows HCOSY NMR of dilactone and levulinic acid. Reaction conditions: deuterated chloroform and deuterated sulfuric acid were used for LA synthesis at 90 °C for 16 hours.

[0027] Figure 13 is a schematic showing elementary steps considered and corresponding reaction free energies and activation free energies (underlined) (kJ / mol) for cz.s.cz.s-muconic acid reduction to levulinic acid and ethyl levulinate via pathway- 1.

[0028] Figure 14 is a schematic showing elementary steps considered and corresponding reaction free energies and activation free energies (underlined) (kJ / mol) for cz.s.cz.s-muconic acid reduction to levulinic acid and ethyl levulinate via pathway-2.

[0029] Figure 15 is a schematic showing elementary steps considered and corresponding reaction free energies and activation free energies (underlined) (kJ / mol) for cz.s.cz.s-muconic acid reduction to levulinic acid and ethyl levulinate via pathway-3.

[0030] Figure 16 shows density functional theory (DFT)-calculated reaction free energies (AG, kJ / mol) and activation free energies (denoted in numbers) (Ga, kJ / mol) of key elementary steps involved in three proposed reaction pathways (Pathway 1, Pathway 2, and Pathway 3) for the conversion of cz.s.cz.s-muconic acid (ccMA) to levulinic acid (LA) and ethyl levulinate (EL) at 353 K in chloroform. Abbreviations: cis, / ZYZz / .s-muconic acid (c / MA), muconolactone (Mlac).

[0031] Figures 17A-17C are graphs showing time-dependent formation of levulinic acid, MLac, Dilac, and the tautomer at 75 °C (Figure 17A), 80 °C (Figure 17B), and 90 °C (Figure 17C). Figure 17D is a graph showing the activation energy barriers for muconic acid consumption, and MLac, Dilac, and levulinic acid formation.

[0032] Figures 18A-18C are graphs showing MATLAB experimental (exp) and simulated fitted (fit) data of levulinic acid (LA) and cv.s.cv.s-muconic acid (CC) to first order differential rate equation at 75°C (Figure 18A), 80°C (Figure 18B), and 90°C (Figure 18C).

[0033] Figure 19 is a schematic depicting the phase barrier of chloroform and water inhibiting the LA formation at 75 °C and surmounting the barrier at 90 °C.

[0034] Figures 20A-20C are graphs showing the effect of temperature on the formation rates of levulinic acid (LA) (Figure 20 A), muconolactone (MLac) (Figure 20B), and dilactone (Dilac) (Figure 20C).

[0035] Figure 21 shows 'H-NMR of muconolactone and esters of muconic acid.

[0036] Figure 22 shows 'H-NMR of ethyl levulinate synthesized at 80°C for 16 hours in chloroform, ethanol, water, and sulfuric acid.

[0037] Figure 23 shows 'H-NMR of levulinic acid synthesized under solvent-free conditions with raw muconic acid catalyzed by lwt% sulfuric acid at 110°C for 16 hours.

[0038] Figure 24 shows GCMS spectra of levulinic acid and ethyl levulinate. Reaction conditions: LA was synthesized in the presence of ethanol and water at 80°C for 16 hours in the presence of 30.5 wt.% sulfuric acid.DETAILED DESCRIPTION

[0039] One aspect of the present disclosure relates to a process for preparation of a compound of Formula (I):where R is H or Ci-6 alkyl. This process includes: providing a compound of Formula (II):salt thereof, where represents a bond of unspecified stereochemistry; and converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (I).

[0040] As used above, and throughout the description herein, the following terms, unless otherwise indicated, shall be understood to have the following meanings. If not defined otherwise herein, all technical and scientific terms used herein have the same meaning as iscommonly understood by one of ordinary skill in the art to which this technology belongs. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0041] In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise.

[0042] The terms “comprising,” “comprises,” and “comprised of’ as used herein are synonymous with “including,” “includes,” or “containing,” “contains,” and are inclusive or open-ended and do not exclude additional, non-recited members, elements, or method steps.

[0043] The terms “comprising,” “comprises,” and “comprised of’ also encompass the term “consisting of.” The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, un-recited elements or method steps. By contrast, the transitional phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed subject matter. In some embodiments or claims where the term comprising is used as the transition phrase, such embodiments can also be envisioned with replacement of the term “comprising” with the terms “consisting of’ or “consisting essentially of.”

[0044] Terms of degree such as “substantially,” “about,” and “approximately” and the symbol as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±0.1% (and up to ±1%, ±5%, or ±10%) of the modified term if this deviation would not negate the meaning of the word it modifies. Unless otherwise clear from context, all numerical values provided herein are modified by the term about. All numerical values provided herein that are modified by terms of degree set forth in this paragraph (e.g.,are also explicitly disclosed without the term of degree. For example, “about 1%” is also explicitly disclosed as “1%”.

[0045] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of’ or “one or more” of the listed items is used or present.

[0046] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints. Any listed range can be easily recognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0047] The term “alkyl” means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 23 carbon atoms in the chain. For example, straight or branched carbon chain could have 1 to 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, / / -propyl, z-propyl, / / -butyl, / -butyl, / / -pentyl, and 3 -pentyl.

[0048] The term “salt” refers to metallic salts made from aluminum, barium, calcium, lithium, magnesium, potassium, sodium, and zinc.

[0049] Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. This technology is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0050] In some embodiments, the compound of Formula (

[0051] In some embodiments, a mixture of two or more compounds of Formula (I) is formed.

[0052] In some embodiments, the step of converting the compound of Formula (II) or a salt thereof at a temperature below 180°C results in the formation of a compound of Formula (IVa):which rearranges to form the compound of Formula (I).

[0053] Another aspect of the present disclosure relates to a process for preparation of a compound of Formula (III):whererepresents a bond of unspecified stereochemistry;R1is Ci -6 alkyl; andR2is Ci-6 alkyl.This process includes: providing a compound of Formula (II):salt thereof; and converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (III).

[0054] In some embodiments, the compound of Formula

[0055] In some embodiments, a mixture of two or more compounds of Formula (III) is formed.

[0056] Another aspect of the present disclosure relates to a process for preparation of a compound of Formula (IV) or Formula (V):whereR3is H or Ci-6 alkyl.This process includes: providing a compound of Formula (II):salt thereof, whererepresents a bond of unspecified stereochemistry; and converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (IV) or Formula (V).O

[0057] In some embodiments, the compound of Formula (IV) isor

[0058] In some embodiments, a mixture of two or more compounds of Formula (IV) or Formula (V) is formed.

[0059] The following embodiments apply to any of the above aspects of the present disclosure.

[0060] According to the present disclosure, the compound of Formula (II) or a salt thereof can be converted to form the compound of Formula (I), Formula (III), Formula (IV), and / or Formula (V). In one embodiment, this conversion is carried out in the presence of a solvent or a mixture of several solvents. In another embodiment, this conversion is carried out in the absence of a solvent (neat).

[0061] According to the present disclosure, any suitable solvent can be used to prepare a compound of Formula (I), Formula (III), Formula (IV), and / or Formula (V) from the compound of Formula (II) or a salt thereof. Such solvents include, but are not limited to acetone, methanol, ethanol, 2-propanol, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), N-methyl-2- pyrrolidone (NMP), dichloromethane (DCM), dimethyl sulfoxide (DMSO), pyridine, diethyl ether, toluene, chloroform, 1 -butanol, hexene, 1, 4-di oxine, ethylene glycol, ethylene glycol monomethyl ether, or combination thereof.

[0062] In some embodiments, the solvent is a non-aqueous solvent.

[0063] In some embodiments, the solvent is chloroform.

[0064] In some embodiments, the compound of Formula (II) or a salt thereof can be converted to form the compound of Formula (I), Formula (III), Formula (IV), and / or Formula (V) in the presence of a catalyst. Suitable catalysts that can be used include mineral acids, such as hydrochloric acid, sulfuric acid, and nitric acid. Other suitable catalysts include sulfonic acids such as p-toluene sulfonic acid, perfurourosulfonic acid, and methanesulfonic acid. In addition to sulfonic acids and sulfur phases, heteropolyacids may be used as catalyst. Useful heteropolyacids include phosphotungstic acid, phosphomolybdic acid, and silicomolybdate. Other useful catalytic acids include Lewis acids such as aluminum chloride, aluminum isopropoxide, aluminum phenoxide, boron trihalide etherates or alcoholates, titanium tetrachloride, zirconium tetrachloride, tin (II) chloride, silicon tetrachloride, and zinc chloride. In some cases, solid acids as well as liquid acids may be used. Solid acids include ion exchange resins (e.g., DuPont™ AmberLyst™), mordenite, silica alumina, tetrasilic mica, activated clay, zeolite, synthetic mica, and clay materials. In one embodiment, the catalyst is sulfuric acid.

[0065] In some embodiments, the compound of Formula (II) or a salt thereof can be converted to form the compound of Formula (I), Formula (III), Formula (IV), and / or Formula (V) at a temperature below 175°C, below 150°C, below 125°C, below 110°C, below 100°C, below 95°C, below 90°C, below 85°C, below 80°C, below 75°C, or below 70°C.

[0066] In some embodiments, the compound of Formula (II) or a salt thereof can be converted to form the compound of Formula (I), Formula (III), Formula (IV), and / or Formula (V) at a temperature from about 50°C to about 100°C, about 50°C to about 95°C, about 50°C to about 90°C, about 55°C to about 90°C, about 60°C to about 90°C, about 60°C to about 85°C, or about 65°C to about 85°C.

[0067] In some embodiments, the step of converting the compound of Formula (II) or a salt thereof to form the compound of Formula (I), Formula (III), Formula (IV), and / or Formula (V) is carried out for at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, or at least 20 hours.

[0068] In some embodiments, a mixture of two or more compounds of Formula (I), Formula (III), Formula (IV), or Formula (V) is formed.

[0069] In some embodiments, a mixture of three or more compounds of Formula (I), Formula (III), Formula (IV), or Formula (V) is formed.

[0070] In some embodiments, the process for preparation of a compound of Formula (I), Formula (III), Formula (IV), or Formula (V) further includes providing a compound of Formula(VI): ROH (VI). The step of converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (I), Formula (III), Formula (IV), or Formula (V) is carried out by reacting the compound of Formula (II) or a salt thereof with the compound of Formula (VI).

[0071] In some embodiments, the process for preparation of a compound of Formula (I), Formula (III), Formula (IV), or Formula (V) further includes providing a compound of Formula (VI): ROH (VI) and providing water. The step of converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (I), Formula (III), Formula (IV), or Formula (V) is carried out by reacting the compound of Formula (II) or a salt thereof with the compound of Formula (VI) and water.

[0072] In some embodiments, the compound of Formula (VI) is selected from the group consisting of methanol, ethanol, n-propanol, and i-propanol. In one embodiment, the compound of Formula (VI) is ethanol.

[0073] In some embodiments, the compound of Formula (II) is

[0074] In some embodiments, a compound of Formula (II) or a salt thereof is provided by providing a compound of Formula (VII):oxidizing the compound of Formula (VII) to form the compound of Formula (II).

[0075] According to the present disclosure, any suitable oxidizing agent can be used to oxidize the compound of Formula (VII) to form the compound of Formula (II). Suitable oxidizing agents include, but are not limited to, hydrogen peroxide, peracetic acid, meta- choloroperbenzoic acid, and performic acid.

[0076] In one embodiment, the compound of Formula (VII) is oxidized in the presence of hydrogen peroxide.

[0077] In some embodiments, a compound of Formula (VII) is provided by providing a lignin source and valorizing the lignin source under conditions effective to form the compound of Formula (VII).

[0078] Various conditions for valorizing the lignin or lignin source known in the literature can be used. In some embodiments, lignin can be valorized by the cracking of alkali lignin over Al-MCM-41 zeolites (Jeenpadiphat et al., “Catechol Production From Lignin by Al-Doped Mesoporous Silica Catalytic Cracking,” Journal of Analytical and Applied Pyrolysis 21 :318-328 (2016), which is hereby incorporated by reference in its entirety). Alternatively, reductive catalytic fractionation, followed by O -demethylation and C-dealkylation can be used (Wu et al., “Lignin-First Monomers to Catechol: Rational Cleavage of C-0 and C-C Bonds over Zeolites,” ChemSusChem 15(7):e202102248 (2022), which is hereby incorporated by reference in its entirety).

[0079] In some embodiments, lignin can be valorized by dissolving it in methanol and then subjecting it to catalytic depolymerization in a Parr reactor at 140 °C - 220 °C under 4MPa H2 (pressurized at room temperature and then heated) under the presence of porous metal oxide catalyst (derived from Cu-doped hydrotalcite precursor) (Barta et al., “Depolymerization of Organosolv Lignin to Aromatic Compounds Over Cu-Doped Porous Metal Oxides,” Green Chemistry 16: 191-196 (2014), which is hereby incorporated by reference in its entirety).

[0080] In some embodiments, lignin can be valorized by dissolving it in 2% NaOH solution, passing through continuous flow reactor at 200 °C at pressure of 130 bar at a flow rate of lOml / min with 2 min residence time, and fractionation followed by O-dem ethylation (Almqvist et al., “Muconic Acid Production Using Engineered Pseudomonas Putida KT2440 and a Guaiacol-Rich Fraction Derived from Kraft Lignin,” ACS Sustainable Chem. Eng.9(24): 8097-8106 (2021), which is hereby incorporated by reference in its entirety).

[0081] In some embodiments, precursors of the compound of Formula (VII) can be prepared by treating the lignin or lignin source with NaOH, heating the mixture at 130 °C, filtering, and subjecting the monomers to biotechnological conversion to protocatechuic acid using S. cerevisiae (Zhang et al., “Lignin Valorization for Protocatechuic Acid Production in Engineered Saccharomyces Cerevisiae, ” Green Chem. 23:6515-6526 (2021), which is hereby incorporated by reference in its entirety).

[0082] Any lignin-containing material can be used as lignin source of the present disclosure. Suitable lignin-containing materials that can be used may include, but are not limited to, hardwoods (e.g., balsa wood, beech, ash, birch, Brazil wood, cherry, chestnut, elm, hickory, mahogany, maple, oak, rosewood, teak, walnut, locust, mango, alder, and the like), softwoods (e.g., pine, southern pine, fir, spruce, cedar, hemlock, and the like), cotton stalk, jute, flax fibers, hemp, sisal, bind, rattan, agave, coconut coir, grass, wheat stalk, rice stalk, barley straw, rye straw, wheat straw, rice straw, hemp stalks, kenaf stalks, sugar cane residue, bamboo, cork, and the like, and any combination thereof.

[0083] In some embodiments, the lignin-containing material is a combination of two or more lignin-containing materials, three or more lignin-containing materials, four or more lignincontaining materials, five or more lignin-containing materials, six or more lignin-containing materials, seven or more lignin-containing materials, eight or more lignin-containing materials, nine or more lignin-containing materials, or ten or more lignin-containing materials.

[0084] In some embodiments the lignin source is Hardwood Kraft Lignin (HKL), Softwood Kraft Lignin (SKL), Oragnosolv Hardwood Lignin, Oragnosolv Softwood Lignin, Herbaceous biomass-derived lignin, Acetosolv Lignin, Milled Wood Lignin (MWL), steamexplosion lignin, plasma-extraction lignin, chemically modified lignins, or combinations thereof.

[0085] The above disclosure is general. A more specific description is provided below in the following examples. The examples are described solely for the purpose of illustration and are not intended to limit the scope of the present disclosure. Changes in form and substitution of equivalents are contemplated as circumstances suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation.EXAMPLES

[0086] The following Examples are presented to illustrate various aspects of the present disclosure, but are by no means intended to limit its scope.Example 1 - Materials and Methods

[0087] Catechol, formic acid, hydrogen peroxide (30%), ammonium iron (III) sulfate hexahydrate, sulfuric acid, chloroform, and ethanol were purchased from Fisher Scientific. Isotopes including deuterated sulfuric acid and deuterated water (D2O) were obtained from Sigma-Aldrich. Deuterated chloroform was purchased from Cambridge Isotope Laboratories.Example 2 - Synthesis of c / v,c / v-Muconic Acid (ccMA)

[0088] The synthesis of ccMA was adapted from Coupe et al., “Sustainable Oxidative Cleavage of Catechols for the Synthesis of Muconic Acid and Muconolactones Including Lignin Upgrading,” Green Chemistry 22:6204-6211 (2020), which is hereby incorporated by reference in its entirety. Catechol (25 g) was dissolved in 125 mL of formic acid. In a separate roundbottom flask formic acid (235.22 g, 5.11 mol) and of H2O2 (30% wt, 115.79 g, 1.02 mol) were stirred together for 1 hour at room temperature. The mixture was then cooled in an ice bath, andthe catechol solution was added dropwise over a period of 2 hours. The mixture was stirred overnight at room temperature. The formed precipitate was filtered, washed several times with water, and dried in a vacuum oven overnight. 'H-NMR analysis in DMSO-de confirmed the complete conversion of catechol to ccMA.Example 3 - Levulinic Acid (LA) Synthesis and Characterization

[0089] A mixture of ccMA (0.4 g), water (50.69 mg), and sulfuric acid (4 mg) was prepared, and it was stirred at 80 °C for 16 hours. 'H-NMR analysis confirmed the formation of high-purity LA. All NMR characterizations were performed on a Bruker AVII-600 MHz NMR spectrophotometer. Peak assignments for LA are shown in Figures 3 and 23. The compound was also characterized using13C-NMR, heteronuclear single quantum coherence spectroscopy (HSQC), and homonuclear correlation spectroscopy (HCOSY). Two-dimensional NMR spectra are shown in Figures 10 (HSQC) and 12 (HCOSY).

[0090] Gas chromatography-mass spectrometry (GCMS) was used to further characterize LA and other products using an Agilent 7250 GC / Q-TOF system equipped with a 30 m long GC DB5-MS column. Agilent’s Mass Hunter software was used for data analysis. GCMS spectra for LA are shown in Figure 4.Example 4 - Computational Analyses

[0091] Computational analyses were performed using the Gaussian 09 software package (Frisch, et al., Gaussian 09, Revision E.01, Wallingford CT, 2013, which is hereby incorporated by reference in its entirety). Gibbs free energies were calculated using the B3LYP functional and the 6-311++G(d,p) basis set for all atoms (McLean et al., “Contracted Gaussian Basis Sets for Molecular Calculations. I. Second Row Atoms, Z=11-18,” The Journal of Chemical Physics 72:5639-5648 (1980); Krishnan et al., “Self-Consistent Molecular Orbital Methods. XX. A Basis Set for Correlated Wave Functions,” The Journal of Chemical Physics 72:650-654 (1980), which are hereby incorporated by reference in their entirety). Dispersion corrections were accounted through Grimme’s zero-damped DFT-D3 method (Grimme et al., “A Consistent and Accurate Ab Initio Parametrization of Density Functional Dispersion Correction (DFT-D) for the 94 elements H-Pu,” The Journal of Chemical Physics 132: 154104 (2010); Grimme et al., “Effect of the Damping Function in Dispersion Corrected Density Functional Theory,” Journal of Computational Chemistry 32(7): 1456-1465 (2011), which are hereby incorporated byreference in their entirety). Geometry optimizations were carried out with “verytighf ’ convergence criteria. Activation free energies were calculated using an explicit H2O or H3O molecule through the Berny optimization algorithm (Schlegel, “Optimization of Equilibrium Geometries and Transition Structures,” Journal of Computational Chemistry 3(2):214-218), which is hereby incorporated by reference in its entirety). A continuum Solvation Model based on the quantum mechanical charge Density of a solute molecule (SMD) variant of the Polarizable Continuum Model (PCM) employing the integral equation formalism variant was used to model the solvent environment of chloroform (Marenich et al., “Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions,” The Journal of Physical Chemistry B 113:6378-6396 (2009), which is hereby incorporated by reference in its entirety). Free energy extrapolations were performed at a temperature of 353.15 K. An isolated EECF ion was used as a reference for the free energies of proton addition steps. Additional details are provided in Bhardwaj et al., “Mild Decarboxylation of Neat Muconic Acid to Levulinic Acid: a Combined Experimental and Computational Mechanistic Study,” RSC Adv. 14:39408 (2024), which is hereby incorporated by reference in its entirety.Example 5 - Results and Discussion of Examples 1-4

[0092] The sulfuric acid-catalyzed reaction of cz.s.cz.s-muconic acid (ccMA) was conducted in a batch reactor with chloroform as the solvent. The concentration of the catalyst was kept constant at 30.5 wt% unless stated otherwise. ccMA underwent esterification, lactonization, and decarboxylation to form various products depending on the concentrations of ethanol and water (Figure 2).

[0093] In the presence of excess ethanol, esterification predominated, leading to the formation of cis, cis- and cz.s, Zzczzz.s-diethyl muconate (Entry 1, Table 1, Figure 21). Increasing the concentration of water prominently shifted the reaction towards lactonization, forming muconolactone (MLac) and dilactone (Dilac). These findings align with previous work by Carraher et al., “Solvent-Driven Isomerization of cz.ycz.s-Muconic Acid for the Production of Specialty and Performance-Advantaged Cyclic Biobased Monomers,” Green Chemistry, 2020, 22:6444-6454, which is hereby incorporated by reference in its entirety. Further experiments were conducted at very low concentrations of ethanol and water, which resulted in the formation of levulinic acid (LA) and ethyl levulinate (EL), for whichJH NMR is shown in Figure 22.GCMS spectra for EL are shown in Figure 24. It was found that the selectivity to the various products can be controlled by fine-tuning the concentrations of ethanol and water. Both ethanol and water played pivotal roles in the conversion to LA.Table 1. Effect of Ethanol and Water on the Formation of Muconolactone (MLac), Dilactone (Dilac), Levulinic Acid (LA), and Ethyl Levulinate (EL)Reactions were conducted at constant sulfuric acid concentration (30.5 wt% w.r.t ccMA), chloroform (4.1gm) and 80 °C temperature for 16 hours.accMA- cis, cis muconic acidbccMAT- cis, cis- diethyl muconatecctMAT- cis, trans- diethyl muconatedMLac- muconolactoneeDilac- dilactonefLA / EL- Levulinic acid / ethyl levulinate*- Only levulinic acid present

[0094] A conversion of 57.8 mol% to cis,cis- ethyl muconate, 24.85 mol% to cis,trans- diethyl muconate, and 17.3 mol% to MLac was observed after 16 hours at the ethanol concentration of 8.47 M (Entry 1, Table 1). Reducing the ethanol concentration to 2.88 M and increasing the water concentration to 1.86 M led to a steep increase in MLac conversion to 44.96 mol% (Entry 3, Table 1). Further reductions in ethanol concentration and increases in water concentration yielded the highest MLac conversion of 72.13 mol% (Entry 4, Table 1). The addition of water significantly influenced the formation of muconate esters by hydrolyzing the ester linkages, thereby shifting the equilibrium towards ccMA. The higher water concentrations favored the formation of MLac (Table 1).

[0095] At lower ethanol and water concentrations (0.35 M and 0.22 M, respectively), the reaction produced LA and EL (Entry 8, Table 1). This shift corresponded to a decrease in the conversion of MLac and dilactone to 6.51 mol% and 6.98 mol%, respectively, suggesting MLac as a possible intermediate for LA and EL.

[0096] LA was the only product observed in 'H-NMR and GCMS in the absence of ethanol and water (Entry 9, Table 1) (Figures 3 and 4). It was assumed that the conversion of ccMA to LA was 100% apart from residual char formation. Formation of char was attributed to the extraction of water by sulfuric acid from ccMA by cleaving C-H bonds. This implied that water was a reactant, as shown in the proposed mechanism (Figure 5).

[0097] This was supported by the experiments conducted in bulk and solvent-free conditions in the presence of stoichiometric amounts of water yielding 100% selectivity to LA in 16 hours with negligible amounts of char residue (Entries 1-2, Table 2). Bulk reactions of ccMA were also conducted in 1 wt% sulfuric acid and found to reach 100% selectivity at 110 °C in 16 hours (Entry 4, Table 2), thereby making this an easily scalable process. The loss in mass of the reaction was around 30% from the initial ccMA weight, implying the stochiometric release of CO2 leading to LA synthesis. This further supported the 100% selectivity for LA and no char formation.Table 2. Effect of the Sulfuric Acid Concentration and Temperature on the Selectivity for Levulinic Acid (LA)Bulk and solvent-free reaction of ccMA were carried out in catalytic amount of sulfuric acid with only stoichiometric amount of water for levulinic acid (LA) synthesis for 16 hours.

[0098] The effects of temperature and reaction time on MLac formation were also explored under the conditions listed in Entry 4 of Table 1. The conversion exhibited interesting trends when the temperature was varied from 50 °C to 95 °C. Conversion increased from 71.4 mol% to 80 mol% as the temperature rose from 50 °C to 60 °C, but decreased gradually at highertemperatures (Figure 6). At 60 °C, neither LA nor EL formed, but they appeared at 95 °C. As LA and dilactone conversions increased, the consumption of MLac and dilactone also increased, implicating them in LA synthesis (Figure 6).

[0099] MLac formation was further examined at different time intervals, focusing on the 80 °C condition. Rapidly formation of MLac was observed within the first 5 minutes of the reaction, reaching a saturation point after 10 hours (Figure 7). These results highlighted the extremely fast reaction kinetics for MLac formation, but with minimal conversion towards LA under the specific temperature and time conditions examined.

[0100] Next, the intermediates involved in LA synthesis were studied. These studies were conducted under conditions where ethanol and water were absent, achieving a 100% selectivity towards LA (Entry 9, Table 1).Identification of Intermediates and Mechanistic Pathway

[0101] In light of the rapid rate of MLac formation and its minimal conversion to LA under specific conditions (Entry 4, Table 1), the focus was shifted to studying the intermediates involved in LA synthesis, leading to the proposal of the reaction mechanism shown in Figure 5. ccMA isomerized to c / MA via proton exchange followed by cyclization to form MLac and then dilactone. The literature reports isomerization of ccMA to cis,trans-mucomc acid (c / MA) under acidic conditions (Carraher et al., “Solvent-Driven Isomerization of cis,cis-Muconic Acid for the Production of Specialty and Performance-Advantaged Cyclic Biobased Monomers,” Green Chemistry, 2020, 22:6444-6454, which is hereby incorporated by reference in its entirety). The tautomerization of MLac led to “tautomer” formation. Subsequent ring opening and then nucleophilic addition of water resulted in formation of 3 -hydroxyhex-3 -ene. It then tautomerized to keto-adipic acid and formed LA though decarboxylation.

[0102] Some intermediates shown in the mechanism were very short lived and highly unstable making it challenging to identify them. Therefore, the reaction was carried out in D2SO4 and CDCI3 at 75 °C for 3 hours. Heavy isotopes reduce the proton exchange rate and hence lower the rate of reaction. Short lived intermediates were observed in proton and carbon NMR. 'H-NMR spectra (Figure 8) showed a pair of alkene peaks assigned at 7.6 ppm and 6.2 ppm and a pair of peaks at 2.8 ppm and 2.65 ppm confirming MLac formation under such reaction conditions.

[0103] Tautomer” characteristic peaks in Figure 8 were identified by ‘e’ , ‘f , and ‘g’ . Peaks ‘e’ and ‘f were attributed to the two alkenes that were formed after MLac tautomerization. The downshift of these peaks indicated the loss of conjugation present in MLac (peaks ‘a’, ‘b’).The tautomer was further corroborated in13C-NMR through the presence peaks of ‘b’, ‘e’, ‘f , and ‘g’ (Figure 9).

[0104] The “tautomer” transformed to 3 -hydroxyhex-3 -ene. Peaks ‘i’ and ‘h’ in Figure 8 correspond to its alkene and methylene groups, which were conspicuously absent when the reaction duration was extended. This suggested the short-lived nature of 3-hydroxyhex-3-ene, which likely undergoes rapid tautomerization and decarboxylation to form LA.13C-NMR peaks ‘j’, ‘k’, and ‘p’ provided additional support to the structural assignment.

[0105] 2D-HSQC NMR was conducted to correlate the1H- and13C-NMR spectra (Figure 10). For example, the alkene protons of MLac at 7.6 ppm and 6.2 ppm, and those of the tautomer at 6.5 ppm and 5.9 ppm, showed direct correlation with carbon peaks at 154 ppm, 122 ppm, 125 ppm, and 101 ppm, respectively. Similarly, the proton assignment for the alkene of 3- hydroxyhex-3-ene at 5.7 ppm was correlated with the carbon peak at 97 ppm. The identities of these intermediates were further confirmed by GC-MS analysis (Figure 11). Collectively, these findings strongly validated the intermediates MLac, the tautomer, and 3-hydroxyhex-3-ene in the mechanistic pathway for LA formation.

[0106] Additionally, the protons for the Dilac at 2.9 ppm and 5.2ppm and for the LA at 2.65 ppm and 2.72 ppm (Figure 8) were found to be coupled with each other in 2d-HCOSY NMR (Figure 12) indicating these protons to be coupled with each other. This provided further evidence that these proton assignment corresponded to Dilac and LA.Density Functional Theory Calculations

[0107] To validate the experimentally observed mechanisms leading to the formation of LA and EL, the reaction free energies (AG) and activation free energies (Ga) of elementary steps in three possible pathways were calculated (Figures 13-15). The thermodynamically most favorable elementary steps in the respective pathways for LA and EL formation are summarized in Figure 16. Additional computational data including calculated zero-point energies (ZPE), entropies (S), and free energies (G) of reaction intermediates involved in cv.ycv.s-muconic acid (ccMA) reduction to levulinic acid (LA) / ethyl levulinate (EL) in chloroform at 353.15 K are provided in Table 3. Free energies were referenced to isolated ccMA (ZPE: 3.16 eV, S: 456.2 J / (mol*K)), H3O+(ZPE: 0.93 eV, S: 208.5 J / (mol*K)), H2O (ZPE: 0.57 eV, S: 200.2 J / (mol*K)), CO2(ZPE: 0.25 eV, S: 228.0 J / (mol*K)), and C2H5OH (ZPE: 2.16 eV, S: 282.4 J / (mol*K)) in implicit chloroform.Table 3. Zero-Point Energies, Entropies, and Formation Free Energies of IndividualIntermediatesAbbreviations: muconolactone (Mlac), dilactone (Dilac).

[0108] The elementary steps considered in Figures 13-15 were based on the most probable reaction mechanism predicted by 'H-NMR and13C-NMR (Figure 5). Isomerization of ccMA to c / MA (AG = -13 kJ / mol, Ga= 13 kJ / mol) and ring-closing of c / MA to Mlac (AG = - 1.95 kJ / mol, Ga= 186 kJ / mol) proceed thermodynamically downhill (Figure 16), with c / MA isomerization to MLac being kinetically sluggish. While the DFT calculated activation free energy barrier for c / MA isomerization to Mlac was in good agreement with previous experiments (Carraher et al., “Solvent-Driven Isomerization of c / yc / .s-Muconic Acid for the Production of Specialty and Performance-advantaged Cyclic Biobased Monomers,” Green Chemistry 22:6444-6454 (2020), which is hereby incorporated by reference in its entirety), it was higher than that expected from the current experiments (Figure 20B). This was anticipated to be due to the DFT-calculated Gahaving only one explicit H2O molecule involved in intramolecular proton transfer, which could be insufficient to accurately sample H+transfer from terminal - COOH of c / MA to -CH- group of Mlac (Chew et al., “Effect of Mixed- Solvent Environments onthe Selectivity of Acid-Catalyzed Dehydration Reactions,” ACS Catalysis 10(3): 1679-1691 (2020), which is hereby incorporated by reference in its entirety). Further, Mlac can readily isomerize to Dilac with AG = -3 kJ / mol (Figure 13). Such close-to-zero AG and presumed low activation barriers for the isomerization steps compared to the later reaction steps (Hackler et al., “Isomerization and Selective Hydrogenation of Propyne: Screening of Metal-Organic Frameworks Modified by Atomic Layer Deposition,” Journal of the American Chemical Society 142:20380-20389 (2020), which is hereby incorporated by reference in its entirety) suggested that all the isomerization steps from c / MA to Dilac could be in thermodynamic equilibrium (c / MA —> MLac <=> Dilac) in the absence of water and sulfuric acid. The proton (H+) in the solution phase can either attack C-C or C-0 of the five-member ring. The reaction energetics of H+addition to C-0 (AG = -62 kJ / mol, Ga= 0 kJ / mol) was much more favorable than H+addition to C-C (AG = 74 kJ / mol, Ga= 102 kJ / mol) of the five-membered ring in Mlac (Figure 16). The reaction intermediate formed by adding H+to C-0 of Mlac (1-2) has a 124 kJ / mol thermodynamic barrier for further deprotonation to form the tautomer. Due to this relatively smaller barrier for forming an experimentally observed tautomer in the NMR results (Figures 8 and 9) compared to an alternative pathway was considered: Mlac —> 1-1 —> Mlac-H2O tautomer which has apparent activation free energy barrier of 164 kJ / mol, the energetically preferred pathway to form tautomer is: Mlac —> 1-2 —> tautomer.

[0109] The other experimentally observed product (Figures 8 and 9) was 3-hydroxyhex- 3-ene, which can be formed by two possible pathways: (i) ((Pathway 1) in Figure 16) protonation of C-C close to -OH group followed by H+removal from -OH group, to form P-2, followed by H2O assisted ring-opening to form experimentally observed 3 -hydroxyhex-3 -ene, or (ii) ((Pathway 2) in Figure 16) hydration to form Mlac~H2O followed by dehydration to form P-2 and water-assisted ring opening to form experimentally 3 -hydroxyhex-3 -ene. Given the insurmountable barrier for dehydration of Mlac-H2O (Ga= 270 kJ / mol), the energetically preferred pathway is: tautomer1-3 —> P-2 —> 3 -hydroxyhex-3 -ene. As shown in Figure 16, 3-hydroxyhex-3-ene can further tautomerize to form experimentally observed keto adipic acid with the overall exergonic energetics (AG = -47 kJ / mol) and thermodynamic barrier of 112 kJ / mol for 1-4 to keto adipic acid. The keto adipic acid has further downhill energetics to release CO2 and thereby form LA (AG = -72 kJ / mol), which can further esterify to EL in the presence of ethanol with exergonic energetics (AG = -13 kJ / mol). Additional details are provided in Bhardwaj et al., “Mild Decarboxylation of Neat Muconic Acid to Levulinic Acid: a CombinedExperimental and Computational Mechanistic Study,” RSC Adv. 14:39408 (2024), which is hereby incorporated by reference in its entirety.

[0110] Overall, the DFT calculations suggested that the thermodynamically most favored pathway for ccMA reduction to LA and EL was: ccMA c / MA Mlac 1-2 tautomer —1-3 P-2 3-hydroxyhex-3-ene 1-4 ketoadipicacid LA EL. This was in line with the experimental1H-NMR (Figure 8) and13C-NMR (Figure 9) analysis of reaction mixtures under deuterated conditions (CDCh + D2SO4) at 348-363 K.Effect of Time and Kinetics Study

[0111] To unravel the mechanistic details and kinetics, time-course studies were performed at three distinct temperatures: 75 °C, 80 °C, and 90 °C at constant deuterated sulfuric acid and deuterated chloroform concentration in the absence of water. The Dilac peak in the1H- NMR spectrum at 5.2 ppm served as the reference for quantitative analyses.

[0112] Within 15 minutes at 75 °C, a rapid formation of MLac was observed, constituting 58 mol% of the mixture. However, its concentration waned over time, with a concomitant increase in both Dilac and LA (Figure 17A). Notably, Dilac formation rate initially exceeded that of LA, as evidenced by a steeper slope in Figure 17 A. The rate of tautomer formation remained low, plateauing at about 2% within the first 4 hours. Similar trends were observed at higher temperatures. At 80 °C, Dilac consumption increased, thereby promoting LA formation (Figure 17B). Even more strikingly, at 90 °C, LA yields soared to 72% within 6 hours (Figure 17C). At each examined temperature, Dilac peaked at around 40% conversion before declining, which corresponded with an uptick in LA formation.

[0113] The observed results suggested the presence of a significant energy barrier which impeded LA formation until a 40% Dilac conversion was achieved. However, once this conversion threshold was surpassed, especially at 90°C, the rate of LA formation accelerated swiftly. A 100% LA formation was observed despite the complete consumption of MLac in 4 hours (Figure 17C). This gave rise to the postulation that a majority of the MLac might have been converted to Dilac, which subsequently reacted to form LA once the thermodynamic energy barrier was surmounted. From these observations, it was inferred that the conversion of MLac to LA presented a higher activation barrier in comparison to the conversion from ccMA to MLac.

[0114] The experimental data collected at these temperatures were fitted to the first order rate equations (Eq. 1-5) by optimizing rate constants in MATLAB using least-square regression. Optimized rate constants presented an excellent fit with the experimental observations (Figures18A-C, Table 4). The differential rate equations (Eq. 1-5) and their corresponding rate constants were based on the reaction scheme reported as mechanism (Figure 5).where [ccMA], [c / MA], [MLac], [Dilac], [Tau] and [LA] signify the concentrations of ccMA, ctMA, Mlac, Dilac, tautomer and LA, respectively, and kCCM4, kMLac, kdiiaci, kdiiac2, ktauand FLA are their corresponding rate constants.Table 4. Rate Constants, Equilibrium Constants, and Activation Energies for the Reaction of c / v,c / v-Muconic Acid (ccMA) to Levulinic Acid (LA)

[0115] As shown in Figures 17A- 17C, the tautomer concentration was nearly undetectable via NMR due to its instability, thereby, providing poor fit to the experimental values in MATLAB kinetic analysis. Therefore, optimized ktauvalues were not included in Table 3 but was taken into consideration for LA formation. The kinetic rate constants evaluation in MATLAB assumed same rate constant of LA (kiA) for all the short-lived and highly unstable intermediate reaction steps after tautomer formation (Figure 5). This can be attributed to the short-lived nature of these compounds reacting instantly to form LA.

[0116] The rate constant for MLac formation (kMLac) exceeded those for LA (FLA), consistent across all temperatures (Table 4). Furthermore, FLA values were significantly higherat 90 °C compared to those at 75 °C and 80 °C, corroborating the extremely fast LA formation observed at this elevated temperature (Figure 17C).

[0117] The temperature dependence of the rate constants is shown in the Arrhenius plot of Figure 17D. The activation energies were calculated as follows: 16.10 kJ / mol for ccMA, 31.2 kJ / mol for MLac, and 158.18 kJ / mol for LA (Table 4). The lower activation energies observed in Entries 1-3 (Table 4) indicated that the isomerization of ccMA to MLac proceeded readily, whereas the conversion of MLac to LA necessitated significantly higher energy input.

[0118] The high activation energy and the tenfold increase in kLA was ascribed to the hindered interaction among MLac, water, and sulfuric acid, essential for LA formation. This hindrance arises due to the immiscibility of chloroform and water phases (Figure 19). However, at a temperature of 90°C, this barrier is surmountable, solubility of MLac in water increases enabling sulfuric acid to catalyze the tautomerization, yielding LA. Consequently, it was assumed that the elevated activation energy for LA formation resulted from mass transfer limitations. These observations implied that Mlac tautomerization could be a rate-determining step in the overall reaction mechanism.Effect of Temperature

[0119] Temperature exhibited a critical impact on the kinetics of LA formation, as well as the consumption of intermediates MLac and Dilac. Raising the temperature from 75 °C to 90 °C significantly increased the yield of LA from 66% to 100% within a 16-hour time frame (Figure 20 A). At 90 °C, the rate of LA formation reached an impressive 72% conversion within just 6 hours (Figure 20A). The elevated temperature not only expedited LA formation but also accelerated the consumption of MLac. This was illustrated by a steeper declining slope in the Dilac curve after 4 hours at 90 °C compared to 75 °C (Figure 20C). Intriguingly, MLac was entirely consumed within the first 2 hours at 90 °C (Figure 20B). Moreover, Dilac consumption rates also surged when compared to those at lower temperatures. The temperature increase resulted in a shift of the transition point at which Dilac formation peaked before decreasing. This point moved to 1 hour at 90°C, compared to longer times at lower temperatures (Figure 20C). In summary, elevating the reaction temperature drastically amplified both the formation rate of LA and the consumption rates of intermediates MLac and Dilac. This suggested that higher temperatures favor faster kinetics and higher conversions, thereby improving the overall efficiency of the LA formation process.

[0120] These results have successfully demonstrated the solvent-free synthesis of levulinic acid (LA) from bulk c / .s,c / .s-muconic acid (ccMA) and unraveled the intricacies of itsreaction mechanism through rigorous experimentation and computational analysis. A set of parameters, including the presence of ethanol and water, temperature, and reaction time, were identified as crucial for governing the reaction kinetics and selectivity. Notably, the selectivity to LA reached an outstanding 100% when both ethanol and water were eliminated from the system. Advanced analytical methods such as1H-NMR,13C-NMR, and two-dimensional correlation NMR techniques (HSQC and HCOSY), coupled with GCMS, were deployed to successfully identify the intermediates involved — MLac, dilactone, tautomer, and 3-hydroxyhex- 3-enedioic acid. These findings were further corroborated by density functional theory (DFT) calculations. An in-depth kinetic study revealed dilactone as a more favorable intermediate than the tautomer, thereby influencing the overall rate of LA formation. It was postulated that the rate-determining step was tautomerization due to the mass transfer limitations, that is also qualitatively in line with the DFT free-energy calculations. The temperature dependence of the reaction was explicitly established. As the reaction temperature was raised from 75°C to 90°C, both the rate constants for ccMA consumption and LA formation exhibited significant increases.

[0121] This work has broader implications for the synthesis of biofuels from ccMA. The comprehensive identification of intermediates and the detailed understanding of the kinetics and rate constants provide a solid foundation for future studies aimed at optimizing the conversion processes.

[0122] In summary, the study shed light on the complex mechanistic and kinetic aspects of LA synthesis from ccMA, serving as a stepping stone for further research in this promising field.

[0123] Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow.

Claims

WHAT IS CLAIMED:

1. A process for preparation of a compound of Formula (I):whereinR is H or Ci-6 alkyl; comprising: providing a compound of Formula (II):represents a bond of unspecified stereochemistry; and converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (I).

2. A process for preparation of a compound of Formula (III):whereinrepresents a bond of unspecified stereochemistry;R1is Ci -6 alkyl; andR2is Ci-6 alkyl; comprising: providing a compound of Formula (II):salt thereof; and converting the compound of Formula (II) or a salt thereof at a temperature below180°C to form the compound of Formula (III).

3. A process for preparation of a compound of Formula (IV) or Formula (V):whereinR3is H or Ci-6 alkyl, compnsing: providing a compound of Formula (II):represents a bond of unspecified stereochemistry; and converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (IV) or Formula (V).

4. The process according to any of claims 1-3 further comprising: providing a compound of Formula (VI):ROH (VI), wherein said converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (I), Formula (III), Formula (IV), or Formula (V) is carried out by reacting the compound of Formula (II) or a salt thereof with the compound of Formula (VI).

5. The process according to any of claims 1-3 further comprising: providing a compound of Formula (VI):ROH (VI); and providing water, wherein said converting the compound of Formula (II) or a salt thereof at a temperature below 180°C to form the compound of Formula (I), Formula (III), Formula (IV), or Formula (V) is carried out by reacting the compound of Formula (II) or a salt thereof with the compound of Formula (VI) and water.

6. The process according to any of claims 1-5, wherein said converting is carried out in the presence of a solvent.

7. The process according to claim 6, wherein the solvent is a non-aqueous solvent.

8. The process according to claim 7, wherein the solvent is chloroform.

9. The process according to any of claims 1-8, wherein said converting is carried out in the presence of a catalyst.

10. The process according to claim 9, wherein the catalyst is an inorganic acid.

11. The process according to claim 10, wherein the catalyst is sulfuric acid.

12. The process according to any of claims 4 or 5, wherein the compound of Formula (VI) is selected from the group consisting of methanol, ethanol, n-propanol, and i-propanol.

13. The process according to claim 12, wherein the compound of Formula (VI) is ethanol.

14. The process according to claim 1, wherein the compound of Formula (I) is15. The process according to claim 1, wherein a mixture of two or more compounds of Formula (I) is formed.

16. The process according to claim 2, wherein the compound of Formula (III) is17. The process according to claim 2, wherein a mixture of two or more compounds of Formula (III) is formed.

18. The process according to claim 3, wherein the compound of Formula (IV) is19. The process according to claim 3, wherein a mixture of two or more compounds of Formula (IV) or Formula (V) is formed.20 The process according to any of claims 1-19, wherein the compound of Formula21. The process according to any of claims 1-20, wherein said converting is conducted at a temperature below 175 °C.

22. The process according to claim 21, wherein said converting is conducted at a temperature below 150°C.

23. The process according to claim 21, wherein said converting is conducted at a temperature below 100°C.

24. The process according to claim 21, wherein said converting is conducted at a temperature from about 50°C to about 95°C.

25. The process according to any of claims 1-20, wherein said converting is conducted for at least 4 hours.

26. The process according to claim 25, wherein said converting is conducted for at least 10 hours.

27. The process according to claim 25, wherein said converting is conducted for at least 16 hours.

28. The process according to claim 1, wherein said converting the compound of Formula (II) or a salt thereof at a temperature below 180°C results in the formation of a compound of Formula (IVa):which rearranges to form the compound of Formula (I).

29. The process according to any of claims 1-5, wherein a mixture of two or more compounds of Formula (I), Formula (III), Formula (IV), or Formula (V) is formed.

30. The process according to any of claims 1-29, wherein said providing a compound of Formula (II) or a salt thereof comprises: providing a compound of Formula (VII):oxidizing the compound of Formula (VII) to form the compound of Formula (II).

31. The process according to claim 30, wherein said oxidizing is carried out in the presence of hydrogen peroxide.

32. The process according to claim 30, wherein said providing a compound of Formula (VII) comprises: providing a lignin source; and valorizing the lignin source under conditions effective to form the compound of Formula (VII).

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