Selective C–O Bond Cleavage of Lignin Systems and Polymers

Research Article Cite This: ACS Catal. 2019, 9, 2252−2260

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Selective C−O Bond Cleavage of Lignin Systems and Polymers Enabled by Sequential Palladium-Catalyzed Aerobic Oxidation and Visible-Light Photoredox Catalysis Gabriel Magallanes,†,∇ Markus D. Kärkäs,†,‡,∇ Irene Bosque,† Sudarat Lee,† Stephen Maldonado,†,§ and Corey R. J. Stephenson*,†

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†

Willard Henry Dow Laboratory, Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States ‡ Department of Chemistry, Organic Chemistry, KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden § Program in Applied Physics, University of Michigan, Ann Arbor, Michigan 48109, United States S Supporting Information *

ABSTRACT: Lignin, which is a highly cross-linked and irregular biopolymer, is nature’s most abundant source of aromatic compounds and constitutes an attractive renewable resource for the production of aromatic commodity chemicals. Herein, we demonstrate a practical and operationally simple two-step degradation approach involving Pd-catalyzed aerobic oxidation and visible-light photoredox-catalyzed reductive fragmentation for the chemoselective cleavage of the β-O-4 linkagethe predominant linkage in ligninfor the generation of lower-molecular-weight aromatic building blocks. The developed strategy affords the β-O-4 bond cleaved products with high chemoselectivity and in high yields, is amenable to continuous flow processing, operates at ambient temperature and pressure, and is moisture- and oxygen-tolerant. KEYWORDS: aerobic oxidation, C−O bond cleavage, lignin, photoredox catalysis, sustainable chemistry

1. INTRODUCTION Because of the increasing costs of fossil-derived resources and their limited long-term supply, the development of technologies for the production of commodity chemicals and fuels from renewable feedstocks has become an area of intense focus in the green chemistry community. In this context, devising green and sustainable strategies for the valorization of lignocellulosic nonfood biomass would afford a notable reduction in the carbon footprint of platform chemicals and liquid fuels. Biomass arising from woody plant matter is composed of three polymeric components: cellulose (∼40%), hemicellulose (∼25%), and lignin (∼20%). While valorization technologies for the cellulosic and hemicellulosic components exist, the utilization of lignin as a valuable feedstock has proven to be challenging and, consequently, is currently regarded as a waste product.1 Lignin is a highly oxygenated polyphenolic polymer derived biosynthetically from three phenylpropanoid monomeric subunits (coumaryl, coniferyl, and sinapyl alcohol), and provides rigidity to plant cell walls (Figure 1). Being one of the few renewable sources comprised of aromatic monomers, lignin constitutes an attractive feedstock for the production of value-added aromatics and would thus complement the products derived from the processing of cellulose. However, the nonuniform polymerization events that form lignin create a © XXXX American Chemical Society

variety of functional groups and stereochemical configurations that present nontrivial challenges for devising controlled depolymerization strategies.2 Of the different linkage motifs featured in native lignin, the β-O-4 linkage (Figure 1) has generally been targeted, because of its abundance (45%−60%). 3 A variety of distinct depolymerization methodologies have been extensively exploited and include acid-catalyzed,4 oxidative,5 reductive,6 and redox-neutral7 approaches. In addition to the aforementioned methods, two-step fragmentation strategies involving the selective oxidation of the Cα benzylic alcohol moiety to a ketone, which activates the β-O-4 linkage8 for the subsequent C−C or C−O bond cleavage, have recently emerged as promising routes for accessing synthetic building blocks from lignin (Scheme 1).9 During the past decade, visible-light photoredox catalysis has experienced a resurgence of interest.10 Our group recently disclosed a method for degradation of oxidized lignin systems employing [Ir(ppy)2(dtbbpy)]+ (dtbbpy = 4,4′-di-tert-butyl2,2′-bipyridine, ppy = 2-phenylpyridine) as the photocatalyst in combination with diisopropylethylamine (iPr2NEt) and Received: October 16, 2018 Revised: January 19, 2019

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DOI: 10.1021/acscatal.8b04172 ACS Catal. 2019, 9, 2252−2260

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ACS Catalysis

significantly reduced reaction times. These results highlight the prospect of C−O bond cleavage methodologies for delivering value-added aromatic commodity chemicals and is a step toward mild and selective lignin processing.

2. RESULTS AND DISCUSSION 2.1. Palladium-Catalyzed Aerobic Oxidation. A dual Pd/photoredox protocol for the efficient oxidation of lignin systems at room temperature was recently disclosed by our group.14 However, this system showed poor chemoselectivity for oxidation of substrates containing both Cα and Cγ alcohol moieties. In order to address this chemoselectivity challenge and with the recognition that O2 would constitute a more desirable oxidant for large-scale applications, we became interested in developing a selective catalytic aerobic oxidation protocol. In nature, tailored metalloenzymes are well-known to activate molecular oxygen (O2) for performing catalytic oxidations.15 In the context of industrial and academic research, the use of O2 as a terminal oxidant in chemical synthesis represents an attractive alternative, because it is an abundant and highly atom-economical oxidant.16 Therefore, we considered exploiting the direct Pd-catalyzed aerobic oxidation, which does not require any redox-active co-catalysts, as an attractive entry for achieving dioxygen-coupled catalytic turnover.17 The Pd(OAc)2/DMSO catalyst system, developed independently by the groups of Larock and Hiemstra in the 1990s, seemed particularly appealing.18,19 Here, DMSO serves to stabilize the reduced Pd catalyst (Pd0) and promotes redox cycling with O2. In addition, aerobic oxidations are becoming increasingly utilized in industrial settings as represented by GlaxoSmithKline’s API Chemistry, in which a high-boiling solvent (sulfolane, bp = 285 °C) was used with heating and bubbling air to oxidize 400 g of material.20 The products were isolated in high purity after distillation. The ease of operation for our reaction lends itself well to future innovations and adaptation for oxidations and the like. Our initial studies focused on using O2 as the terminal oxidant for oxidation of model substrate 1a. The reaction of 1a with 10 mol % Pd(OAc)2 in DMSO under an O2 atmosphere at 65 °C afforded ketone 2a in high yield (Table S1, entry 1). Decreasing the catalyst loading to 5 mol % also delivered ketone 2a in >95% yield after 12 h (Table S1, entry 2). Encouragingly, the aerobic oxidation reaction remained operational when using air as the oxidant, and by extending the reaction time to 18 h (Table S1, entry 5), ketone 2a was obtained in 97% yield. Subsequently, we turned our attention to study the scope of the Pd-catalyzed aerobic oxidation on a series of β-O-4 linked alcohols (Scheme 2). β-O-4 systems bearing γ-alcohol units have previously proven to be particularly challenging in transition metal-based systems.7b,21 Gratifyingly, subjecting the γ-alcohol-containing coumaryl lignin system 1b to the Pd-catalyzed aerobic oxidation conditions exhibited good reactivity, giving ketone 2b in 84% isolated yield with complete selectivity for the benzylic alcohol over the primary alcohol moiety. Coniferyl- and sinapyl-based systems (1c−1g and 1i−1j, respectively) were subsequently investigated in the Pdmediated aerobic oxidation. Both coniferyl systems 1c and 1d afforded the oxidized products 2c and 2d, respectively, in high yields. Both bis-ortho-substituted alcohols 1e and 1f were tolerated with no apparent decrease in yield, delivering ketones 2e and 2f in 96% and 87%, respectively. The 3,5-dimethoxyderived substrate 1g and the less-activated unsubstituted

Figure 1. Representative structure of lignin and its monomeric alcohol constituents.

Scheme 1. Two-Step Approaches for Fragmentation of Lignin Systems to Value-Added Aromatics

formic acid (HCO2H).9b,11−13 In the present study, we disclose a practical and mild method for the selective cleavage of C−O bondsβ-O-4 linkagesthat are prevalent in lignin by sequential Pd-catalyzed aerobic oxidation and visible-light photoredox catalysis. The selective two-step strategy is also amenable to continuous flow processing, allowing for 2253

DOI: 10.1021/acscatal.8b04172 ACS Catal. 2019, 9, 2252−2260

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ACS Catalysis Scheme 2. Scope of the Pd-Catalyzed Aerobic Oxidation of Lignin Systemsa

Reaction conditions: 1 (0.4 mmol) and Pd(OAc)2 (0.02 mmol, 5 mol %) in DMSO (1.0 mL) at 65 °C for 18 h. Yields of isolated products are given.

a

Scheme 3. Two-Step Fragmentation of Lignin Systemsa

Reaction conditions: 1 (0.4 mmol) and Pd(OAc)2 (0.02 mmol, 5 mol %) in DMSO (1.0 mL) at 65 °C for 18 h, then [Ir(ppy)2(dtbbpy)]PF6 (0.12 μmol, 0.03 mol %), iPr2NEt (0.48 mmol, 1.2 equiv) and HCO2H (0.04 mmol, 10 mol %) in MeCN (1.0 mL), room temperature, irradiation with blue LEDs, 32 h. Yields of isolated products are given. a

gave 2j in 85% yield. Attempts were also made to use triol 1k in the Pd-mediated aerobic oxidation. This furnished the doubly oxidized product, diketone 2k, in 78% yield, highlighting the potential application of this reaction to morecomplex β-O-4 systems. 2.2. Visible-Light-Mediated C−O Bond Cleavage. Having established an operationally simple aerobic oxidation procedure for the generation of the oxidized β-O-4 motif, we next sought to study the selective cleavage of the C−O bond. To evaluate the possibility of developing a two-step

alcohol 1h were subsequently evaluated and were successfully converted to ketones 2g and 2h in high yields (93% and 92%, respectively). Oxidation of sinapyl model compound 1i, having a trioxygenated aromatic ring, was also selective and afforded benzylic ketone 2i in 91% isolated yield. Compounds containing free phenolic moieties have previously been proven difficult to dehydrogenate, because of the relative ease by which such substrates decompose and/or produce complex product mixtures.22 Gratifyingly, subjecting lignin model compound 1j bearing a free phenol to the reaction conditions 2254

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ACS Catalysis Scheme 4. Photochemical C−O Bond Fragmentation in Flow

2.3. Photochemical Fragmentation of Lignin Model Polymers. Because of the irregular structure and varying levels of solubility of native lignin, we considered the study of lignin polymer model systems to be significant in determining the efficacy of our photochemical fragmentation method. The study of lignin depolymerization on model polymer systems is often disregarded, because of the insoluble nature of the large polymers. As further evidence of the robust nature of the photocatalytic C−O bond cleavage, we sought to evaluate the fragmentation of lignin model polymers. Polymers 5a−5c were identified as ideal polymer substrates, because of the succinct synthetic access of the embedded C−O bond that replicates that of the β-O-4 linkage in native lignin.24 α-Bromination of 4-hydroxyacetophenone derivatives, followed by polymerization in DMF in the presence of base, afforded white precipitates that were identified as the desired polymers (for full characterization, including GPC, MALDI, and NMR assignments, please see the Supporting Information; the HSQC correlations corresponded to correlations in native lignin, as expected). Subjecting polymers 5a−5c to slightly modified reaction conditions with an extended reaction time afforded the respective fragmentation products 4c−4e in high yields (Scheme 5). The polymers are highly insoluble in MeCN, but the reactions turned clear over time, empirically indicating visually that the polymers underwent fragmentation. To further replicate native lignin, the polymers 5a−5c were subjected to hydroxymethylation conditions to afford varying levels of incorporation of the hydroxymethyl group (polymers 6a−6c; see Scheme 6).25 The relatively low levels of hydroxymethylation are largely due to the insoluble nature of the polymer under the reaction conditions, but the conversion is easily quantified by 1H NMR. Under reaction conditions that were identical to those used for polymers 5a−5c, the fragmentation products from polymers 6a−6c were obtained in overall good yields (Scheme 6). In addition, a mixed polymer (7) containing the three different monomer units was synthesized and subsequently fragmented in good yields (Scheme 7, top). Finally, polymer 5a was subjected to the fragmentation conditions in the presence of sunlight and was compared to a blue LED reaction for the same amount of time (Scheme 7, bottom). Fragmentation occurred with very similar yields, suggesting that this reaction can be solar-powered, which has significant implications for furthering the goals of green chemistry. Of note is that the overall yields for the polymer fragmentations were comparable to the model compound fragmentation yields under blue LED irradiation; however, because of the heterogeneity of the reaction mixture in the polymer fragmentation reactions, slightly higher catalyst loadings (1 mol %) and extended reaction times were necessary for full starting material consumption.

fragmentation process by combining the aerobic oxidation method with the photocatalytic reductive cleavage strategy, the crude reaction mixture obtained after the oxidation of 1a was subjected to [Ir(ppy)2(dtbbpy)]+ (1 mol %), iPr2NEt (3 equiv) and HCO2H (1 equiv) in MeCN. We found an aqueous workup step to be necessary between the oxidation and reduction reaction, as noted by the different solvents, but no purification was required. Upon irradiation with blue LEDs, full conversion to the reductively cleaved products 3a and 4a was reached after merely 3 h. Further optimization revealed that the photochemical reductive cleavage could be performed using 0.03 mol % loading of the photocatalyst, 1.2 equiv of i Pr2NEt, and 0.1 equiv of HCO2H by extending the reaction time to 32 h (Table S2 in the Supporting Information). Under these optimized conditions, the two-step fragmentation of 1athat is, the oxidation of alcohol 1a to ketone 2a, followed by reductive cleavagedelivered the desired lowmolecular-weight aromatic building blocks 4′-methoxyacetophenone (3a) and guaiacol (4a) in 94% and 92% yields, respectively (Scheme 3). Selective C−O bond fragmentation was also accomplished when diol 1b was exposed to the aerobic oxidation-reductive cleavage sequence, delivering βhydroxy ketone 3b and guaiacol (4a) in 83% and 80% isolated yields, respectively. Fragmentation of coniferyl substrates 1c, 1d, and 1f also proceeded well, giving the fragmentation products in high yields. Sinapyl diol substrate 1i was subsequently investigated and underwent efficient fragmentation to afford β-hydroxy ketone 3e and guaiacol (4a) in 87% and 83% yields, respectively. Finally, performing the aerobic Pd oxidation in sequence with the photocatalytic reductive cleavage on triol substrate 1k produced β-hydroxy ketone 3d in 76% yield, along with 78% 4′-hydroxyacetophenone (4c), highlighting the versatility of the developed two-step protocol. The application of continuous-flow reactors in photocatalysis has received particular attention, because it typically allows for reduced reaction times, improved heat, light and mass-transfer rates, and reduced safety hazards, compared to conventional batch processing. 23 Utilizing an in-house assembled flow reactor (for additional details, see the Supporting Information) resulted in a significant decrease in reaction time for the reductive C−O bond cleavage (Scheme 4). In flow, the rate of substrate consumption could be increased from ∼0.013 mmol h−1 in batch to 0.4 mmol h−1, thus highlighting the advantage of flow processing. Our goal in developing this two-step sequence was to bring to fruition a method that was operationally simple, translatable, and selective. Many aspects in this methodology can allow for future scale-up opportunities for both the oxidation step20 and the photochemically induced fragmentation. 2255

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ACS Catalysis Scheme 5. Visible-Light-Mediated Depolymerization of Oxidized Lignin Polymers 5a−5ca

Scheme 7. Depolymerization of Mixed Polymer (Top) and Comparison of Depolymerization When Irradiated by Sunlight Versus Blue LEDs (Bottom)

quenching of [Ir(ppy)2(dtbbpy)]*+, while a three-component mixture consisting of iPr2NEt, ketone 2a, and HCO2H produced a measurable quenching rate of 1.31 × 108 M−1 s−1 (Figures S27 and S28 and Table S5 in the Supporting Information). This suggests that (i) [Ir(ppy)2(dtbbpy)]*+ is quenched by iPr2NEt and (ii) the presence of the other reaction components does not alter the emission quenching efficiency. The fact that HCO2H does not quench [Ir(ppy)2(dtbbpy)]*+ suggests that it merely acts as a proton source for activation of the carbonyl moiety.26 Electrochemical measurements on the [Ir(ppy)2(dtbbpy)]+ photocatalyst in MeCN were also performed and revealed an irreversible reduction event [{Epc(IrIII/IrII)} at −1.53 V vs SCE] and a reversible oxidation event [{E1/2(IrIV/IrIII)} at +1.18 V vs SCE] (Figure S30 in the Supporting Information). The measured redox potentials were subsequently used to determine the excited-state redox potentials of the [Ir(ppy)2(dtbbpy)]+ photocatalyst, thus estimating Eox(IrIV/ IrIII*) and Ered(IrIII*/IrII) to −1.31 V and +0.96 V vs SCE, respectively (Table S6 in the Supporting Information). Together, these results are consistent with a reductive

a Reaction conditions: 5 (0.7 mmol), [Ir(ppy)2(dtbbpy)]PF6 (7.0 μmol, 1.0 mol %), iPr2NEt (2.1 mmol, 3.0 equiv) and HCO2H (2.1 mmol, 3.0 equiv) in MeCN (3.3 mL), room temperature, irradiation with blue LEDs, 48 h. Yields refer to isolated yields of the monomeric units after column chromatography.

2.4. Mechanistic Insight. To gain further insight into the mechanism of the photochemical reductive C−O bond cleavage, quenching experiments were performed. The quenching rates for each of the reaction components were measured using Stern−Volmer analyses. Neither HCO2H nor ketone 2a was shown to decrease the photoluminescence of [Ir(ppy)2(dtbbpy)]+ (Figures S21−S26 in the Supporting Information). However, iPr2NEt was found to significantly quench the excited state ([Ir(ppy)2(dtbbpy)]*+), with a quenching rate (kq) of 1.33 × 108 M−1 s−1 (see Figures S19 and S20 and Table S5 in the Supporting Information). A combination of ketone 2a and HCO2H did not affect the

Scheme 6. Percent Incorporation of the γ-Hydroxy Moiety and Isolated Yields of Monomers from the Photocatalytic Depolymerization of Polymers 6a−6ca

a Reaction conditions: 6 (0.7 mmol), [Ir(ppy)2(dtbbpy)]PF6 (7.0 μmol, 1.0 mol %), iPr2NEt (2.1 mmol, 3.0 equiv) and HCO2H (2.1 mmol, 3.0 equiv) in MeCN (3.3 mL), room temperature, irradiation with blue LEDs, 48 h. Yields refer to isolated yields of the monomeric units after column chromatography.

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ACS Catalysis Scheme 8. Proposed Mechanism for the Two-Step Fragmentation of Lignin Systemsa

a

HAT = hydrogen atom transfer. SET = single electron transfer.

quenching mechanism in which the excited-state IrIII*, produced after visible-light absorption, is quenched by iPr2NEt to generate the reduced photocatalyst (IrII). Single-electron transfer (SET) from the strongly reducing IrII to ketone 2 produces an intermediate ketyl species (2′), which undergoes C−O bond cleavage to afford the desired ketone (3) and phenol (4) fragmentation products after hydrogen atom transfer (HAT) and protonation, respectively (Scheme 8). These mechanistic studies inform our group’s interest in developing methods with catalysts that can be recycled and reused. The small-scaled nature of the reported reactions typically afforded negligible amounts of materials to isolate for recycling.27 Moving forward, we recognize that understanding catalyst degradation pathways can guide reaction and catalyst development for recycling strategies. Commercially available Pd(OAc)2 has been shown to contain impurities, or generate impurities (i.e., oligomeric structures) under common Pdmediated coupling conditions that can impede reactivity.28 Similarly, our group has studied Ir-based photocatalyst functionalization, and subsequent catalyst deactivation, in synthetically relevant conditions using reaction progress kinetics.29 While these conditions are not immediately relevant to the conditions reported in this manuscript, they do offer insight into deactivation modes of Ir-based photocatalysts and will guide future explorations in the development of catalysts that are active at lower loadings.

the future for the programmable deconstruction of synthetic and natural polymers. The ability to efficiently produce these ketone-based products under mild conditions provides support for these photoinduced electron transfer processes to assist in the target-driven cleavage of complex polymer systems as well as lignin for production of value-added aromatic commodity chemicals. The application of the Pd-mediated oxidation to native organosolv lignin has not proven fruitful in our hands, showing some limitations of the catalytic system. However, we only considered reaction conditions that were relatively mild (