Quinone Methide Formation Research Articles

Treatment of Organophosphorus Poisoning with 6-Alkoxypyridin-3-ol Quinone Methide Precursors: Resurrection of Methylphosphonate-Aged Acetylcholinesterase.

Organophosphorus (OP) nerve agents inhibit acetylcholinesterase (AChE), creating a cholinergic crisis in which death can occur. The phosphylated serine residue spontaneously dealkylates to the OP-aged form, which current therapeutics cannot reverse. Soman's aging half-life is 4.2 min, so immediate recovery (resurrection) of OP-aged AChE is needed. In 2018, we showed pyridin-3-ol-based quinone methide precursors (QMPs) can resurrect OP-aged electric eel AChE in vitro, achieving 2% resurrection after 24 h of incubation (pH 7, 4 mM). We prepared 50 unique 6-alkoxypyridin-3-ol QMPs with 10 alkoxy groups and five amine leaving groups to improve AChE resurrection. These compounds are predicted in silico to cross the blood-brain barrier and treat AChE in the central nervous system. This library resurrected 7.9% activity of OP-aged recombinant human AChE after 24 h at 250 μM, a 4-fold increase from our 2018 report. The best QMP (1b), with a 6-methoxypyridin-3-ol core and a diethylamine leaving group, recovered 20.8% (1 mM), 34% (4 mM), and 42.5% (predicted maximum) of methylphosphonate-aged AChE activity over 24 h. Seven QMPs recovered activity from AChE aged with Soman and a VX degradation product (EA-2192). We hypothesize that QMPs form the quinone methide (QM) to realkylate the phosphylated serine residue as the first step of resurrection. We calculated thermodynamic energetics for QM formation, but there was no trend with the experimental biochemical data. Molecular docking studies revealed that QMP binding to OP-aged AChE is not the determining factor for the observed biochemical trends; thus, QM formation may be enzyme-mediated.

Tacrine First-Phase Biotransformation and Associated Hepatotoxicity: A Possible Way to Avoid Quinone Methide Formation.

Tacrine was withdrawn from clinical use as a drug against Alzheimer's disease in 2013, mainly due to drug-induced liver injury. The culprit of tacrine-associated hepatotoxicity is believed to be the 7-OH-tacrine metabolite, a possible precursor of quinone methide (Qmeth), which binds to intracellular -SH proteins. In our study, several different animal and human models (liver microsomes, primary hepatocytes, and liver slices) were used to investigate the biotransformation and hepatotoxicity of tacrine and its 7-substituted analogues (7-methoxy-, 7-phenoxy-, and 7-OH-tacrine). Our goal was to find the most appropriate in vitro model for studying tacrine hepatotoxicity and, through rational structure modifications, to develop derivatives of tacrine that are less prone to Qmeth formation. Our results show that none of animal models tested accurately mimic human tacrine biotransformation; however, the murine model seems to be more suitable than the rat model. Tacrine metabolism was overall most accurately mimicked in three-dimensional (3D) spheroid cultures of primary human hepatocytes (PHHs). In this system, tacrine and 7-methoxytacrine were hydroxylated to 7-OH-tacrine, whereas 7-phenoxytacrine formed, as expected, only trace amounts. Surprisingly, however, our study showed that 7-OH-tacrine was the least hepatotoxic (7-OH-tacrine < tacrine < 7-methoxytacrine < 7-phenoxytacrine) even after doses had been adjusted to achieve the same intracellular concentrations. The formation of Qmeth-cysteine and Qmeth-glutathione adducts after human liver microsome incubation was confirmed by all of the studied tacrine derivatives, but these findings were not confirmed after incubation with 3D PHH spheroids. Therefore, the presented data call into question the suggested previously hypothesized mechanism of toxicity, and the results open new avenues for chemical modifications to improve the safety of novel tacrine derivatives.

Chemistry of Isoeugenol and Its Oxidation Products: Mechanism and Kinetics of Isoeugenol as a Skin Sensitizer.

Structurally similar phytochemical compounds may elicit markedly different skin sensitization responses. Eugenol and isoeugenol are natural phenylpropanoids found in various essential oils are frequently used as fragrance ingredients in consumer products due to their pleasing aromatic properties. Both compounds are also skin sensitizers with isoeugenol being a stronger sensitizer than eugenol. The most commonly accepted mechanisms for haptenation by eugenol involve formation of a quinone methide or an ortho-quinone intermediate. The mechanism for the increased skin response to isoeugenol remains elusive, although quinone methide intermediates have been proposed. The recent identification of diastereomeric 7,4'-oxyneolignans as electrophilic, thiol-depleting isoeugenol derivatives has revived interest in the possible role of elusive reactive intermediates associated with the isoeugenol's haptenation process. In the present work, integrated non-animal skin sensitization methods were performed to determine the ability of syn-7,4'-oxyneolignan to promote haptenation and activation of further molecular pathways in keratinocytes and dendritic cells, confirming it as a candidate skin sensitizer. Kinetic NMR spectroscopic studies using dansyl cysteamine (DCYA) confirmed the first ordered nature of the nucleophilic addition for the syn-7,4'-oxyneolignan. Computational studies reaffirmed the "syn" stereochemistry of the isolated 7,4'-oxyneolignans along with that of their corresponding DCYA adducts and provided evidence for the preferential stereoselectivity. A plausible rationale for isoeugenol's strong skin sensitization is proposed based on the formation of a hydroxy quinone methide as a reactive intermediate rather than the previously assumed quinone methide.

Self-Immobilizing Quinone Methides for the Fluorescent Sensing of Enzyme Activity

Gaining insight into biological processes relies on sensitive analytical techniques. These often require labeling of biomolecules that help visualize them. Selective covalent labeling without preliminary modification of the biomolecules is an advantageous method. For example, this can be achieved by using probes that are capable of in situ quinone methide (QM) formation. The QM can be masked to give a stable precursor, and the highly reactive form is only generated upon activation by a specific trigger. The in situ formed QM then binds covalently to the nucleophilic side chains of either the target protein or a protein in close proximity. Using fluorogenic probes further improves this method by reducing non-specific background signals, thus improving signal-to-noise ratios. In this review we summarize the development of quinone methide-based probes from mechanism-based inactivation to red-emitting, fluorogenic activity probes, focusing on enzyme-triggered activation.

Photodehydration mechanisms of quinone methide formation from 2-naphthol derivatives

Photogeneration of quinone methides (QM) from 3-hydroxymethyl-2-naphthol (1) and 3-(2-hydroxy-2-adamantyl)-2-naphthol (2) was investigated using femtosecond and nanosecond transient absorption spectroscopy and supported with theoretical analysis of possible reaction pathways. Our results indicate that adamantylnaphthol 2 after UV excitation undergoes a non-adiabatic excited state intramolecular proton transfer coupled with dehydration via a conical intersection, delivering the corresponding QM (S0) within 1 ns. Surprisingly, in naphthol 1 on femtosecond time scale only formation of radical cation and solvated electrons was observed where the photoionization is a competing process not connected to the photochemical reaction of QM formation. Radical cations decay fast (45 ps) due to the back electron transfer. By quenching with ascorbate we identified phenoxyl radicals as a QM precursor, which are formed in a slower H-transfer reaction taking place on nanosecond time scale. Our combined experimental and theoretical investigation points to a polycyclic substituent effect, which profoundly changes the photochemical reaction pathway.

Synthesis and Evaluation of Marine Natural Product-Inspired Meroterpenoids with Selective Activity toward Dormant Mycobacterium tuberculosis.

Tuberculosis is a disease caused primarily by the organism Mycobacterium tuberculosis (Mtb), which claims about 1.5 million lives every year. A challenge that impedes the elimination of this pathogen is the ability of Mtb to remain dormant after primary infection, thus creating a reservoir for the disease in the population that reactivates under more ideal conditions. A better understanding of the physiology of dormant Mtb and therapeutics able to kill these phenotypically tolerant bacilli will be critical for completely eradicating Mtb. Our groups are focusing on characterizing the activity of derivatives of the marine natural product (+)-puupehenone (1). Recently, the Rohde group reported that puupehedione (2) and 15-α-methoxypuupehenol (3) exhibit enhanced activity in an in vitro multi-stress dormancy model of Mtb. To optimize the antimycobacterial activity of these terpenoids, novel 15-α-methoxy- and 15-α-acetoxy-puupehenol esters were prepared from (+)-puupehenone (1) accessed through a (+)-sclareolide-derived β-hydroxyl aldehyde. For added diversity, various congeners related to (1) were also prepared from a common borono-sclareolide donor, which resulted in the synthesis of epi-puupehenol and the natural products (+)-chromazonarol and (+)-yahazunol. In total, we generated a library of 24 compounds, of which 14 were found to be active against Mtb, and the most active compounds retained the enhanced activity against dormant Mtb seen in the parent compound. Several of the 15-α-methoxy- and 15-α-acetoxy-puupehenol esters possessed potent activity against actively dividing and dormant Mtb. Intriguingly, the closely related triisobutyl derivative 16 showed similar activity to 1 in actively dividing Mtb but lost about 178-fold activity against dormant Mtb. However, the monopivaloyl compound 13 showed a modest 3- to 4-fold loss in activity in both actively dividing and dormant Mtb relative to the activity of 1 revealing the importance of the free OH at C19 supporting the potential role of quinone methide formation as critical for activity in dormant Mtb. Elucidating important structure–activity relationships and the mechanism of action of this natural product-inspired chemical series may yield insights into vulnerable drug targets in dormant bacilli and new therapeutics to more effectively target dormant Mtb.

Photogeneration of quinone methide from adamantylphenol in an ultrafast non-adiabatic dehydration reaction.

The ultrafast photochemical reaction of quinone methide (QM) formation from adamantylphenol was monitored in real time using femtosecond transient absorption spectroscopy and fluorescence upconversion in solution at room temperature. Experiments were complemented by theoretical studies simulating the reaction pathway and elucidating its mechanism. Excitation with sub-20 fs UV pulses and broadband probing revealed ultrafast formation of the long-lived QM intermediate directly in the ground state, occurring with a time constant of around 100 fs. UV-vis transient absorption data covering temporal dynamics from femtoseconds to hundreds of milliseconds revealed persistence of the absorption band assigned to QM and partially overlapped with other contributions tentatively assigned to triplet excited states of the adamantyl derivative and the phenoxyl radical that are clearly distinguished by their evolution on different time scales. Our data, together with the computations, provide evidence of a non-adiabatic photodehydration reaction, which leads to the formation of QM in the ground state via a conical intersection, circumventing the generation of a transient QM excited state.

Ferrocifen Loaded Lipid Nanocapsules: A Promising Anticancer Medication against Multidrug Resistant Tumors.

Simple SummaryOne of the primary causes of chemotherapy failure is the occurrence of cancer multidrug resistance (MDR). Uncontrolled growth of resistant tumor cells leads to metastasis and recurrence, associated with high mortalities. Ferrocifens have been shown to possess anticancer properties via an original mechanism dependent on redox properties and generation of active metabolites that can cause disruption of cell metabolism. However, these molecules are highly insoluble in water, requiring a formulation stage before being administered in vivo. Lipid nanocapsules (LNCs) have already demonstrated their ability to successfully encapsulate various hydrophobic therapeutic agents, such as ferrocifens, and offer the option of surface modification, making it possible to adapt the pharmacological behavior of the nanocarrier. The aim of this review is to give, for the first time, an overview of the in vitro and in vivo studies performed with ferrocifen-loaded LNCs on several MDR cancers.Resistance of cancer cells to current chemotherapeutic drugs has obliged the scientific community to seek innovative compounds. Ferrocifens, lipophilic organometallic compounds composed of a tamoxifen scaffold covalently bound to a ferrocene moiety, have shown very interesting antiproliferative, cytotoxic and immunologic effects. The formation of ferrocenyl quinone methide plays a crucial role in the multifaceted activity of ferrocifens. Lipid nanocapsules (LNCs), meanwhile, are nanoparticles obtained by a free organic solvent process. LNCs consist of an oily core surrounded by amphiphilic surfactants and are perfectly adapted to encapsulate these hydrophobic compounds. The different in vitro and in vivo experiments performed with this ferrocifen-loaded nanocarrier have revealed promising results in several multidrug-resistant cancer cell lines such as glioblastoma, breast cancer and metastatic melanoma, alone or in combination with other therapies. This review provides an exhaustive summary of the use of ferrocifen-loaded LNCs as a promising nanomedicine, outlining the ferrocifen mechanisms of action on cancer cells, the nanocarrier formulation process and the in vivo results obtained over the last two decades.

Pivotal Reactions in the Creation of the Polycyclic Skeleton of Cryptotrione

AbstractThree pivotal reactions, namely, enyne cycloisomerization, polyene cyclization, and quinone methide formation, are applied to synthesize the complex polycyclic skeleton of cryptotrione. This review summarizes the most prominent applications of these three reactions to the total syntheses of natural products, covering results published in the literature between 2011 and 2020.1 Introduction2 Three Pivotal Reactions Applied to Create the Polycyclic Framework of Cryptotrione2.1 Enyne Cycloisomerization2.2 Polyene Cyclization2.3 Quinone Methide Formation3 Conclusion

Chemical Reactivities of ortho-Quinones Produced in Living Organisms: Fate of Quinonoid Products Formed by Tyrosinase and Phenoloxidase Action on Phenols and Catechols.

Tyrosinase catalyzes the oxidation of phenols and catechols (o-diphenols) to o-quinones. The reactivities of o-quinones thus generated are responsible for oxidative browning of plant products, sclerotization of insect cuticle, defense reaction in arthropods, tunichrome biochemistry in tunicates, production of mussel glue, and most importantly melanin biosynthesis in all organisms. These reactions also form a set of major reactions that are of nonenzymatic origin in nature. In this review, we summarized the chemical fates of o-quinones. Many of the reactions of o-quinones proceed extremely fast with a half-life of less than a second. As a result, the corresponding quinone production can only be detected through rapid scanning spectrophotometry. Michael-1,6-addition with thiols, intramolecular cyclization reaction with side chain amino groups, and the redox regeneration to original catechol represent some of the fast reactions exhibited by o-quinones, while, nucleophilic addition of carboxyl group, alcoholic group, and water are mostly slow reactions. A variety of catecholamines also exhibit side chain desaturation through tautomeric quinone methide formation. Therefore, quinone methide tautomers also play a pivotal role in the fate of numerous o-quinones. Armed with such wide and dangerous reactivity, o-quinones are capable of modifying the structure of important cellular components especially proteins and DNA and causing severe cytotoxicity and carcinogenic effects. The reactivities of different o-quinones involved in these processes along with special emphasis on mechanism of melanogenesis are discussed.

In vitro and in vivo evaluation of the antimalarial MMV665831 and structural analogs

Antimalarial candidates possessing novel mechanisms of action are needed to control drug resistant Plasmodium falciparum. We were drawn to Malaria Box compound 1 (MMV665831) by virtue of its excellent in vitro potency, and twelve analogs were prepared to probe its structure–activity relationship. Modulation of the diethyl amino group was fruitful, producing compound 25, which was twice as potent as 1 against cultured parasites. Efforts were made to modify the phenolic Mannich base functionality of 1, to prevent formation of a reactive quinone methide. Homologated analog 28 had reduced potency relative to 1, but still inhibited growth with EC50 ≤ 200 nM. Thus, the antimalarial activity of 1 does not derive from quinone methide formation. Chemical stability studies on dimethyl analog 2 showed remarkable hydrolytic stability of both the phenolic Mannich base and ethyl ester moieties, and 1 was evaluated for in vivo efficacy in P. berghei-infected mice (40 mg/kg, oral). Unfortunately, no reduction in parasitemia was seen relative to control. These results are discussed in the context of measured plasma and hepatocyte stabilities, with reference to structurally-related, orally-efficacious antimalarials.

Directing Quinone Methide-Dependent Alkylation and Cross-Linking of Nucleic Acids with Quaternary Amines.

Polyamine and polyammonium ion conjugates are often used to direct reagents to nucleic acids based on their strong electrostatic attraction to the phosphoribose backbone. Such nonspecific interactions do not typically alter the specificity of the attached reagent, but polyammonium ions dramatically redirected the specificity of a series of quinone methide precursors. Replacement of a relatively nonspecific intercalator based on acridine with a series of polyammonium ions resulted in a surprising change of DNA products. Piperidine stable adducts were generated in duplex DNA that lacked the ability to support a dynamic cross-linking observed previously with acridine conjugates. Minor reaction at guanine N7, the site of reversible reaction, was retained by a monofunctional quinone methide-polyammonium ion conjugate, but a bisfunctional analogue designed for tandem quinone methide formation modified guanine N7 in only single-stranded DNA. The resulting intrastrand cross-links were sufficiently dynamic to rearrange to interstrand cross-links. However, no further transfer of adducts was observed in duplex DNA. An alternative design that spatially and temporally decoupled the two quinone methide equivalents neither restored the dynamic reaction nor cross-linked DNA efficiently. While di- and triammonium ion conjugates successfully enhanced the yields of cross-linking by a bisquinone methide relative to a monoammonium equivalent, alternative ligands will be necessary to facilitate the migration of cross-linking and its potential application to disrupt DNA repair.

Effects of lignin structure and solvent on the formation rate of quinone methide under alkaline conditions

Abstract The purpose of this study was to examine how differences in the type of aromatic nucleus, side-chain structure and type of solvent affect the formation rate of quinone methide (QM) in the alkaline reaction of lignin. The reaction was done at a NaOH concentration of 1.0 mol l−1 and temperature of 75–140°C under an anaerobic condition. The formation rates of QM were in the order: syringyl &gt; guaiacyl &gt; p-hydroxyphenyl, when model compounds with lignin-type aromatic nuclei were compared. This and other results on various phenolic compounds suggested that the formation of QM is rapid from compounds having a high electron density in the aromatic π-electron system. The formation of QM was faster from a C6-C2-type than from a C6-C1-type lignin model compound, which was attributed to the fact that QM is an alkene and hence more stable when an unsaturated carbon in QM has an alkyl substituent, like the C6-C2-type compound. When aqueous 1,4-dioxane solutions with different 1,4-dioxane contents were used, the formation of QM became slower with increasing 1,4-dioxane content. This can be explained by the variation in the negative charge density in the rate-determining step, where the density is larger at the transition than at the initial state and consequently the activation energy is lower in a solvent with higher polarity.

Formation of Quinone Methides by Ultrafast Photodeamination: A Spectroscopic and Computational Study.

Formation of quinone methides (QMs) by photoelimination of an ammonium salt from cresol derivatives was investigated by femtosecond transient absorption spectroscopy (fs-TA) and computationally by time-dependent density functional theory using the PCM(water)/(TD-)B3LYP/6-311++G(d,p) level of theory. The photoelimination takes place in an adiabatic ultrafast reaction on the S1 potential energy surface delivering the corresponding QMs(S1), which were detected by fs-TA. Computations predicted a high-energy cation intermediate in the pathway between the Franck-Condon state of a monoammonium salt and the corresponding QM(S1) that was not detected by fs-TA. On the other hand, elimination from a disalt in H2O takes place in one step, giving directly the QM(S1). The combined experimental and theoretical investigation fully disclosed the formation of QMs by the deamination reaction mechanism, which is important in the application of cresols or similar molecules in biological systems.

Bifunctional Phenol Quinone Methide Precursors: Synthesis and Biological Activity

New bifunctional quinone methide (QM) precursors, bisphenols 2a–2e, and monofunctional QM precursor 7 were synthesized. Upon treatment with fluoride, desilylation triggers formation of reactive intermediates, QMs, which was demonstrated by trapping QM with azide or methanol. The ability of QMs to alkylate and cross-link DNA was assayed by investigation of the effects of QMs to DNA denaturing, but without conclusive evidence. Furthermore, treatment of a plasmid DNA with compounds 2a–2e and KF, followed by the analysis by alkaline denaturing gel electrophoresis, did not provide evidence for the DNA cross-linking. MTT test performed on two human cancer cell lines (MCF7 breast adenocarcinoma and SUM159 pleomorphic breast carcinoma), with and without fluoride, indicated that 2a–2e or the corresponding QMs did not exhibit cytotoxic activity, in line with the lack of ability to cross-link DNA. The lack of reactivity with DNA and biological activity were explained by sequential formation of QMs where bifunctional cytotoxic reagent is probably never produced. Instead, the sequential generation of monofunctional QM followed by a faster hydrolysis leads to the destruction of biologically active reagent. The findings described here are particularly important for the rational design of new generation of QM precursor molecules that will attain desirable DNA reactivity and cytotoxicity.

A thiol-inducible and quick-response DNA cross-linking agent

Three new 2,4-dinitrobenzenesulfonyl derivatives 1–3 were successfully prepared for the first time using a simple process. They were efficiently triggered by thiols (glutathione and l-cysteine) to release the corresponding phenol derivatives (4–6) within 5 min. The quick response of 1–3 toward thiols was determined by 1H NMR and HPLC. Moreover, our results indicated that 1 could induce DNA cross-linking in the presence of glutathione, probably due to the quinone methide formation of phenol intermediate 4 followed by departure of 2,4-dinitrobenzenesulfonyl group.

Ultrafast Adiabatic Photodehydration of 2-Hydroxymethylphenol and the Formation of Quinone Methide.

The photochemical reactivity of 2-hydroxymethylphenol (1) was investigated experimentally by photochemistry under cryogenic conditions, by detecting reactive intermediates by IR spectroscopy, and by using nanosecond and femtosecond transient absorption spectroscopic methods in solution at room temperature. In addition, theoretical studies were performed to facilitate the interpretation of the experimental results and also to simulate the reaction pathway to obtain a better understanding of the reaction mechanism. The main finding of this work is that photodehydration of 1 takes place in an ultrafast adiabatic photochemical reaction without any clear intermediate, delivering quinone methide (QM) in the excited state. Upon photoexcitation to a higher vibrational level of the singlet excited state, 1 undergoes vibrational relaxation leading to two photochemical pathways, one by which synchronous elimination of H2 O gives QM 2 in its S1 state and the other by which homolytic cleavage of the phenolic O-H bond produces a phenoxyl radical (S0 ). Both are ultrafast processes that occur within a picosecond. The excited state of QM 2 (S1 ) probably deactivates to S0 through a conical intersection to give QM 2 (S0 ), which subsequently delivers benzoxete 4. Elucidation of the reaction mechanisms for the photodehydration of phenols by which QMs are formed is important to tune the reactivity of QMs with DNA and proteins for the potential application of QMs in medicine as therapeutic agents.

Direct Observation of Photoinduced Ultrafast Generation of Singlet and Triplet Quinone Methides in Aqueous Solutions and Insight into the Roles of Acidic and Basic Sites in Quinone Methide Formation.

Femtosecond time-resolved transient absorption spectroscopy experiments and density functional theory computations were done for a mechanistic investigation of 3-(1-phenylvinyl)phenol (1) and 3-hydroxybenzophenone (2) in selected solvents. Both compounds went through an intersystem crossing (ISC) to form the triplet excited states Tππ* and Tnπ* in acetonitrile but behave differently in neutral aqueous solutions, in which a triplet excited state proton transfer (ESPT) induced by the ISC process is also proposed for 2 but a singlet ESPT without ISC is proposed for 1, leading to the production of the triplet quinone methide (QM) and the singlet excited QM species respectively in these two systems. The triplet QM then underwent an ISC process to form an unstable ground state intermediate which soon returned to its starting material 2. However, the singlet excited state QM went through an internal conversion process to the ground state QM followed by the formation of its final product in an irreversible manner. These differences are thought to be derived from the slow vinyl C-C rotation and the moderate basicity of the vinyl C atom in 1 as compared with the fast C-O rotation and the greater basicity of the carbonyl O atom of 2 after photoexcitation. This can account for the experimental results in the literature that the aromatic vinyl compounds undergo efficient singlet excited state photochemical reactions while the aromatic carbonyl compounds prefer triplet photochemical reactions under aqueous conditions. These results have fundamental and significant implications for understanding of the ESPT reactivity in general, as well as for the design of molecules for efficient QM formation in aqueous media with potential applications in cancer phototherapy.

Mechanism of Base-Catalyzed Resorcinol-Formaldehyde and Phenol-Resorcinol-Formaldehyde Condensation Reactions: A Theoretical Study.

The base-catalyzed resorcinol-formaldehyde condensation reactions were theoretically investigated in this study by employing a quantum chemistry method. The condensation reaction includes two steps: (1) formation of the quinonemethide (QM) intermediate from hydroxymethylresorcinol; (2) Michael addition between the quinonemethide and resorcinol anion. The first step is the rate-determining step. Two mechanisms, unimolecular elimination of the conjugate base (E1cb) and water-aided elimination (WAE), were identified for the formation of QM. The hydroxymethylresorcinol anion produces neutral QM while the dianion produces a quinonemethide anion (QMA). The calculated potential energy barriers suggested that the QMA formation is much more favorable. Although resorcinol-formaldehyde and phenol-formaldehyde condensations share a common mechanism, the former would be faster if the QMA participates in condensations. The potential energy barriers for formation of 2-QM, 4-QM, 6-QM, 2-QMA, and 4-QMA were calculated. The results show that the formations of 6-QM and 4-QMA have relatively lower energy barriers. This rationalized previous experimental observations that the 2,4-(2,6-) and 6,6′-(4,4′-) methylene linkages were dominant, whereas the 2,2′-linkage was almost absent. The resorcinol-phenol-formaldehyde co-condensations were also calculated. The cold-setting characteristic of phenol-resorcinol-formaldehyde co-condensed resin can be attributed to participation of resorcinol quinonemethides in condensations.

Chemoselective Methylation of Phenolic Hydroxyl Group Prevents Quinone Methide Formation and Repolymerization During Lignin Depolymerization

Chemoselective blocking of the phenolic hydroxyl (Ar–OH) group by methylation was found to suppress secondary repolymerization and charring during lignin depolymerization. Methylation of Ar–OH prevents formation of reactive quinone methide intermediates, which are partly responsible for undesirable secondary repolymerization reactions. Instead, this structurally modified lignin produces more relatively low molecular weight products from lignin depolymerization compared to unmodified lignin. This result demonstrates that structural modification of lignin is desirable for production of low molecular weight phenolic products. This approach could be directed toward alteration of natural lignification processes to produce biomass that is more amenable to chemical depolymerization.