Base-catalyzed Isomerization Research Articles

Toward Understanding Base-Catalyzed Isomerization of Saccharides

This Perspective addresses recent advances in isomerization of aldoses into ketoses catalyzed by bases. In recent years, catalytic activity of a number of bases was reported, but the structure–performance correlations are typically missing or remain poorly understood. In this Perspective, the reaction mechanism and kinetics of the base-catalyzed isomerization are discussed. An overview of products obtained via base-catalyzed transformations of d-glucose (Glc), d-lactose (Lac), d-galactose (Gal), and aldopentoses d-ribose (Rib), d-arabinose (Ara), d-xylose (Xyl), and d-lyxose (Lyx) is provided. Side reactions that occur under base conditions are summarized. Catalysis by soluble metal hydroxides and general bases is considered. Moreover, structure–selectivity relationships observed for soluble bases as well as methods for stabilization of ketoses via complexation are discussed. Influences of organic (co-)solvents on reaction kinetics and acceleration of the reaction rate in aqueous phase in the presence of soluble salts–also referred to as salt effect–are addressed. Next, solid bases applied as catalysts for isomerization are considered with a focus on contributions of homogeneous and heterogeneous catalysis into the isomerization processes. The applicability of a filtration test and a contact test as tools to estimate impact of leached species onto catalysis is critically discussed.

Study of base-catalyzed isomerization of d-glucose with a focus on reaction kinetics

We explored the isomerization of d-glucose into d-fructose using the simplest possible base catalyst, aqueous NaOH, to maintain a constant pH value during the reaction. Under the applied mild conditions (T 50–90 °C, pH 9.5–11.5), yields of d-fructose of up to 31% were observed. Selectivity-conversion plots were not significantly influenced by variation of the temperature, pH value or substrate concentration. A reaction network for kinetic modelling includes d-glucose-d-fructose interconversion, co-production of d-mannose and d-allulose (also known as d-psicose) as well as decomposition paths after deprotonation of the hexoses. All four hexoses were employed as substrates in the isomerization. Thermodynamic ionization constants of the saccharides were measured by means of potentiometric titration. In the kinetic studies, pH-independent rate constants as well as activation energies were determined. The obtained kinetic and thermodynamic results as well as selectivity-conversion correlations present a useful benchmark for soluble and solid base catalysts.

Stereoselective synthesis towards (+)-trans-kumausyne employing vinylogous Mukaiyama type reaction on an α-chloro sulfide

A stereoselective synthesis towards (+)- trans- kumausyne is disclosed. The key steps of the synthesis include stereoselective C-C formation employing vinylogous Mukaiyama type reaction of an α-chloro sulfide with 2-trimethylsiloxy furan and base-catalyzed isomerization followed by intramolecular oxa-Michael reaction.

Mechanistic Insights into the Conversion of Biorenewable Levoglucosanol to Dideoxysugars

A molecular understanding of the conversion of biorenewable threo- and erythro-levoglucosanol (LGOL) to 3,4-dideoxysugars in aqueous medium is provided based on first-principles simulations. The synthetic importance of this transformation is that these intermediates can be quantitatively hydrogenated to (S,S)/(S,R) hexane-1,2,5,6-tetrol (tetrol), whose stereochemistry depends on which dideoxy sugar intermediates are formed during LGOL conversion. The thermodynamic and kinetic feasibility of the acetal (R₂C(OR)₂) hydrolysis in LGOL is investigated via computing the free energy profile. In aqueous medium, the rate-determining step of LGOL hydrolysis is the protonation of the anhydro-bridge oxygen atom of LGOL concurrent with ring opening, yielding the cyclic forms of 3,4-dideoxymannose (DDM) and 3,4-dideoxyglucose (DDG) from threo- and erythro-LGOL, respectively. The measured activation energies of LGOL hydrolysis are 20.5 and 23.6 kcal/mol for DDM and DDG formation, respectively. These values are in agreement with the computed protonation free energies of 17.1 and 18.2 kcal/mol, respectively. Based on the simulations, a Bronsted base-catalyzed isomerization from DDG or DDM to 3,4-dideoxy fructose (DDF) is preferred with lower apparent activation free energy barriers compared to the acid-catalyzed isomerization. In summary, this study provides mechanistic information about the conversion of the biomass-derived anhydro-sugar LGOL to 3,4-dideoxy sugars, which are precursors to renewable high-value chemicals.

Migratory Hydrogenation of Terminal Alkynes by Base/Cobalt Relay Catalysis

Migratory functionalization of alkenes has emerged as a powerful strategy to achieve functionalization at a distal position to the original reactive site on a hydrocarbon chain. However, an analogous protocol for alkyne substrates is yet to be developed. Herein, a base and cobalt relay catalytic process for the selective synthesis of (Z)-2-alkenes and conjugated E alkenes by migratory hydrogenation of terminal alkynes is disclosed. Mechanistic studies support a relay catalytic process involving a sequential base-catalyzed isomerization of terminal alkynes and cobalt-catalyzed hydrogenation of either 2-alkynes or conjugated diene intermediates. Notably, this practical non-noble metal catalytic system enables efficient control of the chemo-, regio-, and stereoselectivity of this transformation.

Base-catalyzed aryl halide isomerization enables the 4-selective substitution of 3-bromopyridines.

The base-catalyzed isomerization of simple aryl halides is presented and utilized to achieve the 4-selective etherification, hydroxylation and amination of 3-bromopyridines. Mechanistic studies support isomerization of 3-bromopyridines to 4-bromopyridines proceeds via pyridyne intermediates and that 4-substitution selectivity is driven by a facile aromatic substitution reaction. Useful features of a tandem aryl halide isomerization/selective interception approach to aromatic functionalization are demonstrated. Example benefits include the use of readily available and stable 3-bromopyridines in place of less available and stable 4-halogenated congeners and the ability to converge mixtures of 3- and 5-bromopyridines to a single 4-substituted product.

Control of Chemical Reactions by Using Molecules that Buffer Non-aqueous Solutions.

Control of chemical reactions is necessary to obtain designer chemical transformation products and for preventing decomposition and isomerization reactions of compounds of interest. For the control of chemical events in aqueous solutions, the use of aqueous buffers is a common practice. However, no molecules that buffer non-aqueous solutions were commonly used. Herein, we demonstrate that 1,3-cyclohexanedione derivatives have buffering functions in non-aqueous solutions. It was also shown that these molecules can be utilized to alter and control chemical reactions. 1,3-Cyclohexanedione derivatives inhibited both acid- and base-catalyzed isomerizations and decompositions in organic solvents. The reaction products obtained in the presence of the buffering molecule 2-methyl-1,3-cyclohexanedione differed from those obtained in the absence of the buffering molecule. The use of buffering molecules that work in organic solvents provides a strategy to control chemical reactions and expands the range of compounds that can be synthesized.

3D Printing of Poly(propylene fumarate) Oligomers: Evaluation of Resin Viscosity, Printing Characteristics and Mechanical Properties.

Complex three-dimensional (3D) pore geometries, useful for tissue engineering scaffolds, can be fabricated via photo-crosslinking of resorbable poly(propylene fumarate) (PPF) resins using stereolithography (SLA) and/or continuous digital light processing (cDLP) methods. Physico-chemical parameters inherent to 3D printable resin design, include viscosity, polymer concentration, degree of polymerization, and resin printing temperature. We report here on our study of these parameters and their influence the cDLP 3D printing process and the resulting mechanical properties. A series of PPF oligomers were synthesized by the ring-opening copolymerization (ROCOP) of maleic anhydride and propylene oxide followed by a base-catalyzed isomerization. The resin viscosities were measured as a function of number-average molecular mass ([Formula: see text]) of the PPF oligomers (1.1, 1.7 and 2.0 kDa), concentrations of PPF in the reactive diluent diethyl fumarate (DEF) (50 and 75 wt %) and resin temperature (25 to 55 °C). The zero-shear viscosity (η0) of the resins was found to be temperature-dependent and follow a linear Arrhenius relationship. Tensile tests demonstrated mechanical properties within the range of trabecular bone, with the ultimate strength at break above 15 MPa and elastic moduli between 178 and 199 MPa.

Kinetic Resolution of Allylic Alcohol with Chiral BINOL-Based Alkoxides: A Combination of Experimental and Theoretical Studies.

The development and characterization of enantioselective catalytic kinetic resolution of allylic alcohols through asymmetric isomerization with chiral BINOL derivatives-based alkoxides as bifunctional Brønsted base catalysts were described in the study. A number of chiral BINOL derivatives-based alkoxides were synthesized, and their structure-enantioselectivity correlation study in asymmetric isomerization identified a promising chiral Brønsted base catalyst, which afforded various chiral secondary allylic alcohols (ee up to 99%, S factor up to >200). In the mechanistic study, alkoxide species were identified as active species and the phenol group of BINOL largely affected the high reactivity and enantioselectivity via hydrogen bonding between the chiral Brønsted base catalyst and substrates. The strategy is the first successful synthesis strategy of various chiral secondary allylic alcohols through enantioselective transition-metal-free base-catalyzed isomerization. The applicability of the strategy had been demonstrated by the synthesis of the bioactive natural product (+)-veraguensin.

Preparation of Three Impurities in Cefoxitin

Three known impurities of cefoxitin have been prepared and characterised. One is a double-bond isomer of cefoxitin, Δ3-cefoxitin, which was easily prepared by base-catalysed isomerisation of cefoxitin. The second is a side-chain methoxylated derivative, methoxycefoxitin, which required a four-step synthesis from cephalothin. The last impurity is a lactone lacking the carbamyl grouping in cefoxitin, cefoxitin lactone, which was also prepared in four steps from cephalothin. The accessibility of these three impurities and methods for their analysis could be important for quality control in the manufacture of cefoxitin.

One-step preparation of novel 1-(N-indolyl)-1,3-butadienes by base-catalysed isomerization of alkynes as an access to 5-(N-indolyl)-naphthoquinones.

A series of novel 1-(N-indolyl)-1,3-butadienes, as (1 : 1) mixtures of the (E) and (Z) dienes, was prepared in one step by base-catalysed isomerization of N-alkylindoles with a terminal butyne chain. The reaction conditions are mild, and in all cases the yields were very high (>90%). The (E) and (Z) dienes were separable by preparative TLC and could be fully characterized. This isomerization proceeded readily in the case of a butynyl chain, but didn't take place with a pentynyl chain. A mechanism was proposed for this reaction, based on previous studies on the isomerization of alkynes in basic media, and a key intermediate that supports the proposed mechanism could be isolated and fully characterized. A theoretical study of the proposed mechanism was performed by computational methods and the results validated the proposal. The reactivity of the synthesized dienes was studied in Diels–Alder reactions with p-benzoquinone, to obtain a small library of new 5-(N-indolyl)-1,4-naphthoquinones.The lack of reactivity in the case of the (Z) isomers was explained by calculation of the rotational curves of the central bond of the (Z) and (E) dienes. Finally, the cytotoxicity of the new 5-(N-indolyl)-1,4-naphthoquinones was tested against a panel of three cell lines.

Anion-π transaminase mimics

The possibility to stabilise anionic transition states on π-acidic aromatic surfaces has been explicitly demonstrated first in 2013. Since then, anion-π catalysis has been introduced to asymmetric enamine and iminium chemistry and to cascade processes, and the first anion-π enzyme has been created. Moving beyond systems that operate with nitronate-π interactions, this report adds transamination to the repertoire of anion-π catalysis. Whereas bioinspired approaches to transamination with pyridoxalphosphate appeared less obvious in this context, the base-catalyzed isomerisation of trifluoromethylimines contains suitable anionic transition states. Run on increasingly π-acidic aromatic surfaces in covalent and supramolecular trifunctional systems, we find that both rate and enantioselectivity of this reaction increase. These results support that anion-π interactions with 2-azaallyl anion intermediates catalyse the isomerisation of trifluoromethylimines by cumulative asymmetric umpolung on π-acidic surfaces.

Base-Catalyzed Stereospecific Isomerization of Allylic Alcohols and Ethers

Base-Catalyzed Stereospecific Isomerization of Allylic Alcohols and Ethers

A Qualitative Analysis of a "Bora-Brook Rearrangement": The Ambident Reactivity of Boryl-Substituted Alkoxide Including the Carbon-to-Oxygen Migration of a Boryl Group.

A bora-Brook rearrangement, i.e., the migration of boryl group from a carbon to an oxygen atom in an isolated α-boryl-substituted alkoxide, was examined, and decisive factors for the acceleration of this reaction are disclosed. In this rearrangement, the boryl-substituted alkoxide exhibited ambiphilic reactivity toward electrophiles to afford two types of products, which are electrophiles bound either at the oxygen or at the carbon atom. Using polar solvents, a saturated backbone of the boron-containing heterocycle, or larger alkali metal cations resulted in a significantly increased reaction rate of base-catalyzed isomerization of α-borylbenzyl alcohol including the bora-Brook rearrangement.

Why base-catalyzed isomerization of N-propargyl amides yields mostly allenamides rather than ynamides

The base-catalyzed isomerization of N-propargylamides or carbamates may furnish N-allenyl compounds (allenamides/allencarbamates) or further evolve to N-alkynyl compounds (ynamides or yncarbamates). The particular fate of this reaction varies from experiment to experiment and there is no clear rule for predicting the reaction outcome for a particular structure. With the support of ab initio and DFT computations, this work shows that observed results can be explained by assuming an exchange equilibrium between energetically close N-propargyl, allenyl and N-alkynyl forms and that the reaction outcome correlates to a particular equilibrium mixture. Due to the very small energy gap between the N-allenyl and N-alkynyl forms, small structural changes may easily alter the equilibrium position, explaining the variety of observed experimental results. Based on CBS-QB3 computations, the ωB97 functional provided reasonably accurate isomerization energies and could successfully predict the experimentally observed behavior for several examples from the literature.

Kinetic and Mechanistic Study of Glucose Isomerization Using Homogeneous Organic Brønsted Base Catalysts in Water

The isomerization of glucose to fructose represents a key intermediate step in the conversion of cellulosic biomass to fuels and renewable platform chemicals, namely, 5-hydroxymethyl furfural (HMF), 2,5-furandicarboxylic acid (FDCA), and levulinic acid (LA). Although both Lewis acids and Bronsted bases catalyze this reaction, the base-catalyzed pathway received significantly less attention due to its lower selectivity to fructose and the poor yields achieved (<10%). However, we recently demonstrated that homogeneous organic Bronsted bases present a similar performance (∼31% yield) as Sn-containing beta zeolite, a reference catalyst for this reaction. Herein, we report on the first extensive kinetic and mechanistic study on the organic Bronsted base-catalyzed isomerization of glucose to fructose. Specifically, we combine kinetic experiments performed over a broad range of conditions (temperature: 80–120 °C; pH 9.5–11.5; reactant: glucose, fructose) with isotopic studies and in situ 1H NMR spectroscopy. Pat...

Evidence for tunneling in base-catalyzed isomerization of glyceraldehyde to dihydroxyacetone by hydride shift under formose conditions

Hydrogen atom transfer reactions between the aldose and ketose are key mechanistic features in formose chemistry by which formaldehyde is converted to higher sugars under credible prebiotic conditions. For one of these transformations, we have investigated whether hydrogen tunneling makes a significant contribution to the mechanism by examining the deuterium kinetic isotope effect associated with the hydrogen transfer during the isomerization of glyceraldehyde to the corresponding dihydroxyacetone. To do this, we developed a quantitative HPLC assay that allowed us to measure the apparent large intrinsic kinetic isotope effect. From the Arrhenius plot of the kinetic isotope effect, the ratio of the preexponential factors AH/AD was 0.28 and the difference in activation energies Ea(D) - Ea(H) was 9.1 kJ·mol(-1). All these results imply a significant quantum-mechanical tunneling component in the isomerization mechanism. This is supported by multidimensional tunneling calculations using POLYRATE with small curvature tunneling.

Rhodium-catalyzed asymmetric arylation of allyl sulfones under the conditions of isomerization into alkenyl sulfones.

The reaction of 3-sulfolene with arylboronic acids in the presence of a chiral diene-rhodium catalyst under highly basic conditions (10 equiv of KOH) gave high yields of 3-arylsulfolanes with high enantioselectivity, where 3-sulfolene is in equilibration with 2-sulfolene by base-catalyzed isomerization and the more reactive 2-sulfolene undergoes the rhodium-catalyzed asymmetric arylation.

Selective Base-Catalyzed Isomerization of Glucose to Fructose

Fructose is a key intermediate in the conversion of cellulosic biomass to biofuels and renewable platform chemicals. Biomass-derived glucose can be isomerized to fructose using either Lewis acid or Bronsted base catalysts. Lewis acids are typically preferred as alkaline conditions promote a large number of side reactions. It is widely admitted that only low fructose yields, below 10%, are achievable with inorganic bases. Here, fructose was synthesized with 32% yield using commercially available organic amines. Glucose conversion and fructose selectivity were comparable to Lewis acids, which opens new perspectives for the base-catalyzed pathway.

Fused Quinazolinoquinazolinones: Synthesis, Isomerization, Spectroscopic Identification, and Anticancer Activity

13H-quinazolino[3,4-a]quinazolin-13-ones have been synthesized from 2-aminobenzamides in four steps. An acid-catalyzed or base-catalyzed isomerization of 13H-quinazolino[3,4-a]quinazolin-13-ones to 8H-quinazolino[4,3-b]quinazolin-8-ones in excellent yields (90–95%) has been reported. The differences in the infrared and nuclear magnetic resonance (1H & 13C) data of these isomeric fused quinazolinoquinazolinones afford a useful method for distinguishing between the two series. These analogs showed moderate anticancer activity (EGFR-TK inhibition).