Development and mechanistic investigation of the dehydrogenation of alcohols with an iron(III) salen catalyst.

The iron(III) salen complex (R,R)-N,N'-bis(salicylidene)-1,2-cyclohexanediamineiron(III) chloride has been developed as a catalyst for the acceptorless dehydrogenation of alcohols. The complex catalyzes the direct synthesis of imines in good yields from different primary alcohols and amines with the liberation of hydrogen gas. The mechanism has been investigated experimentally with labelled substrates and theoretically with density functional theory calculations. In contrast to the corresponding manganese(III) salen-catalyzed dehydrogenation, it has not been possible to identify a homogeneous catalytic pathway with the iron complex. Instead, poisoning experiments with trimethylphosphine and mercury indicated that the catalytically active species are heterogeneous small iron particles.

Sensitive NMR method for detecting carbohydrate influx into competing chemocatalytic pathways.

Reaction pathways are often tracked with stable isotopes in order to determine the provenance of products in the pathway and to deduce mechanistic information. NMR spectroscopy can provide direct insight into the specific labelling position of the stable isotope. We suggest a simple assay that allows rapid quantitative measurements of isotope distributions in biomass-derived products using commercially available carbohydrate substrates and routine instrumentation. In the assay, biomass-derived products in post reaction material are quantitatively reduced with NaBH4 to install hydrogens at each carbon site in the product. In this manner, the detection of 13C and 12C sites becomes possible in multiplets of the sensitive 2D 1H-1H TOCSY experiment. The approach detects the usage of competing upstream reactions from isotope patterns in chemically identical reaction products. Changing influx into Sn-Beta-catalysed carbohydrate conversion reactions in the absence and in the presence of K+ was quantitatively assessed, showing how the presence of K+ alters the intial reactions towards methyl lactate.

Manganese(III) Porphyrin-Catalyzed Dehydrogenation of Alcohols to form Imines, Tertiary Amines and Quinolines.

Manganese(III) porphyrin chloride complexes have been developed for the first time as catalysts for the acceptorless dehydrogenative coupling of alcohols and amines. The reaction has been applied to the direct synthesis of imines, tertiary amines and quinolines where only hydrogen gas and/or water are formed as the by-product(s). The mechanism is believed to involve the formation of a manganese(III) alkoxide complex which degrades into the aldehyde and a manganese(III) hydride species. The latter reacts with the alcohol to form hydrogen gas and thereby regenerates the alkoxide complex.

Synthesis of Arabinoxylan Oligosaccharides by Preactivation-Based Iterative Glycosylations.

A concise synthetic strategy has been developed for assembling densely substituted arabinoxylan oligosaccharides, which are valuable substrates for characterizing hemicellulose-degrading enzymes. The xylan backbone has been prepared by an iterative preactivation-based glycosylation approach with phenyl thioglycosides. The preactivation has been performed with in situ generated p-nitrobenzenesulfenyl triflate prior to addition of the acceptor. The glycosylation temperature was shown to have an important impact on the yield of the coupling. The arabinose substituents have been introduced in one high-yielding glycosylation with an N-phenyl trifluoroacetimidate donor. The strategy has been successfully employed for the synthesis of three heptasaccharides in seven steps and overall yields of 24-36% from the corresponding monosaccharide building blocks.

Zinc Oxide-Catalyzed Dehydrogenation of Primary Alcohols into Carboxylic Acids.

Zinc oxide has been developed as a catalyst for the dehydrogenation of primary alcohols into carboxylic acids and hydrogen gas. The reaction is performed in mesitylene solution in the presence of potassium hydroxide, followed by workup with hydrochloric acid. The transformation can be applied to both benzylic and aliphatic primary alcohols and the catalytically active species was shown to be a homogeneous compound by a hot filtration test. Dialkylzinc and strongly basic zinc salts also catalyze the dehydrogenation with similar results. The mechanism is believed to involve the formation of a zinc alkoxide which degrades into the aldehyde and a zinc hydride. The latter reacts with the alcohol to form hydrogen gas and regenerate the zinc alkoxide. The degradation of a zinc alkoxide into the aldehyde upon heating was confirmed experimentally. The aldehyde can then undergo a Cannizzaro reaction or a Tishchenko reaction, which in the presence of hydroxide leads to the carboxylic acid.

Synthesis of Two Tetrasaccharide Pentenyl Glycosides Related to the Pectic Rhamnogalacturonan I Polysaccharide.

The synthesis of two protected tetrasaccharide pentenyl glycosides with diarabinan and digalactan branching related to the pectic polysaccharide rhamnogalacturonan I is reported. The strategy relies on the coupling of N-phenyl trifluoroacetimidate disaccharide donors to a common rhamnosyl acceptor. The resulting trisaccharide thioglycosides were finally coupled to an n-pentenyl galactoside acceptor to access the two protected branched tetrasaccharides.

Silver-Catalyzed Dehydrogenative Synthesis of Carboxylic Acids from Primary Alcohols.

A simple silver-catalyzed protocol has been developed for the acceptorless dehydrogenation of primary alcohols into carboxylic acids and hydrogen gas. The procedure uses 2.5 % Ag2 CO3 and 2.5-3 equiv of KOH in refluxing mesitylene to afford the potassium carboxylate which is then converted into the acid with HCl. The reaction can be applied to a variety of benzylic and aliphatic primary alcohols with alkyl and ether substituents, and in some cases halide, olefin, and ester functionalities are also compatible with the reaction conditions. The dehydrogenation is believed to be catalyzed by silver nanoparticles that are formed in situ under the reaction conditions.

Synthetic Applications and Mechanistic Studies of the Hydroxide-Mediated Cleavage of Carbon-Carbon Bonds in Ketones.

The hydroxide-mediated cleavage of ketones into alkanes and carboxylic acids has been reinvestigated and the substrate scope extended to benzyl carbonyl compounds. The transformation is performed with a 0.05 M ketone solution in refluxing xylene in the presence of 10 equiv of potassium hydroxide. The reaction constitutes a straightforward protocol for the synthesis of certain phenyl-substituted carboxylic acids from 2-phenylcycloalkanones. The mechanism was investigated by kinetic experiments which indicated a first order reaction in hydroxide and a full negative charge in the rate-determining step. The studies were complemented by a theoretical investigation where two possible pathways were characterized by DFT/M06-2X. The calculations showed that the scission takes place by nucleophilic attack of hydroxide on the ketone followed by fragmentation of the resulting oxyanion into the carboxylic acid and a benzyl anion.

Dehydrogenative Synthesis of Carboxylic Acids from Primary Alcohols and Hydroxide Catalyzed by a Ruthenium N-Heterocyclic Carbene Complex.

Primary alcohols have been reacted with hydroxide and the ruthenium complex [RuCl2(IiPr)(p-cymene)] to afford carboxylic acids and dihydrogen. The dehydrogenative reaction is performed in toluene, which allows for a simple isolation of the products by precipitation and extraction. The transformation can be applied to a range of benzylic and saturated aliphatic alcohols containing halide and (thio)ether substituents, while olefins and ester groups are not compatible with the reaction conditions. Benzylic alcohols undergo faster conversion than other substrates, and a competing Cannizzaro reaction is most likely involved in this case. The kinetic isotope effect was determined to be 0.67 using 1-butanol as the substrate. A plausible catalytic cycle was characterized by DFT/B3LYP-D3 and involved coordination of the alcohol to the metal, ß-hydride elimination, hydroxide attack on the coordinated aldehyde, and a second ß-hydride elimination to furnish the carboxylate.

Experimental and theoretical mechanistic investigation of the iridium-catalyzed dehydrogenative decarbonylation of primary alcohols.

The mechanism for the iridium-BINAP catalyzed dehydrogenative decarbonylation of primary alcohols with the liberation of molecular hydrogen and carbon monoxide was studied experimentally and computationally. The reaction takes place by tandem catalysis through two catalytic cycles involving dehydrogenation of the alcohol and decarbonylation of the resulting aldehyde. The square planar complex IrCl(CO)(rac-BINAP) was isolated from the reaction between [Ir(cod)Cl]2, rac-BINAP, and benzyl alcohol. The complex was catalytically active and applied in the study of the individual steps in the catalytic cycles. One carbon monoxide ligand was shown to remain coordinated to iridium throughout the reaction, and release of carbon monoxide was suggested to occur from a dicarbonyl complex. IrH2Cl(CO)(rac-BINAP) was also synthesized and detected in the dehydrogenation of benzyl alcohol. In the same experiment, IrHCl2(CO)(rac-BINAP) was detected from the release of HCl in the dehydrogenation and subsequent reaction with IrCl(CO)(rac-BINAP). This indicated a substitution of chloride with the alcohol to form a square planar iridium alkoxo complex that could undergo a ß-hydride elimination. A KIE of 1.0 was determined for the decarbonylation and 1.42 for the overall reaction. Electron rich benzyl alcohols were converted faster than electron poor alcohols, but no electronic effect was found when comparing aldehydes of different electronic character. The lack of electronic and kinetic isotope effects implies a rate-determining phosphine dissociation for the decarbonylation of aldehydes.

Dimethylzinc-Initiated Radical Coupling of ß-Bromostyrenes with Ethers and Amines.

A new coupling reaction has been developed in which ß-bromostyrenes react with ethers and tertiary amines to introduce the styryl group in the α-position. The transformation is mediated by Me2 Zn/O2 with 10 % MnCl2 and is believed to proceed by a radical addition-elimination mechanism. The ether and the amine are employed as solvent and the coupling takes place through the most stable α radical for unsymmetrical substrates. The products are obtained in moderate to good yields as the pure E isomers. The coupling can be achieved with a range of smaller cyclic and acyclic ethers/amines as well as various substituted ß-bromostyrenes.

Enzymatic degradation of lignin-carbohydrate complexes (LCCs): model studies using a fungal glucuronoyl esterase from Cerrena unicolor.

Lignin-carbohydrate complexes (LCCs) are believed to influence the recalcitrance of lignocellulosic plant material preventing optimal utilization of biomass in e.g. forestry, feed and biofuel applications. The recently emerged carbohydrate esterase (CE) 15 family of glucuronoyl esterases (GEs) has been proposed to degrade ester LCC bonds between glucuronic acids in xylans and lignin alcohols thereby potentially improving delignification of lignocellulosic biomass when applied in conjunction with other cellulases, hemicellulases and oxidoreductases. Herein, we report the synthesis of four new GE model substrates comprising α- and É£-arylalkyl esters representative of the lignin part of naturally occurring ester LCCs as well as the cloning and purification of a novel GE from Cerrena unicolor (CuGE). Together with a known GE from Schizophyllum commune (ScGE), CuGE was biochemically characterized by means of Michaelis-Menten kinetics with respect to substrate specificity using the synthesized compounds. For both enzymes, a strong preference for 4-O-methyl glucuronoyl esters rather than unsubstituted glucuronoyl esters was observed. Moreover, we found that α-arylalkyl esters of methyl α-D-glucuronic acid are more easily cleaved by GEs than their corresponding É£-arylalkyl esters. Furthermore, our results suggest a preference of CuGE for glucuronoyl esters of bulky alcohols supporting the suggested biological action of GEs on LCCs. The synthesis of relevant GE model substrates presented here may provide a valuable tool for the screening, selection and development of industrially relevant GEs for delignification of biomass.

Hydroformylation of olefins and reductive carbonylation of aryl halides with syngas formed ex situ from dehydrogenative decarbonylation of hexane-1,6-diol.

A variety of primary alcohols have been investigated as convenient substrates for the ex situ delivery of carbon monoxide and molecular hydrogen in a two-chamber reactor. The gaseous mixture is liberated in one chamber by an iridium-catalysed dehydrogenative decarbonylation of the alcohol and then consumed in the other chamber in either a rhodium-catalysed hydroformylation of olefins or a palladium-catalysed reductive carbonylation of aryl halides. Hexane-1,6-diol was found to be the optimum alcohol for both reactions where moderate to excellent yields were obtained of the product aldehydes. A relatively low pressure of 1.5-2.4 bar was measured in the closed system during the two transformations.

Ruthenium-catalyzed self-coupling of primary and secondary alcohols with the liberation of dihydrogen.

The dehydrogenative self-condensation of primary and secondary alcohols has been studied in the presence of RuCl2(IiPr)(p-cymene). The conversion of primary alcohols into esters has been further optimized by using magnesium nitride as an additive, which allows the reaction to take place at a temperature and catalyst loading lower than those described previously. Secondary alcohols were dimerized into racemic ketones by a dehydrogenative Guerbet reaction with potassium hydroxide as the additive. The transformation gave good yields of the ketone dimers with a range of alkan-2-ols, whereas more substituted secondary alcohols were unreactive. The reaction proceeds by dehydrogenation to the ketone, followed by an aldol reaction and hydrogenation of the resulting enone.

Mechanistic investigation of the ruthenium-N-heterocyclic-carbene-catalyzed amidation of amines with alcohols.

The mechanism of the ruthenium-N-heterocyclic-carbene-catalyzed formation of amides from alcohols and amines was investigated by experimental techniques (Hammett studies, kinetic isotope effects) and by a computational study with dispersion-corrected density functional theory (DFT/M06). The Hammett study indicated that a small positive charge builds-up at the benzylic position in the transition state of the turnover-limiting step. The kinetic isotope effect was determined to be 2.29(±0.15), which suggests that the breakage of the C-H bond is not the rate-limiting step, but that it is one of several slow steps in the catalytic cycle. Rapid scrambling of hydrogen and deuterium at the α position of the alcohol was observed with deuterium-labeled substrates, which implies that the catalytically active species is a ruthenium dihydride. The experimental results were supported by the characterization of a plausible catalytic cycle by using DFT/M06. Both cis-dihydride and trans-dihydride intermediates were considered, but when the theoretical turnover frequencies (TOFs) were derived directly from the calculated DFT/M06 energies, we found that only the trans-dihydride pathway was in agreement with the experimentally determined TOFs.

Iridium-catalyzed dehydrogenative decarbonylation of primary alcohols with the liberation of syngas.

A new iridium-catalyzed reaction in which molecular hydrogen and carbon monoxide are cleaved from primary alcohols in the absence of any stoichiometric additives has been developed. The dehydrogenative decarbonylation was achieved with a catalyst generated in situ from [Ir(coe)(2)Cl](2) (coe = cyclooctene) and racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (rac-BINAP) in a mesitylene solution saturated with water. A catalytic amount of lithium chloride was also added to improve the catalyst turnover. The reaction has been applied to a variety of primary alcohols and gives rise to products in good to excellent yields. Ethers, esters, imides, and aryl halides are stable under the reaction conditions, whereas olefins are partially saturated. The reaction is believed to proceed by two consecutive organometallic transformations that are catalyzed by the same iridium(I)-BINAP species. First, dehydrogenation of the primary alcohol to the corresponding aldehyde takes place, which is then followed by decarbonylation to the product with one less carbon atom.

Mechanistic investigation of the iridium-catalysed alkylation of amines with alcohols.

The [Cp*IrCl(2)](2)-catalysed alkylation of amines with alcohols was investigated using a combination of experimental and theoretical methods. A Hammett study involving a series of para-substituted benzyl alcohols resulted in a line with a negative slope. This clearly documents that a positive charge is built up in the transition state, which in combination with the measurement of a significant kinetic isotope effect determines hydride abstraction as being the selectivity-determining step under these conditions. A complementary Hammett study using para-substituted anilines was also carried out. Again, a line with a negative slope was obtained suggesting that nucleophilic attack on the aldehyde is selectivity-determining. A computational investigation of the entire catalytic cycle with full-sized ligands and substrates was performed using density functional theory. The results suggest a catalytic cycle where the intermediate aldehyde stays coordinated to the iridium catalyst and reacts with the amine to give a hemiaminal which is also bound to the catalyst. Dehydration to the imine and reduction to the product amine also takes place without breaking the coordination to the catalyst. The fact that the entire catalytic cycle takes place with all the intermediates bound to the catalyst is important for the further development of this synthetic transformation.

Synthesis of tocopheryl succinate phospholipid conjugates and monitoring of phospholipase A2 activity.

Tocopheryl succinates (TOSs) are, in contrast to tocopherols, highly cytotoxic against many cancer cells. In this study the enzyme activity of secretory phospholipase A(2) towards various succinate-phospholipid conjugates has been investigated. The synthesis of six novel phospholipids is described, including two TOS phospholipids conjugates. The studies revealed that the TOS conjugates are poor substrates for the enzyme whereas the phospholipids with alkyl and phenyl succinate moieties were hydrolyzed by the enzyme to a high extent.

Ruthenium-catalysed synthesis of 2- and 3-substituted quinolines from anilines and 1,3-diols.

A straightforward synthesis of substituted quinolines is described by cyclocondensation of anilines with 1,3-diols. The reaction proceeds in mesitylene solution with catalytic amounts of RuCl(3)·xH(2)O, PBu(3) and MgBr(2)·OEt(2). The transformation does not require any stoichiometric additives and only produces water and dihydrogen as byproducts. Anilines containing methyl, methoxy and chloro substituents as well as naphthylamines were shown to participate in the heterocyclisation. In the 1,3-diol a substituent was allowed in the 1- or the 2-position giving rise to 2- and 3-substituted quinolines, respectively. The best results were obtained with 2-alkyl substituted 1,3-diols to afford 3-alkylquinolines. The mechanism is believed to involve dehydrogenation of the 1,3-diol to the 3-hydroxyaldehyde which eliminates water to the corresponding α,ß-unsaturated aldehyde. The latter then reacts with anilines in a similar fashion as observed in the Doebner-von Miller quinoline synthesis.

Structural insights into substrate specificity and the anti beta-elimination mechanism of pectate lyase.

Pectate lyases harness anti beta-elimination chemistry to cleave the alpha-1,4 linkage in the homogalacturonan region of plant cell wall pectin. We have studied the binding of five pectic oligosaccharides to Bacillus subtilis pectate lyase in crystals of the inactive enzyme in which the catalytic base is substituted with alanine (R279A). We discover that the three central subsites (-1, +1, and +2) have a profound preference for galacturonate but that the distal subsites can accommodate methylated galacturonate. It is reasonable to assume therefore that pectate lyase can cleave pectin with three consecutive galacturonate residues. The enzyme in the absence of substrate binds a single calcium ion, and we show that two additional calcium ions bind between enzyme and substrate carboxylates occupying the +1 subsite in the Michaelis complex. The substrate binds less intimately to the enzyme in a complex made with a catalytic base in place but in the absence of the calcium ions and an adjacent lysine. In this complex, the catalytic base is correctly positioned to abstract the C5 proton, but there are no calcium ions binding the carboxylate at the +1 subsite. It is clear, therefore, that the catalytic calcium ions and adjacent lysine promote catalysis by acidifying the alpha-proton, facilitating its abstraction by the base. There is also clear evidence that binding distorts the relaxed 2(1) or 3(1) helical conformation of the oligosaccharides in the region of the scissile bond.