Jaime A. S. Coelho

An Integrated Approach for the Production and Isolation of 5‐Hydroxymethylfurfural from Carbohydrates

In the near future, the world will need to gradually replace the use of fossil resources for energy consumption and platform chemicals with other resources. For the energy issue, the ongoing approach is based mainly on a diversity of resources, such as nuclear, coal, hydraulic and wind power, photovoltaics, and biofuels. In the case of chemical platforms, probably the major resource will be based on a bioplatform either by intensive biotransformation processes or by functional transformation of existing biorenewable resources, for example, woodderived materials such as cellulose, lignin, and other polysaccharides. Among several building blocks derived from renewable resources (e.g. , ethanol, glycerol, lactic acid, furfural,) 5-hydroxymethylfurfural (HMF) has been identified as a very promising building block, being the starting point for different applications such as biofuels (dimethylfuran), polymer monomers (2,5-diformylfuran and 2,5-furandicarboxyllic acid), levulinic acid, and many other specific molecules, for example, a shorter synthesis of the active pharmaceutical ingredient ranitidine (Zantac) reported recently. The most desirable route for the production of HMF involves widely available biorenewable resources such as cellulose and inulin. However, an efficient direct transformation of cellulose into HMF appears less feasible, mainly because of (1) the occurrence of side reactions (e.g. , humin formation); (2) different reactivity pathways that require complementary catalysts, for example, glucose isomerization is more efficiently catalyzed by a base 5] whereas fructose dehydration is catalyzed by acids; and (3) experimental conditions that are not compatible with HMF, which is unstable. The most-often explored synthetic route is based on a multistep approach, comprising hydrolysis of cellulose to glucose, isomerization of glucose to fructose, and dehydration of fructose to HMF. Because the dehydration of fructose to HMF is less demanding, the one-pot transformation of glucose to HMF has also been intensely explored. The catalysts CrCln (n = 2,3) appears to be the best ones at the present stage, requiring temperatures above 100 8C. 6] For dehydration of fructose to HMF, a broader range of efficient catalysts has been reported. In general, homogeneous and heterogeneous mineral and organic acids are used, at temperatures ranging from RT to above 100 8C. In addition, the transformation is also possible in the absence of a catalyst. In these cases specific solvents, such as dimethyl sulfoxide (DMSO) and ionic liquids, are used to promote the reaction, although higher temperatures are generally required (up to 120 8C). Isolation of HMF from the reaction mixture is a very important issue due to the specific properties of HMF, such as (1) its high solubility in aqueous media and polar solvents; (2) its low vapor pressure (114–116 8C/1 mbar) ; (3) its low melting point (30–34 8C); and (4) its thermal and chemical instability. These factors complicate the large-scale isolation of HMF by solvent extraction, distillation, or crystallization. In fact, the majority of literature reports provide HMF conversion and/or yields based on HPLC, and to a lesser extent GLC, analysis of the reaction mixture, rather than isolated yields. In the case of the best traditional organic solvent (i.e. , DMSO), isolation requires partial distillation of HMF under vacuum followed by column chromatography. 7] For reaction media based on imidazolium, choline, and betaine cations extractions with diethyl ether, ethyl acetate, or methyl isobutyl ketone have been reported, with continuous or repeated extraction required. It appears that currently, there is still no literature report on a combined methodology for the production and isolation of HMF that is applicable to large-scale production. Because crystallization is one of the best separation processes to use industrially, we explored the possibility of using readily available, easily crystallized, and low-volatility solids as efficient reaction media, promoting the production of HMF under homogeneous conditions by melting of the reaction media and solubilization of carbohydrates at the temperature required for the reaction. Furthermore, after cooling, precipitation could occur at room temperature when using the appropriate organic solvent, allowing isolation of the HMF in the mother liquor just by evaporation of the organic solvent, which can then be reused (Scheme 1). Considering that DMSO is one of the best solvents for the dehydration of fructose to HMF, 11] the use of other solid sulfoxides such as p-tolyl sulfoxide (m.p. 94–96 8C) in the presence of Amberlyst-15 as catalyst was explored. Under these conditions, 90 % of the p-tolyl sulfoxide could be recovered by crystallization. Unfortunately, the isolated yield of HMF was very low (28 %) compared to DMSO (70 %; see Table 1, entries 1 and 2; Supporting Information). Furthermore, purification by chro[a] S. P. Simeonov , J. A. S. Coelho , Prof. C. A. M. Afonso Research Institute for Medicines and Pharmaceuticals Sciences Faculdade de Farm cia da Universidade de Lisboa 1049-001 Lisboa (Portugal) Av. Prof. Gama Pinto, 1649-019 E-mail : carlosafonso@ff.ul.pt [b] S. P. Simeonov , J. A. S. Coelho , Prof. C. A. M. Afonso CQFM, Centro de Qu mica-F sica Molecular and IN-Institute of Nanosciences and Nanotechnology Instituto Superior T cnico 1049-001 Lisboa (Portugal) [c] S. P. Simeonov Institute of Organic Chemistry with Centre of Phytochemistry Bulgarian Academy of Sciences Acad. G.Bonchev str. , bl.9, 1113 Sofia (Bulgaria) Supporting Information for this article is available on the WWW under http://dx.doi.org/10.1002/cssc.201200236.

Integrated Chemo-Enzymatic Production of 5-Hydroxymethylfurfural from Glucose

Sweets for my sweet: The production and isolation of 5-hydroxymethylfurfural (HMF) in high yield and purity is demonstrated by using a combination of glucose-fructose isomerization with sweetzyme in wet tetraethylammonium bromide (TEAB) and clean fructose dehydration to HMF catalyzed by using HNO₃ under moderate conditions, which allow the reuse of any unreacted glucose and TEAB.

Synthesis of Symmetric Bis(N-alkylaniline)triarylmethanes via Friedel–Crafts-Catalyzed Reaction between Secondary Anilines and Aldehydes

The first general protocol for the preparation of symmetric triarylmethanes bearing secondary anilines by ytterbium-catalyzed Friedel-Crafts reaction of hetero(aryl) aldehydes and secondary anilines is reported. Mechanistic studies indicated that the iminium ion intermediate is the electrophilic partner. The reaction is greatly accelerated by high pressure (9 kbar) and showed a broad substrate scope on the hetero(aryl) aldehyde. The new triarylmethanes exhibited activity against HT-29 cancer cell lines, with the best result scoring an IC50 of 1.74 μM.

NHC catalysed direct addition of HMF to diazo compounds: synthesis of acyl hydrazones with antitumor activity

NHC umpolung catalysis between 5-hydroxymethyl furfural (HMF) derivatives and diazo compounds overcomes the usual multistep synthesis of acylhydrazones and gives direct access to an unexplored family of HMF-based acylhydrazones displaying promising anti-tumor activity. A preliminary screening of hydroxymethyls protection groups allowed the identification of the tert-butyldimethylsilyl group as being essential for the desired biological activity. Compound 25 was found to be very active against MCF-7 breast cell line (with an IC50s of 3.60 μM) and while exerting a much lower toxicity in differentiated CaCo-2 monolayer.

Bifunctional Cr3+ modified ion exchange resins as efficient reusable catalysts for the production and isolation of 5-hydroxymethylfurfural from glucose

Cr3+ modified readily available cation exchange resins were prepared and explored as heterogeneous bifunctional catalysts for the dehydration of glucose to 5-hydroxymethylfurfural (HMF) in tetraethyl ammonium bromide (TEAB)/water as reaction medium. Excellent HMF isolated yields of up to 70% were achieved using simple crystallization of the reaction medium (TEAB) from ethyl acetate/ethanol which allowed the isolation of HMF in high purity. The best identified catalyst (Amberlyst 15/Cr3+) exhibited high activity over 4 cycles. The loss of activity was attributed to the decreased number of acidic sites of the catalyst, thus a simple treatment of the catalyst with 10% HCl efficiently restored its activity in the following cycles.

Evaluating the toxicity of biomass derived platform chemicals

Furans and their derivatives are well-known chemical building blocks common in plant biomass, and are abundantly used in food, medicines and industrial processes. As a bio-renewable resource, obtainable from the abundant and inexpensive lignocellulosic biomass, there is a growing interest in their study, physico-chemical characterization and application. Due to their biological origin, there is a presumption of low toxicity and high biodegradability for these compounds, which makes them “green” solvents, and thus potential substitutes of the classical organic solvents or oil derived commodities. Surprisingly, their ecotoxicity is poorly characterized. The few studies dealing with the toxicity of furans, namely towards animals, have presented contradictory results. In this work, the toxicity of eighteen furans and their derivatives was evaluated by the Microtox toxicity assay, using the marine bacterium Vibrio fischeri. Different levels of toxicity were observed among the furan derivatives investigated. The results obtained suggest that it might not be adequate to consider furans and their derivatives as “green” solvents as, in general, furans are more toxic than the classical solvents. Nevertheless, more data and studies across more trophic levels are necessary to fully understand the effects of furans on the environment as well as their biodegradability.

An emerging platform from renewable resources: selection guidelines for human exposure of furfural-related compounds

5-Hydroxymethylfurfural (HMF) is a precursor for the synthesis of potential chemical building blocks and biofuel products. Therefore, it is expected to be a very important bioplatform player in the future due to reduction of fossil resources. Controversial data exist about HMF toxicity and, in addition, toxicological data of its derivatives are scarce. We evaluated the impact of several HMF derivatives in human skin fibroblast cells and data demonstrate that the dialdehyde (10), dihydroxymethyl (12), dimethyl (18) and the dimer (20) derivatives are potentially more harmful than the dicarboxylic acid derivative (17). HMF was not cytotoxic whereas the reported derivative 5-sulfoxymethylfurfural (SMF) was weakly cytotoxic. Some examples of derivatives are presented which are considerably more toxic than SMF.

Copper(II) Triflate As a Reusable Catalyst for the Synthesis of trans-4,5-Diamino-cyclopent-2-enones in Water

trans-4,5-Diamino-cyclopent-2-enones (CP) are usually prepared by Lewis acid-catalyzed condensation of furfural and a secondary amine in an organic solvent. The reaction proceeds through the formation of a Stenhouse salt (SS) intermediate followed by an electrocyclization reaction to afford the desired CP. Herein, we described the use of Cu(OTf)2 as a very efficient catalyst for the synthesis of CP in water at room temperature. Furthermore, the mild reaction conditions, catalyst reusability, and outstanding functional group tolerance suggest that this CP platform can be further used in chemical biology.

Valorization of Oleuropein via Tunable Acid-Promoted Methanolysis

The acid-promoted methanolysis of oleuropein was studied using a variety of homogeneous and heterogeneous acid catalysts. Exclusive cleavage of the acetal bond between the glucoside and the monoterpene subunits or further hydrolysis of the hydroxytyrosol ester and subsequent intramolecular rearrangement were observed upon identification of the most efficient catalyst and experimental conditions. Furthermore, selected conditions were tested using oleuropein under continuous flow and using a crude mixture extracted from olive leaves under batch. Formation of (-)-methyl elenolate was also observed in this study, which is a reported precursor for the synthesis of the antihypertensive drug (-)-ajmalicine.

Synthesis and Applications of Stenhouse Salts and Derivatives

In recent years, Stenhouse salts have attracted much attention as intermediates for the synthesis of cyclopenten-2-enones. This Minireview aims to present an overview of the methods for preparation, further transformation and applications of Stenhouse and Stenhouse-like salts. In this context, the Piancatelli rearrangement and its variants, and the recently reported donor-acceptor Stenhouse salts (DASA) will be addressed. The photophysical properties of DASA and its applications in colorimetric detection of amines, functionalization of polymers for detection of heat and nerve agents, photolithography and orthogonal photoswitching systems are discussed.