Svilen P. Simeonov

5-Hydroxymethylfurfural (HMF) as a building block platform: Biological properties, synthesis and synthetic applications

The biorefinery is an important approach for the current needs of energy and chemical building blocks for a diverse range of applications, that gradually may replace current dependence on fossil-fuel resources. Among other primary renewable building blocks, 5-hydroxymethylfurfural (HMF) is considered an important intermediate due to its rich chemistry and potential availability from carbohydrates such as fructose, glucose, sucrose, cellulose and inulin. In recent years, considerable efforts have been made on the transformation of carbohydrates into HMF. In this critical review we provide an overview of the effects of HMF on microorganisms and humans, HMF production and functional group transformations of HMF to relevant target molecules by taking advantage of the primary hydroxyl, aldehyde and furan functionalities.

Synthesis of Chiral Cyclopentenones

The cyclopentenone unit is a very powerful synthon for the synthesis of a variety of bioactive target molecules. This is due to the broad diversity of chemical modifications available for the enone structural motif. In particular, chiral cyclopentenones are important precursors in the asymmetric synthesis of target chiral molecules. This Review provides an overview of reported methods for enantioselective and asymmetric syntheses of cyclopentenones, including chemical and enzymatic resolution, asymmetric synthesis via Pauson-Khand reaction, Nazarov cyclization and organocatalyzed reactions, asymmetric functionalization of the existing cyclopentenone unit, and functionalization of chiral building blocks.

Direct transformation of 5-hydroxymethylfurfural to the building blocks 2,5-dihydroxymethylfurfural (DHMF) and 5-hydroxymethyl furanoic acid (HMFA) via Cannizzaro reaction

An efficient, simple, scalable and atom efficient method for the synthesis of 2,5-dihydroxymethylfuran (DHMF) and 5-hydroxymethylfuranoic acid, as sodium salt (HMFA), in 80% yield from 5-hydroxymethylfurfural (HMF) in water using NaOH (0.9 eq.) via a Cannizzaro reaction is described. Both the building blocks DHMF and HMFA were successfully isolated merely using selective crystallisation.

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.

Exploiting Tautomerism for Switching and Signaling

Herein, we demonstrate a conceptual idea for a tautomeric switch based on implementation of a flexible piperidine unit in 4-(phenyldiazenyl)naphthalen-1-ol. The results show that a directed shift in the position of the tautomeric equilibrium can be achieved through protonation/deprotonation in a number of solvents. The developed molecular switch, in spite of the simple host–guest system, has shown acceptable complexation ability towards small alkaliand alkalineearth-metal ions and can be a promising basis for further development of effective molecular sensors through implementation of azacrown ethers. Organic molecular materials are increasingly recognized as suitable molecular-level elements (such as switching, signaling, and memory elements) for molecular devices, because the wide range of molecular characteristics can be combined with the versatility of synthetic chemistry to alter and optimize molecular structure in the direction of desired properties. Virtually every molecule changes its behavior when acted upon by external fields or other stimuli. True molecular switches undergo reversible structural changes, caused by a number of influences, which give a variety of possibilities for control. Several classes of photoresponsive molecular switches are already known; these operate through processes such as bond formation and bond breaking, cis– trans isomerization, and photoinduced electron transfer upon complexation. A conceptual scheme of a molecular switch based on molecular recognition is shown in Scheme 1. The host–guest system represents, for instance, a crown ether that can bind ions or a cyclodextrin that can bind other small molecules. It is bound to a signal converter. The complexation behavior is monitored by the state of the signal converter, and in turn its optical or electronic properties are determined by the complexation state of the host–guest system. The main requirement in the design of new molecular switches is to provide fast and clean interconversion between structurally different molecular states (on and off). Tautomerism could be a possibility, because change in the tautomeric state can be accomplished by a fast proton transfer reaction between two or more structures, each of them with clear and different molecular properties. Therefore, our aim herein is to show how tautomerism can be exploited for signal conversion. The conceptual idea of such a device is presented in Scheme 1. In this structure, a change in tautomeric state, labeled A and B, is linked to changes in the complexation abilities of the host–guest system by modulating the propensity of the system to hydrogen bond to the antenna. At the same time, engagement of this antenna causes a change in the tautomeric state. The sensitivity of the electronic ground and excited states of the tautomeric forms to environment stimuli (light, pH value, temperature, solvent) and to the presence of a variety of substituents or to hydrogen bonding can be exploited in the design of flexible tools for control. Obviously, such a device should be based on a tautomeric structure with easy proton exchange between the tautomers, which means that they must coexist in solution. At the same time, a main feature of systems of tautomers coexisting in solution is that the overall optical response is a mixture of the optical responses of the individual tautomers. Consequently, in the design of tautomeric switches, conditions for obtaining pure end tautomer in the corresponding off and on states must be provided. Herein we report the properties of two tautomeric switches, namely 3 and 4 (Scheme 2), based on 4-(phenyldiazenyl)phenol (1) and 4-(phenyldiazenyl)naphthalen-1-ol (2). The parent compound 2 is the first dye that was shown to tautomerize by Zincke and Bindewald in 1884. It has been the object of many spectral and theoretical studies because its tautomeric forms coexist in solution and the equilibrium Scheme 1. Molecular switch based on molecular recognition (left) and conceptual idea for a tautomerism-based molecular switch (right).

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.

Toxicological evaluation of magnetic ionic liquids in human cell lines

Magnetic ionic liquids (MILs) are new solvents with an interesting broad of applications however their toxicity is still an open issue. In this paper we report the toxicity of [C(8)MIM] and [Choline-C(n)] based magnetic ionic liquids assessed in two human cell lines: normal skin fibroblasts (CRL-1502) and colorectal adenocarcinoma cells (CaCo-2), acquiring this last characteristics of human enterocytes after differentiation. The results showed that [CoCl(4)] and [MnCl(4)] are more prone to generate cytotoxicity.

Basicity and stability of urea deep eutectic mixtures

The stability and basicity origin of some common urea based deep eutectic mixtures/solvents (DES) were studied. We have observed an unexpected Hantzsch dihydropyridine reaction in sorbitol/urea DES, where the source of ammonia was found not to be originated from the individual ingredients of the DES. Our results showed that decomposition of urea occurs in DES at lower than expected temperatures, namely below 100 °C and is enhanced in diol DES by the formation of carbonates causing their unexplained basicity. Carbohydrates and choline chloride (ChCl) DES exhibit lower rates of decomposition, while no decomposition was observed from neat urea or MeOH and EtOH urea solutions.

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.

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.