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 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. 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. 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, 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 : [email protected] [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.