DOI: 10.1002/cssc.201200236
An Integrated Approach for the Production and Isolation of
5-Hydroxymethylfurfural from Carbohydrates
Svilen P. Simeonov ,[a, b, c] Jaime A. S. Coelho,[a, b] and Carlos A. M. Afonso*[a, b]
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.[1] For the energy issue, the on-
going 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 inten-
sive biotransformation processes or by functional transforma-
tion of existing biorenewable resources, for example, wood-
derived materials such as cellulose, lignin, and other poly-
saccharides.
tion 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 1008C.[3c,6] For de-
hydration of fructose to HMF, a broader range of efficient cata-
lysts has been reported. In general, homogeneous and hetero-
geneous mineral and organic acids are used, at temperatures
ranging from RT to above 1008C.[3c] In addition, the transfor-
mation 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 1208C).[3c]
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 (114–1168C/1 mbar); (3) its low melting point
(30–348C); 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.[3c]
Among several building blocks derived from renewable re-
sources (e.g., ethanol, glycerol, lactic acid, furfural,[2]) 5-hy-
droxymethylfurfural (HMF) has been identified as a very prom-
ising building block, being the starting point for different ap-
plications such as biofuels (dimethylfuran), polymer monomers
(2,5-diformylfuran and 2,5-furandicarboxyllic acid), levulinic
acid, and many other specific molecules,[3] for example, a short-
er synthesis of the active pharmaceutical ingredient ranitidine
(Zantac) reported recently.[4]
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 oc-
currence 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[2a,5] whereas fructose dehydration is catalyzed by acids;
and (3) experimental conditions that are not compatible with
HMF, which is unstable.[3c] 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 transforma-
In the case of the best traditional organic solvent (i.e.,
DMSO), isolation requires partial distillation of HMF under
vacuum followed by column chromatography.[3c,7] For reaction
media based on imidazolium,[8] choline,[9] and betaine[10] cat-
ions extractions with diethyl ether, ethyl acetate, or methyl iso-
butyl ketone have been reported, with continuous or repeated
extraction required.[3c] It appears that currently, there is still no
literature report on a combined methodology for the produc-
tion and isolation of HMF that is applicable to large-scale
production.
Because crystallization is one of the best separation process-
es to use industrially, we explored the possibility of using read-
ily available, easily crystallized, and low-volatility solids as effi-
cient reaction media, promoting the production of HMF under
homogeneous conditions by melting of the reaction media
and solubilization of carbohydrates at the temperature re-
quired for the reaction. Furthermore, after cooling, precipita-
tion could occur at room temperature when using the appro-
priate 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).
[a] S. P. Simeonov , J. A. S. Coelho, Prof. C. A. M. Afonso
Research Institute for Medicines and Pharmaceuticals Sciences
Faculdade de Farmꢀcia da Universidade de Lisboa
1049-001 Lisboa (Portugal)
Av. Prof. Gama Pinto, 1649-019
[b] S. P. Simeonov , J. A. S. Coelho, Prof. C. A. M. Afonso
CQFM, Centro de Quꢁmica-Fꢁsica Molecular and
IN-Institute of Nanosciences and Nanotechnology
Instituto Superior Tꢂcnico
Considering that DMSO is one of the best solvents for the
dehydration of fructose to HMF,[3c,11] the use of other solid sulf-
oxides such as p-tolyl sulfoxide (m.p. 94–968C) in the presence
of Amberlyst-15 as catalyst was explored. Under these condi-
tions, 90% of the p-tolyl sulfoxide could be recovered by crys-
tallization. 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-
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
ChemSusChem 0000, 00, 1 – 4
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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