Dihydrolevoglucosenone (Cyrene) as a bio-based alternative for dipolar aprotic solvents

Article abstract of DOI:10.1039/c4cc04133j

Dihydrolevoglucosenone (Cyrene) is a bio-based molecule, derived in two simple steps from cellulose, which demonstrates significant promise as a dipolar aprotic solvent. The dipolarity of dihydrolevoglucosenone is similar to NMP, DMF and sulpholane. Dihydrolevoglucosenone demonstrates similar performance to NMP in a fluorination reaction and the Menschutkin reaction. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04133j

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Dihydrolevoglucosenone (Cyrene) as a bio-based
alternative for dipolar aprotic solvents†
Cite this: Chem. Commun., 2014,
0, 9650
5
a
a
a
a
James Sherwood, Mario De bruyn, Andri Constantinou, Laurianne Moity,
a
a
b
b
Received 29th May 2014,
Accepted 1st July 2014
C. Rob McElroy, Thomas J. Farmer, Tony Duncan, Warwick Raverty,
a
a
Andrew J. Hunt and James H. Clark*
DOI: 10.1039/c4cc04133j
www.rsc.org/chemcomm
Dihydrolevoglucosenone (Cyrene) is a bio-based molecule, derived
in two simple steps from cellulose, which demonstrates significant
promise as a dipolar aprotic solvent. The dipolarity of dihydrole-
voglucosenone is similar to NMP, DMF and sulpholane. Dihydrole-
voglucosenone demonstrates similar performance to NMP in a
fluorination reaction and the Menschutkin reaction.
Solvents are ubiquitous throughout the chemical industry. In
recent times environmental health and safety concerns and
1
stricter legislation have created an interest in greener solvents.
Within the fine chemical industry, existing organic solvents
could be directly substituted for greener alternatives with
similar properties yet preferably derived from a renewable Fig. 1 (A) Scheme for the production of dihydrolevoglucosenone
2
feedstock as part of a solvent replacement strategy.
(Cyrene) and (B) s-surface (COSMO surface) of dihydrolevoglucosenone.
Typical examples of bio-based solvents include protic compounds
3
such as bio-ethanol and glycerol, and 2-methyltetrahydrofuran as a
4
medium polarity solvent. Terpenes and their derivatives have also such as the EU are encouraging a bio-based economy including the
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been proven as valuable bio-based hydrocarbon solvents. However production and use of chemicals from biomass. Concerning the
few bio-derived solvent solutions have been established as replace- hydrogenation of levoglucosenone, at present hydrogen is predo-
9
ments for highly dipolar aprotic solvents, yet it is these solvents that minantly generated through steam reforming of natural gas, as
are currently the subject of considerable attention under REACh and electrolysis from water using renewable energy is not yet economic-
10
other chemical legislation. N-Methylpyrrolidinone (NMP) for exam- ally viable. There are however numerous studies into sustainable
ple, which is widely used in chemical and pharmaceutical processing hydrogen generation and it is conceivable that a competitive and
11
and in formulations, is on the European candidate list of substances renewable source of H
of very high concern due to its toxicity.
2
will be available in the near future.
The hydrogenation of levoglucosenone over supported palla-
Herein is evidence that levoglucosenone, which can be made in dium catalysts has been reported before and is highly selective
6,7
8
12
a single step from biomass (cellulose), can be readily hydrogenated (yield 4 90%). While originally performed in an excess of ethyl
to dihydrolevoglucosenone, hence named ‘‘Cyrene’’, which is able acetate it was found that the quantity of solvent could be greatly
to serve as a bio-based substitute for toxic petrochemical-derived reduced at the expense of suppressing the reaction rate (see ESI†).
solvents such as NMP (Fig. 1). The renewable nature of dihydrole- Conducting the reaction at higher hydrogen pressures (3–80 bar)
voglucosenone makes it particularly attractive especially as regions allowed for greater reaction rates without affecting selectivity. It was
also found possible to conduct this room temperature hydrogena-
a
Green Chemistry Centre of Excellence, Department of Chemistry,
University of York, Heslington, York, YO10 5DD, UK.
tion in the absence of an auxiliary solvent. This solvent-free reaction
proceeds best using higher hydrogen pressures, again with no loss
of selectivity. The possibility to perform this reaction in the absence
of a solvent imparts significant economic advantages and makes
the commercialisation of Cyrene as a solvent viable. The high
stability of the cyclic acetal in dihydrolevoglucosenone relates to a
E-mail: james.clark@york.ac.uk; Tel: +44 (0)1904 322559
b
Circa Group Pty Ltd, 551 Burwood Highway, Knoxfield, Victoria, 3180, Australia.
E-mail: tony.duncan@circagroup.com.au; Tel: +61 (3)9955904
Electronic supplementary information (ESI) available. See DOI: 10.1039/
†
c4cc04133j
9650 | Chem. Commun., 2014, 50, 9650--9652
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double anomeric effect due to the fused ring system, moreover boiling point of 194 1C (HSPiP) although more precise analysis
acetal groups are known to be stable towards bases and nucleo- is ongoing. The density of dihydrolevoglucosenone as deter-
À1
philes. A preliminary Ames mutagenicity screening has been mined experimentally is 1.25 g mL at 293 K.
completed on Cyrene with no mutagenicity observed.
Two substitution reactions with special importance to the
It is crucial that the polarity profile of prospective solvents is pharmaceutical and agrochemical industries (which are major
known in order to correctly assign suitable applications for them. users of dipolar aprotic solvents like NMP) were used to evaluate
Dihydrolevoglucosenone has been modelled using full DFT/ the solvent performance of dihydrolevoglucosenone in relation to
COSMO geometry optimisations that describe a discrete surface other established solvents. The Menschutkin reaction is an alkyla-
around dihydrolevoglucosenone embedded in a perfect virtual tion reaction that progresses via a S
N
2 mechanism. It is now
21
conductor, the so-called s-surface (as generated via COSMOtherm, the basis for the synthesis of imidazolium ionic liquids. More
13
see Fig. 1). This surface shows the charge density distribution of generally, heteroatom alkylation is the most prevalent reaction
22
dihydrolevoglucosenone: green to yellow corresponds to weakly performed in the pharmaceutical industry, meaning the synthesis
polar surfaces, while red represents a strongly negative charge of 1-decyl-2,3-dimethylimidazolium bromide from 1,2-dimethyl-
density and blue a positive charge density. The distinct dipoles imidazole and 1-bromodecane is an appropriate generalised case
suggest dihydrolevoglucosenone may behave similarly to conven- study in the assessment of Cyrene as a bio-based solvent (Fig. 2).
tional dipolar aprotic solvents if used as a reaction medium.
The Kamlet–Abboud–Taft parameters were also obtained.
These indicate that dihydrolevoglucosenone is aprotic with a the reaction rate. A linear solvation energy relationship (LSER)
The rate of this reaction has been established as being proportional
to the dipolarity of the solvent, with protic solvents suppressing
14
23
2
4
similar p* value (corresponding to dipolarity) to those of highly is used to quantify this type of empirical relationship (Fig. 2).
dipolar aprotic solvents, but with a slightly lower b value which is It shows dihydrolevoglucosenone as one of the best solvents
an indicator of hydrogen bond accepting ability (Table 1). Conse- for this reaction, outperforming most other dipolar aprotic
quently dihydrolevoglucosenone is one of only a few solvents with solvents (e.g. dioxane, DMF, DMAc and NMP) and only slightly
the potential to offer an alternative to the traditional dipolar aprotic inferior to sulphur-containing DMSO and sulpholane in a
solvents. This observation is made more remarkable by the fact that comparison of experimental rate constants.
the molecule does not contain nitrogen and sulphur heteroatoms
In addition a model fluorination reaction was investigated
as typically found in polar aprotic solvents. Avoidance of these (Fig. 2). Fluorination is highly relevant to the pharmaceutical
heteroatoms is beneficial as they are known to lead to atmospheric industry, and new greener methods for conducting this type
15
25
pollution when the solvent is incinerated.
of reaction are of significant commercial interest. Of the top
Whereas the Kamlet–Abboud–Taft polarity scales are useful in 200 drugs as gauged by US retail sales in 2012, over 15%
2
6
correlations with reaction kinetics and equilibria, the Hansen contain fluorine. The simplest method of introducing fluo-
16
solubility parameters provide a measure of solvency power. In rine into an aromatic molecule is via a S
this approach, solvents are located in the ‘‘Hansen space’’, a three- rate of reaction is dependent on the stabilisation afforded to
dimensional representation of dispersion (d ), polar (d ) and the Meisenheimer intermediate, but meanwhile not deactiva-
hydrogen bonding (d ) interactions (combined these intermole- ting the fluoride nucleophile. This role is typically fulfilled by
N
Ar reaction, where the
d
p
2
7
h
cular forces express the Hildebrand parameter). The closer two conventional dipolar aprotic solvents, and as such dihydrole-
solvents are in the Hansen space, the more likely they are to exhibit voglucosenone would offer an interesting alternative reaction
the same solubilising properties. Dihydrolevoglucosenone has been medium.
mapped in the Hansen space and compared to classical organic
solvents (see Fig. S7 of the ESI†). Considering all three parameters, dipolarity (p*) of the solvent. Outside of a small domain of highly
the closest solvent match to Cyrene is NMP (Table 1). dipolar aprotic solvents, the rate of observable fluorination falls to
The rate of the fluorination is strongly dependent on the
The boiling point of dihydrolevoglucosenone was deter- negligible levels. Dihydrolevoglucosenone was found to possess
mined using TGA under a low nitrogen flow, to give a value the correct attributes to promote the reaction, albeit providing
of approximately 203 1C. This figure is similar to a predicted the slowest kinetics of those solvents successfully tested. As in the
Table 1 Physical properties of selected dipolar aprotic solvents
Cyrene
NMP
Cyclohexanone
DMF
0.386
DMAc
DMSO
Sulpholane
N
T
17
17
17
17
17
17
E
a
b
0.333
0.00
0.61
0.93a
18.8
0.355
0.00
0.75
0.90
0.281
0.377
0.444
0.410
5
18
18
18
0.005
0.00
0.71
0.88
17.4
13.7
11.3
0.00
0.73
0.85
16.8
11.5
10.2
0.00
0.74
1.00
18.4
16.4
10.2
0.00
0.30
0.96
19
19
19
16
16
16
19
19
16
16
16
0.585
0.71
19
16
16
16
p*
0
.5
16
16
16
d
d
d
D
/MPa0
18.0
12.3
7.2
17.8
20.3
.5
a
16
16
16
P
/MPa
10.6
6.9
6.3
18.2
0
.5
a
16
16
16
H
/MPa
5.1
10.9
1
1
1
1
1
1
BP/1C
r/g mL
203
1.25
202
1.03
155
153
165
189
282
À1
20
20
20
20
20
0.95
0.94
0.94
1.10
1.26
a
Calculated with HSPiP software.
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Heteroatom alkylations and nucleophilic fluorinations are two
commonly used reactions in the pharmaceutical and other high-
value chemical manufacturing sectors. Both types of reaction can
be carried out in dihydrolevoglucosenone with minimal losses in
performance compared to traditional but non-renewable alterna-
tives. Additional testing of dihydrolevoglucosenone and other
derivatives of levoglucosenone is being conducted to further under-
stand the capacity of these bio-based solvents to replace NMP and
similar solvents in synthetic chemistry and other applications.
The Authors would like to thank Circa Group for the supply
of levoglucosenone and for financial support of the research.
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9652 | Chem. Commun., 2014, 50, 9650--9652
This journal is ©The Royal Society of Chemistry 2014