A green alternative to THF - Romil

The solvent 2-methyl tetrahydrofuran
(2-MeTHF) can provide
a cost-effective, green
alternative to tetrahydrofuran
(THF) chemistry. 2-MeTHF’s
advantages include its origin from
renewable and price stable resources as
well as beneficial physical and chemical
properties that can provide increased
yields at reduced costs. The major benefits
are summarised in table 1.
The solvent 2-MeTHF is obtained
from furfural through hydrogenation.
In turn, furfural is obtained from
renewable resources, such as corn cobs
and sugar cane, through the intramolecular
cyclisation of the naturally-occurring
pentoses. In contrast, THF is
obtained from 1,4-butanediol, an oilderived
substance.
The incineration of solvents is the
main fine chemicals industry contributor
to the greenhouse effect. The recent
political and legislative drive for reduction
of CO 2 emissions should make solvents
derived from renewable
resources highly desirable due to their
reduced CO 2 emissions impact. Incineration
of 2-MeTHF does not increase
the CO 2 concentration in the atmosphere
as it simply returns the CO 2 captured
by the previous year’s crop from
the air.
2-MeTHF is currently the only aprotic
solvent similar to THF that is
derived from renewable resources and
industrially available 1 . The market
share for 2-MeTHF is growing rapidly
driving the price of the compound
lower. This is in sharp contrast to the
long term trend for oil-derived THF,
where prices have increased over the
past decade by approximately 50%.
innovation opportunities
The methyl substituted version of THF
is not miscible with water. It is comparable
or even better than THF in terms
of its chemical properties. However, 2-
MeTHF resembles toluene in terms of
physical properties and this creates
huge innovation opportunities for cutting
costs both in existing and new
processes.
The work-up for the THF-based reaction
is complicated by THF’s miscibility
with water. For oily products, THF
is distilled first and then the oily crude
is extracted with a saturated saline
solution. For solid products, a nonpolar
solvent such as toluene needs to be
added to achieve phase separation and
avoid precipitation. In both cases emulsions,
rag layers at the phase interfaceand
poor extraction yields are frequent
complications.
2-MeTHF is not water miscible and
provides easy and clean phase separation
during work-up. These advantages
make the process simpler and more
robust, translating into higher throughput
and reduced cost of quality.
organic synthesis
A green
alternative to THF
Table 1: MeTHF vs THF
Dr Rainer Aul, of Chemetall GmbH, and Dr
Bogdan Comanita, of Penn Specialty
Chemicals propose 2-methyl tetrahydrofuran
as a cost-effective alternative to widely used
tetrahydrofuran chemistry
Advantages Source of savings
Renewable resource CO2 emissions credits; solvent from renewable resources
Decreasing price trend; supply risk decoupled from oil
Physical properties Increased throughput; easy aqueous phase separation
Less solvent; more efficient extraction
Less solvent; solvent reuse & recycling: azeotrope with water
Chemical properties Less impurities; better solvent stability to acids and base
Increased throughput; higher reaction yields
Less solvent; higher saturation concentrations
Improved safety; lower volatility, higher flash point
Figure 1: Degradation
of THF and MeTHF,
using homogenous
50:50 % solutions
THF/MeTHF with 2 N
HCl at 60°C.
The methyl-substituted
THF reduces
the solvent and
energy variable costs.
Thus 2-MeTHF has
better extractive properties
than the classic
THF/ toluene mixture
2 . This means the
number of extraction
steps can be reduced
while the recovery of
the product is simultaneously
increased.
The 2-MeTHF solution
of crude product can be dried
through a simple distillation at atmospheric
pressure. The water-rich MeTHF
azeotrope will create rapidly an anhydrous
solution providing the option to
add a new reagent without product isolation.
For example, the classic reaction
sequence carbonyl to alcohol followed
by alcohol to ester is particularly
adequate for MeTHF. The solvent consumption
is cut by 50% and the
throughput is vastly improved by
avoiding isolation of the intermediate
alcohol.
Last but not least, 2-MeTHF is much
easier to recycle and dry than THF.
This has important advantages for
www.manufacturing-chemist.info May 2007 manufacturing chemist 33

dedicated production capacities consuming
hundreds of metric tons of solvent
per year. In these capacities THF is
recycled and dried using ‘swing distillation’.
In contrast 2-MeTHF needs
only a simple distillation at atmospheric
pressure. The recycling and drying
process is much more cost efficient
for 2-MeTHF because the energy cost of
distillation is reduced by an estimated
70% 3 . The need for an upfront capital
investment for a specialised distillation
unit for THF recycling is also eliminated.
chemical advantages
2-MeTHF is a versatile reaction solvent
covering a range of applications including
Grignard, organopalladium,
organozinc, lithium hydride reductions
and biphasic reactions 4 . It shows
increased stability to strong bases compared
with THF, a fact that is well documented
and explains its use in
organolithium chemistry applications 5 .
MeTHF is also more stable than THF
in acidic conditions. Figure 1 shows
the intrinsic difference of stability
between THF and MeTHF under acidic
conditions in a homogenous solution 6 .
In a real life situation, the hydrolysis of
2-MeTHF will be much slower due to
its immiscibility with water. This has
important implications relative to the
impurity profile and cost of quality
associated to a given process.
THF is currently the most common
solvent used in Grignard reactions. 2-
MeTHF is challenging this position
based on its very limited water solubility
and better pH stability allowing for
phase separation and improved yields.
Additional washing steps are eliminated
and a dry solution can be obtained by
simple azeotropic distillation.
34
organic synthesis
Table 2: Grignard bromides solubility in 2-MeTHF
RMgBr Solution in MeTHF Solution in THF
w/w % Mol/l Cryst. Temp. w/w% Mol/l Cryst. Temp.
MethylMgBr 35 3.2