organic synthesis
A green
alternative to 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
The methyl-substituted THF reduces
the
solvent
and
Advantages
Source of savings
energy variable costs.
Renewable resource
CO2 emissions credits; solvent from renewable resources
Thus 2-MeTHF has
Decreasing price trend; supply risk decoupled from oil
better extractive propPhysical properties
Increased throughput; easy aqueous phase separation
erties than the classic
THF/ toluene mixLess solvent; more efficient extraction
ture2. This means the
Less solvent; solvent reuse & recycling: azeotrope with water
number of extraction
Chemical properties
Less impurities; better solvent stability to acids and base
steps can be reduced
Increased throughput; higher reaction yields
while the recovery of
Less solvent; higher saturation concentrations
the product is simulImproved safety; lower volatility, higher flash point
taneously increased.
The 2-MeTHF solulong term trend for oil-derived THF,
tion of crude product can be dried
where prices have increased over the
through a simple distillation at atmospast decade by approximately 50%.
pheric pressure. The water-rich MeTHF
azeotrope will create rapidly an anhyinnovation opportunities
drous solution providing the option to
The methyl substituted version of THF
add a new reagent without product isois not miscible with water. It is compalation. For example, the classic reacrable or even better than THF in terms
tion sequence carbonyl to alcohol folof its chemical properties. However, 2lowed by alcohol to ester is particularly
MeTHF resembles toluene in terms of
adequate for MeTHF. The solvent conphysical properties and this creates
sumption is cut by 50% and the
huge innovation opportunities for cutFigure 1: Degradation
throughput is vastly improved by
ting costs both in existing and new
avoiding isolation of the intermediate
of THF and MeTHF,
processes.
alcohol.
using homogenous
The work-up for the THF-based reacLast but not least, 2-MeTHF is much
50:50 % solutions
tion is complicated by THF’s miscibileasier to recycle and dry than THF.
THF/MeTHF with 2 N
ity with water. For oily products, THF
This has important advantages for HCl at 60°C.
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.
Table 1: MeTHF vs THF
he 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 CO2 emissions should make solvents derived from renewable
resources highly desirable due to their
reduced CO2 emissions impact. Incineration of 2-MeTHF does not increase
the CO2 concentration in the atmosphere as it simply returns the CO2 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 available1. The market
share for 2-MeTHF is growing rapidly
driving the price of the compound
lower. This is in sharp contrast to the
T
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May 2007 manufacturing chemist
33
organic synthesis
While the general
advantages enumerated above hold true
Solution in THF
Mol/l Cryst. Temp. for Grignard reagents
there are also a num1.2
<15°C
ber of advantages that
0.6
<5°C
are specific to this
0.9
<20°C
class of organometallic reagents. It has
been
shown,
for
example, that benzyl and allyl
organogrignards are generated in considerably better yields in 2-MeTHF versus THF. In particular, benzyl derivatives with electron withdrawing substituents systematically display a much
improved behaviour7.
Table 2: Grignard bromides solubility in 2-MeTHF
MethylMgBr
EthylMgBr
PhenylMgBr
RMgBr
w/w % Mol/l
35
3.2
40
3.4
45
2.9
Solution in MeTHF
Cryst. Temp. w/w%
<-10°C
15
<-10°C
8
<-10°C
17
higher solubility
dedicated production capacities con-
suming 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.
Figure 2: RADEX
diagram for
phemylmagnesium
bromide in THF and
2-MeTHF
chemical advantages
2-MeTHF is a versatile reaction solvent
covering a range of applications including
Grignard,
organopalladium,
organozinc, lithium hydride reductions
and biphasic reactions4. It shows
increased stability to strong bases compared with THF, a fact that is well documented and explains its use in
organolithium chemistry applications5.
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 solution6.
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. 2MeTHF 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
Figure 3: 2-MeTHF is
an excellent solvent
for lithiation
contact
Grignard compounds, especially bromogrignard reagents, tend to be much
more soluble in 2-MeTHF than THF.
For example 3.4 M ethylmagnesium
bromide, 2.9 M phenylmagnesium bromide and 3.2 M methylmagnesium
bromide solutions are available on
industrial scale from Chemetall. The
concentrations of the alkylmagnesium
bromides in 2-MeTHF are up to four
times higher than in THF and the stability to crystallisation is improved at
lower temperatures (see table 2)7.
Higher reagent concentration and
lower crystallization temperature in 2MeTHF have an
important impact
in
improving
throughput, shipping and storage
conditions as well
as reduced solvent
consumption.
From a process safety perspective,
the 2-MeTHF Grignard solutions show
the same thermal stability as their THFanalogues even at much higher saturation concentration. In a typical RADEX
experiment the solutions were heated
up in a closed cup with a rate of
45°C/h. The phenyl magnesium bromide solution was 50% in 2-MeTHF
and 17% in THF (see figure 2). The
start of exothermic thermal decomposition (Tonset) is observed around
180°-200°C for both solutions,
demonstrating that 2-MeTHF
solutions are safe even at much
higher concentration than THF
saturated solutions.
Dr Rainer Aul
Chemetall GmbH
Trakehner Strasse 3
D-60487 Frankfurt am Main
Germany
T+49 69 71 65 23 44
F+49 69 71 65 20 3
www.chemetall.com
Li organometallic uses
Lithium aluminum hydride (LiAlH4)
has good solubility in 2-MeTHF and
concentrations of 10% (2.2M) can be
easily obtained on an industrial scale.
Reduction of aldehydes, esters and
acids with LiAlH4 in 2-MeTHF showed
similar product yields as in THF with
the added benefit of simplified work-up
as described above6.
2-MeTHF is a good solvent for low
temperature lithiation reactions because
of its low melting point, low viscosity at
low temperature and similar Lewis base
strength as THF. Figure 3 shows an
illustrative example of lithium
exchange of n-butyllithium with 3-bromofuran at -70°C in 2-MeTHF, followed
by reaction with dimethylformamide to
give 3-furaldehyde6.
Methyl lithium is one of the most
versatile lithiation reagents commonly
sold commercially in diethylether 5%
(1.6 M) or diethoxyethane 8% (3 M)
solutions. Both solutions show excellent stability, however have significant
limitations due to high volatility/low
flash point and, in the case of
diethoxymethane, lack of chemical stability to strongly acidic conditions.
We have found that 2-MeTHF in
combination with cumene is an excellent substitute for the MeLi solution in
diethyl ether and diethoxymethane.
MeLi in 2-MeTHF/cumene 3% (1.2M)
solution displays similar reactivity
while providing an improved safety
profile during transportation, storage
and handling along with reduced costs
and ease of work-up.
conclusions
The introduction of 2-MeTHF and
related reagents can provide an excellent opportunity for cost cutting solutions through innovation. Migration of
technologies from THF to 2-MeTHF
will automatically render technologies
greener as the 3R dedesiderates –
reduce, recycle and reuse – are all met
by the introduction of 2-MeTHF.
Achieving cost-savings through
innovation and sustainable technologies are quintessential drivers for continued growth in the globalisation era.
This is why we believe that companies
seeking new competitive advantages
will continue to scrutinise carefully the
advantages of 2-MeTHF.
■
references
1 Penn Specialty Chemicals and Chemetall are industrial scale producers of MeTHF and MeTHF
based organolmetallic reagents and are developing this market through a joint global marketing
Dr Bogdan Comanita
Penn Specialty Chemicals, Inc.
14-145 North Centre Road
N5X 4C7 London, Ontario
Canada
T +519 850-3232
F +519 663-4446
www.pschem.com
manufacturing chemist May 2007
agreement
2 B. Comanita, Industrie Pharma Magazine, 22, October 2006
3 B. Comanita, Specialty Chemicals Magazine, October 2006
4 B. Comanita; D. Aycock, Industrie Pharma Magazine, No.17, 2005, 54-56
5 R. Bates, J. Org. Chem. (1972) 37(4), p560.
6 David. F. Aycock, Org. Process Research & Development 2007, 11, 156-159
7 P. Rittmeyer et al., Chemetall DE 19808570
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