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Special Solvents
for Synthesis
Special Solvents for Synthesis

Clariant´s Polyethylene glycol dialkyl ethers are among the most

powerful solvents available today for a wide range of applications
in pharmaceutical and chemical processes, be it synthesis of APIs
or extraction of naturally occurring actives from plants.
Polyethylene glycol dialkyl ethers are polar, aprotic solvents which are chemically inert and
exert high thermal stability.

They share the excellent solvation properties of other ethers, but Clariant´s Polyethylene glycol
dialkyl ethers combine these advantages with higher boiling and flash points, resulting in the
obvious benefits of a broader range of processes, higher yields, easier recycling as well as safer
and easier handling. The presence of lone pairs of electrons on the oxygen atoms enables the
Polyethylene glycol dialkyl ethers to act as Lewis bases. Consequently, solvation of cations is
common which leaves anions active, greatly enhancing reaction rates.

In the following, just two examples are given of how you might improve your reaction times
and yields as well as recycling and safety issues with some compounds from Clariant´s broad
portfolio of Special Solvents for synthetic applications.

Example 1: Diethylene glycol dibutyl ether for Grignard Reactions

Solvent selection plays a pivotal role in the preparation of Grignard reagents. Most frequently
used for these reactions are nucleophilic solvents such as Diethylether, THF and 2-MethylTHF;
some of them are cheap commodities, but they show several operational difficulties: All have
low boiling points as well as low flash points, limiting reaction temperatures and requiring
additional safety efforts. Furthermore, Diethyl ether and THF both mix well with water which
results in extra work-ups and waste water streams with high COD values.

Diethyl ether THF 2-MethylTHF Diethylene glycol

dibutyl ether

Melting Point -116 °C -108 °C -136 °C -60 °C

Boiling Point 35 °C 66 °C 80 °C 252 °C

Flash Point -40 °C -17 °C -11 °C 117 °C

Solubility in Water 65 g/L Completely 14g/L 2.8 g/L

@ 20 °C miscible

Azeotrope 34 °C 65 °C 71 °C –
Solvent/Water 98.7/1.3 wt% 95/5 wt% 89.4/10.6 wt%

Classification –

Table 1. Comparison of Solvents

Diethylene glycol dibutyl ether offers an attractive alternative to these conventional solvents:
Lower water solubility and the absence of an azeotrope of Diethylene glycol dibutyl ether with
water allows for easy processing and recycling of the solvent. Compared to THF and Diethyl
ether, the higher boiling point and better chemical stability over a wider temperature range
permits formation of Grignard reagents even from less reactive halides.

Another positive effect is the higher complexing ability of Diethylene glycol dibutyl ether. A
number of isolated crown ether complexes of Mg ions have been characterized by X-ray ana-
lysis, showing that Diethylene glycol dibutyl ether coordinates with at least two coordination
sites per molecule compared to only one for THF or diethyl ether.
Figure 1.
Suggested complex of Ph-Mg-Hal with Diethylene glycol dibutyl ether as tridentate coordinating solvent.

Thanks to this chelating effect, Grignard reagents prepared in Diethylene glycol dibutyl ether
show improved yields and stability, including storage stability. For example, in the preparation
of phenyl magnesium chloride the induction period is noticeably reduced and the reaction rate
is faster when Diethylene glycol dibutyl ether is used in place of THF. Subsequent reactions
with Grignard solutions in Diethylene glycol dibutyl ether usually result in shorter reaction
times and higher yields compared to THF, for example, as shown below.

Solvent Yield Reaction time

THF 78% 3h

Diethylene glycol 78% 1h

dibutyl ether
Figure 2. Preparation of 2-phenyl-2-butanol.

Replacing Diethyl ether with Diethylene glycol dibutyl ether results in safer procedures as well
as higher yields (see Figure 4).

Solvent Yield Reaction time

Diethyl ether 78% 3h

Diethylene glycol 94% 3h

dibutyl ether

Figure 3. Preparation of 1-phenyl-1-propanol

Investigations have shown that the kinetics of the Grignard reagent formation can be positively
influenced by small additions of Diethylene glycol dibutyl ether. Its use for the purification of
Grignard reagents from side compounds or for the preparation of pure dialkyl magnesium sub-
strates, free from RMgX, has also been published.
Example 2: Polyethylene glycol statt PEG DME 500, 1000 and 2000
as Phase Transfer Catalysts (PTC)
Like crown ethers, Clariant´s Polyethylene glycol dimethyl ethers are chemically and thermally
very stable compounds, but additionally less toxic. For PTC reactions the following solubilisa-
tion step is discussed in which Polyethylene glycol dimethyl ethers act as linear, “one size fits
all” crown-ethers which can adapt to the size of the cation. Additionally, Polyethylene glycol
dimethyl ethers have a decisive edge in price over crown-ethers

Figure 4. Proposed Solubilisation Step for Polyethylene glycol dimethyl ethers in PTC reactions.

In some cases, the catalytic activity of Polyethylene glycol dimethyl ethers is found to even
surpass previously known PTCs, e.g. in the base catalysed oxidation of fluorene to fluorenone:

Contration in (mol%)
100%
0% 73% 82% 80% 85% 86% 84%
90&

80%

70%

60%

50%
1. without Catalyst
40% 2. Tetraethylene glycol dimethyl ether
3. Polyethylene glycol DME 250
30%
4. Polyethylene glycol DME 500
20%
5. Polyethylene glycol DME 1000
10% 6. Polyethylene glycol DME 2000
7. 18-Crown-6
0%
1. 2. 3. 4. 5. 6. 7.

Figure 5. Yields of Base catalysed Oxidation using different PTCs

For more information on Clariant´s broad portfolio of Special Solvents for synthesis could
enhance your reactions please go to www.ics.clariant.com
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