Towards cleaner PolarClean: Efficient synthesis and extended applications of the polar aprotic solvent methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate

Article abstract of DOI:10.1039/c9gc01958h

As a result of recent efforts in green solvent selection, methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate, sold under the brand name Rhodiasolv PolarClean, has received considerable scientific and industrial attention as a possible non-toxic replacement

Full text of DOI:10.1039/c9gc01958h

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DOI: 10.1039/C9GC01958H
PAPER
Towards Cleaner PolarClean: Efficient Synthesis and Extended
Applications of the Polar Aprotic Solvent Methyl
5-(Dimethylamino)-2-methyl-5-oxopentanoate†
Received 00th January 20xx,
Accepted 00th January 20xx
Levente Cseri*a and Gyorgy Szekely*a,b
DOI: 10.1039/x0xx00000x
As a result of recent efforts in green solvent selection, methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate, sold under
the brand name Rhodiasolv PolarClean, has received considerable scientific and industrial attention as a possible non-toxic
replacement for common polar aprotic solvents. However, the multicomponent nature and multi-step synthesis of this
solvent remains an obstacle for its more widespread use and niche applications. In this work, a retrosynthetic approach
was taken to identify novel shorter synthetic routes in alignment with green chemistry principles. High purity methyl
5-(dimethylamino)-2-methyl-5-oxopentanoate was obtained in novel single-step reactions via two different base-catalysed
Michael additions from readily available building blocks. The more advanced synthetic route shows great potential owing
to the swift (30 min), solvent-free reaction and catalytic amounts of base (<6.5 mol%). Green metrics analysis, including
Atom Economy, Complete E factor, Carbon Intensity and hazard analysis found the new synthesis to be more sustainable
than the patented routes. The applicability of this green solvent in so far unexplored fields of chemistry, O- and N-arylation
in SNAr reaction with solvent recovery, was demonstrated with similar or superior yields compared to other green solvents.
Moreover, broad opportunities for this green solvent in membrane science were identified, where the use of conventional,
toxic polar aprotic solvents in large quantities is unavoidable. Important practical solvent properties and parameters such
as dielectric constant, solubility parameters, solvent miscibility and NMR residual shifts have been determined to facilitate
the uptake of methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate as a green solvent.
toxicity, decreased environmental impact and fewer safety
issues compared to their conventional counterparts.
Furthermore, they are often renewables-based and thus more
Introduction
The alarming environmental concerns of the past decade have
resulted in series of ambitious sustainability plans
attractive from a sustainability point of view. However, green
alternatives are not equally available for all solvent classes.
While the landscape of green alcohols or low-polarity esters is
highly populated, there are only a few examples of green
solvents with polar aprotic characteristics as shown in Fig. 1.
The latest GSK’s solvent sustainability guide features 154
solvents with 53 of them earning a green (recommended)
flag.3 However, none of the 14 assessed dipolar aprotic
solvents was ranked in this category.
a
established by international organisations and companies.1
These efforts have manifested themselves in stricter
regulatory environment and soaring research interest in
sustainable technologies and green chemistry. Solvents have
always been of central interest in green chemistry simply
because they account for the largest proportion of total mass
used in chemical manufacturing.1 To mitigate the
environmental, health and safety concerns associated with the
use of organic solvents, a series of green solvents have been
developed and reported in the literature. These green solvents
usually can be characterised by lower acute and chronic
Polar aprotic solvents are extremely useful for their
solvation characteristics and promotion of a variety of
chemical reactions. The need for green alternatives in this
solvent class has been repeatedly articulated due to the
reproductive toxicity of the conventional members, N,N-
dimethylformamide (DMF), N,N-dimethylacetamide (DMAc)
and N-methylpyrrolidone (NMP).4 The few promising green
alternatives for polar aprotic solvents include γ-valerolactone
(GVL),5 Cyrene,6 propylene carbonate (PC),7 N-butylpyrrolidone
a
School of Chemical Engineering and Analytical Science, University of Manchester,
The Mill, Sackville Street, Manchester, M1 3BB, United Kingdom, E-mail:
levente.cseri@manchester.ac.uk, gyorgy.szekely@manchester.ac.uk, Phone:
+441613062662
b
Advanced Membranes & Porous Materials Center, Physical Science Engineering
(NBP)8
and
methyl
5-(dimethylamino)-2-methyl-5-
Division (PSE), King Abdullah University of Science and Technology (KAUST),
Thuwal 23955-6900, Saudi Arabia, E-mail: gyorgy.szekely@kaust.edu.sa, Phone:
+966128082769
† Electronic Supplementary Information (ESI) available: materials and methods;
synthetic procedures; green analysis data; instrumental procedures; solvent
miscibility table, NMR, MS, FTIR spectra; GC and HPLC chromatograms. See DOI:
10.1039/x0xx00000x
oxopentanoate (1).9 While some of these solvents are only
available commercially on a gram scale, 1 is the main
component of the solvent PolarClean, which is produced at the
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Green Chemistry
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Green Chemistry
for polar aprotic solvents. In this work, new synthetic
View Article Online
DOI: 10.1039/C9GC01958H
strategies leading to the selective production of 1 were
developed. The syntheses were evaluated against the current
routes, using green metric analysis. The produced solvents
were explored for membrane science via polymer dissolution
and miscibility tests, and in nucleophilic aromatic substitution
(SNAr) as reaction medium, against other green polar aprotic
solvent candidates. Moreover, practically relevant physical and
spectroscopic analysis, as well as NMR chemical shifts in
different deuterated solvents, are reported to promote the
application of 1 even from the early stages of research and
development.
Results and Discussion
Synthesis
To identify new, potentially more efficient synthetic strategies
leading to 1, a retrosynthetic approach was taken (Table 1). In
the commercial synthesis (route A, Scheme 1) the carbon
backbone of 1 (2-methylglutarate) is constructed in a C4+C1+C1
manner. Alternatively, C4+C2 (route B, Scheme 1) or C3+C3
(route C, Scheme 1) strategies could be considered. Owing to
the C–H acidic character of the α position in carbonyl
derivatives, Michael addition can be an obvious choice for the
C–C bond formation in both approaches. In the early stage
development of this work, the C4+C2 strategy was favoured
Fig. 1 Landscape of solvent types among the 53 solvents marked with green
composite colour in GSK’s solvent sustainability guide3 with the structures of
new, potentially green polar aprotic solvents over the horizon: PolarClean (1),
Cyrene and N-butylpyrrolidone (NBP).
ton scale by Solvay. A toxicological study of 1 found low acute
toxicity (no observed adverse effect at 1000 mg kg-1 day-1 rat)
and no evidence of carcinogenity, genotoxicity or
mutagenicity.10 The eco-friendly nature and high solvency of 1
enabled applications of PolarClean in crop formulation,11
membrane technology12-15 and chemical synthesis.16-18
A significant effort is invested into the development of
greener synthetic routes for green solvents.19 There are
several major obstacles to overcome for producing a greener
PolarClean. First, this solvent is a yellowish, multicomponent
mixture. The patented production procedure of PolarClean
reports three synthetic routes (A1-3 in Scheme 1) leading to
1.20 All three routes start from 2-methylglutaronitrile –
produced by hydrocyanation of butadiene – which contains
around 14% dinitrile isomers. 2-Methylglutaronitrile
undergoes hydrolysis to produce 2-methylglutaric acid. In
routes A1 and A2, 2-methylglutaric acid is cyclised in the next
step to 2-methylglutaric anhydride. The esterification and
amidation of the two carbonyl groups in different orders
ultimately lead to 1 by these routes. The dinitrile isomers
present in the starting material react identically with the main
compound and are therefore present in the product.
Moreover, the ring opening of the cyclic anhydride can occur
in two positions resulting in the formation of methyl 5-
a)
Route A
(Commercial)
1) NaOH/H2O
100 °C
NC
CN
HOOC
COOH
2 HCN
2) H2SO4/H2O
20 eq.
65 °C MeOH
Amberlyst 36
O
Ac2
eq.
°C
2.2
140
O
O
O
O
O
20 eq.
MeOH
MeOOC
COOMe
HO
OMe
60 °C
3.3 eq. DMA
H2O
r.t. 2 eq. SOCl2
40 °C
1) 1.2 eq. DMA
5% NaOMe
MeOH
0-5 °C
O
O
O
O
2) H2SO4
Cl
OMe
N
OH
O
O
O
2 eq. DMA
2.4 eq. SOCl2
MeOH
-20 °C 1.25 eq. TEA
toluene
30 °C
O
N
O
O
O
O
Route A3
N
O
N
(dimethylamino)-4-methyl-5-oxopentanoate. Thus, the
1
Route A1
Route A2
1) 1.25 eq. LDA
PolarClean
content of the products from routes A1 and A2 are rather low,
around 37% and 69%, respectively. Route A3 leads to 1 from 2-
methylglutaric acid via subsequent diesterification and
amidation. For this route, the final isomeric composition is not
reported. Second, its synthesis cannot be considered efficient
from a green chemistry point of view. It consists of multiple
synthetic and purification steps and entails the generation of
considerable amounts of waste. Consequently, there is a need
for a selective and green synthesis of 1 to boost its
applications in the fine chemical industry as a green alternative
b)
c)
Route B
MeTHF
O
O
O
O
O
-78 °C
+
+
N
N
O
O
N
N
O
O
2) HCl/H2O
1B
1C
Route C
1) 5 mol% KOtBu
neat
O
O
O
0-5 °C
2) (COOH)2/H2O
Scheme 1 Synthetic strategies leading to methyl 5-dimethylamino-2-methyl-5-
oxopentanoate (1) reported in the literature (a) and in this work (b–c).
2 | Green Chem., 2019, xx, x-x
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Table 1 Retrosynthetic approach to identify different routes for the synthesis of 1. The
industrial production of the synthetic equivalent is detailed in the ESI†.
KOtBu has enhanced basicity, which allows the reversible
View Article Online
deprotonation of weak C–H acids.27 To emulate this polar
DOI: 10.1039/C9GC01958H
environment through the high concentration of DMAA and to
minimise waste, no solvent was used, in line with the 5th
principle of green chemistry.26 The Michael addition
proceeded rapidly in the presence of a catalytic amount of
KOtBu and thus the 9th principle of green chemistry has been
addressed.26 100% conversion was achieved in less than 2.5
minutes upon addition of the base at the laboratory scale.
During the swift exothermic reaction, a considerable amount
of heat was evolved which necessitated the cooling of the
reaction mixture. Nonetheless, 0–5 °C proved to be sufficient
in contrast with the extreme −78 °C for route B. The reaction
was quenched upon the addition of saturated aqueous oxalic
acid, a less corrosive alternative for HCl,28 and the pure 1C was
obtained by vacuum distillation.
Route
A
Synthons
Synthetic equivalents
O
C
O
C
N
C
N
C
O
N
CH
Cyanide H2C
ion
Cyanide
ion
C1
H2C
CH
C1
1,3-Butadiene
C4
O
O
O
O
O
H2C
H2C
CH3
N
CH2
O
N
B
C
Quality assessment
The purity and impurity profile of 1B and 1C was compared
with commercial PolarClean from two different batches
denoted with X and Y (Table 2). 1C is transparent, while the
commercial 1B, PolarCleanX and PolarCleanY have a yellow
colour. Solvents and impurities with colours are highly
undesirable in the pharmaceutical industry, where
discolouration of the product could result in failed batches,
even if the analytical purity meets the requirements.29 The UV-
Vis spectroscopy based ASTM D1209 Standard Test Method
was used to quantify the colour difference.30 Both batches,
PolarClean X and Y, showed a medium yellow colour with
values of 233±1 and 203±1 on the Pt-Co scale, respectively.
The colouration of 1B is stronger with a value higher than the
upper end point of the Pt-Co scale (>500). On the other hand,
1C is virtually transparent, as proved by its low Pt-Co colour
value (22±1).
Table 2 shows the quantitative analysis of the solvent
components performed by GC-MS. PolarCleanX and
PolarCleanY have similar impurity profiles and purities (85.7%
and 83.8%, respectively). For both solvents, the main impurity
is the regioisomer methyl 4-(dimethylamino)-2-ethyl-4-
oxobutanoate (2), while 2,N,N,N’,N’-pentamethylglutaramide
(3) and dimethyl 2-methylglutarate (4) are also present in low
quantities. The ratio of regioisomers was found to be around
9:1 (1:2) in both cases, which is close to the ratio of 2-
methylglutaronitrile and 2-ethylsuccinonitrile reported for the
starting material.31 The impurity profile and the absence of
C2
C4
DMAc
O
MMA
O
O
O
CH2
CH2
N
H2C
O
N
HC
O
C3
C3
DMAA
MeOProp
since both building blocks, methyl methacrylate (MMA) and
N,N-dimethylacetamide (DMAc) are inexpensive, readily
available, large volume chemicals. Although current industrial
production of both building blocks rely on fossil feedstock,
renewable-based strategies in the future will plausibly be
derived from bio-based itaconic acid and acetic acid.21,22
The Michael addition begins with the deprotonation of the
C–H acidic reagent, in this case DMAc. The pKa value of DMAc
is around 29.4;23 therefore a very strong base, such as lithium
diisopropylamide (LDA; pKa of conjugated acid: 35.724) is
required. Michael reactions of the Li-enolate form of DMAc
with other α,β-unsaturated carbonyl compounds have been
reported previously.25 In line with our expectations, the
reaction proceeded swiftly at −78 °C and served 1B after acidic
work-up and vacuum distillation. The synthesis provided 1 in a
single step as opposed to the 4–6 step commercial routes.
Consequently, the 8th principle of green chemistry has been
addressed.26 However, the stoichiometric amount of the
pyrophoric and highly reactive LDA poses a safety hazard,
while the −78 °C reaction temperature requires substantial
energy. Furthermore, the purification including the acidic
work-up and extraction generates both aqueous and organic
waste. These issues ultimately originate from the inherently
weak C–H acidic character of DMAc.
methyl
5-(dimethylamino)-4-methyl-5-oxopentanoate
regioisomer suggest that the commercially available
PolarClean is produced via the patented route A3. However,
significantly different purity and impurity profile was reported
earlier for commercial PolarClean.9 The impurities present in
that case indicate that those solvent batches were produced
through a different route (route A1 or A2), which consolidates
the demand for a more consistent synthetic procedure. The
GC-MS chromatogram shows higher purity of 1B at around
90%, while diphenylbutane isomers contribute the remaining
The C3+C3 strategy allows the utilisation of the higher C–H
acidity of esters (pKa: ~25). Similarly to DMAc and MMA, the
building blocks methyl propionate (MeOProp) and
dimethylacrylamide (DMAA) are also readily available and they
can potentially be obtained through renewable based
production.21,22 In route C, potassium tert-butoxide (KOtBu)
was used as a base. In polar solvents, such as DMSO or HMPA,
10%.
5 (1,4-diphenylbutane) and 6 (1,3-diphenylbutane)
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C9GC01958H
Table 2 Composition and impurity profile of commercial PolarCleanX and PolarCleanY and synthesized 1B and 1C solvents.
O
O
O
O
N
O
N
N
1
3
5
O
O
O
O
N
O
O
O
O
O
O
O
N
O
2
4
N
OH
N
O
6
7
8
GC-MS composition (%)
Sample
Yellow colourationa
1
2
3
4.3
5.0
trace
-
4
1.1
1.2
trace
-
5
6
-
7
8
-
PolarCleanX
PolarCleanY
Reference9
1B
85.7
83.8
95.1
90.1
>99
8.9
-
-
-
-
233±1
203±1
<10031
>500
10.0
-
-
-
-
-
-
-
4.6
-
-
8.9
-
1.0
-
-
1C
-
-
-
-
22±1
aPlatinum-Cobalt Color, Test Method D1209.30
originate from the lithium diisopropylamide solution, which the key process performance indicators having a complexity of
become enriched in the product as their boiling points are 1 and an ideality of 100% that confirms the simplicity and
close to that of 1. The presence of aromatic hydrocarbons can straightforward nature of the proposed synthetic
also explain the strong yellow colour developed by 1B. As a methodologies.
consequence of this impurity, 1B forms an oil-in-water-type
The Atom Economy (AE) values of the individual steps in
emulsion when diluted with water that can affect and limit its routes A1–3 cover a broad range, from 31% to 100%. The
range of applications. This impurity and discolouration can be overall AE in these cases falls within the range of 21–33%,
avoided by using lithium diisoproylamide from a styrene-free indicating that even if the use of exact stoichiometric
synthetic route. 1C has the highest purity (above 99%) among quantities of starting materials and a chemical yield of 100% is
the analysed solvents. Although the formation of by-product assumed, less than one third of the mass of starting materials
4,N,N,N',N'-pentamethyl-4-(methoxycarbonyl)pimelamide (8) is incorporated into the product. In contrast, the single step in
was observed due to the Michael addition of 1 to DMAA; its route B has a significantly higher AE of 57%, while the only
substantially higher boiling point enabled its complete step in route C has an ideal AE of 100%. However, the
retention during vacuum distillation. The GC-MS results synthetically less challenging steps in the patented routes
confirmed that
a solvent with higher purity than the result in good overall yields, ranging from 47% for A1 to 83%
commercial PolarClean can be obtained via the newly for A3, while the overall yields for route B and C are 27% and
proposed synthetic route, which could open new opportunities 48%, respectively.
for its exploitation in fine chemical production.
The AEs, the yields and the amount of auxiliary chemicals
(such as solvents and catalysts) and water used in the
synthesis all have an effect on the Complete E factor (cEF) of a
Green metrics analysis
Green metrics analysis was used to compare the patented process. The cEF values of the different routes are presented
synthetic procedures with those proposed in this work (Fig. 2). relative to route A1 in Fig. 2. Route A2 and A3 have about 9%
The key process performance indicators are the number of and 45% lower cEFs, i.e. waste generated per mass unit of
steps, complexity and ideality. All three previously reported PolarClean produced. On the other hand, route B has a higher
routes have a complexity of 3, meaning that there are three cEF owing to the large amount of solvent used in the
construction steps involved. However, the idealities are extraction step. The key reagent LDA was supplied as a
different, namely 60%, 75% and 100% for routes A1, A2 and solution, which also has an adverse effect on cEF. Route C in
A3, respectively. This indicates a gradual improvement among contrast represents a drop in cEF by almost 80% relative to
the patented routes by eliminating the concession steps. Both route A1, due to the solvent-free synthesis and catalytic
routes B and C in this work demonstrate an improvement in amount of base used.
4 | Green Chem., 2019, xx, x-x
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The breakdown of contributors to the CI of difVfeierweAnrtticrleoOuntlienes
DOI: 10.1039/C9GC01958H
is shown in Fig. 3. In all cases, the two main contributors are
the energy consumption associated with the heating and the
produced chemical waste, accounting for 71–83% of the
totalvalue. In all patented routes, the heat energy constitutes
more than half of the total CI. However, this contribution is
reduced to below 40 % for route B and C due to the fewer
synthetic and purification steps.
The health and safety risks associated with the chemicals
used in the different synthetic routes are summarised in Fig. 4.
Instead of focusing on the risks of one specific chemical or
another, the figure attempts to give an easily comprehensible,
intuitive overview of the chemical hazards through the
Globally Harmonized System of Classification and Labelling of
Chemicals (GHS) hazard pictograms. The area of the
pictograms shown in the figure is proportional to the amount
of chemicals (including reagents, catalysts, solvents, isolated
intermediates and product) used for the synthesis of unit mass
of product via that route. The patented routes exhibit more or
less similar chemical hazard profiles but in route A3 there are
no unknown chemical hazards originating from the isolated
intermediates. Route C demonstrates a clear improvement in
the amount and nature of hazardous chemicals. Significantly
less toxic (one third to one fifteenth in mass) and corrosive
chemicals are used compared to the patented routes, and the
need for hazardous chemicals is completely eliminated.
Although more chemicals are used in route B in total, none of
them are classified as toxic.
Fig. 2 Green metrics comparison of the synthetic routes leading to 1. The green
and orange reactors symbolise construction steps and concession steps,
respectively. The percentage values in the reactors show the Atom Economy (AE)
of that synthetic step. ΔCI and ΔcEF are the relative differences in the estimated
CI and the cEF compared to the longest reported route (CI=222.9 kg kg−1 and
cEF=25.8). ΣYield and ΣAE are the overall yield and cumulated AE, respectively.
Extr.: Extraction; Dist.: Distillation.
Although cEF is an important measure of the waste
generation associated with a chemical process, it does not take
into account other important process metrics such as the
energy consumption. To achieve an overall view of the
sustainability of the different synthetic routes, carbon intensity
(CI) was estimated for comparison. The obtained CI values
given in kg CO2 eq. per kg of product provide an estimation of
the CO2 emissions associated with the laboratory scale
synthesis. CI values are presented relative to route A1 in Fig. 2.
Similarly to cEF, routes A2 and A3 have lower CIs than A1 due
to the fewer synthetic and purification steps and the lower
waste generation. Route B has a CI around 35% lower than A1
despite the much higher cEF, which can be attributed to the
substantially lower energy consumption of the one-step
synthesis and single vacuum distillation. Meanwhile, the
Reaction optimisation
Among the investigated synthetic routes, route C proved to be
the most promising in terms of synthetic design, purity and
green metrics analysis. The main drawback is the generation of
considerable amounts of the double Michael adduct, 8, which
can be easily crystallised from the distillation residue of 1C
relative CI associated with route
C is around −87%,
representing an almost tenfold decrease in CO2 emissions
compared to the patented A1 route.
Fig. 3 Overall carbon intensities (CI) and their breakdown to the different
contributors for synthetic routes A–C leading to 1. The areas of the pie charts
correspond to the total CI.
Fig. 4 Chemical hazards associated with the different synthetic routes. The area
of a pictogram is proportional to the amount of corresponding chemicals used.
The question mark denotes chemicals with unknown hazards.
This journal is © The Royal Society of Chemistry 20xx
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O
O
O
O
with as high as >99% purity. Although using excess amounts of
MeOProp mitigates the by-product formation as it shown in
Table 3, it compromises the cEF and CI of the synthesis and
more base catalyst is needed to achieve 100% conversion of
DMAA. If the high-purity 8 by-product could also be utilised,
the overall economy of the proposed synthesis would
improve,and the cEF and CI would further decrease by 14%
(0.8) and 9% (4 kg kg−1), respectively. For instance, diamides
similar in structure to 8 have applications as diuretic agents.32
Nonetheless, we hypothesise that the formation of 8 could be
eliminated via the development of efficient and selective
Brønsted base catalysts. Strong, commercially available non-
ionic bases were explored for route C to replace KOtBu. The
catalyst candidates were chosen from the bases marked with
yellow or green composite flags in GSK’s base selection
guide.28 The P4-phosphazene base exhibited similar activity
and selectivity as KOtBu. However, there was no conversion
with weaker organic bases such as P1-phosphazene (BEMP),
methyltriazabicyclodecene (MTBD), tetramethylguanidine
(TMG) or diazabicycloundecene (DBU).
A slight variation of the MeOProp building block could
prevent the addition of a second DMAA molecule and
subsequently eliminate the formation of 8. Methyl isobutyrate
readily reacts with DMAA in the presence of a catalytic amount
of KOtBu in solvent-free conditions to provide 9, an analogue
of 1 containing an extra methyl group (Scheme 2). In light of
the facile production, 9 could be an attractive green solvent if
it proves to have similar non-toxic and non-harmful
characteristics to 1.
View Article Online
KOtBu
+
DOI: 10.1039/C9GC01958H
O
N
N
O
neat
30 min, 0-5 °C
9
(86%)
Scheme 2 Simple and efficient synthesis of methyl 5-(dimethylamino)-2,2-
dimethyl-5-oxopentanoate (9), a close structural analogue of 1.
aprotic solvents. SNAr reactions are widely used in different
fields of chemical synthesis including pharmaceuticals, fine
chemicals and polymer syntheses. To evaluate the
performance of 1 as a reaction media and to compare it with
other alternative green solvents, O-arylation with SNAr
mechanism was selected as
a test reaction (Table 4).
(4-Phenoxyaryl) aryl sulfones have importance due to their
applications in polymer science and also as antiviral agents,
advanced optical materials or microelectronic materials.
Yields as high as 92% and 91% were achieved for bis(4-
phenoxyphenyl) sulfone (10) in PolarCleanX and 1C,
respectively. The product crystallised from the reaction
mixture and it was isolated by filtration. No by-product of the
reaction mixture was observed by HPLC analysis. These results
emphasize the chemical stability of 1 and its good solvent
properties for SNAr reaction. Among other green solvents,
reaction in GVL provided the best performance with a high
yield of 86%. The reaction in Cyrene and PC resulted in a
complex mixture of compounds indicating the reactive nature
of these solvents under SNAr conditions (Fig. S61 and S63,
ESI†). The product could not be crystallised, it could only be
obtained in low yields after subsequent extraction and
preparative HPLC purification steps. The instability of Cyrene in
basic media,34 and the use of PC as an alkylating agent for
phenols have been reported.35
Extending the application of PolarClean
Nucleophilic aromatic substitution (SNAr) is among the
most commonly used chemical transformations in polar
Solvent recovery experiments were performed to study the
feasibility of recycling of 1C after the reaction. Vacuum
distillation proved to be a straightforward way to recover 1C
with high purity (>99%) from the aqueous mother liquor
Table 3 of the effect of base selection on the synthesis of 1 via route C.
O
O
O
O
base
Table 4 Screening green polar aprotic solvents for the SNAr reaction of phenol with
bis(4-fluorophenyl) sulfone.a
+
N
N
O
O
neat
30 min, 0-5 °C
1
Relative
amounts
of 1 : 8a
O
O
O O
OH
Base
[pKa]
Amount of
base (mol%)
nMeOProp
nDMAA
:
Isolated
yield of 1 (%)
Entry
S
S
K2CO3
+ 2
Solvent
160 °C, 6h
F
F
PhO
OPh
1
2
KOtBu [19.2]
KOtBu [19.2]
KOtBu [19.2]
KOtBu [19.2]
P4-phos.b [42.1]
P4-phos.b [42.1]
BEMP [27.6]
MTBD [25.4]
TMG [13.6]
2.5
3
1:1
2:1
5:1
10:1
1:1
2:1
2:1
2:1
2:1
2:1
17
32
48
62
14
22
0
30:70
46:54
65:35
78:22
25:75
35:65
-
10
Solvent
Dielectric
Constant
Isolated Yield HPLC
Entry
Solvent
3
5
(%)
Purity (%)
4
6.5
2.5
3
1
2
3
4
5
6
1C
28.3
29.9
91
92
86
11b
1b
98
95
5
PolarCleanX
GVL
6
36.5
92
7
3
Cyrene
37.3
99
8
10
10
10
0
-
PC
65.5
37
9
0
-
DMAc/toluene33
37.8/2.4
70
N/A
10
DBU [12.5]
0
-
aThe product crystallised upon the addition of water and it was collected by
filtration unless otherwise stated. bThe product was purified by extraction and
subsequent preparative HPLC.
aBased on the relative peak areas determined by HPLC. bP4-phosphazene.
6 | Green Chem., 2019, xx, x-x
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Green Chemistry
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Paper
Table 6 Solubility tests of various polymers in different green polar aprotic solvents
(Vwater:V1C = 10:3). For the less energy intensive extraction, the
aqueous mother liquor was washed with toluene to remove
apolar impurities including any residual product or substrate.
1C was retained in the aqueous phase due to its polar nature,
however its polarity was sufficiently low to be extracted with
EtOAc from the aqueous phase. 1C was obtained with high
purity (>99%) after drawing off EtOAc from the extract.
The dielectric constant of 1 has been experimentally
determined to be 28.3±3.5, which places it between acetone
(20.7) and DMF (36.7) of the polarity scale. The actual value
has shown a slight variation depending on the synthetic
method and thus the impurity profile, but no direct correlation
between the dielectric constants and the yield was found.
The same set of solvents have been tested for N-arylation
of benzimidazole with bis(4-fluorophenyl) sulfone (Table 5).
Similarly to the O-arylation, PolarCleanX, 1C and GVL provided
the product with good isolated yields ranging 77–87%, while
Cyrene and PC did not prove to be inert under the reaction
conditions. The test reaction results indicate good stability and
solvency of 1 even under the harsh conditions of SNAr reaction,
suggesting a broader range of applicability as a reaction media
compared to some other green polar aprotic solvent
candidates.
Polar aprotic solvents are essential for polymer synthesis
and polymer membrane fabrication.36 The results of the SNAr
reactions provide a good indication on the applicability of 1 in
polymer synthesis. To study the potential of 1 for membrane
fabrication, polymer solubility tests were performed and
compared with other aprotic green solvent candidates
(Table 6).
Both 1C and PolarCleanX exhibited similar solvency. In
agreement with previously reported membrane fabrication
procedures,13,14 polysulfone (PSf) and polyvinylidene fluorid
View Article Online
performed at 5 wt% polymer concentration and 50 °C. (+++: Dissolved; +: Partially
DOI: 10.1039/C9GC01958H
dissolved; ES: Extensively swollen; –: Not dissolved.)
Solvent
Polymer
1C
+
PolarcleanX GVL Cyrene
PC MeTHF ISDME
PBI
PSf
+
+++
+
–
+++
ES
+
–
+++
+++
+
–
–
–
+++
–
–
+++
+
+++
+
PI
ES
+++
–
PAN
PVDF
PLA
+
+
–
+
+++
–
+++
–
+++
+
–
–
–
+++
+
ES
–
+
+++
+++
–
PIM-1
PVA
+
+
+
+++
–
–
–
–
–
–
PIM-COOH +++
PDMBI-I
+++
–
+++
–
+++
–
+
+++
–
+++
–
–
–
(PVDF) were soluble in PolarCleanX as well as in 1C.
Polybenzimidazole (PBI), polyimide (PI), polyacrylnitrile
(PAN)and PIM-1 were dissolved only partially in these solvents.
Therefore, 1 is not applicable as a solvent for membrane
fabrication from these polymers, although it may find an
application as an activating solvent.38 Furthermorethe
hydrolysed form of PIM-1, PIM-COOH, exhibited good
solubility in both PolarCleanX and 1C alongside the majority of
tested green polar aprotic solvents. Polyvinylalcohol (PVA) and
the anion exchange polymer PDMBI-I (permethylated
derivative of PBI) were generally insoluble in all tested
solvents.
Table 5 Screening green polar aprotic solvents for the SNAr reaction of benzimidazole
with bis(4-fluorophenyl) sulfone.
Because solubility data is indispensable for solvent
selection, prediction tools are on the rise. Solubility
parameters have been established in the literature to predict
polymer solubility in various solvents; for instance the
Hildebrand Solubility Parameter (δ) relates the solvency
behaviour of a solvent to its heat of vaporisation. The δ value
for PolarClean was calculated to be 18.3 MPa0.5 (8.94 cal0.5
O
O
H
N
K2CO3
S
+
2
Solvent
N
F
F
140 °C, 4h
O
O
S
cm−1.5
Estimation of δ provided a value of 22.5 MPa0.5 (11.0 cal0.5
cm−1.5
for based on functional group-contribution
)
based on experimental vapour pressure data.9
N
N
11
N
N
)
1
a
method.39 The more commonly used Hansen solubility
parameters were estimated using a similar functional group-
contribution method.40 Values of 16.6, 13.4 and 9.5 were
obtained for the dispersion (δd), polar (δp) and hydrogen
Solvent
Dielectric
Constant
HPLC
Purity (%)
Entry
Solvent
Yield (%)
1
2
3
4
5
6
PolarCleanX
1C
29.9
28.3
77a
87a
75
83
bonding (δh) parameters. The miscibility of
1 with 33
traditional and green organic solvents plus water was tested
(summarised in Table S18, ESI†). 1B, 1C and PolarCleanX all
proved to be miscible with the vast majority of the tested
solvents with the highly apolar n-heptane, n-hexane and
cyclohexane being the exceptions. These miscibility data are of
high importance in solvent selection for multicomponent
reaction media, extraction, membrane phase inversion and
thin film composite membrane fabrication.
GVL
36.5
86a
93
Cyrene
PC
37.3
~51b
~36b
97a
N/A
N/A
N/A
65.5
DMAc/toluene37
37.8/2.4
aIsolated yield. bDetermined from the reaction mixture by HPLC analysis.
This journal is © The Royal Society of Chemistry 20xx
Green Chem., 2019, xx, x-x | 7
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Paper
Green Chemistry
Table 7 Stability test of commercially available and in-house prepared membranes in
different green solvents at 25 °C. The symbol  indicates solvent resistance while 
indicates the disintegration of the membrane.
Table 9 13C NMR chemical shifts of 1 in different NMR solvents
View Article Online
DOI: 10.1039/C9GC01958H
H
H
H
H
O
C3
O
C7
H
H
H
H
C1
C5
H
C9
C4
C6
C8
H
Solvent
H
N
C2
H
O
Membrane
1C


PolarcleanX GVL Cyrene PC MeTHF ISDME
H
H
H
H
H
GMT-oNF-1
NF030705
Nadir NP010
Duramem 900
PBIa






















13C Chemical shift (ppm)
C4 C5 C6 C7
Solvent
CDCl3
C1-2
C3
C8
C9

37.3 172.4 39.1 29.1 31.0 177.0 17.5 51.8










35.6
CD3CN
CD3OD
(CD3)2SO
C4D8O
C7D8
37.3 172.7 39.5 29.8 31.2 177.5 17.5 52.0
35.3
37.7 174.9 40.1 30.1 31.7 178.3 17.6 52.1
35.8
36.6 171.3 38.0 28.6 29.9 176.1 16.9 51.4
34.8
36.9 171.7 39.6 29.9 31.2 176.7 17.7 51.4
35.1
aIn-house prepared membrane. Refer to the ESI† for the protocol.
Table 7 shows the resistance of commercially available
organic solvent nanofiltration (OSN) membranes in 1 and other
green solvents. The results have correlation with the polymer
solubility tests shown in Table 6. Membranes made of
polymers, which were insoluble in a particular solvent, were
expected to show good stability in it and vice versa. The in-
house prepared PBI membrane was unstable in 1 but showed
good resistance to the other tested solvents. The good solvent
properties of 1 caused disintegration of NF030705 and Nadir
NP010 in 1, which were stable in some other green solvents.
On the contrary, both GMT-oNF-1 and Duramem 900 showed
good stability in 1, allowing them to be used for OSN.
36.0 170.9 39.0 29.3 30.7 176.2 17.5 50.9
34.7
C6D6
36.1 171.1 39.1 29.4 30.8 176.4 17.6 51.1
34.9
D2O
37.4 175.3 38.8 28.4 30.4 179.0 16.2 52.2
35.4
(CD3)2CO
TFA
37.0 172.1 39.4 ~29.8a 31.1 176.9 17.5 51.6
35.1
b
b
b
–
–
41.4 29.7 30.7
–
17.6 55.3
Table 8 1H NMR chemical shifts of 1 in different NMR solvents.
aOverlapping with solvent signal; bCannot be detected under the applied
experimental conditions.
H1
H6
H9
O
O
H1
H1
H5 H7
H9
H9
Many relatively new green solvents are side-lined in
laboratories due to the lack of experimental data and practical
experience working with them. Trace NMR peaks – commonly
from solvents – can be tricky to identify although their
assignation is essential for reliable data interpretation.
Residual NMR peak compilations are available for common
solvents41,42 and a recent extension for green solvents has
been specifically aimed to advance green chemistry
initiatives.43 The trace residual NMR shifts of 1 have been
identified in 10 different NMR solvents to provide a reference
for chemists (Tables 8 and 9).
N
O
H4
H3
H2 H2 H8 H8
H2
H8
1H Chemical shift (ppm)
H5-6 H7
CDCl3 2.99 (s) 2.40–2.25 (m) 2.00–1.90 (m) 2.54 (h) 1.19 (d) 3.68 (s)
Solvent
H1-2
H3-4
H8
H9
2.94 (s)
CD3CN 2.94 (s)
2.83 (s)
CD3OD 3.05 (s)
2.92 (s)
(CD3)2SO 2.93 (s)
2.79 (s)
C4D8O 2.94 (s)
2.83 (s)
1.87–1.78 (m)
1.83 (dq) 2.49 (dp) 1.12 (d) 3.62 (s)
1.66 (dq)
1.90 (dq) 2.53 (h) 1.17 (d) 3.67 (s)
1.73 (dq)
1.76 (dq)
1.58 (dq)
1.85 (dq)
~1.70a
2.28 (t)
2.39 (t)
2.26 (t)
2.27 (t)
~2.47a 1.08 (d) 3.59 (s)
Conclusion
~2.50b 1.12 (d) ~3.59*
Two different one-step syntheses of methyl 5-
(dimethylamino)-2-methyl-5-oxopentanoate (1) – the main
component of the green solvent, PolarClean – have been
C7D8
C6D6
D2O
2.61 (s) 1.94–2.03 (m) 2.01–1.92 (m) 2.48 (h) 1.07 (d) 3.34 (s)
2.22 (s)
2.62 (s)
2.15 (s)
3.04 (s)
2.89 (s)
1.90–1.78 (m)
2.12–2.03 (m) 2.53 (h) 1.08 (d) 3.33 (s)
1.96–1.86 (m)
1.86 (dq) 2.56 (h) 1.14 (d) 3.68 (s)
1.72 (dq)
developed via Michael additions using
a retrosynthetic
2.01 (t)
2.40 (t)
2.31 (t)
approach. The most advanced, solvent-free synthetic route
was optimised in terms of reagent excess and base catalyst
selection. An excess of methyl propionate was shown to have a
positive effect on the selectivity and yield. KOtBu and organic,
non-ionic phosphazene bases were found to be effective
catalysts (<6.5 mol%). The produced solvents had excellent
purities up to 99% and colourations down to 23 Pt-Co colour
units in contrast to the respective values of 83–85% and
(CD3)2CO 2.99 (s)
2.83 (s)
1.86 (dq) 2.51 (h) 1.12 (d) 3.62 (s)
1.69 (dq)
TFA 3.27 (brs) 2.76 (br)
3.19 (brs)
1.88 (br) 2.64 (br) 1.17 (br) 3.73 (brs)
aOverlapping with solvent signal; bOverlapping with water signal.
8 | Green Chem., 2019, xx, x-x
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6
7
J. E. Camp, ChemSusChem, 2018, 11, 3048–3055.
View Article Online
203–233 for commercial PolarClean. Green metrics analysis of
the synthetic routes revealed that the novel synthesis could
cut the Complete E factor and Carbon Intensity associated with
the production of 1 by 59–78% and 76–87%, respectively,
compared to patented procedures. The efficient synthetic
design of the novel routes was also supported by their high
Atom Economies of 57% and 100% in contrast to the 22–33%
for the patented routes. The sustainability of the proposed
synthesis was also demonstrated by the use of low-hazard
chemicals employing a new, intuitive approach to quantify
process health and safety.
J. S. Bello Forero, J. A. Hernández Muñoz, J. Jones Junior and
F. M. da Silva, Curr. Org. Synth., 2016,D1O3,I:8103.410–3894/6C.9GC01958H
J. Sherwood, H. L. Parker, K. Moonen, T. J. Farmer and A. J.
Hunt, Green Chem., 2016, 18, 3990–3996.
A. Randová, L. Bartovská, P. Morávek, P. Matějka, M.
Novotná, S. Matějková, E. Drioli, A. Figoli, M. Lanč, K. Friess,
J. Mol. Liq., 2016, 224, 1163–1171.
8
9
10 US Environmental Protection Agency, Methyl 5-
(dimethylamino)-2-methyl-5-oxopentanoate; Exemption from
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11 T. Vidal, V. Bramati, K. Murthy and B. Abribat, J. ASTM Int.,
2011, 8, 1–8.
1 as a reaction media was successfully applied for O- and
N-arylations with SNAr mechanism for the first time to replace
traditional polar aprotic solvents. 1 showed good stability
under the harsh reaction conditions, and resulted in good
yields of 77–91%, which are similar or better than green polar
aprotic solvent candidates. 1 was recovered from the post-
reaction mixtures in excellent purities (>99%) both with
vacuum distillation and extraction. NMR chemical shifts in
trace amounts were recorded in 10 different common NMR
solvents. Applications of 1 in polymer and membrane science
have been proposed. Solubility tests of 8 polymers and 4
commercial membranes revealed that 1 is i) an excellent
solvent for processing 3 of the polymers, and ii) suitable as a
filtration media using two of the membranes. Hildebrand and
Hansen solubility parameters were calculated. In conclusion,
the novel green and straightforward synthesis, the new
exemplary applications and the practical experimental
characterisation of 1 presented in this work can pave the way
for a replacement for common toxic polar aprotic solvents.
12 N. T. Hassankiadeh, Z. Cui, J. H. Kim, D. W. Shin, S. Y. Lee, A.
Sanguineti, V. Arcella, Y. M. Lee and E. Drioli, J. Membr. Sci.,
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgement
The authors are thankful to Ms Hai Anh Le Phuong and Mr Fan
Fei (both from The University of Manchester) for their
assistance with UV-Vis spectroscopy and capacitance
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10 | Green Chem., 2019, xx, x-x
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DOI: 10.1039/C9GC01958H
Table of Contents Entry
Greener syntheses routes, physical-chemical properties, green metrics performance and applications
for the eco-friendly polar aprotic solvent, methyl 5-dimethylamino-2-methyl-5-oxopentanoate
(PolarClean).