D3.6 - Application of NMP Replacement Solvents

Ref.
Ares(2020)2610246 - 18/05/2020
Project number: 745450

Project acronym: ReSolve
Project Title: Renewable solvents with high performance in application and improved
toxicity profile
D3.6 - Application of NMP replacement

solvents
Due date of deliverable: 31 May 2020
Actual submission date: 18 May 2020
Lead beneficiary
Name of organisation: University of York
Responsible Author
Thomas Farmer Email: thomas.farmer@york.ac.uk
Additional Author(s)
Linda Gootjes Wageningen Food & Biobased Research
Marinella van Leeuwen Wageningen Food & Biobased Research
Daan van Es Wageningen Food & Biobased Research
Fergal Byrne University of York
James Sherwood University of York
Type Dissemination Level

R Document, report ☒ PU Public ☒
DEM Demonstrator, pilot, prototype ☐ CO Confidential, only for members of ☐
the consortium (including the
DEC Websites, patent fillings, ☐
Commission Services)
videos, etc.
OTHER ☐
This project has received funding from the Bio Based Industries Joint Undertaking under the European
Union’s Horizon2020 research and innovation programme under agreement No 745450.
The sole responsibility for the content of this publication lies with the authors. It does not necessarily
reflect the opinion of Bio Based Industries Joint Undertaking. The Bio Based Industries Joint
Undertaking is not responsible for any use that may be made of the information contained therein.
D3.6 Application of NMP replacement solvents
Contents
Contents ............................................................................................................................... 2
1 Executive summary........................................................................................................ 4
2 Introduction .................................................................................................................... 5
3 Paint stripping ................................................................................................................ 7
Context .............................................................................................................................. 7
Experimental ..................................................................................................................... 7
Results .............................................................................................................................. 9
Initial solvent set: ........................................................................................................... 9
Expanded solvent set: .................................................................................................. 11
Summary: .................................................................................................................... 17
4 DMPA solubility ............................................................................................................ 18
Context ............................................................................................................................ 18
Experimental ................................................................................................................... 18
Results ............................................................................................................................ 18
5 Polymer solubility screening ......................................................................................... 21
Context ............................................................................................................................ 21
Experimental ................................................................................................................... 22
Dissolution testing protocol (PVC1-7, PS, PET): .......................................................... 23
PVC welding: ............................................................................................................... 24
Results ............................................................................................................................ 24
PVC: ............................................................................................................................ 24
PS/PET/Elastane: ........................................................................................................ 27
Summary: .................................................................................................................... 28
6 Polymer solutions for membrane fabrication ................................................................ 29
Context ............................................................................................................................ 29
Experimental ................................................................................................................... 29
Solubility test: ............................................................................................................... 29
Membrane fabrication: ................................................................................................. 29
Results ............................................................................................................................ 29
Solutions: ..................................................................................................................... 29
Membrane fabrication: ................................................................................................. 30
7 Bioactives solubility ...................................................................................................... 32
Context ............................................................................................................................ 32
Experimental ................................................................................................................... 32
Results ............................................................................................................................ 33
Solutions: ..................................................................................................................... 33
Emulsion: ..................................................................................................................... 34
8 Graphene dispersion .................................................................................................... 36
Context ............................................................................................................................ 36
www.resolve-bbi.eu page 2 from 67

Experimental ................................................................................................................... 36
Results ............................................................................................................................ 36
9 Hydrocarbon extraction ................................................................................................ 39
Context ............................................................................................................................ 39
Experimental ................................................................................................................... 39
Results ............................................................................................................................ 42
10 Menschutkin reaction................................................................................................ 46
Context ............................................................................................................................ 46
Experimental ................................................................................................................... 46
Reaction between 1-bromodecane with 1,2-dimethylimidazole: ................................... 46
Reaction between 1-bromooctane and 1-methylimidazole: .......................................... 46
Results ............................................................................................................................ 46
Levoglucosenone derived solvents: ............................................................................. 46
Additional solvents: ...................................................................................................... 47
11 Nucleophilic fluorination............................................................................................ 50
Context ............................................................................................................................ 50
Experimental ................................................................................................................... 50
Results ............................................................................................................................ 50
12 Suzuki reaction ......................................................................................................... 52
Context ............................................................................................................................ 52
Experimental ................................................................................................................... 52
Results ............................................................................................................................ 53
13 Heck reaction ........................................................................................................... 56
Context ............................................................................................................................ 56
Experimental ................................................................................................................... 56
Results ............................................................................................................................ 56
14 C-H bond activation .................................................................................................. 58
Context ............................................................................................................................ 58
Experimental ................................................................................................................... 58
Results ............................................................................................................................ 58
15 Heterocycle synthesis............................................................................................... 60
Context ............................................................................................................................ 60
Experimental ................................................................................................................... 61
Results ............................................................................................................................ 61
16 Conclusions .............................................................................................................. 62
17 Acknowledgements .................................................................................................. 64
18 References ............................................................................................................... 65

1 Executive summary
This report documents attempts to substitute the solvent N-methyl pyrrolidone (NMP) with bio-
based alternatives. In order to avoid the hazards of NMP, the alternative solvents have been
designed with different chemical functionalities. Case studies have been taken from synthetic
chemistry and the formulation sciences. Examples of paint removal, the solubility of monomers
and bioactive molecules, extraction of hydrocarbons, dispersion of materials, catalysis and the
chemistry of nucleophiles are reported here. It was found that there is not one bio-based
solvent that satisfactorily matches the performance of NMP across all case studies. Rather,
solvent substitution must be addressed individually for each application. The differences in
solubility, viscosity, stability, and other properties between NMP and its potential replacements
has sometimes impaired performance, but has also maintained or exceeded performance in
other case studies. Generally, the solubility of small polar molecules was poor in the alternative
solvents. However, polymers and materials have successfully been dispersed. NMP can be
eliminated from synthetic chemistry if precautions are made to prevent the reactivity of novel
solvents interfering with the desired reactions.

2 Introduction
N-Methyl pyrrolidone (NMP) is a dipolar aprotic lactam solvent. It has desirable physical
properties but is also reprotoxic. NMP is banned from consumer products in the European
Union under the terms of the REACH regulation (EC) No 1907/2006. Additionally, a restriction
on the use of NMP has been implemented as of 9th May 2020 for industrial and other
professional uses (delayed until 2024 for uses in the production of wire coatings) (Sherwood
et al., 2018). For this reason, alternative, high performance solvents are being sought across
a variety of manufacturing sectors. Typical uses of NMP are the dispersion of polyvinyl
difluoride (PVDF) for use in battery electrodes, fabrication of polyamideimide (PAI) wire
enamels, the synthesis of fine chemicals and polymers, extractions, paint removal products,
and for dispersing graphene and other nanomaterials.
This report documents attempts to use bio-based solvents in place of NMP in representative
applications. Bio-based solvents are made by processing biomass, either by physical methods
(e.g. extraction), biological methods (e.g. fermentation), or chemical transformation (Clark et
al., 2015). Prominent examples include limonene from orange oil, bio-ethanol, and 2-
methyltetrahydrofuran (2-MeTHF). None of these solvents have similar properties to NMP. In
order to find suitable alternatives to NMP that can be made sustainably from biomass, the
ReSolve project has undertaken an extensive programme of property modelling, solvent
synthesis, application testing, toxicology, life cycle assessment and techno-economic
evaluation. Application testing for solvents selected as NMP replacements are reported here.
The leading bio-based NMP substitute is dihydrolevoglucosenone (brand name Cyrene™).

Cyrene™ has been designated with the code LG1 for the purposes of this project. All the
solvents appearing in this report are listed in Table 2-1. The names of some candidates are
not disclosed publicly. Only application performance is described here. Additional testing has
suggested some of the solvents appearing in this work are unsuitable for commercial uses
(e.g. because they are hazardous or are made by an unproductive synthesis). This information
is reported elsewhere (see https://cordis.europa.eu/project/id/745450/results for publicly
available deliverables and open-access publications).
Table 2-1. Solvents appearing in this report.
Code Name Renewable source
LG1 6,8-Dioxabicyclo[3.2.1]octan-4-one Levoglucosenone

(dihydrolevoglucosenone)
LG2 spiro[6,8‐Dioxabicyclo[3.2.1]octane‐4,2′‐[1,3]dioxolane] Levoglucosenone
LG6 Confidential - Disclosed in D2.7 Levoglucosenone
LG13 6,8-Dioxabicyclo[3.2.1]octan-2-methoxy-4-one Levoglucosenone
LG23 4-Methoxy-6,8-dioxabicyclo[3.2.1]octane Levoglucosenone
LG59 1,6-Anhydro-3,4-dideoxy-hexopyranose Levoglucosenone
LG60 1,6-Anhydro-3-deoxy-4-O-methyl-hexopyranose Levoglucosenone
LG64 Confidential - Disclosed in D2.7 Levoglucosenone

LV1 γ-Valerolactone Levulinic acid
LV3 Methyl levulinate Levulinic acid
LV5 Ethyl levulinate Levulinic acid
LV34 Butyl levulinate Levulinic acid
IS2 Dimethyl isomannide Isohexides
IS3 Dimethyl isosorbide Isohexides
IS92 Confidential - Disclosed in D2.1 Isohexides
IT13 Dimethyl itaconate Itaconic acid
OT3 N-Butyl pyrrolidinone Succinic acid
OT4 1,4-Dimethyl-7-oxabicyclo[2.2.1]heptane Succinic acid
OT5 N,N'-Dibutyl-N,N'-diethylsuccinamide Succinic acid
OT6 N,N,N',N'-Tetrabutylsuccinamide Succinic acid
OT7 N,N'-Dibutyl-N,N'-dimethylsuccinamide Succinic acid
OT16 Confidential - Disclosed in D2.4 Hydroxymethylfurfural
IDL Confidential - Disclosed in D2.4 Confidential
AK1 2,2,5,5-Tetramethyloxolane Alkenes
AK2 Confidential - Disclosed in D2.4 Alkenes
Thirteen applications are presented here relating to polymer (and polymer precursor)
solubility, chemical synthesis, formulation and extraction. Procedures have been performed
using NMP, and then replicated for applicable solvents without otherwise changing the
conditions (unless noted). Other traditional solvents have also been used when necessary to
understand the exact role of the solvent.

3 Paint stripping
Context
A major application of NMP is in paint stripper formulations, predominantly in the United
States, where it was hailed as a safer replacement for dichloromethane (C&EN, 2018). The
principle of solvent based paint strippers is penetration of the paint film by the active ingredient,
causing the paint to swell. This causes internal strains, which leads to a weakening of the
adhesion of the paint to the surface. At the start of this task, various methods were evaluated
to quantitatively asses the ability of solvents to aid in the removal of (layers of) paint. Although
various standardised methods exist for determining drying aspects of paint (some of these
techniques are used at ReSolve partner WFBR), this is far less the case for the reverse
process, i.e. paint removal/stripping.
Earlier attempts were based on the application of a thin layer of paint on a glass substrate
which was allowed to dry, followed by application of 5 μl of solvent and observation of the
effects. An example is given in Figure 3-1.
Figure 3-1. Early attempt to quantify paint stripper efficacy of solvents (left to right): toluene, THF,
DMAc, NMP, DMF.
Although this method appeared favourable at first, closer inspection showed that this method
suffers from poor reproducibility and depends on various experimental conditions, such as
solvent evaporation rate and degree of hardening/curing of the coating, etc. Based on the
variability of the results it was decided to discontinue this approach.
Another method that was considered was the so-called double rub test (ASTM, 2019). Usually
these tests are performed using a standard solvent (such as acetone) in order to test the
quality of a coating. The amount of double rubs (i.e. back and forth) until a coating is visually
removed from a test surface is counted. This test was also considered too qualitative and
person dependent to be of general use for this task.
Discussions with experts from Akzo-Nobel Coatings led to the conclusion that there are no
quantitative industry standards for paint stripping, and that qualitative methods are widely
used. Hence it was decided to continue with a more qualitative method, using old mulitlayer
coated wood substrates, and a LyondellBasell, NMP-based, paint stripper formulation protocol
(LyondellBasell, 2011).
Experimental
Substrates: 2 pieces of old wood panelling with several layers of paint;
• Substrate 1: a white/green piece of wood panelling with at least 3 layers of paint and at
least 20 years old (Figure 3-2).

Figure 3-2. Substrate 1 example.
• Substrate 2: a brown piece of wood panelling with at least 2 layers of paint and at least 20
years old (Figure 3-3).
Figure 3-3. Substrate 2 example.
The substrates were degreased (acetone and water) before applying test solvents. Solvents
were applied as part of a formulation according to a LyondellBasell NMP formulation protocol
(LyondellBasell, 2011), and as straight solvent.
• LyondellBasell protocol: 2.0 g solvent, 2.85 g propylene glycol methyl ether acetate (PMA),
0.1 g Triton X100 (surfactant), 0.05 g Klucel-H (thickener).
• Solvent application: 50 µl as neat solvent or as paint stripper formulation was applied on

the substrate.
• Project solvents tested: IS3, IS92, LV1, LV3, LV34, OT3, OT16, OT31, OT32, AK1, LG1,
LG64.
• Reference solvents tested: propylene glycol methyl ether acetate (PMA), Alabastine Super
Afbijt (ALA, commercial paint stripper formulation from Akzo-Nobel containing calcium
Sulphate (50-75%), n-butyl acetate (10-25%), DMSO (10-25%), and cyclohexanone (2.5-
10%), NMP, triglyme, triethylene glycol diacetate.
Observations were made after 5, 30, and 60 minutes after application. After 1 hour, the solvent
and detached paint were removed by wiping it off with paper towel.
Substrate 2 was probably painted with a different type of paint than substrate 1. The solvents
(neat or as mixture) flowed on the surface of the paint of substrate 2. On substrate 1 the
solvents remained on the surface as droplets.

Results
Initial solvent set:

For the first test series, substrate 1 was used. Figure 3-4 shows the appearance of the
substrate approx. 5 min after application of a range of solvent formulations, including the
reference solvents NMP and PMA, as well as the commercial paint stripper product AlaSA.
Project solvents in this test series were LG1 (Cyrene™), IS3 (DMI), AK1 (TMO), OT16 and
IS92. Already after 5 min it can be seen that AlaSA and NMP induce blistering of the top paint
layer. Note TDM is the precursor to OT16, which was expected to be inert during this test.
Figure 3-4. Substrate 1 approx. 5 min. after application of formulation.
In Figure 3-5 the effect of the formulations on substrate 1 after 60 min can be seen. Note that
LG1, TDM, and IS92 remain as droplets on the surface. AK1 has evaporated. AlaSA, NMP,
PMA, IS3 and OT16 have caused severe blistering of the paint. After removal of the paint
stripper formulation (manually wiping off with a cloth) various effects results can be observed
(Figure 3-6).
Figure 3-5. Substrate 1 approx. 60 min. after application of formulation.

Figure 3-6. Substrate 1 after manually wiping off of formulation.
The commercial paint stripper product AlaSA removed multiple layers of paint as bare wood
can be seen. The same result is obtained with NMP, which was capable of removing all layers
of paint. PMA and IS3 (DMI) application resulted in the removal of the top layer, exposing the
underlying green layer. The application of LG1 (Cyrene™), AK1 (TMO), and IS92 had no
effect. Where AK1 had already evaporated after less than 1 hour, IS92 was still present as a
droplet. Surprisingly, TDM had some effect. Most effective thus far was OT16, which was
capable of removing multiple layers, almost comparable to AlaSA.
In test series 1, the solvents were also applied neat, in order to investigate the effect of the
formulation components on the performance. As can be seen from Figure 3-7, again blistering
is observed for NMP, PMA and OT16 only. Interestingly, in the case of neat solvent application
IS3 (DMI) and TDM no longer had any effect. The effect observed earlier in the formulation
can be attributed to the PMA (here also capable of removing the top layer, Figure 3-8). Since
in the formulation series the LG1, AK1 and IS92 formulations contained PMA, yet had no
effect on the paint, it can be concluded that in the case of IS3 and TDM some form of
synergism with the PMA occurs.

Figure 3-7. Substrate 1 approx. 60 min. after application of neat solvents.
Figure 3-8. Substrate 1 after manually wiping off of neat solvents.
Expanded solvent set:

For the second test series substrate 2 was exposed to the formulation and neat solvents.
Substrate 2 was probably painted with a different type of paint than substrate 1 (Figure 3-9).
The solvents (both as part of the formulation, and applied neat) flowed on the surface of the
paint on substrate 2. In comparison, all applied solvents remained as distinct droplets on the
surface of substrate 1. Note: since the colours of the different paint layers of substrate 2 differ
less than those of substrate 1, the paint stripping effects are less obvious than observed for
substrate one.

Figure 3-9. Substrate 2 (left half) before application.
From Figure 3-10 and Figure 3-11 it can be seen that 60 min after application on substrate 2
only the commercial AlaSA product and the formulations containing NMP and OT3 (NBP)
results in blistering of the paint. In contrast to substrate 1, neat PMA has no effect, which could
explain the lack of effect observed for all other solvents (except NMP and OT3), since in the
formulation PMA is present in approx. 60%, hence diluting the solvent under investigation.
This effect is clearly visible in the case of LV1 (GVL) and OT16. Both solvents only show
blistering effects when applied neat. This suggests that LV1 and OT16 are still less effective
than NMP/NBP, which is supported by the observation that NMP already shows blistering 2-5
min after application, OT3 (NBP) 10-15 min, while OT16 and LV1 require up to 60 min (results
not shown here).
Figure 3-10. Substrate 2 (left half) 60 min after application of neat solvents (top) and formulation
(bottom).

Figure 3-11. Substrate 2 (right half) 60 min after application of neat solvents (top) and formulation
(bottom).
Although less clearly visible than in the case of substrate 1, after wiping off the neat
solvents/formulation after 1 hour, it is clear from Figure 3-12 that out of all ReSolve solvents
tested here only OT16 is effective in removing the top layer of paint. Note: PMA is not effective,
nor LG1 (Cyrene™), IS3 (DMI), LV3 (labelled ML), LV34 (BL), OT31, OT32, AK1 (TMO),
LG64 (labelled YorkA), triglyme or triethylene glycol diacetate. These results were reproduced
for the neat solvents (third test series, not shown here). Given that even in the case of the
commercial paint stripper product (AlaSA) no bare wood is visible, it can be concluded that
substrate 2 is a far more challenging substrate than substrate 1.
Figure 3-12. Substrate 2 (right half) after wiping off neat solvents (top) and formulation (bottom).
In the fourth test series substrate 1 was reused, this time in combination with the solvent series
tested on substrate 2 (Figure 3-13 and Figure 3-14).

Figure 3-13. Substrate 1 (right half) before application.
Figure 3-14. Substrate 1 (left half) before application.
Again, in the case of NMP and the AlaAS commercial product, blistering started in 5-7 min
after application, OT3 followed after 15 min (not shown here). After 30 min the LV1 (GVL)
formulation showed blistering while the same was observed for the neat triglyme (TEG-Me)
as can be seen in Figure 3-15 and Figure 3-16.

Figure 3-15. Substrate 1 (right half) 30 min. after application.
Figure 3-16. Substrate 1 (left half) 30 min. after application.
After 90 min., LV3 (ML), LV1, OT16 and triglyme (TEG-ME) also showed blistering, both when
applied neat and in the formulation (see Figure 3-17 and Figure 3-18). LG1 (Cyrene™), IS3
(DMI), LV34 (BL), OT31, OT32, LG64 (York A) and TEG-Ac still remain as distinct droplets on
the surface of substrate 1. AK1 (TMO) and PMA appear to have evaporated. PMA is known
to be volatile, e.g. from its application in the semiconductor industry.
Figure 3-17. Substrate 1 (left half) 90 min. after application.

Figure 3-18. Substrate 1 (right half) 90 min. after application.
After wiping off the solvents and formulations (after 90 min. exposure) several effects can be
observed. Both NMP and OT3 (NBP) are again very effective, resulting in the removal of all
layers of paint in the formulation, showing bare wood (Figure 3-19). Note that this result
exceeds that of the AlaSA commercial product (Figure 3-20). LV3 (ML), LV1 (GVL) and OT16
resulted in removal of the top layer of paint, exposing the green under layer (Figure 3-19). A
similar effect is observed for triglyme (TEG-Me, Figure 3-20).
Figure 3-19. Substrate 1 (left half) after wiping off neat solvents (top) and formulation (bottom).
Figure 3-20. Substrate 1 (right half) after wiping off neat solvents (top) and formulation (bottom).

Summary:
From all four test series it can be concluded that:
• NMP is superior, both applied neat and in the NMP paint stripper protocol formulation on
both substrates.
• OT3 gives similar end results as NMP (although NMP works faster).
• In the case of substrate 1, LV3, LV1, and triglyme are capable of removing one paint layer
both neat and as a formulation.
• In the case of the more challenging substrate 2, only LV1 is capable of removing one paint
layer, and only when applied neat.
• OT16 is the only oxygenated ReSolve candidate tested that is consistently capable of
removing at least one paint layer, both neat and in the formulation (except for substrate
2). Other ReSolve candidates were ineffective.

4 DMPA solubility
Context
For the production of water borne polyurethane dispersions (PUDs) for water borne coating-
and paint systems, NMP is still a major solvent used for preparing the polyurethane (PU) pre-
dispersion. Thus far NMP (and ethyl analogue NEP) is the major industrially relevant solvent
that is a) non-reactive in the PU formation reaction, b) is capable of dissolving all starting
materials as well as the PU polymers, c) is capable of dispersing the polymer in water, d) is
fully soluble in water, and e) acts as coalescing agent, aiding film formation. According to
industrial PUD producers the most difficult to dissolve component in current PUD formulations
is DMPA (dimethylolpropanoic acid; 2,2-bis(hydroxymethyl)propionic acid), which is essential
for obtaining water dispersible polymers. Since industry is using DMPA solubility as a
benchmark test for the first evaluations of alternative solvents (to NMP), we also set up a test
protocol based upon DMPA solubility. The protocol is based on an existing one by Perstorp
(DMPA producer).
Experimental
A suspension of a known amount of DMPA in the solvent is magnetically stirred for 24 h, at
room temperature (RT). Next, approximately 0.3 ml of a well-mixed sample was filtered over
a 13 mm filter with 0.2µm PTFE membrane. A weighed amount of filtered sample (20-30 mg)
was dissolved with a known amount of internal standard (maleic acid, 7-8 mg) in 0.8 ml D2O,
followed by 1H-NMR analysis. From the ratios of the integrals of internal standard and DMPA,
the concentration of DMPA is then calculated.
Results
The results of the solvents tested are listed in Table 4-1. The only aprotic solvents that are
capable of dissolving DMPA in a significant amount are either sulfoxide (DMSO), amides
(DMAc, DMF) or lactams (NMP, NBP, NMPP, NMC). DMSO is well known for being able to
solvate cations as well as being Bronsted basic (Bordwell et al., 1980, Bordwell, 1988,
Laurence, 2009). All amide/lactams are capable of hydrogen bonding and are slightly Bronsted
basic (Bagno and Scorrano, 1988), which would explain the high solvation power of these
solvents in this case. Surprisingly, ring size in the lactam has less influence than the
substituent at nitrogen: e.g. NMP (5-membered ring) and NMPP (6-membered ring) give
virtually identical results. Increasing the ring size further to a 7-membered ring like in the case
of N-methyl caprolactam (NMC) results in decreased performance probably due to decreased
polarity. Yet NMC is capable of dissolving more DMPA than the 5-membered ring lactam OT3,
carrying a butyl group on the nitrogen atom. Hence steric hindrance at nitrogen may also be
a decisive factor.
Table 4-1. Results for DMPA solubility, in order of solubilising efficiency.
Solvent % DMPA solubility Type

(w/w)
44 Reference
DMSO
34 Reference
DMAc

Solvent % DMPA solubility Type

(w/w)
32 Benchmark
NMP
31 Reference
DMF
31 Reference
NMPP
25 Reference
NMC
OT3 19 Reference
Water 13 Reference
Methanol 13 Reference
Ethyl acetate 3 Reference
OT16 1.2 NMP alternative
IS2-IS3 (20/80) 1.0 NMP alternative
IS3 0.6 NMP alternative
LG13 0.5 NMP alternative
Butanone (MEK) 0.4 Reference
LV3 0.3 NMP alternative
OT32 0.2 NMP alternative
Propylene carbonate 0.2 Reference
IS92 0.2 NMP alternative
AK1 0 Toluene Alternative
AK2 0 Toluene Alternative
LV34 0 Toluene Alternative
Interestingly, strongly protic solvents like water and methanol are far less efficient than the
dipolar aprotic solvents discussed above. Solvents that contain only aprotic oxygen functional
groups (ethers, esters, ketones, acetals) are not capable of dissolving DMPA in any significant
amounts, with the possible exception of OT16. Noteworthy are the poor performances of the

isohexide derivatives, OT32, and also LG1 and propylene carbonate. Not surprising, the
toluene alternatives AK1, AK2 and LV34 were completely unable to dissolve DMPA.
Hence, according to this testing protocol, none of the solvents developed in ReSolve are viable
alternatives to amide/lactam type solvents. Nevertheless, various inert ether type fossil
derived solvents are being promoted as potential alternatives for NMP in PUD production,
such as dipropylene glycol dimethyl ether (Tang and Zhao, 2014). Follow-up research could
include a back to back comparison of OT16 with structural analogues in PUD synthesis under
industrially relevant conditions.

5 Polymer solubility screening
Context
A broad set of solvents was tested for their ability to dissolve or swell four types of industrially
important polymers, i.e. polyvinyl chloride (PVC), polystyrene (PS), polyethylene terephthalate
(PET) and Elastane (aka Spandex or Lycra, a polyether-polyurea copolymer). These polymers
were chosen because like many other materials, they face challenges with respect to recycling
and integration in a circular economy. The use of safe bio-based solvents could be a solution
to these challenges.
PVC is a commodity polymer with an annual production of over 40 million tons worldwide
(Plastics Insight, 2020). PVC can be applied in rigid form (electrical pipes, sewage and
drainage pipes, window profiles, etc.), and by addition of a plasticiser in flexible form (vinyl-
flooring, vinyl-wall covering, flexible tubes and pouches (e.g. medical equipment), tarpaulin,
etc). In ReSolve two possible applications for solvents with respect to PVC have been
investigated. The first application is the dissolution of PVC, which is an integral part of the
recycling strategy for flexible PVC, although previous initiatives like the VinyLoop process
were thwarted by regulatory issues relating to additives in the PVC (Sherwood, 2020a).
Nevertheless, there remains a demand for technology to efficiently recycle (predominantly
flexible) PVC. Secondly, there is a demand for safer solvent-based adhesives for rigid PVC,
predominantly for welding rigid PVC parts like tubes and connectors.
Polystyrene is also a commodity polymer with a myriad of applications. In solid form it is used
for various packaging applications (e.g. disposable coffee cups, yoghurt cups), while foamed
(EPS or styrofoam) it is used for packaging, insulation and construction. While currently PS
recycling is highly challenging, and EPS recycling not economically viable due to its low
density, there is a desire to recycle PS. As one of the few vinyl-type polymers PS that can be
thermally depolymerised to the monomer (styrene), chemical recycling is possible. The use of
solvents for PS extraction and compaction can be an enabling factor in PS recycling.
PET (polyethylene terephthalate) is the most common thermoplastic polymer resin of the
polyester family and is used in fibres for clothing (known simply as polyester fibre) and carpets,
and containers for liquids and foods, such as the well-known PET bottles. In comparison to
other synthetic materials, PET can be relatively easily sorted and recycled, both mechanically
and chemically. A growing challenge in textile recycling is the increased use of elastane fibre
(vide infra) to increase elasticity and wear comfort. However, especially in composite yarns
containing more than one material (e.g. cotton, polyester, elastane, nylon) it becomes
increasingly difficult to separate the components without damaging them. Approaches like
selective dissolution of components like elastane could significantly aid the development of
efficient textile recycling technology. Similarly, removal of small fractions of polymeric
contaminants (e.g. PVC or PS) from PET packaging recycle streams could improve the quality
of r-PET (recycled PET). Since PET is notoriously difficult to dissolve (e.g. only effective with
solvents like phenol/cresol or HFIP) the aim could be to identify non-solvents for PET that are
capable of dissolving PVC, PS and/or elastane.
Elastane is a polyether-polyurea copolymer use to impart high elasticity to textile fibres.

Removal of elastane from these fibres is necessary for effective textile fibre recycling. Elastane
can be dissolved in amide type dipolar aprotic solvents such as DMAc and DMF, yet these
substances are undesirable due to their reprotoxicity. Hence in ReSolve the ability of various
bio-based solvents to dissolve/swell elastane was evaluated.

Experimental
Solutes (Table 5-1) and solvents (Table 5-2) are listed below. PVC 1-4 and 7 were free flowing
powders and used as received. PVC 5 and 6, PS and PET were manually cut into small pieces
(Figure 5-1). The elastane fibre was also cut into smaller fibres (Figure 5-2).
Table 5-1. list of materials tested.
Material Supplier Type Description

PVC1 Vestolit P1430; K70 ultra Powder (Nov2019)
PVC2 Inovyn PVC271PC; K71 Powder (Jan2020)
PVC3 Vynova S7102, K70 Powder (Jan2020)
PVC4 Vynova S5702, K57 Powder (Feb2020)
PVC7 Vynova S6706, K66 Powder (Feb2020)
PVC5 WFBR Vestolit P1430 + 50 phr Flexible transparent compression
Vestinol 9, DINP, Evonik moulded sheet (Nov2019)
PVC6 Akonyl PVC 8506, 5/8” tube Rigid non-pigmented electrical pipe
(Feb2020)
PS WFBR Standard lab disposable 1 L standard disposable container
(Jan2020)
PET WFBR Indorama N180 Extruded clear sheet (2019)
Elastane Hyosung CSSpandex Fibre (March2020)
Corp. (SK)
Table 5-2. list of solvents tested.
ReSolve code Remarks, supplier

NMP Sigma-Aldrich
OT3 NMP alt, Sigma-Aldrich
LG1 NMP alt, supplied by Circa
IS3 Commercial, supplied by Croda
Triglyme Tox issues, Sigma-Aldrich
Triethylene glycol diacetate Sigma-Aldrich
OT16 WFBR
OT31 WFBR
LV3 Sigma-Aldrich
LV34 Sigma-Aldrich
LV1 Sigma-Aldrich
LG6 UoY
LG64 UoY
THF PVC solvent, Sigma-Aldrich
2-MeTHF Sigma-Aldrich
AK1 UoY
Cyclohexanone PVC solvent, Sigma-Aldrich

Figure 5-1. From left to right: PVC6 (rigid PVC), PVC5 (flexible sheet), PET (sheet), and PS.
Figure 5-2. Elastane fibre.
Dissolution testing protocol (PVC1-7, PS, PET):

A 2 ml GC vial was charged with 1 ml of solvent and 40-70 mg of polymeric material (exact
amounts were recorded). These mixtures were mixed in a rotator (head over tail) at RT for
24h (Figure 5-3). Next the mixture was left to sediment/separate, and observations were
recorded. Subsequently, the mixture was mixed in a ventilated oven set at 60 °C for 24h. Again
the mixture was left to sediment/separate, and an observation was recorded. Next the mixture
was allowed to cool down to RT over a period of 18-24, and significant changes (such as
precipitation, sedimentation etc) were recorded (Table 5-3).
Figure 5-3. Examples of sample mixing in head over tail rotator, left at RT, right at 60 °C in a
ventilated oven.

Table 5-3. Scaling/observation of polymer dissolution; examples.
+++ ++ + --
completely partly swollen not
dissolved dissolved dissolved
PVC welding:
PVC gluing/welding experiments were performed on rigid PVC electrical pipe and couplers.
The solvent was applied with a brush. After drying, the bonding was qualitatively assessed
(break/no-break) by applying manual tension by 2 different persons (Figure 5-4).
Figure 5-4. Example of rigid PVC welding test. Left: component parts. Right: adhered piping.
Results
PVC:
The results obtained from the dissolution experiments of the different types of PVC are shown
in Table 5-4. 2-MeTHF and AK1 are not included since these solvents did not dissolve any of
the PVC samples. As expected both THF and cyclohexanone, which are known PVC solvents,
were able to fully dissolve all PVC samples at room temperature (RT), thereby validating our
test methodology (see Figure 5-5). NMP and OT3 also completely dissolved all PVC samples
at RT. In contrast, LG1 did not dissolve any PVC samples at RT, with the exception of the
plasticised flexible sample (PVC5). However, after heating at 60 °C, most samples fully
dissolved. This can be attributed in part to a kinetic effect and the higher viscosity of LG1 at
RT. Furthermore it was noticed that the fully dissolved samples in LG1 at 60 °C were highly
viscous or even gel-like, and yellow in colour. IS3 proved to be a rather poor solvent for PVC.
Since IS3 is rather viscous at room temperature, it was expected that results would improve
at 60°C, yet little improvement was observed. Interestingly, similar results were obtained with
triglyme, which is the linear analogue of IS3.

Table 5-4. Results of PVC dissolution experiments; 24 h, RT/60°C.
Solvent PVC1 K70 PVC2 K71 PVC3 K70 PVC4 K57 PVC7 K66 PVC5 Flex PVC6 Rigid
THF +++/+++ +++/+++ +++/+++ +++/+++ +++/+++ +++/+++ +++/+++
Cyclohexanone +++/+++ +++/+++ +++/+++ +++/+++ +++/+++ +++/+++ +++/+++
NMP +++/+++ +++/+++ +++/+++ +++/+++ +++/+++ +++/+++ +++/+++
OT3 +++/+++ +++/+++ +++/+++ +++/+++ +++/+++ +++/+++ +++/+++
LG1 --/+++ --/+++ --/+++ --/+++ --/+++ ++/+ --/++
IS3 --/-- --/-- --/-- --/+ --/+ +/+ --/+
Triglyme ++/++ --/+ --/+ --/+ --/+ --/+ --/+
OT16 ++/+++ ++/+++ ++/+++ ++/+++ ++/+++ ++/++ ++/++
OT31 --/-- --/-- --/-- --/-- --/-- +/+ --/+
Triethylene glycol diacetate ++/++ --/-- --/-- --/-- --/-- --/-- --/--
OT32 --/-- --/-- --/-- --/-- --/-- +/+ --/+
LV3 --/-- --/-- --/-- --/+ --/-- +/+ --/--
LV34 ++/+++ --/+++ --/+++ +/+++ --/++ +/+ --/+
LV1 +/+++ +/+++ +/+++ +/+++ +/+++ ++/+++ +/++
LG6 ++/++ --/+ --/+ --/+ --/+ +/+ --/+
LG64 ++/+++ --/+++ --/+++ --/+++ --/+++ +/+++ --/+++

Figure 5-5. Examples of PVC1-3 (top, middle, bottom), after 24 RT, 24 h 60°C, and 24 RT; from left to
right: OT32, OT31, OT16, LG1, IS3, cyclohexanone, LV1, LV3, NMP, THF.
In contrast, OT16 was capable of dissolving a significant part of all PVC samples at RT, while
after heating to 60 °C full dissolution was achieved. As can be seen from Figure 5-5 and Figure
5-6, the OT16 containing solutions were slightly yellow; less than in the case of LG1, yet more
than THF or cyclohexanone for example. Furthermore, comparable to LG1, the fully dissolved
OT16 solutions were highly viscous gels. In contrast to OT16, the related OT31 was
completely ineffective, comparable to triethylene glycol diacetate. A striking difference can
also be observed between the levulinic acid esters LV3 and LV34. While the former is only
capable of swelling the flexible PVC compound, the latter fully dissolves most PVC types upon
heating. Similar, yet more consistent results were obtained with LV1. LG6 is far less efficient
than the parent substance LV1. In contrast, the more lipophilic variant LG64 is capable of fully
dissolving all PVC compounds upon heating.
Figure 5-6. Example of PVC1-3 in OT16. Left: after 24 h at RT. Right: after 24 h at 60 °C followed by
24 h at RT.
Overall it can be concluded that next to the known PVC solvents THF and cyclohexanone,
OT16, LV1, and to a lesser extent LG1 and LG64, are interesting bio-based alternative

solvents. More investigation is required to asses if these solvents can be used in potential
recycling processes.
Experiments directed at rigid PVC welding/gluing showed that all solvents tested (NMP, OT3,
THF, cyclohexanone, triglyme, LG1, IS3, OT16, OT31, OT32, LV34, LV1, LG6, LG64) were
capable of welding the PVC pipe to the coupler in such a way that it could not be removed
manually. A more quantitative test is required to investigate the efficacy of the different
solvents (e.g. using a tensile testing machine).
PS/PET/Elastane:
Similarly to the PVC dissolution experiments, PS, PET and the polyurethane fibre Elastane
were tested for solubility in the solvent panel (Table 5-5). Polystyrene (PS) was very soluble
in most solvents. Notable exceptions are triethylene glycol diacetate and OT32. Furthermore,
IS3, LV3, LV34 and LG6 were unable to dissolve PS at RT, yet showed improved performance
at 60 °C. In contrast, yet as expected, PET did not dissolve in any of the solvents tested here
(see also Figure 5-7). Although finding an alternative solvent for PET would have been a
breakthrough result, it does offer possibilities for using these solvents in PET recycling by
selective dissolution of polymeric contaminations (such as PVC or PS). Unfortunately, the new
bio-based oxygenated solvents tested here are not suitable for the solvent assisted separation
of Elastane fibre from e.g. polyester, since only NMP and amide OT3 were able to dissolve
Elastane, either at RT or elevated temperature (see also Figure 5-8).
Table 5-5. Results of PS, PET and Elastane dissolution experiments; 24 h, RT/60°C.
Solvent PS PET Elastane
THF +++/+++ --/-- --/--
Cyclohexanone +++/+++ --/-- --/--
NMP +++/+++ --/-- +++/+++
OT3 +++/+++ --/-- ++/+++
LG1 +++/+++ --/-- --/--
IS3 +/++ --/-- --/--
Triglyme +++/+++ --/-- --/--
OT16 +++/+++ --/-- --/--
OT31 +++/+++ --/-- --/--
Triethylene glycol diacetate --/-- --/-- --/--

OT32 --/+ --/-- --/--
LV3 +/+++ Not tested --/--
LV34 --/+++ Not tested --/--
LV1 +++/+++ --/-- --/--
LG6 +/++ Not tested --/--
LG64 ++/+++ --/-- --/--

Figure 5-7. Example of undissolved PET particles in a variety of solvents; from left to right, NMP, OT3,
LG1, IS3, LV1, OT16, THF, cyclohexanone, LG64, TEG-Me
Figure 5-8. Example of dissolved (from left to right NMP and OT3) and undissolved Elastane fibres,
(continuing left to right); LG1, IS3, LV3, LV34, LV1, OT16, OT31, OT32.
Summary:
Overall from this polymer solubility test series with respect to ReSolve solvents it can be
concluded that:
• PVC powders dissolved well in OT16, and in LG1, LV34 and LG64 after heating.
• Rigid PVC dissolved well in OT16, and in LG64 and LG1 after heating.
• Flexible PVC dissolved well in LG1, OT16 and LG64.
• Rigid PVC welding was possible with all ReSolve solvents tested.
• PS dissolved well in OT16, OT31, and LG64.
• PET did not dissolve at all (as expected).
• Elastane did not dissolve at all, except in NMP and OT3.

6 Polymer solutions for membrane fabrication

Published at https://doi.org/10.1002/cssc.202000462 (open access)
Context
Dipolar aprotic solvents are necessary to dissolve a range of polymers in the manufacture of
films and membranes. NMP, DMAc and DMF are traditionally the go-to solvents, so safer
alternatives are sought. Three polymers have been used in the ReSolve project as probe
solutes to test NMP replacement solvents: polyamide imides (PAIs), polyethersulfones (PES)
and polyvinyl difluoride (PVDF). Solubilities in OT3, OT5, OT6 and OT7 were tested as part of
the ReSolve project, and OT7 was tested for its ability to fabricate a membrane.
Polyamide imides (PAIs) are used as a hard coating for kitchen appliances, a laminating resin
and most profusely as a wire enamel. (Murray, T.J., 2008) The PAI utilized in this work is
Torlon AI-10. Polyethersulfone (PES) is a high-temperature engineering thermoplastic
principally used in formation of membranes due to its excellent physical characteristics and
the degree of control that can be achieved through modification of the casting system (Zhao,
C., et al., 2013). The PES investigated in this work is Ultrason E3020. Finally, polyvinyl
difluoride (PVDF) is a chemically and thermally stable but electronically active polymer
(Holmes-Siedle et al., 1984). PVDF has many applications, including in membrane formation,
medical sensors and as a binder in lithium-ion batteries. The grade of PVDF applied here is
Solef 5130 widely utilized in battery production.
Water filtration using membranes has established itself as an important area of research.
Several polymers have been reported for this application, such as polyvinyl difluoride (PVDF),
polyvinyl alcohol (PVA), cellulose acetate and polyethersulfone (PES). PES offers high
thermal, hydrolytic and chemical stability and as such, it has emerged as particularly effective
polymer for membrane fabrication.
Experimental
Solubility test:
PVDF, PES and PAI were dissolved in OT3, OT5, OT6 and OT7 at 10 wt%. Dissolution was
carried out at 80 °C with agitation for 1 hour at which point they were examined.
Membrane fabrication:
The casting solution was prepared by dissolving 10 wt% of PES pellets (relative to the mass
of solvent) in OT7 at 100 °C for 6h. The casting solution was degassed, then placed on a glass
plate using a manual casting knife with a thickness of 150 μm. The plate containing the casted
polymer was immersed in a bath of non-solvent in a non-solvent phase inversion technique
(NIPS), causing the PES membrane to precipitate.
Results
Solutions:
All of the ReSolve candidates were able to dissolve PVDF at the test temperature but formed
a gel upon cooling to room temperature with varying degrees of turbidity (Figure 6-1). OT3
and OT7 fully dissolved PES, while only partial dissolution was achieved with OT5 and no
interaction was observed with OT6. Finally, OT3 and OT7 could fully dissolve PAI, while
precipitation of some polymer was observed in OT5 and OT6 upon cooling.

Figure 6-1. Polymer dissolution at 10 wt% of (A) PVDF (B) PES (C) PAI in (left to right) OT7, OT5,
OT6 and OT3. Dissolution carried out at 80 °C with agitation for 1 hours, images taken at room
temperature.
Membrane fabrication:
The success of OT7 in dissolving PES prompted its testing in the formation of a PES
membrane. To form a membrane, the PES polymer is first dissolved in a suitable dipolar
aprotic solvent and degassed, before being cast onto a glass plate. The plate is then
submerged in an anti-solvent, usually water, thus removing the dipolar aprotic solvent and
producing a porous membrane.
OT7 is immiscible with water but miscible with non-polar solvents such as hexane so
alternative anti-solvents were also tested. Hexane and AK1 were both identified as potential
anti-solvents, with AK1 being a greener alternative to hexane. The performance of each anti-
solvent in demixing the PES/solvent can be seen by the SEM images in Figure 6-2. Partial
dissolution of the polymer was observed when hexane was used, producing dense regions at
the surface and negatively affecting the morphology of the membrane. The membrane yield
was also affected due to the partial solubility of PES in hexane. AK1 performed far better,
producing a quality membrane with a finger-like porous structure. Somewhat surprisingly,
using water as the non-solvent generated a similar morphology to when AK1 was used, but
with slightly smaller macro- voids at the bottom surface. The porosity of the PES/OT7
membranes produced using AK1 and water as non-solvents (Byrne et al., 2020), were
comparable to those previous reported in the literature (Milescu et al., 2019) and provide a
fully green solvent system for their production.

Figure 6-2. Scanning Electron Microscopy images of cross-section of the membranes casted using (a)
water, (b) AK1 and (c) hexane as non-solvent.

7 Bioactives solubility
Context
Medicinal and biocidal formulations can be made from an emulsifiable concentrate consisting
of an active ingredient dissolved in a dipolar aprotic solvent (e.g. NMP). The inclusion of a
surfactant allows the concentrate to be diluted in water prior to use. Medicinal and crop
protection applications are exempt from the REACH regulation because they are covered by
other regulations, but the benefits of minimising human exposure to NMP are still applicable.
Here, the concentration of four compounds was tested in four ReSolve candidates to assess
the feasibility of substituting NMP. Firstly paracetamol (acetaminophen), the ubiquitous
analgesic; also thiamphenicol, a poorly-water soluble antibiotic; the fungicide tebuconazole,
and finally abamectin, a relatively high molecular weight insecticide. These substrates were
chosen in consultation with the external advisory board of the ReSolve project.
Experimental
Solutions of four selected bioactive compounds (paracetamol, thiamphenicol, tebuconazole,
and abamectin, see Figure 7-1) were made by saturating selected solvents at 21 °C. The
concentration was calculated after at least 24 hours by filtering an aliquot, diluting in CDCl3 or
DMSO-d6, and analysing by 1H-NMR spectroscopy.
Figure 7-1. Four bioactive molecules.

Results
Solutions:
Overall, the solute concentrations observed in NMP were significantly higher compared to the
oxygenated solvents tested (LG1, IS3, LV5, LV34). This includes water-organic solvent
systems for paracetamol and thiamphenicol where NMP was compared to LG1. The solubility
of paracetamol was found to be higher in LG1 and LV5 than IS3 and LV34, but all considerably
lower than NMP (Figure 7-2). Aqueous LG1, a reactive system that creates a geminal diol,
showed a maximum paracetamol concentration at 50 vol% LG1 in water. For thiamphenicol
the highest solubility was observed at 75 vol% LG1-25 vol% water (Figure 7-3). Other work
has also shown small molecule solubilities to be higher in aqueous LG1 than in neat LG1 (De
bruyn et al., 2019). Both paracetamol and thiamphenicol are functionalised with alcohol and
amide chemical groups. All the tested solvents will be able to engage in hydrogen bonding
with these two substrates and yet the solubility of paracetamol and thiamphenicol in NMP
remains higher. This can be attributed to the small molar volume and greater electron donating
ability of NMP.
Figure 7-2. Paracetamol concentrations in ReSolve candidates (left) and aqueous mixtures of LG1
and NMP (right).
Figure 7-3. Thiamphenicol concentrations in ReSolve candidates (left) and aqueous mixtures of LG1
and NMP (right). Solubility in LV34 is 0.695 μg/mL.

Abamectin is a high molecular weight natural product, and there was only sufficient sample to
reach the saturation point in LV5 (Figure 7-4). The high cost of this fungicide did not justify
further experimentation in light of the general trend of the superior solubility of bioactive
compounds in NMP compared to oxygenated solvents.
Figure 7-4. Abamectin concentrations in ReSolve candidates (LV34 not tested).
Of the ReSolve candidates, IS3 was the best performing solvent for thiamphenicol and
tebuconazole. Again, the highest observed concentrations are lower than that achieved in
NMP, indicating an amide functionality and comparatively low molar volume is beneficial.
However, the lesser performance compared to NMP was not as pronounced for tebuconazole
as it was for paracetamol and thiamphenicol, with IS3 approximately one-third as efficient as
NMP (Figure 7-5).
Figure 7-5. Tebuconazole concentrations in ReSolve candidates (LV34 not tested).
Emulsion:
To investigate the possibility of producing a viable emulsifiable concentrate, the formulation
recipe exemplified by Bramati and Lourenco (2008) was repeated with IS3 and NMP as the
solvents. Mixtures of 25 wt% tebuconazole, 10 wt% TWEEN-20 surfactant, and 65 wt%
solvent were prepared. Both concentrates were placed in a fridge at 3 °C for 7 days, after
which, no crystallisation of tebuconazole was observed. Then to replicate the application of
emulsifiable concentrates a 250:1 (by mass) dilution with water was performed to assess the
stability of the formulation. Both NMP and IS3 (pictured, Figure 7-6) created an emulsion with

no obvious solid precipitation. However, the emulsions were not stable overnight.
Crystallisation of tebuconazole was observed, as was a transparent supernatant (Figure 7-7).
Had the maximum concentration of tebuconazole in IS3 been closer to that in NMP, a more
thorough investigation of appropriate surfactants would have been pertinent for the formulation
of more stable emulsions.
Figure 7-6. Emulsion created with tebuconazole (0.025 g) TWEEN-20 (0.010 g), IS3 (0.065 g), and
water (6.25 mL).
Figure 7-7. Collapsed tebuconazole emulsions in NMP (left) and IS3 (right).

8 Graphene dispersion
Context
The production methods available to form graphene are diverse. However, the method most
directly applicable to potential bulk manufacturing is the delamination of graphite. To do so,
graphite is added to a solvent and subject to ultrasound. This creates a dispersion of graphene
and any residual graphite is filtered. NMP is the preferred organic solvent. Aqueous
dispersions are also known, but residual surfactant can reduce the properties (e.g.
conductivity) of the graphene once deposited and fabricated into materials. The concentration,
quality (flake size, thickness, number of edge defects) and stability of the graphene dispersion
depends to a large extent on the solvent. The ability to delaminate graphite is related to the
surface tension of the solvent. The concentration of graphene achieved is dependent on
solvent polarity. The stability of a dispersion is proportional to solvent viscosity. LG1 has
previously been shown to create higher concentrations of graphene compared to NMP
(Salavagione et al., 2017), and thus produce higher quality conductive inks (Pan et al., 2018),
by delamination of graphite.
To elaborate on previous work, the solvent dispersion aspect of graphene production was
investigated by treating graphene nanoplatelets with ultrasound in NMP, LG1 and IS3. By
dispersing pre-made graphene, solvent performance can now be attributed to only polarity.
This study is applicable to the utilisation of graphene made by any method, not just by graphite
delamination e.g. potentially for the combination of graphene and organic polymers in solution.
Experimental
To 1 mg of graphene was added 1mL of solvent, and the mixture treated by ultrasonic probe
for 15 minutes. Samples were allowed to stand for one week, and filtered. The concentration
of graphene dispersed in the solvent was then measured using UV spectroscopy according to
the established method defined by Hernandez et al. (2008) using the UV absorbance of the
solution at 660 nm. Calibration of absorbances was performed separately for each solvent
with known concentrations of graphene. The maximum concentration was determined by
extrapolation of the calibration curve in each case.
Results
As might have been anticipated, the maximum concentration of graphene under the chosen
experimental conditions in NMP (0.21 mg/mL) and LG1 (0.22 mg/mL) is virtually identical
owing to their very similar Hansen solubility parameters. However, IS3 was much less effective
(0.08 mg/mL). The TEM images in Figure 8-1 show some agglomeration after dispersion (for
comparison, the graphene nanoplatelets as received are shown in Figure 8-2). Note however
that the material before and after dispersion is not homogeneous and so the images provided
here do not represent the samples as a whole. The advantage of LG1 over NMP when
graphene is made by delamination of graphite can be attributed to the actual delamination
process (not analysed here, see Salavagione et al., 2017, where analysis on graphene flake
size and thickness is also presented).

Figure 8-1. Left: Cyrene-dispersed graphene nanoplatelets (scale bar is 200 nm); Right: NMP-
dispersed graphene nanoplatelets (scale bar is 1000 nm). The images are sized to account for the
different scales.

Figure 8-2. Undispersed graphene nanoplatelets (scale bar is 1000 nm).

9 Hydrocarbon extraction
Context
The separation of aromatic compounds from alkanes is a major practice in commodity
chemical manufacturing. Distillation is able to perform the majority of separations, but
particular mixtures have components with very similar boiling points that require solvent
extraction, for example cyclohexane (boiling point = 81 °C) and benzene (80 °C). Solvent
extraction studies also regularly use a model system of n-heptane (98 °C) and toluene
(111 °C) because of its relevance to fuel refining (Farshad et al., 2011). To assess the ability
of ReSolve candidates to perform these separations, 5:5:1 volume ratios of extraction solvent-
alkane-arene were thoroughly mixed and the liquid phases analysed. The extraction efficiency
(proportion of aromatic compound in the extraction solvent phase) and selectivity (quantity of
aromatic compound compared to alkane in the extraction solvent phase) were calculated.
Conventional extraction solvents (NMP, sulpholane, ethylene glycol) were compared to the
following ReSolve candidates: IT13, IS3, LV1, LG1, and LG59. Additional mixtures with
ethylene glycol as a co-solvent and aqueous LG1 were also tested.
Experimental
1. Binary system. Either benzene (0.1 mL) in cyclohexane (0.5 mL) or toluene (0.1 mL) in
n-heptane (0.5 mL) was extracted by 0.5 mL of the chosen solvent. The composition of the
extract was analysed by 1H-NMR spectroscopy. Examples are shown in Figure 9-1-Figure
9-4.
Figure 9-1. 1H-NMR spectra of upper (alkane rich phase) of toluene extraction from n-heptane with
NMP.

Figure 9-2. 1H-NMR spectra of lower (NMP rich phase) of toluene extraction from n-heptane with
NMP.
Figure 9-3. 1H-NMR spectra of upper (alkane rich phase) of toluene extraction from n-heptane with
LG1.

Figure 9-4. 1H-NMR spectra of lower (LG1 rich phase) of toluene extraction from n-heptane with LG1.
2. Six component mixture. A mixture of C -C hydrocarbons (sum of 4 g, composition given in

6 8
Table 9-1) was extracted with LG1-water (3:1 wt/wt, 8 g). The composition of the phases
was analysed by 1H-NMR spectroscopy.
Table 9-1. Composition of model hydrocarbon mixture.
Component Mass /g Molar composition
n-Hexane 0.22 6 mol%
n-Heptane 0.64 15 mol%
Cyclohexane 0.43 12 mol%
Benzene 0.27 8 mol%
Toluene 1.45 37 mol%
o-Xylene 0.99 22 mol%
Total 4.00 100 mol%

Results
For the simplified binary systems, Figure 9-5 and Figure 9-6 show the efficiency of arene
extraction (as a percentage rather than the partition constant) versus the selectivity (molar
proportion of arene in extracted phase compared to alkane). NMP was the most efficient
extraction solvent for toluene from n-heptane, but the least selective. The selectivity is more
critical than the efficiency for a purification process that can be repeated as necessary to
complete the separation. The selectivity of toluene extraction in LG59 was over 70%. By
comparison LG1 sacrifices some selectivity for greater efficiency. However, the addition of
ethylene glycol to NMP (as practiced in petrochemical refining) vastly improved the selectivity.
The highest selectivities (approaching 90%) were obtained when using sulpholane, ethylene
glycol, and aqueous LG1. Of these solvents, sulpholane provided the greatest extraction
efficiency.
Figure 9-5. Extraction efficiency and selectivity of toluene from n-heptane in different solvents. Ratio
(wt/wt) of co-solvents is 1:1 unless otherwise indicated. Key: EG, ethylene glycol.
The extraction of benzene from cyclohexane is less selective in general than the previous
case study. Cyclohexane is more polar than n-heptane and an extraction that successfully
differentiates between cyclohexane and benzene is challenging. Note that IT13, IS3 and NMP
were found to be miscible with cyclohexane and so could not be used to extract benzene.
Sulpholane was the best performing solvent again, but aqueous LG1 also provided good
selectivity (albeit with poor efficiency). Addition of ethylene glycol to either LG1 or NMP
resulted in a similar extraction selectivity but the efficiency was greater when utilising NMP,
thus the advantage of LG1 over the cyclohexane-miscible NMP is lost once ethylene glycol is
added as a co-solvent.

Figure 9-6. Extraction efficiency and selectivity of benzene from cyclohexane in different solvents.
Ratio (wt/wt) of co-solvents is 1:1 unless otherwise indicated. Key: EG, ethylene glycol.
Greater quantities of ethylene glycol (2:1 wt/wt) resulted in reactivity with ketone LG1 that was
not observed in equal mass proportions. The formation of a hemiketal improved the selectivity
of toluene extraction but reduced the selectivity of the benzene extraction. This phenomenon
has contributed to a non-linear effect on extraction performance arising from blending LG1
and ethylene glycol.
It is worth highlighting that ethylene glycol is poisonous and sulpholane is classified as

reprotoxic, and so these solvents do not provide an acceptable alternative to NMP on
toxicological grounds. That said, the performance of NMP (Arosolvan process), glycols (UDEX
process), sulpholane (Shell process) has all been proven in commercial applications (Coker,
2018), and any alternative would need to perform an economically sound separation to be
competitive.
To see whether the leading candidates from the previous case studies translate to a feasible
extraction solvent for the separation of aromatics from naphtha reformate, a representative
mixture of hydrocarbons was made based on the work of Ali et al. (2003), who showed
propylene carbonate to be a valid solvent for this application. The extraction of a model mixture
of hydrocarbons (see Table 9-1) with LG1 failed to produce separate phases after mixing. This
is due to the greater proportion of aromatic components present. Repeating with LG1-water
(3:1) resulted in three phases after mixing (Figure 9-7 and Figure 9-8). The top phase was the
least voluminous and rich in aliphatic compounds (Figure 9-9, blue spectra). The middle and
lower phases were nearly equal in mass and both contained LG1. The middle phase retained
a similar composition to the original mixture of hydrocarbons (Figure 9-9, green spectra). The

lower phase did enrich the proportion of aromatic content, but was mostly LG1 with traces of
hydrocarbons (Figure 9-9, red spectra). The inability of LG1 to separate aromatic-rich
petrochemical mixtures, and the low saturation of hydrocarbons in LG1-water makes this an
impractical separation.
Figure 9-7. Mass distribution of phases upon extraction of mixed hydrocarbons with aqueous LG1.
Figure 9-8. Top left: Molar composition of original hydrocarbon mixture (aliphatic-aromatic). Top right:
Composition of top phase upon addition of aqueous LG1. Bottom left: Composition of middle phase.
Bottom right: Composition of bottom phase.

Figure 9-9. Overlaid annotated 1H-NMR spectra of the three phases obtained upon extracting a
petrochemical mixture with LG1-water.

10 Menschutkin reaction
Context
First discovered by Menschutkin in 1890 using triethylamine and iodoethane in 23 different
solvents, the Menschutkin reaction is a useful tool to study solvent polarity (Menschutkin,
1890). It is a bimolecular nucleophilic substitution reaction that is promoted in dipolar aprotic
solvents, as the transition state can be stabilized without deactivating the nucleophile. A
correlation is observed between the rate constant of the reaction and the polarity of the
solvent. Plotting the natural logarithm of the rate constant, ln(k 2), against dipolarity (π*), a
linear solvation-energy relationship (LSER) can be determined. LSERs have proven useful in
the characterization of solvent effects, and many examples of their use have previously been
reported (Kamlet et al., 1983).
As part of ReSolve, the Menschutkin reaction was a useful tool in helping to define the polarity
of new solvents, and to identify any potential unexpected solvent effects. Solvent performance
is expected to correspond to the magnitude of π* (polarity/polarizability). Any deviations from
this trend would point to other solvent effects contributing to the reaction rate, e.g. viscosity.
ReSolve candidates LG1, LG6, LG59, LG64, OT3, OT5, OT6, OT7, OT16, OT31, OT32,
OT34, LV1, LV3, AK1, LG59 and IDL were tested across 2 case studies.
Experimental
Reaction between 1-bromodecane with 1,2-dimethylimidazole:

1,2-dimethylimidazole (0.356 mL, 4.00 mmol) was added to a 5 mL DrySyn vial followed by
solvent (4 mL). The solution was heated to 50 °C and stirred at 500 rpm using a magnetic
stirrer, at which point 1-bromodecane (0.913 mL, 4.40 mmol) was added. The conversion
determined using. The product peak at 4.06 ppm and the reactant peak at 3.67 ppm on the 1H
NMR spectrum were used to determine conversion.
Reaction between 1-bromooctane and 1-methylimidazole:

1-Methylimidazole (0.318 mL, 4.00 mmol) was added to the chosen solvent (4 mL) and heated
to 50 °C. The reaction mixture was stirred at 500 rpm using a magnetic stirring bead. 1-
Bromooctane (0.76 mL, 4.40 mmol) was added and conversion was monitored by removing
aliquots for 1H NMR spectroscopy.
Results
Levoglucosenone derived solvents:

The Menschutkin reaction carried out for testing LG1, LG6 and LG64 was the reaction
between 1-bromodecane and 1,2-dimethylimidazole (Figure 10-1). LG1 performed
comparably to the traditional solvents NMP and DMSO, as previously reported (Sherwood et
al., 2014). LG6 and LG64 performed according to the correlation with dipolarity (π*, Figure
10-2), suggesting other solvent properties, such as viscosity, did not have an effect on the rate
of reaction. LG64 is the least polar of the candidates, and this is reflected in the slower reaction
rate.

Figure 10-1. The Menschutkin reaction between 1-bromodecane and 1,2-dimethylimidazole.
-4.00 Traditional solvents

Resolve Candidates DMF
-4.50 NMP DMSO
LG1
ln(k2) / mol dm-3 s-1
-5.00 LG6
LG64
-5.50
Chloroform
-6.00
Toluene
-6.50
0.40 0.50 0.60 0.70 0.80 0.90 1.00
π*
Figure 10-2. LSER showing the performance of LG1, LG6 and LG64 in the Menschutkin reaction
between 1-bromodecane and 1,2-dimethylimidazole.
Additional solvents:
A variety of solvents were tested in a model Menschutkin reaction between 1-methylimidazole
and 1-bromooctane (Figure 10-3) in comparison with a selection of traditional solvents. As not
all π* values were available solvents are ordered by the obtained rate constant in Figure 10-4.
Figure 10-3. The Menschutkin reaction between 1-bromooctane and 1-methylimidazole.

Figure 10-4. Rate constants for the reaction between 1-bromooctane and 1-methylimidazole in
ReSolve candidates (blue) and other solvents (green).
The most effective ReSolve candidate is IDL (ln(k) = -9.85). Comparison of OT16 (ln(k)
= -11.29) and OT31 (ln(k) = -10.03) shows that as expected the polarity of the latter is much
higher than that of the former, and the performance of OT31 even surpasses that of NMP.
However, this increased polarity does not translate into a comparable performance under
other conditions, as was obvious from the effects observed during paint removal testing (see
Section 3). Remember that the viscosity of a solvent at a given temperature will influence
diffusion and mass transfer effects. While the Menshutkin reactions were all performed at
50 °C, differences in viscosity at that temperature is expected to have some influence on the
observed rate constants. Similarly, all paint stripping experiments were performed at room
temperature which could significantly increase the differences in performance due to larger
differences in viscosity and higher viscosity at lower temperatures.
The ability of OT6 and OT5 to promote the Menschutkin reaction followed the trend according
to π*. However, OT3 facilitated a higher rate of reaction than any of the succindiamides.
Interestingly, it appears that OT7 performs worse than expected, perhaps due to its higher
viscosity than the common solvents, thus prohibiting efficient mixing of the reactants. The
combination of OT7 with the highly polar DMSO showed dramatic improvements to reaction
rate.

When comparing the amide/lactam series, it is interesting to note that in the Menshutkin
reaction the non-cyclic amides DMAc and DMF show slightly higher rates than the benchmark
NMP. Furthermore, increasing the ring size from 5-membered (NMP), to 6-membered
(NMPP), to finally 7-membered (NMC) surprisingly leads to a rate increase, in spite of the
increased size of the apolar part of the molecule. Whereas, as expected DMSO (π* = 1.00)
outperforms NMP (π* = 0.90), the even higher reaction rates observed for propylene
carbonate and LV1 come as some surprise. Also surprising is the observed rate for LV3 (ln(k)
= -10.26) which exceeds that of NMP. Note that Menshutkin reactions performed with
isohexide derivatives have already been reported in deliverable D2.1.
Overall based on this set of Menshutkin reactions, while also bearing in mind this case study
is not significantly impacted by solvent functionality, stability, and other factors, several
conclusions can be drawn:
• While the Menshutkin reaction is a valuable tool for assessing the polarity of a solvent,
a high observed Menshutkin reaction rate does not necessarily imply high performance
in specific applications (see other sections of this report).
• Discrepancies between Menshutkin data obtained at elevated temperature and

applications studied at RT can be caused by differences in viscosity and other scales
of solvent polarity (e.g. Hansen solubility parameters; multi-parameter relationships
should be studied more carefully.
• Keep in mind that functional groups that contribute to overall polarity (e.g. ketones,
esters, acetals, ketals, amides) and which are inert in the Menshutkin reaction could
be actively involved in chemical and physical processes in other applications, making
the solvent non-inert.

11 Nucleophilic fluorination
Context
Fluorination via nucleophilic aromatic substitution using KF is a simple method of fluorinating
suitable substrates, the rate of which is strongly dependent on the choice of solvent (more so
than the Menschutkin reaction). Solvents which can stabilize the Meisenheimer intermediate,
without deactivating the fluoride nucleophile, will facilitate a quick rate of reaction (Clark and
Macquarrie, 1987). Dipolar aprotic solvents such a DMSO are particularly effective at this. The
fluorination of 2-chloro-5-nitropyridinde using potassium fluoride has previously been reported
as a model reaction for testing solvents (Sherwood, et al., 2014) and as such, was used as
the model reaction in this project (Figure 11-1). Three related ReSolve candidates were tested
in this reaction: LG1, LG6 and LG64.
Figure 11-1. The fluorination of 2-chloro-5-nitropyridine with potassium fluoride.
Experimental
Potassium fluoride (0.058 g, 1.00 mmol) and solvent (3 mL) were added to a 5 mL DrySyn vial
and preheated to 130 °C under stirring for 2 hours, at which point the temperature was lowered
to 90 °C. Once temperature stabilized, 2-chloro-5-nitropyridinde (0.106 g, 0.67 mmol) was
added in a single dose. The progression of the reaction was monitored by 1H NMR
spectroscopy.
Results
The reaction was preheated to 130 °C in order to maximise the KF in solution. Upon cooling
to 90 °C, 2-chloro-5-nitropyridine was added. The results of the reaction can be seen in Figure
11-2. DMSO was the best solvent, in agreement with previously published work. LG6 and
LG64 were also successful in hosting this reaction, but LG1 degraded under the reaction
conditions. As the reaction mixture was not dried, the degradation of LG1 is perhaps due to
residual water in the mixture resulting in the formation of KOH, a strong base. It is known that
LG1 is unstable in base, so its degradation in such conditions is not unexpected. It is
interesting and encouraging that the lactones, LG6 and LG64, also not dried, are both stable
in high temperature and potentially basic conditions. This suggests that the lactones may be
a suitable green dipolar aprotic solvent for use in other processes with basic conditions.

14
12
ln(k*106 / mol dm-3 s -1)

10
0
DMSO DMF NMP LG6 LG64 LG1
Figure 11-2. Rates of reaction for the fluorination of 2-chloro-5-nitropyridine with KF.

12 Suzuki reaction
Published at https://doi.org/10.3762/bjoc.16.89 (open access)
Context
The Suzuki reaction is the most versatile cross-coupling reaction to form carbon-carbon bonds
between aromatic moieties. It is widely used in fine chemical manufacturing. More than any
other cross-coupling, the Suzuki reaction tolerates a variety of solvents. Three model reactions
were performed under different conditions to see if ReSolve candidates tolerate inorganic
bases and facilitate the isolation of the products.
Experimental
1. Biphenyl methyl ketone (Figure 12-1). To 4-bromoacetophenone (0.1194 g, 0.6 mmol) was
added phenylboronic acid (0.0878 g, 1.2 eq.), palladium acetate (0.0013 g, 1 mol%),
potassium carbonate (0.0995 g, 1.2 eq.), water (0.6 mL) and the chosen solvent (1.8 mL).
The reaction mixture was stirred for 2 hours at the ambient temperature, and then diluted
with diethyl ether (20 mL) and washed with water. The organic phase was concentrated
and the resulting solid analysed by 1H-NMR spectroscopy (Figure 12-4).
Figure 12-1. Reaction scheme of the synthesis of biphenyl methyl ketone.
2. Felbinac (Figure 12-2). To 4-bromophenyl acetic acid (0.1290 g, 0.6 mmol) was added
phenylboronic acid (0.0878 g, 1.2 eq.), palladium acetate (0.0013 g, 1 mol%), potassium
carbonate (0.0995 g, 1.2 eq.), water (0.6 mL) and the chosen solvent (1.8 mL). The reaction
mixture was stirred for 20 hours at 65 °C, and then allowed to cool to the ambient
temperature. The reaction mixture was diluted with water (10 mL), acidified with
hydrochloric acid to produce a precipitate, and extracted with dichloromethane (2 x 15 mL).
The organic phase was concentrated and the resulting solid analysed by 1H-NMR
spectroscopy (Figure 12-4).
Figure 12-2. Reaction scheme of the synthesis of Felbinac.
3. 4-Phenyltoluene (Figure 12-3). To 4-bromotoluene (0.1026 g, 0.6 mmol) was added

phenylboronic acid (0.0878 g, 1.2 eq.), [1,1′-
bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM complex (0.0196 g, 4 mol%),
potassium phosphate (0.382 g, 3 eq.), water (0.6 mL) and the chosen solvent (1.8 mL). The
reaction mixture was stirred for 1 hours at 50 °C, and then diluted with diethyl ether (20 mL)
and washed with water. The organic phase was concentrated and the resulting solid
analysed by 1H-NMR spectroscopy (Figure 12-4).

Figure 12-3. Reaction scheme of the synthesis of 4-phenyltoluene.
Figure 12-4. Example 1H-NMR spectra for calculating conversions (overlayed, 4-2 ppm range). Key
(left to right): Green, conversion during felbinac synthesis; red, conversion during synthesis of p-
phenylacetophenone; blue, conversion during p-phenyltoluene synthesis.
Results
The reaction between phenylboronic acid and 4-bromoacetophenone in the presence of
palladium acetate (1 mol%) and potassium carbonate (1.2 equivalents) was sensitive to the
choice of solvent and produced a range of conversions (Figure 12-5). The cause of the solvent
effect could be due to one of several possible factors, for example the relative rate of reaction
compared to catalyst decomposition, the reduction of the palladium(II) catalyst precursor to
an active species (whereby the solvent may be oxidised, e.g. isopropanol to acetone), the
stability of that catalyst (with solvent coordination in the absence of formal ligands), or the
equilibrium between boronic acid and borate upon reaction with the base. In the reference
solvents NMP and 2-propanol (IPA), conversion to biphenyl methyl ketone was complete. IS3
and LG59 provided moderate conversions of 74% and 82% respectively. The ability of LG59
to be oxidised to LG1 may have a beneficial role in the catalytic cycle, but the conversion still
remained uncompetitive with the reference solvents. LG1 is prone to base catalysed
decomposition, and the intended Suzuki reaction was hampered accordingly. Changing the
base from potassium carbonate (5% conversion) to triethylamine (10% conversion) in LG1 did
not provide a significant improvement.

Figure 12-5. Coupling of 4-bromoacetophenone. Propylene carbonate (propylene carb.) and 2-

methyltetrahydrofuran (2-MeTHF) are abbreviated in the axis label.
The second example converted 4-bromophenylacetic acid to Felbinac, a topical anti-

inflammatory, by reaction with phenylboronic acid. Conversions were low at room temperature
and so reactions were performed at 65 °C. Otherwise the pre-catalyst, base, and quantity of
water added remained the same. These conditions permitted complete conversion in
conventional solvents (Figure 12-6). However, only LV1 of the ReSolve candidates was able
to match their performance. LG1 (2% conversion) failed again, while IS3 (63%) and LG59
(64%) both offered modest conversions.
Figure 12-6. Coupling of 4-bromophenylacetic acid. Propylene carbonate (propylene carb.) and 2-

Finally, a ligand was introduced to investigate the possibility of diminishing the impact of
changing the solvent. This case study, reacting phenylboronic acid with 4-bromotoluene, used
the same ratio of organic solvent to water (3:1 vol/vol) as in previous examples but with 3
equivalents of potassium phosphate as base and [1,1′-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a pre-catalyst (4 mol%). This
catalytic system has previously been optimised, primarily through the quantity of water added,
for LG1 (Wilson et al., 2018a) and IS3 (Wilson et al., 2018b). Despite that, conversions to 4-
phenyl toluene were broadly similar across solvents (Figure 12-7). A notable result was
achieved in LG1, with comparable performance to NMP despite failing in the previous
examples of the Suzuki reaction without an auxiliary ligand. IS3 was the highest performing
solvent with 96% conversion obtained, demonstrating a clear advantage over other solvents.
Figure 12-7. Coupling of 4-bromotoluene. Propylene carbonate (propylene carb.) and 2-

The Suzuki reaction can, in theory, be influenced by the choice of solvent in a multitude of
ways (Sherwood et al., 2019a). In practice, with appropriate ligands, the Suzuki reaction is
rapid under mild conditions and the choice of solvent becomes less important. This permits
solvent substitution in favour of less hazardous solvents. This is in contrast to other cross-
coupling methods in which the solvent has a more crucial role stabilising organometal
reactants or activated complexes throughout the catalytic cycle. Without ligands, base
instability of the solvent became a factor (where applicable). In general, the performance of
green solvents such as IPA and propylene carbonate was superior to the ReSolve candidates
across the case studies (Sherwood, 2020b).

13 Heck reaction
Published at https://doi.org/10.1002/cssc.202000462 (open access)
Context
The Heck reaction is an important palladium catalysed C-C bond forming reaction. It is
dependent on solvent polarity, being promoted in polar solvents. (Beletskaya and Cheprakov,
2000, Parker et al., 2014) As such, the ReSolve candidates OT3, OT5, OT6 and OT7 were
tested for their ability to facilitate a model Heck reaction between methyl acrylate and
iodobenzene (Figure 13-1).
Figure 13-1. The reaction scheme of the Heck reaction between iodobenzene and methyl acrylate.
Experimental
Iodobenzene (1.67 mL, 15 mmol), methyl acrylate (1.63 mL, 18 mmol), triethylamine (2.51 mL,
18 mmol) and the chosen solvent (6 mL) were added to a 25 mL round-bottomed flask and
pre-heated to 100 °C and stirred with a magnetic stirring bead at 500 rpm. Palladium acetate
(10 mg, 3 mol%) was added to the flask to begin the reaction. Aliquots were taken after 30-60
minutes to determine conversion by NMR spectroscopy.
Results
The reaction was found to be first order with respect to methyl acrylate. OT7 was particularly
effective for this reaction, performing comparably to DMSO and marginally better than OT3
(Figure 13-2). OT6 and OT5 fitted the linear trend and performed as expected according to
their polarity. Interestingly, during the reaction it was observed that the triethylammonium
iodide salt formed during the coupling precipitated out of solution in ReSolve candidates. In
contrast, the traditional dipolar aprotic solvents kept the ammonium salt in solution throughout
the reaction. This is potentially very useful as it makes product isolation easier compared to
traditional dipolar aprotic solvents. This suggests a lack of ionic character and hydrogen
bonding ability, an unusual property for dipolar aprotic solvents, which is consistent with the
high Log P(o/w) of OT5, OT6 and OT7. This may be beneficial in many future chemical
processes where at lower catalyst loadings deactivation by salts may be an issue.

-4
Traditional solvents
Succindiamides DMF
-6 DMAc
NMP
OT7
-8 OT5 DMSO
OT6 OT3
ln(k1)
-10
-12 1,4-Dioxane
Toluene
p-Cymene
-14
-16
0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00
π*
Figure 13-2. A LSER for the Heck reaction between iodobenzene and methyl acrylate.

14 C-H bond activation
Context
The activation of carbon-hydrogen bonds of aromatic substrates is receiving a lot of attention
in the academic community as a way to avoid the use of organometal reactants. Unlike cross-
coupling chemistry, there are a very large number of methodologies that are generally quite
specific to certain reactants. Broadly speaking, the choice of solvent reflects the general
approach that has been adopted, be it an oxidative method or through deprotonation of the
substrate. The former often requires 1,2-dichloroethane as a solvent. The latter can be
achieved using mild bases but at high temperature in NMP. The ability of ReSolve candidates
to withstand reactions at 150 °C is tested with this case study (Figure 14-1).
Figure 14-1. The synthesis of N-methyl-2-(4’-acetylphenyl)pyrrole.
Experimental
To 4-bromoacetophenone (0.3734 g, 1.876 mmol) and potassium acetate (0.3682 g,
2 eq.) was added a solution of palladium acetate (0.1 mol%) in the chosen reaction solvent
(2 mL) and heated to 150 °C. N-Methylpyrrole (0.50 mL) was added in one portion, and the
resultant mixture was stirred for 16 hours. The reaction was then cooled, vacuum filtered
through celite and washed with diethyl ether. The filtrate was concentrated in vacuo and the
conversion analysed by 1H-NMR spectroscopy.
Results
The reaction was attempted in NMP, DMF, LG1, LG2, OT3 and IS3. The conversion to the
intended product was good in NMP and DMF (Figure 14-2). LG1 and IS3 appeared to
decompose shortly upon the initiation of the reaction. A mild base was used, that at the
ambient temperature is tolerated by LG1 and IS3. However, heating at 150 °C caused
darkening of the reaction solution, and in the case of LG1, eventual solidification of the
reaction mixture. However, LG2 matched the performance of NMP. As a solid at room
temperature, LG2 is appropriate for high temperature, base activated chemistry but is not
useful for chemistry below 70 °C. This conclusion corroborates an earlier investigation of LG2
for SAr2 reactions (Pacheco et al., 2016). An excellent conversion was also obtained in OT3,
an amide included as a reference solvent.

Figure 14-2. Conversion of 4-bromoacetophenone in different solvents.

15 Heterocycle synthesis
Published at https://doi.org/10.3390/molecules24122209 (open access)
Context
Multicomponent reactions are a green approach to shortened syntheses of complex
molecules. The synthesis of tetrahydropyridines can be performed on mixtures of an aniline,
an aldehyde, and a 1,3-dicarbonyl compound with Lewis acid catalysts (Figure 15-1). Previous
reports suggest dipolar aprotic solvents maximise the yield so long as the product precipitates
to avoid an equilibrium limiting step.
Figure 15-1. The proposed mechanism of tetrahydropyridine synthesis from p-methoxyaniline,

benzaldehyde and methyl acetoacetate. The yield limiting equilibrium is drawn in the box. Key: [M],
indium trichloride or any derivative Lewis acid.

Experimental
To a solution of p-anisidine (0.517 g, 4.2 mmol) in the chosen solvent (1 mL or 4 mL), was
added indium trichloride hydrate (0.159 g, 33 mol%), benzaldehyde (0.424 g, 4.0 mmol) and
methyl acetoacetate (1, 0.323 g, 2.0 mmol). The mixture was stirred under air at room
temperature for typically 16 hours (up to 64 hours). The resulting precipitate was isolated by
filtration, washed with methanol, and recrystallised from methanol-dichloromethane to give
methyl 1,2,5,6-tetrahydro-1- (4-methoxyphenyl)-4-[(4-methoxyphenyl)amino]-2,6-diphenyl-3-
pyridine-3-carboxylate (up to 73%). δH (400 MHz; CDCl3) 2.64 (1 H, m, CH2), 2.79 (1 H, m,
CH2), 3.64 (3 H, s, CH3), 3.73 (3 H, s, CH3), 3.89 (3 H, s, CH3), 5.03 (1 H, m, CH), 6.16 (2 H,
d, J 9, Ar-CH), 6.32 (1 H, s, CH), 6.42 (2 H, d, J 9, Ar-CH), 6.60 (2 H, d, J 9, Ar-CH), 6.65 (2
H, d, J 9, Ar-CH), 7.12-7.32 (10 H, m, Ar-CH), 10.08 (1 H, s, NH). m/z 521.2445 (M + H+,
calculated 521.2435, ESI).
Results
The tetrahydropyridine product yield is generally proportional with the dipolarity of the solvent,
particularly under dilute conditions (Sherwood et al., 2019b). For the most polar solvents
concentrated conditions were required to precipitate the product (applies to NMP, DMF, OT3,
IS3, LG59, and LG60). The isolated yields were recorded after recrystallisation, and shown in
Figure 15-2 from least polar solvent (left) to most polar (right) according to the Kamlet-Abboud-
Taft solvatochromic dipolarity scale. Concentrated conditions reduced the dependency of the
yield on the solvent, however, some variation between solvents remained. LG59 outperformed
NMP, while the yield in IS3 and LG60 was lower than anticipated. The precipitation of the
product is encouraged by protic solvents, hence an advantage is provided by LG59 as an
alcohol. Note LG1 is reactive in these conditions and no product could be obtained.
Figure 15-2. Isolated yields of the piperidine product from 0.5 M (standard) or 2 M (concentrated)
reaction conditions.

16 Conclusions
An overview of the testing results is given in Table 16-1. In the majority of case studies, a
ReSolve candidate is suitable, and good performance justifying the replacement of NMP was
observed in 6 case studies. Other applications are promising but require further work, for
example in formulations. The areas where conventional dipolar aprotic solvents excel and
remain difficult to replace relate to the solubility of small, polar molecules.
Table 16-1. Summary of solvent performance.
Application (sub-set) Challenge Comparison to NMP
Paint stripping (polymer Swelling or OT16 is a promising candidate but further

interactions) dissolution of work is required to optimise a suitable
polymers. formulation.
DMPA solubility (small High Low concentrations achieved in ReSolve

molecule solubility) concentrations. candidates.
Polymer solubility (for High OT16 and LG64 dissolve PVC and PS. OT3
further processing) concentrations. and OT7 fully dissolved PES and PAI.
Membrane fabrication Porous structure. OT7 produces a PES membrane.

(materials science)
Bioactives solubility High Low concentrations achieved in ReSolve

(small molecule concentrations. candidates.
solubility and
formulation)
Graphene dispersion High LG1 can replace NMP.

(materials science) concentrations.
Hydrocarbon extraction High selectivity. At low aromatic content, LG1 and LG59
(extraction) provide equal or higher selectivity compared
to NMP in different case studies (when using
co-solvents) but with a loss of mass
efficiency.
Menschutkin reaction High reaction rate. Several ReSolve candidates outperform

(organic synthesis) NMP.
Nucleophilic fluorination High reaction rate. The reaction occurs in LG6 and LG64, but
(organic synthesis) slower than in NMP.
Suzuki reaction (organic Base stability and ReSolve candidates are competitive with
synthesis) high conversion to traditional solvents with suitable catalytic
product. complexes.
Heck reaction (organic High reaction rate The reaction occurs in OT3 and OT7, but
synthesis) and conversion. slower than in NMP.

Application (sub-set) Challenge Comparison to NMP
C-H bond activation Stability at high LG2 and OT3 can replace NMP.
(organic synthesis) temperature and
high conversion to
product.
Heterocycle synthesis Overcome yield LG59 outperforms NMP, while OT3 and
(organic synthesis) and isolation LG60 are also appropriate substitutes.
difficulties.
The results of this research broadly concur with other contemporary investigations. No
universal replacement for NMP is known and is unlikely to be discovered. Thus a
diversification of the solvent market is probable once the most hazardous solvents are phased
out of use. Historically, solvents have been a small proportion of operation costs, but it may
transpire that the use of specialised solvents becomes necessary and manufacturing
operations will have to reevaluate costs.
In light of ongoing work outside of the ReSolve consortium, some applications became less of
a priority. Of particular note is the fabrication of polyamideimide (PAI) wire enamels. It is the
largest European market for NMP, and has been granted an exemption from the REACH
restriction of NMP for another 4 years. A couple of months before the ReSolve project began,
Huntsman filed a patent describing the successful preparation of a PAI and subsequent wire
coating using LG1 as a solvent (Weidmann, 2017). In addition, several papers have recently
emerged describing LG1 as a solvent for the preparation of polymer membranes (Carner et
al., 2020, Marino et al., 2019, Milescu et al., 2019). The successful dispersion of graphene
and other materials in LG1 also diminished the necessity to retest these applications in detail
(Budarin et al., 2018, Notley and Gharib, 2017). In response, we shortened case studies in
these areas and focused on underdeveloped applications where an advantage over NMP
might have been gained.

17 Acknowledgements
The following students contributed some of the work: Douwe Duijn performed the nucleophilic
fluorinations and some Menschutkin reactions. Yijia Zhang performed the graphene dispersion
experiments. Marriyum Hasany performed some of the bioactive molecule solubility tests.

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D3.6 - Application of NMP Replacement Solvents

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D3.6 - Application of NMP replacement

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The leading bio-based NMP substitute is dihydrolevoglucosenone (brand name Cyrene™).

Table 2-1. Solvents appearing in this report.

Code Name Renewable source

LG1 6,8-Dioxabicyclo[3.2.1]octan-4-one Levoglucosenone

LG2 spiro[6,8‐Dioxabicyclo[3.2.1]octane‐4,2′‐[1,3]dioxolane] Levoglucosenone

LG6 Confidential - Disclosed in D2.7 Levoglucosenone

LG13 6,8-Dioxabicyclo[3.2.1]octan-2-methoxy-4-one Levoglucosenone

LG23 4-Methoxy-6,8-dioxabicyclo[3.2.1]octane Levoglucosenone

LG59 1,6-Anhydro-3,4-dideoxy-hexopyranose Levoglucosenone

LG60 1,6-Anhydro-3-deoxy-4-O-methyl-hexopyranose Levoglucosenone

LG64 Confidential - Disclosed in D2.7 Levoglucosenone

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LV1 γ-Valerolactone Levulinic acid

LV3 Methyl levulinate Levulinic acid

LV5 Ethyl levulinate Levulinic acid

LV34 Butyl levulinate Levulinic acid

IS2 Dimethyl isomannide Isohexides

IS3 Dimethyl isosorbide Isohexides

IS92 Confidential - Disclosed in D2.1 Isohexides

IT13 Dimethyl itaconate Itaconic acid

OT3 N-Butyl pyrrolidinone Succinic acid

OT4 1,4-Dimethyl-7-oxabicyclo[2.2.1]heptane Succinic acid

OT5 N,N'-Dibutyl-N,N'-diethylsuccinamide Succinic acid

OT6 N,N,N',N'-Tetrabutylsuccinamide Succinic acid

OT7 N,N'-Dibutyl-N,N'-dimethylsuccinamide Succinic acid

OT16 Confidential - Disclosed in D2.4 Hydroxymethylfurfural

OT31 Confidential - Disclosed in D2.4 Hydroxymethylfurfural

OT32 Confidential - Disclosed in D2.4 Hydroxymethylfurfural

OT33 Confidential - Disclosed in D2.4 Hydroxymethylfurfural

OT34 Confidential - Disclosed in D2.4 Hydroxymethylfurfural

IDL Confidential - Disclosed in D2.4 Confidential

AK1 2,2,5,5-Tetramethyloxolane Alkenes

AK2 Confidential - Disclosed in D2.4 Alkenes

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Figure 3-2. Substrate 1 example.

Figure 3-3. Substrate 2 example.

• Solvent application: 50 µl as neat solvent or as paint stripper formulation was applied on

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Initial solvent set:

Figure 3-4. Substrate 1 approx. 5 min. after application of formulation.

Figure 3-5. Substrate 1 approx. 60 min. after application of formulation.

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Figure 3-6. Substrate 1 after manually wiping off of formulation.

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Figure 3-7. Substrate 1 approx. 60 min. after application of neat solvents.

Figure 3-8. Substrate 1 after manually wiping off of neat solvents.

Expanded solvent set:

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Figure 3-9. Substrate 2 (left half) before application.

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Figure 3-13. Substrate 1 (right half) before application.

Figure 3-14. Substrate 1 (left half) before application.

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Figure 3-15. Substrate 1 (right half) 30 min. after application.