Explorations With Deep Eutectic

Solvents For Chemical Extractions

Douglas E. Raynie
Department of Chemistry and Biochemistry
South Dakota State University
douglas.raynie@sdstate.edu

Green
Chemistry

Supercritical
Fluid
Technology

Analytical
Separations

Fundamental
Studies

Environmental
Analysis

Bioprocessing

Chemical
Problem
Solving

DIFFUSION COEFFICIENT
SUMMARY

DECREASING THE IMPACT OF SOLVENTS

1.Reduce the volume of solvent
use higher concentra/ons
use solvent for more than one step

2. Make the solvents greener
carefully chosen conven/onal solvents
new green solvents

GREEN SOLVENTS
We know guidelines such as like dissolves like,
but when it comes to green solvents, how will we
recognize one when we see it?

General Guidelines for PredicHng the Toxicity of Solvents

As the number of alipha/c carbons increases, toxicity increases up to about
eight carbons. Including subs/tu/ons, toxicity increases as molecular weight
increases up to eight carbons.

As the number of carbon-carbon double bonds increases, toxicity increases.

As the degree of halogena/ons increases, toxicity increases. Brominated
compounds are more toxic than chlorinated, which are more toxicity than
uorinated.

These same general statements are true for alipha/c subs/tu/on on aroma/c
compounds.

Subs/tu/on of aroma/cs increases toxicity. Subs/tu/on on phenols para- or
ortho-, para- to the hydroxyl are more toxic.

PROPERTIES OF CONCERN
For greenness
boiling point/energy to dis/ll
ash point
cumula/ve energy demand

For uHlity
polarity
basicity/hydrogen-bond accep/ng ability
acidity/hydrogen-bond dona/ng ability
viscosity

WHAT IS A GREEN SOLVENT?

C. Capello, U. Fischer, and K. Hungerbuhler, Green Chem., 9, 927-934 (2007).

GSK
SOLVENT
SELECTION
GUIDE

C. Jimenez-Gonzalez, A. D. Curzons, D. J. Constable, and

V. L. Cunningham, J. Clean Technol. Environ. Policy, 7, 42-50 (2005).

PFIZER MEDICINAL CHEMISTRY

SOLVENT SELECTION GUIDE
Preferred
Water
Acetone
Ethanol
2-Propanol
1-Propanol
Heptane
Ethyl acetate
Isopropyl acetate
Methanol
MEK
1-Butanol
t-Butanol

Usable
Cyclohexane
Toluene
Methylcyclohexane
TBME
Isooctane
Acetonitrile
2-Me THF
THF
Xylenes
DMSO
Acetic acid
Ethylene glycol

Undesirable
Pentane
Hexane(s)
Di-isopropyl ether
Diethyl ether
Dichloromethane
Dichloroethane
Chloroform
NMP
DMF
Pyridine
DMAc
Dioxane
Dimethoxyethane

PFIZER SOLVENT REPLACEMENT TABLE

Red Solvents

Alternative

Pentane

Heptane

Hexane(s)

Heptane

Di-isopropyl ether or ether

2-MeTHF or t-Butyl methyl ether

Dioxane or dimethoxyethane

2-MeTHF or t-Butyl methyl ether

Chloroform, dichloroethane or carbon

tetrachloride

DCM

DMF, NMP or DMAc

Acetonitrile

Pyridine

Et3N (if pyridine used as base)

DCM (extractions)

EtOAc, MTBE, toluene, 2-MeTHF

DCM (chromatography)

EtOAc/Heptanes

Benzene

Toluene

Deep Eutectic Solvents (DES)

Eutectic mixtures of quaternary ammonium salts (QAS)
and hydrogen bond donors (HBD)
Bulky cations and smaller anions which are bound to a
HBD

Diagrammatic representation of how HBD interacts with a QAS

Abbott, A. P.; Boothby, D et al.; J. Am. Chem. Soc., 2004, 126 (29), 9142-9147.

Choline chloride-Urea (1:2)

Choline chloride melts at
302C and urea melts at 133C
Molar ratio of choline chloride
to urea is 1:2
The eutectic mixture melts at
12C
The depression in freezing
point is 178C
Andrew P. Abbott.; Glen Capper et al.; Chem. Eur. J., 2004, 10, 3769-3774

Choline chloride-Urea

Synthesis
General formula
(R1R2R3R4N+) (X-) (R5) (YH)
A

106 combinations
Not possible to study all the combinations
QAS:
HBD:
O
ClHO

N+

OH

N+
O
Cl-

Choline chloride Acetylcholine chloride

HO
NH2

H2N

Urea

Andrew P. Abbott.; Glen Capper et al.; Chem. Eur. J., 2004, 10, 3769-3774

OH

Glycerol

Synthesis
16 different combinations of DES were synthesized by
changing the QAS, HBD, and their composition
Binary:
QAS+HBD (4 combinations)
Ternary:
QAS+HBD+HBD (6 combinations)
QAS+QAS+HBD (6 combinations)

QAS+HBD
(4combinations)

QAS+HBD+HBD
(6 combinations)

QAS+QAS+HBD
(6 combinations)

Components

Composition

Choline chloride: Urea

1:2

Choline chloride: Glycerol

1:2

Acetyl choline chloride: Urea

1:2

Acetyl choline chloride: Glycerol

1:2

Choline chloride: Urea: Glycerol

1:1:1

Choline chloride: Urea: Glycerol

2:3:1

Choline chloride: Urea: Glycerol

2:1:3

Acetyl choline chloride: Urea: Glycerol

1:1:1

Acetyl choline chloride: Urea: Glycerol

2:3:1

Acetyl choline chloride: Urea: Glycerol

2:1:3

Choline chloride: Acetyl choline chloride: Urea

1:1:4

Choline chloride: Acetyl choline chloride: Urea

1:2:6

Choline chloride: Acetyl choline chloride: Urea

2:1:6

Choline chloride: Acetyl choline chloride: Glycerol

1:1:4

Choline chloride: Acetyl choline chloride: Glycerol

1:2:6

Choline chloride: Acetyl choline chloride: Glycerol

2:1:6

Phase Properties
Tc range from -37C to -15C
Tm range from 12C to 25C
Tc and Tm values of DES were far less than the
corresponding QAS and HBD used in their synthesis
Tdecomp (10%) range from 186C to 208C

Viscosity
Range from 5.4294 x 10-1 Pa.sec to 0.9243 x 10-2 Pa.sec
As the choline chloride concentration increased, viscosity
decreased
Viscosity studied as a function of temperature from 25C
-150C, with increasing temperature viscosity decreased

Density
Range from 1.1684 g/mL to 1.264 g/mL
As the glycerol concentration increased, density increased

pH
Range from 10.44 to 5.42
As the acetylcholine chloride concentration increased, pH
decreased
As the urea concentration increased, pH increased

Kow
Range from 0.061 to 0.141
As the glycerol concentration increased, Kow increased

RefracHve Index

Ranges from 1.43-1.51
Relates to polarity (water is 1.33)

Miscibility with Common Solvents

Choline
Chloride

Urea

Glycerol

1:2 Choline
Chloride: Urea

1:2 Choline
Chloride:
Glycerol

1:1:1 Choline
Chloride:Urea:
Glycerol

Water

Acetone

IS

IS

IS

IS

IS

IS

Acetonitrile

IS

IS

IS

IS

IS

IS

Methanol

Ethanol

Isopropanol

IS

IS

IS

IS

Dichloromethane

IS

SS

IS

IS

IS

IS

Chloroform

SS

SS

IS

IS

IS

IS

DMSO

SS

Pentane

IS

IS

IS

IS

IS

IS

Hexane

IA

IS

IS

IS

IS

IS

Toluene

IS

IS

IS

IS

IS

S= soluble SS = slightly soluble IS = insoluble

DES soluble with polar solvents

Kamlet-TaQ Solvatochromic Parameters

Cyclohexane

Benzene

0.1

0.59

Acetonitrile

0.19

0.31

0.75

Water

1.17

0.47

1.09

1:2 Choline
Chloride:Urea

0.734

0.632

0.987

1:2 Choline
Chloride:Glycerol

0.927

0.642

0.979

1:1:1 Choline
Chloride:Urea:Glycerol

0.917

0.765

0.985

= acidity, H-bond dona/ng ability

= basicity, H-bond accep/ng ability
* = polarity and polarizability

DES

DES

DES

DES

Dissolution of Sugars
Glucose

Sucrose

Dextrose

Xylose

1:2 Choline chloride:

Urea

Soluble

Soluble

Soluble

Soluble

1:2 Choline chloride:

Glycerol

Soluble

Soluble

Soluble

Soluble

1:2 Acetyl choline

chloride: Urea

Soluble

Soluble

Soluble

Soluble

1:2 Acetyl choline

chloride: Glycerol

Soluble

Soluble

Soluble

Soluble

Naturally Occurring DES

1:2, 1:3 Citric Acid:Choline Chloride

1:1, 1:2, 1:3 Malic Acid:Choline Chloride
1:1, 1:2, 1:3 Maleic Acid:Choline Chloride
1:1 Aconi/c Acid:Choline Chloride
1:1:1 Glucose:Choline Chloride:Water
1:1:1 Fructose:Choline Chloride:Water
1:1:1 Sucrose:Choline Chloride:Water
1:1, 1:2, 1:3 Citric Acid:Proline
1:1 Malic Acid:Glucose
4:1 Maleic Acid:Glucose
1:1 Malic Acid:Fructose 1:1 Maleic Acid:Sucrose
1:1 Malic Acid:Sucrose
1:1 Glucose:Fructose
2:2 Citric Acid:Glucose
1:1 Fructose:Sucrose
2:1 Citric Acid:Trehalose 1:1 Glucose:Sucrose
1:1 Citric Acid:Sucrose
1:1:1 Sucrose:Glucose:Fructose
Plant Physiology 156: 1701-1705 (2011).

Analy.cal Chemistry 85: 6272-6278 (2013).

CONCLUSIONS

Deep eutec/c solvents comprise a class of novel, green solvents
suitable for separa/ons and other chemical processes.