IL Origins What Were ILs? ILs and Green Chemistry What Are ILs

5/16/2015
Are Alternative Solvent Systems such as
Ionic Liquids Green or not Based on
Toxicity, Chemical or Energy Use, or
Utilization? (Hint: It Depends)
Robin D. Rogers
Canada Excellence Research Chair in
Green Chemistry and Green Chemicals
Department of Chemistry
McGill University
Montreal, QC, Canada
IL Origins
What Were ILs?
ILs and Green Chemistry
What Are ILs?
ILs as Solvents
ILs as Materials
ILs as Pharmacueticals
ILs and Innovation
1
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What are
Ionic Liquids
Anyway?
Ionic Liquids Are:
♦ Toxic
♦ Expensive
♦ An Academic Curiosity
♦ Green
♦ Edible
♦ Biosourced
♦ Magic
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Perhaps Better
to Ask,
What were
Ionic Liquids?
A Short Ionic
Liquid History
3
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Paul von Walden
Bull. Acad. Impér. Sci. St. Pétersbourg, 1914, 8, 405-422
The First IL?
[EtNH3][NO3]
mp 12 °C
1914
Frank Hurley and Thomas Wier (Rice Institute)
[1]
[2]
[3]
[4]
Hurley, F.H., Electrodeposition of aluminum, U.S.
Pat., 4,446,331 (1948).
Hurley, F.H. and Wier, T.P., “The
electrodeposition of aluminium from nonaqueous
solutions at room temperature”, J. Electrochem.
Soc. 98, 207-212 (1951).
Hurley, F.H. and Wier, T.P., “Electrodeposition of
metals from fused quaternary ammonium salts”, J.
Electrochem. Soc. 98, 203-206 (1951).
Wier Jr., T.P. and Hurley, F.H., U.S. Pat.,
4,446,349 (1948).
1948-51
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Bob Osteryoung, Bernard Gilbert, et al.
[1] Chum, H.L., Koch, V.R., Miller, L.L. and Osteryoung,
R.A., “An electrochemical scrutiny of organometallic iron
complexes and hexamethylbenzene in a room temperature
molten salt”, J. Am. Chem. Soc. 97, 3264-3265 (1975).
[2] Koch, V.R., Miller, L.L. and Osteryoung, R.A.,
“Electroinitiated Friedel-Crafts transalkylations in a
room-temperature molten-salt medium”, J. Am. Chem.
Soc. 98 (17), 5277-5284 (1976).
[3] Gilbert, R.J. and Osteryoung, R.A., “Raman spectra of
molten aluminium chloride: 1-butylpyridinium chloride
systems at ambient temperatures”, Inorg. Chem. 17, 27282729 (1978).
1975-78
Chuck Hussey and John Wilkes
Wilkes, J.S., Levisky, J.A., Wilson, R.A. and Hussey,
C.L. “Dialkylimidazolium chloroaluminate melts - a
new class of room-temperature ionic liquids for
electrochemistry, spectroscopy, and synthesis”
Inorg. Chem. 21 (3), 1263-1264 (1982).
1982
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John Wilkes and Mike Zaworotko
Wilkes, J.S. and Zaworotko, M.J. “Air and water
stable 1-ethyl-3-methylimidazolium based ionic
liquids,” J. Chem. Soc., Chem. Commun. (13), 965967 (1992).
1992
Chauvin Nobel Address
2005
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The First Philosophy of Ionic Liquids
The general picture of these organic salts
at low temperatures (below, or around
100 ºC) corresponds to the experiences
made with inorganic (single, noncomplexing) molten salts at much higher
temperatures (ca. 300-600 ºC).
NaCl
800 oC
40 oC
[C10mim][PF6]
IL Definitions:
low melting salts
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800 oC
NaCl
“The important thing in science is
not so much to obtain new facts as
to discover new ways of thinking
about them.”
Sir William Bragg
British physicist (1862 - 1942)
Liquid Salts that can be used as solvents
Water Ionic Liquid
that won’t evaporate or burn
and can be immiscible with water!
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So What Were Ionic Liquids?
– Low melting organic
salt
– Little/no vapor
pressure
– Non-flammable
Cations
– Typically
has wide
liquid range R5
R2
R3
R1 N
+ N
R5
R4
R4
+
R3
N
– Viscous
– Solvent properties are
different to molecular
solvents
– Solvent properties can be
varied (and controlled)
Anions
Cl-/[AlCl3]
R6
Cl , Br , I
R1
[NO3]-, [SO4]2-
R2
-
-
Reactive to water
-
Air and water stable
[CF3COO]-, [CF3SO2][BF4]-
R1
N R2
R4
R3
R1
P R2
R4
R3
[PF6]-
Decreasing
coordinating ability
Increasing
hydrophobicity
[CF3SO2)2N]
Where did the
connection between
Ionic Liquids and Green
Chemistry start and
what happened?
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Principles of Green Chemistry
• The use of auxiliary substances (e.g.,
solvents, separation agents, etc.) should be
made unnecessary wherever practicable,
and in cases where they are necessary,
should be innocuous.
P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, New York, 1998.
Chemical Releases by
Industry Sector
a:
b:
c:
d:
e:
1,000
800
600
f:
g:
h:
i:
j:
400
200
0
a
b
c
d
e
f
g
h
i
chemicals
primary metals
paper
(multiple codes)
transportation
equipment
plastics
fabricated metals
petroleum
furniture
printing
j
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Chemical ReleasesSurface
Water (2.9%)
In 1994, 2.3 billion
pounds of ca. 300
Toxic Release
Inventory (TRI)
chemicals were
reported as
released to the
environment by
TRI-reporting
facilities.
Air (68.9%)
Land
(12.8%)
Underground
Injection (15.4%)
Motivation/Green Chemistry
Non-volatile ILs can
eliminate THE major
pathway to environmental
chemical release.
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•Crete 2000
In 2000, a group of scientists and engineers met to
plan a research agenda for this growing field.
Green Industrial Applications of
Ionic Liquids
A NATO Advanced Research Workshop
Crete, Greece - April 12-16, 2000
The first international meeting dedicated to the study
and application of RTIL (ambient temperature melts).
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Green Industrial Applications of Ionic Liquids
A NATO Advanced Research Workshop
Crete, Greece - April 12-16, 2000
Green Industrial Applications of
Ionic Liquids
• NATO Science Series,
II/92
• From NATO
Advanced Research
Workshop, April1216, 2000, Heraklion,
Crete.
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Green Industrial Applications of Ionic Liquids
A NATO Advanced Research Workshop
Crete, Greece - April 12-16, 2000
Outcomes
IL are intrinsically interest and worthy of study
for advancing science (ionic vs. molecular
solvents) with the expectation that something
useful may be derived.
Combined with green chemistry, a new
paradigm in thinking about synthesis in general,
IL provide an opportunity for
science/engineering/business to work together
from the beginning of the fields' development.


What was Driving This Activity?
Generation 1:
ILs with unique tunable physical properties
Physical property
R1
R4 N
R1
R2
R3
N
R4 P
- melting point
- density
- viscosity
- thermal
stability
- conductivity
- hydrophobicity
- refractive index
R2
R3
N
O
N
R
N
N
F3C
S
Physical property
O
N
O
S
CF3
O
lower melting point / hydrophobicity
C6H13
C6H14
P
C14H29
NC
N
CN
C6H14
hydrophobicity / lower viscosity
- melting point
- density
F 3C
- viscosity
- thermal
stability
NC
- conductivity
- hydrophobicity
- refractive index
S
O
N
O
N
S
N
N
N
N
FeCl4
CN
high thermal stability / hydrophilicity
S
O
HO
S
O
O
O
O
O
O
BF4
O
O
Cl
Cl
CF3
O
O
OH
N
O
S
O
PF6
O
SOLVENTS
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Using Unusual IL
Solubility/Solvation for
Sustainable Technology
♦ Many ILs are water soluble
and can also dissolve waterinsoluble compounds.
♦ Products can be recovered
by precipitation using water
as an anti-solvent.
Ionic Liquid Solvents
Ionic Liquids are able to dissolve biopolymers
cellulose
chitin
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But, the attention was on how
ILs can really be used as
reaction media.
ILs – Common Advantages
♦ Safety – Many ILs are non-flammable and have low volatility.
♦ Environmental Impact – Low volatility of many ILs averts this
release pathway and facilitates recycling.
♦ Wide liquid range – ILs allow excursions into temperatures
and pressures inaccessible for many solvents.
♦ Tunability – Changing one of the ions preserves some chemical
function while greatly changing the physical properties.
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ILs – Common(ly Perceived)
Disadvantages
♦ Not always safe – ILs can be toxic, flammable, or explosive.
♦ Low volatility can be a disadvantage – ILs are incompatible
with common evaporative methods of product isolation.
♦ Physical properties – ILs tend to be more viscous than organic
solvents and may be supercooled at room temperature.
♦ Expensive – Probably the most cited drawback to ILs.
“Typical” IL Ions
Cations
Anions
Drawbacks of some ions synonymous with ILs include
high cost and presence of fluoride.
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What about ‘[Bmim][PF6]
1-butyl-3-methylimidazolium hexafluorophosphate
[C4mim][PF6]
♦ Was widely studied for a range of applications:
electrochemistry, separations (aqueous/IL, scCO2/IL),
and chemical reactions
♦ Reasons for choice
♦
♦
♦
♦
♦
♦
widely used within peer group
hydrophobic
[PF6]- anion is non-coordinating
easy to prepare (chloro- and bromobutane are not volatile, IL
separates from water)
Supercritical CO2 is soluble in [C4mim][PF6]
Miscibility with ethanol in [Cnmim][PF6] varies with water
Hexafluorophosphate anions
are unacceptable in water!
♦ The hexafluorophosphate anion is known to be
hydrolytically unstable, releasing HF on
decomposition
♦ Why should this be different in an IL?
♦ Decomposition can cause dissolution of glass
flasks or damage to steel autoclaves and
reactors
♦ Do [PF6]- ILs have a use? Yes, mostly in
primary research
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What About
ILs and Toxicity?
Ionic Liquids and C. elegans
A Study in Toxicity (2004)
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Lethality and Aversion
Alkyl chain increase  lethality increases
When animals are exposed to 1.0
mg/mL ionic liquid the lethality
•0.0%  C4mimCl
•11%  C8mim
•97%  C14mimCl
Likewise the trend continues with
5.0 mg/mL ionic liquid exposure
1.0
2.5
5.0
•1.0%  C4mim
•66%  C8mim
•100%  C14mim
Swatloski, R. P.; Holbrey, J. D.; Memon, S. B.; Caldwell, G. A.; Caldwell, K. A.; Rogers, R. D. Chem.Commun. 2004, 6, 668-669
Preliminary Results on Other ILs
80
N
+
N
CH
3
Cl
N
+
N
CH
3
B r
N
CH
N
+
2
F
3
F
B
LC50 (mg/mL)
F
60
N
N
+
CH
F
F
F
3
P
F
N
N
N
20
HO
F
F
N
+
40
F
CH
N
+
N
N
+
CH
3
6
7
N
+
5 Cl-
3
CH
8
3
N
0
N
Compound Number
Toxicity Category
Very highly toxic
Highly toxic
Moderately toxic
Slightly toxic
Not acutely toxic
N
+
14 7 2 8 10 1 3 9 13 12 11 4 5 6
B r
+
N
B r
LC50 (mg/mL)
< 10-4
10-4 – 10-3
10-3 – 10-2
10-2 – 10-1
> 10-1
+
N
CH
N
+
B r
3
F
N
CH
F
B
3
F
F
O
N
+
N
10
O
S
O
O
14
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Finding the RIGHT Ionic Liquid
GRAS/Biologically Derived
IL Ions
♦ More to the point – ILs do not need to be made out of a
specific set of ions at all.
♦ Many solid compounds on food additive/Generally
Recognized as Safe lists have been incorporated into ILs:
♦ Choline
♦ Small carboxylic acids
♦ Most biogenic amino acids
♦ Active pharmaceutical ingredients
♦ Biosourced ions
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Ionic Liquids Are:
♦ Toxic
♦ Expensive
♦ An Academic Curiosity
♦ Green
♦ Edible
♦ Biosourced
♦ Magic
– but not one ionic liquid
has all these properties!
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and, Green is in the eye of the
beholder
1-Butyl-3Himidazolium
Nitrate
Overgeneralizations and
The Green Counter-Revolution
Oversimplification in reports on ILs as solvents led to a host of
studies cautioning against their application in green chemistry.
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Overgeneralizations Can Be Misleading
Benzene is carcinogenic
(expensive/toxic/fill-in-the-blank) =
ALL ‘solvents’ are carcinogenic
(expensive/toxic/fill-in-the-blank)
Water is green (cheap/nontoxic/___) =
ALL ‘solvents’ are green
(cheap/nontoxic/___)
A Few Cations and Anions
now found in Ionic Liquids
N
N
N
N
N
N
N
NH2
NC
N
NC
N
NH2
N
NO2
H2 N
N N
N
P
O
N
C
N
N
N
S
N
S
C
N
N
O
C
N
I-
S
NO2
N
N
N
Br-
Cl-
N
O2N
N
N
F F
O
F
C
O
N
NO2
N N
N
O2N
O2N
N
N
N
N
F F
O
F
S
O
O
F F
F
N
F
F F
F
F
S
O2N
O
O
F
N
O
S
N
O O
N N
NO2
N
O S O
S
O
N
H2N
O
N
F
N F F F
O
F
F B F
F
F
F P
O
B
F
F
O
N
F
N
F3 C
O
N
O
CF2
F
O B O
F P F CF3
C
O
F2 C
F B C CF3
O
F F2
F F
F3 C
2
O
O
O2N
N
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Dual-functionality Imparts a
Unique Architectural Platform
The chemist has independent design control via
modification of either the cation, the anion, or both.
Parent cation
Structural modification
to cation
Parent anion
Combination
of functionalized
anion and cation
Multifunctional ionic liquid
composed of independently
designed components
Structural modification
to anion
ILs are a platform strategy to deliver
different chemical and physical
functionality in the same compound, but
segregated into different ion components;
this has applicability in many different
materials areas, but is currently underutilized.
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What Are Ionic Liquids?
Nonvolatile monopropellant
for advanced propulsion
systems1
Room-temperature liquid
dual biological action for
pharmaceutical applications2
Magnetically responsive liquid
crystal for advanced displays3
Ionic liquids are tools for unlocking new technologies
1.
Shamshina, J. L.; Smiglak, M.; Drab, D. M.; Parker, T. G.; Dykes, H. W. H., Jr.; Di Salvo, R.; Reich,
A. J.; Rogers, R. D. Chem. Commun. 2010, 46, 8965.
Bica, K.; Rijksen, C.; Nieuwenhuyzen, M.; Rogers, R. D. Phys. Chem. Chem. Phys. 2010, 12, 2011.
Getsis, A.; Balke, B.; Felser, C.; Mudring, A. –V. Crys. Growth Des. 2009, 9, 4429.
2.
3.
Generation 1:
ILs with unique tunable physical properties
Physical property
R1
R1
- melting point
- density
R4 N R2
R4 P R2
- viscosity
R3
R3
- thermal
stability
ILs with targeted
chemical
- conductivity
N
N
- hydrophobicity
Chemical Nproperty
- refractive index
R
OH
N
N
N

N
O
OEt
N
N
N
N
N
N
N
N
n
SO3H
N
CN
- chemical
N
reactivity
- high energy
density
- electrochemical
window
- flammability
- coordination
- solvation
- chiral induction
O
N
N
F3C
Physical property
O
S
N
O
S
CF3
O
lower melting point / hydrophobicity
Generation
2:
C
6H13
NC
CNwith
properties
combined
C6H14 P C14H
29
N
C6H14
hydrophobicity
/Olower
viscosity
N
N
NO2
2N
N
- melting point
O
O
Cl
- density
F3C S N S CF3
- viscosity
O
O
- thermal
FeCl4
stability
NC properties
CN
chosen
physical
O
- conductivity
N
BF4
- hydrophobicity
HO S O
O
Chemical
property
- refractive
index
O
N
O
NCl N
NN N
energy density / oxygen balance
high thermal stability / hydrophilicity
N
N
Cl
lower density / solvation
N
N
N
N

O
F3C
OEt
O
S
O
O
N
S
O
N
O2N
CF3
O
OH
O
- high energy
O S N O N PF6
S
density
O
COO
O
O
- electrochemical
H
CN
window
N
- flammability
N
N
I
CO
- oxygen balance
Rh
- UV blocker
I
CO
NC
CN
- chiral induction
- solvation
Cl
N
NO2
COO
N
chiral induction/ hydrophobicity
An Example:
ENERGETIC MATERIALS
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Ideal IL Energetic Material:
Desired Properties
Physical Properties
Melting point
< -40 °C
Surface tension
< 100 dyne cm-1
Density
> 1.4 g cm-3
Viscosity
As low as possible
Hazard Sensitivity
Thermal stability
TGA (75 °C,
< 1% loss of material
isothermal)
over 24 h
TGA (rate 10oC/min)
> 120 °C for Tdecomp
Thermodynamic properties
Heat of formation
as positive as possible
Heat of combustion
> 6 kcal g-1
Impact
> 50 kg cm
Friction
Detonation
Electrostatic discharge
> 120 N
LD50
> 0.5 g kg-1
> 5000 V at 0.25 J
AMES
Negative
Toxicology
Independent, Modular Design of
Components in Multifunctional EILs
Project Goal
To develop synthetic strategies for the introduction of energetic functions and
components into potential ionic liquids (IL) and to determine the resultant physical
properties.
Targeted Properties
Cation
Anion
New Energetic IL
Materials Utilizing IL Tools
New, functionalized material
Cation
Anion
New Synthesis and Properties
• Drab, D. M.; Smiglak, M.; Rogers, R. D. Chim. Oggi 2006, 24, 27.
• Smiglak, M.; Metlen, A.; Rogers, R. D. Acc. Chem. Res., 2007, submitted.
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Endless possibilities
– Azolium Azolates
Cations
NH2
N N
N
N
N
H2N
N
N
N
NH2
N
NO2
CN
N
N N
N
NH2
N N
N
N
N
NH2
OH
N N
O2N
O2 N
NO2
N
O2N
N
N
NC
N
O 2N
N
N
N
NC
N
N
NO2
NC
N
N
N
N
NC
O2N
N
NO2
N
N
N
N
NO2
N
O2N
N
NH2
N
N
N
N
N
O2N
N
NO2
O 2N
O2N
NO2
N
O2N
N
Anions
N3
N
N N
N
N
NH2
NC
N
NC
N
O2 N
N
N
N
NO2
N
O2N
N
N
O2N
N
N
Examples of possible ions for use in formation of azolium azolate EILs.
ILs as Hypergols
• ILs with certain anions have been reported to hypergolic with a
variety of oxidizers
Clark, J. D. Ignition: An Informal History of Liquid Rocket Propellants, Rutgers University Press, New Brunswick, NJ, 1972.
Schneider et al. Energy Fuels 2008, 22, 2871-2872.
56
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Boron NPs Enhance
Hypergolic Properties
[C4mim][DCA] B NPs milled in [MAT][DCA]
[MAT][DCA] B NPs milled in
[MAT][DCA]
57
NC
O2 N
N
N
NC
N
N
N
N
N
NH2
N
N
NC
N
NC
N
NH2
N
NO2
N
H2N
N N
N
P
N
S
N
H3C
N
N
C
N
N
N
N
HO
S
C
CH3
N
N
O
N
S
O
C
N
N
F F
O
F
C
O
H3C
O
Cellulose Solvent
Physical: Low Melting Salts
N
F F
O
F
S
O
NO2
O
N N
O2N
N
N
O2N
F F
F
N
N
F
F F
F F
O
N
F
S
O
N
S
2
O
N
O
N
O
O
O S O
N N
NO2
N
S O
N
F
F
H2N
O
F
N
F
O
N
F B F
N N
F
N
O
F
N
B
O
F P F
N
F
N
F
O
F
N
O
F3C
CF2
F
O B O
F
F P
CF3
O
O
F B C CF3
C
F2C
F F
F F2
2
F3C
O
N
O O2N
O2N
N
N
O2N
N
N
O
N
I-
N
NO2
N
Br-
Cl-
N
N
N
N
O2N
N
NO2
N N
Energetic Material
Chemical: High Energy Content
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5/16/2015
Generation 1:
ILs with unique tunable physical properties
Physical property
R1
R1
R4 N
R2
R4 P
R3
N
- melting point
- density
- viscosity
- thermal
stability
- conductivity
- hydrophobicity
- refractive index
R2
R3
N
N
R
O
N
N
F3C
Physical property
O
S
N
S
O
CF3
O
lower melting point / hydrophobicity
C6H13
C6H14
P
C14H29
NC
CN
N
C6H14
hydrophobicity / lower viscosity
- melting point
- density
F3 C
- viscosity
- thermal
stability
NC
- conductivity
- hydrophobicity
- refractive index
O
S
O
N
S
O
N
FeCl4
CN
O
BF4
HO
O
S
O
O
O
OH
Cl
CF3
O
O
O
What Is The Next Step In The
Evolution of Ionic Liquids?
N
N
N
N
N
Cl
S
O
high thermal stability / hydrophilicity
O
O
S
PF6
O
O
Generation 2:
ILs with targeted chemical properties combined with chosen physical properties
Chemical property
Chemical property
N
N

O
OEt
N
N
N
N
N
N
N
N
n
SO3H
N
CN
- chemical
reactivity
- high energy
density
- electrochemical
window
- flammability
- coordination
- solvation
- chiral induction
N
N
N
N
NO2
N
energy density / oxygen balance
N
N
Cl
lower density / solvation
N
N
N
O2N
N
N
N

O
F3C
OEt
O
S
O
O
N
S
O
OH
- high energy
density
- electrochemical
window
- flammability
- oxygen balance
- UV blocker
- chiral induction
- solvation
Cl
N
I
CO
CN
N
N
N
I
NC
N
O2N
CF3
N
COO
H
N
Rh
CO
CN
NO2
COO
N
chiral induction/ hydrophobicity
30
5/16/2015
Can Toxicity be Useful?
• Previous literature has shown that ionic liquids can
possess biological activity
• Also others have used biologically active ions in the
synthesis of ionic liquids
• Typically, however, these ionic liquids did not
focus on the biological property but the ability of
the ions to form ionic liquids
1. Pernak, A., Iwanik, K., Majewski, P., Grzymislawski, M., & Pernak, J. Ionic liquids as an alternative to formalin in histopathological diagnosis,
Acta Histochemica, 107(2), 149-156 (2005).
2. Pernak, J., Sobaszkiewicz, K., & Mirska, I., Anti-microbial activities of ionic liquids, Green Chem., 5(1), 52-56 (2003)
3. Nockemann, P., Thijs, B., Driesen, K., Janssen, C., Van Hecke, K., Van Meervelt, L., Kossmann, S., Kirchner, B., Binnemans, K., J. Phys. Chem.
B, 111(19), 5254-5263 (2007)
ILs as Poisons?
Theophrastus Paracelsus (14931541)
“All things are poison
and nothing is without
poison, only the dose
permits something not to
be poisonous.”
Circa Survive
“The Difference Between
Medicine and Poison is in
the Dose” (2007) from On
Letting Go
Image: http://en.wikipedia.org/wiki/Paracelsus; http://en.wikipedia.org/wiki/Circa_Survive
31
5/16/2015
Biological Activity?
Generation 3:
ILs with targeted biological properties combined with chosen physical and chemical properties
O
O
Biological property
n=14
Biological property
N
COO
n=5-15
anti-bacterial / UV blocker
NH
COO
n
O
Ph
HO Ph
- emollient
- anti-acne
H2N
- antibiotic
- non-steroidal
anti-inflammatory drug
(NSAID)
- vitamin
N
O3S
O
n=7
O
n
lower melting, antibacterial / NSAID
O
COO
O
S N
O
COO
O
O
O
n=7
n
n
O
NH
N
local anesthetic / emollient
N
n=5-15
n
O
O
- antibacterial
- local anesthetic
- anticholinergic
- antifungal
n
N
O
NH
Why not consider, biological
activity, as the primary IL
property and look at ILs as APIs?
n
N
O3S
NH
Ph
O
NH H
S
N
O
O
COO
Hough, W. H.; Smiglak, M.; Rodríguez, H.; Swatloski, R. P.; Spear, S. K.; Daly, D. T.; Pernak, J.; Grisel, J. E.; Carliss, R. D.;
Soutullo, M. D.; Davis, Jr., J. H.; Rogers, R. D. “The Third Evolution of Ionic Liquids: Active Pharmaceutical Ingredients,” New J.
Chem. 2007, 31, 1429-1436.
Ionic Liquids as Active
Pharmaceutical Ingredients
(APIs)
32
5/16/2015
We have proposed, that in addition to the
traditional crystalline salt screening and
selection that most pharmaceuticals
undergo, that pure liquid salt forms of
APIs should be considered as a design
strategy to overcome potential problems
such as polymorphism, solubility, and
bioavailability.
Stoimenovski et al. “Crystalline vs. Ionic Liquid Salt Forms of Active
Pharmaceutical Ingredients: A Position Paper,” Pharm. Res. 2010, 27, 521.
O
NH
O
O
N
O
n
n = 10
(2-acetoxyethyl)dodecyloxymethyldimethylammonium
Anti-bacterial
NH
O
Lidocainium
Pain Reliver
N
n
n = 14
Hexadecylpyridinium
n
Anti-bacterial
n=9
(2-hydroxyethyl)undecyloxymethyldimethylammonium
Anti-bacterial
OH
N
n
n=7
Didecyldimethylammonium
Anti-bacterial
O
O
N
O
O
O
(2-acetoxyethyl)heptyloxymethyldimethylammonium
Anti-bacterial
O
NH
S
N
Sulfathiazole
Antibacterial
O
O
O
NH
O
O
O
N
S
O
O
NH
Naproxenate
2
Cinnamate
Sulfacetamide
Anti-Inflammatory UV Blocker
O Antibacterial
O
OH
Cl
SO3
O
NH
n
O
n
Cl
n=7
O
Colawet MA-80
Wetting Agent
NH
O
O
O
O
NH
O
Diclofenac
Anti-Inflammatory
O
SO3
N
S O
O
Acesulfamate
Artifical Sweetener
Ibuprofenate
Anti-Inflammatory
O
n
n = 5 to 15
NO2
Ranitidinium
Histamine H2-receptor antagonist
O
O
S
N
N
S
NH2
N
Benzalkonium
Anti-bacterial
NH
O
O
Hg
Thimerosal
Preservative
O
Docusate
Emollient
Mepenzolate
Anticholinergic
n
n=5
S
O
OH
N
O
O
SO3
O
n
O
O
N
O
S O
O
OH
O
Salicylate
Saccharinate
Artifical Sweetener Anti-Acne
N
n
n = 5 to 15
O
O
IL-API: Lidocainium Docusate
IL-API: Benzalkonium Cinnamate
Biological: Hydrophobic Pain Reliever Biological: Anti-Bacterial Sunscreen
33
5/16/2015
ILs - Tools and Strategies
Easy
modification of
Physical
Properties
Ionic Liquid Toolbox
H3C
N
N
N
N
N
N
F F
F
F P
F F
Tuning of
Hydrophobicity/
Lipophilicity
O
O
NO2
N
N N
F F
N
HF N N N O
F P 2
F F
O2N
N
NO2 O2N
N N
O
n N
O2N
n
n=7
NH2
Oligomers
NO2
O
O
O
N
N
N
N
O
S N
O
Dual
Functionality
NO2
Dissolution
O
O
Physical properties
♦ Ionic Liquid formation will influence the physical
properties of a solid drug.
Polymorphism
Solid
drug
Ionic
Liquids
Toxicity
Stability
Dissolution rate
Solubility
Permeability
Bioavailability
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5/16/2015
Ionic Liquid ToolBox Approach
O
O3S
O
O
O
O
O
Sodium Docusate
Emollient
N
n
n = 5 to 15
Sodium Ibuprofenate
Anti-Inflammatory
O
N
S
O
O
Lidocaine HCl
Pain Reliever
O
O
NH
H 2N
Benzalkonium Chloride Sodium Sulfacetamide
Anti-Bacterial
Anti-Acne
O
-O S
3
O
O
O
S
H
N
H
N
Ranitidine HCl
NO2
Histamine H2-receptor
Antagonist
n
Colawet MA-80
Wetting Agent
H
N
HN
N
n
n=7
Didecyldimethylammounium Chloride
Anti-Bacterial
Overcoming Polymorphism:
Ranitidine Docusate
O
H3C
H2
NH C
H3C
O
H2
H2 H2
C S C C NH NH CH3
O3S
O
O
CHNO2
O
Form
Dark Red Liquid
Melting Point
Liquid at R.T.
Tg (glass transition)
-12 °C
Thermal Stability
T5%onset = 163 °C, Tonset = 249 °C, Tdec = 278
°C
• Anti-ulcer drug (Zantac™) by GlaxoSmithKline
• Subject of litigation over polymorphic forms and purity1
1. Goho, A. “The crystal form of a drug can be the secret to its success.” Science News
<http://www.sciencenews.org/articles/20040821/bob9.asp> (2004).
35
5/16/2015
Tuning of
Hydrophobicity/
Lipophilicity
Hydrophobicity/Lipophilicity
♦ Ion pairing with appropriate counterions increases
hydrophobicity and lipophilicity of the API which
could tune solubility and bioavailability.
Hydrophilicity
Lipophilicity
Hydrophobicity
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5/16/2015
Dual
Functionality
Dual functionality
♦ Ionic Liquids can be composed of 2 active ions with
complimentary functions or even the possibility of synergistic
effects.
Active Cation
+
•
•
•
•
•
•
•
•
Local anaesthetics & Analgesics
Antibacterials /antiparasitics
Antiemetics
Stimulants /appetite suppressants
Antiarrhythmics
Vitamins
Antimalarias
Chemotherapeutics
Active Anion
–
NSAIDs
Emollients
Vitamins
Sweeteners
UV protectors
Penetration
enhancers
• Antivirals
•
•
•
•
•
•
37
5/16/2015
Dual Functionality
N
O
n
n = 5 to 15
antibacterial, hydrophobic
N
O
Antiinflammatory, hydrophilic
n
n = 5 to 15
O
O
[Benzalkonium][Ibuprofenate]
Anti-bacterial + Anti-Inflammatory, yellow gel, mp -41 °C,
glass transition -77 °C
Aspirin
Ionic liquid salt forms of aspirin and its main
metabolite salicylic acid can be prepared with
pharmaceutically active cations.
38
5/16/2015
Antibacterial (1, 2, 3, 4, 5), analgesic (6), local anesthetic (7, 8) and
antiarrhythmic (9) cations used in combination with the salicylate (a) and
acetylsalicylate anion (b)
Bica, K.; Rijksen, C.; Nieuwenhuyzen, M.; Rogers, R. D. “In Search of Pure Liquid
Salt Forms of Aspirin: Ionic Liquid Approaches with Acetylsalicylic Acid and Salicylic
Acid,” Phys. Chem. Chem. Phys. 2010, 12, 2011-2017.
A DISRUPTIVE TECHNOLOGY?
One Dual Drug, Liquid Salt!
New, patentable material of matter, as well as new
formulation and use patents
Current Industry Practice - Compounding:
Drug A + Drug B In One Pill
Old Paradigm:
B
Not a new material of matter,
only formulation or use patents possible
39
5/16/2015
Dual Functionality – Are there any
Commercial Applications?
(Press Release, May 26th, 2009, MEDRx Co.)
♦ Patent Application: “Tape Preparation Comprising Etodolac in Ionic
Liquid Form” (Priority Date: December 11th, 2007)
♦ Etodolac patch now under Phase III clinical trial
♦ In March 2011, KOWA Company and MedRx signed an agreement that
gives KOWA exclusive sales rights in in US and Commonwealth of Puerto
Rico to sell the etodolac patch
(http://www.medrx.co.jp/english/newsrelease.html, last accessed 05-06-12)
….but let’s expand our thinking a
bit into not so well defined areas…
40
5/16/2015
Oligomers: a
liquifaction and
dosing strategy
Oligomeric ions
• Hydrogen-bonded oligomeric ions in ILs can expand
the liquid range and modify properties of a salt.
– Reduced melting point or glass transition temperature
– Reduced viscosity
– Individual dosing of 2 or more active compounds in one
liquid formulation
41
5/16/2015
Confused Ionic Liquid Ions – A “Liquification” and
Dosage Strategy for Pharmaceutically Active Salts
The liquid and compositional ranges of ionic liquids,
specifically pharmaceutically active ionic liquids, can be
expanded by simple mixing with a solid acid or base to
form oligomeric ions.
Bica, K.; Rogers, R. D. “Confused Ionic Liquid Ions – A “Liquification” and Dosage
Strategy for Pharmaceutically Active Salts,” Chem. Commun. 2010, 46, 1215.
DSC Evidence
42
5/16/2015
Oligomeric ions - Examples
• Lidocaine salicylate: local anaesthetic & NSAID
Lid:Sal 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3
Oligomeric Ions - Tools
It is important to note that the concept of
oligomeric ions enables liquefaction of
solid ILs (or other salts) by simply
changing the stoichiometry or complexity
of the ions and the strategy need not
employ the parent of the anion or cation in
use.
43
5/16/2015
Liquid Engineering?
Liquid Formulation via
Grinding
♦ Liquid formulations can be obtained by simple
grinding of 2 solid materials
Grinding
H
N
N
O
OH
O
Lidocaine
mp 68 °C
[Lidocaine][Decanoic acid]
Tg - 38 °C
Decanoic acid
mp 36 °C
44
5/16/2015
Lidocaine Stearates vs. Lidocaine Decanoates
Lidocaine Oleates
Phase Diagram of Lidocaine Oleic acid
Melting Point, oC
80
60
40
20
0
“Deep Eutectic
Region”
-20
-40
-60
-80
0.0
0.2
0.4
0.6
0.8
1.0
Mol Fraction lidocaine
45
5/16/2015
Liquid Co-Crystals
♦
While ILs are often considered to have weak intermolecular
interactions, the melting point of lidocaine oleate is reduced
by forming a strongly associated acid-base pair
Lidocaine Oleate
Bica, K.; Shamshina, J. L.; Hough, W. L.;
MacFarlane, D. R.; Rogers, R. D. Chem. Commun.
2010, 47, 2267-2269.
Lidocaine Oleate –
Ionic Liquid or Eutectic?
Hydrogen bonding
Mixture
Complete or partial
ionization
Ionic liquid
Is this ‘pure’ hydrogen bonding which persists in solution?
Bica, K.; Shamshina, J.; Hough. W. L.; MacFarlane, D. R.; Rogers, R. D. “Liquid Forms of
Pharmaceutical Co-crystals: Exploring the Boundaries of Salt Formation,”
Chem. Commun. 2011, 47, 2267-2269.
46
5/16/2015
Or is it partial ionization and strong interaction?
Lidocaine Ibuprofen
♦ Synthesis
♦ Characterization
♦ Membrane transport
Lidocaine & Ibuprofen
Partial Ionization?
Hydrogen bonding
Mixture
Complete or partial
ionization
Ionic liquid
Where is the proton in these liquids?
47
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Synthesis of [Lid]m[Ibu]n
Lidocaine
Ibuprofen
+
grinding
mp: 68 ºC
mp: 76 ºC
Lidocaine ibuprofen ([Lid]m[Ibu]n)
Enhanced
Membrane
Transport
48
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Membrane transport
Membrane transport: a technique to measure the permeation of drugs through the
skin.
Lidocaine Ibuprofen ([Lid][Ibu])
Tetrabutylphosphonium
Ibuprofen ([P4444][Ibu])
Tg: -26 ºC
Ephedrine Ibuprofen ([Eph][Ibu])
Tg: -43 ºC
mp: 110 ºC
Experimental Setup
Goal: To test the membrane transport ability of IL-APIs
Franz cell:
Donor solution: APIs in ethanol, propylene
glycol solution, or neat IL-APIs
+‒‒+
‒+
+ ‒ ‒+
+
+
‒
‒
‒
‒
Silicone membrane
Sample collecting port
+
+
‒ +
After sample collection, fresh,
prewarmed and degassed PBS
were injected.
Phosphate Buffered
Saline (PBS)
49
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Membrane transport
Neutral compounds
Donor solutions:
APIs/EtOH, 0.5
mmol/mL
Commercial salts
♦ Membrane transport decreases in the order: neutral compounds > ILAPIs > commercial salts.
♦ [Lid][Ibu] permeates the membrane faster than the other two salts,
[Eph][Ibu] and [P4444][Ibu].
Membrane Transport
♦ The transport ability of partially ionized IL-APIs
through the model silicone membrane is shown to be
higher than their corresponding commercial drugs,
suggesting that IL-APIs can change the bioavailability
of orally delivered APIs.
♦ Neat liquid IL-APIs could readily transport through
the membrane, in the absence of any solvents.
50
5/16/2015
BUT … There are a Few
Disadvantages of the ‘Liquid’ Form …
Liquid form
♦ The ‘liquid’ property can have a negative
impact on:
♦ Ease of preparation
♦ Handling and use
♦ Special devices for dosing and
administration
Solids
Handling of
Ionic Liquids
51
5/16/2015
When an Ionic Liquid
is on a
Solid Support …
Supported Ionic Liquid Phases
(SILPs)
♦ SILPs have been successfully used for immobilization of transition
metal catalysts (heterogenous catalysis as hydroformylation1)
1Riisager
et al. Eur. J. Inorg. Chem. 2006, 695.
IL-APIs Used
an active anion paired with an
“ionic liquid maker” cation
two active ions combined in a
weakly ionized ionic liquid
52
5/16/2015
How are SILPs Made?
Porous network
SILP
catalyst
particle
Ionic
liquid
film
Solid Carrier
Solid
support
Solid carriers - any inorganic
or carbon support
(e.g. mesoporous silica)
combines the advantages of
IL-APIs with the
advantages of a solid drug
form.
Improved Handling
♦ Liquid state properties have significant impact on ease of preparation and
handling compared to solid drugs and need of special devices for dosing and
administration.
♦ By supporting the IL-APIs on solid carrier, an easier way to handle and dose is
provided.
♦ Due to the mesoporous structure of the used silica, the adsorbed ionic liquid can
be obtained as solid material even in high loading of 50% (wt/wt).
10, 20, and 50% [wt/wt] [P4444][Ibu] on SiO2-90
53
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Controlled Release?
(Please pay attention to the different X-axis scales)
PBS
(pH = 7.4)
SGF
(pH = 6.8)
250
Concentration (ppm)
200
150
100
50
[P4444][Ibu], 20%
250
[P4444][Ibu], 20%
[LidI][bu], 20%
200
Concentration (ppm)
250
Concentration (ppm)
SIF
(pH = 1.2)
150
100
50
200
150
100
50
[Lid][Ibu], 20%
[Lid][Ibu], 20%
0
0
0
0
10
20
30
40
50
60
[P4444][Ibu], 20%
70
0
60
Time (min)
120
180
240
300
0 10 20 30 40 50 60 70 80 90 100
Time (min)
Time (min)
O
P
HO
O
O
H
H
N
O
[P4444][Ibu]
N
[Lid][Ibu]
Pharmaceutically Active Ionic Liquids
with Solids Handling, Enhanced Thermal
Stability, and Fast Release
Katharina Bica, Héctor Rodríguez, Gabriela Gurau,
O. Andreea Cojocaru, Anders Riisager, Rasmus Fehrmann, and
Robin D. Rogers* (Chem. Comm., 2012, 48, 5422-5424.)
♦ Biologically active ionic liquids supported on mesoporous silica
provide solid handling with fast and complete release in an aqueous
environment.
54
5/16/2015
Application of Ionic Liquids in
the Pharmaceutical Industry
Separation
Drug
extraction
Drug detection
Crystallization
ILs
Solvents
Active pharmaceutical
ingredients (APIs)
Will Ionic Liquids be
transformational?
Ionic Liquids for Solubilization
(Hydrotropes)
♦ ILs can be used as solvents for hard-to-dissolve actives
♦ Tunable properties of ILs for specific dissolution
♦ Simple modification of HLB (Hydrophilic - Lipophilic Balance) of ILs by choice of ions
HLB-IL
McCrary, P. D.; Beasley, P. A.; Gurau, G.; Narita, A.; Barber, P. S.; Cojocaru, A.; Rogers, R. D. “Drug specific,
tuning of an ionic liquid’s hydrophilic–lipophilic balance to improve water solubility of poorly soluble active
pharmaceutical ingredients,” New J. Chem. 2013, 37, 2196-2202.
55
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IL Design Strategy
Amphotericin B – 1.0 ng/mL
Itraconazole – 0.2 µg/mL
Left: [OAc]- based ILs to dissolve Amp B by tuning cation hydrophobicity;
Right: PEG-based ILs with a hydrophilic cation and tunable hydrophobicity
in the anion to dissolve itraconazole.
ILs to Dissolve Amp B
Solubility dominated by H-bonding
Hydrophilic portion
Hydrophobic portion – 15 C-C bonds
♦ [OAc]- was chosen as the hydrophilic anion due to its
ability to dissolve cellulose by preferentially hydrogen
bonding with cellulose molecules.1
♦ A cation was chosen to pair with [OAc]- to allow for
flexibility in design tuning the IL’s overall HLB to
match the structure of Amp B
1 – Swatloski, R. P.; Spear, S. K.; Holbrey, J. D.; Rogers, R. D. J. Am. Chem. Soc. 2002, 124, 4974-4975.
56
5/16/2015
HLB Balance through a
lipophilic amine
Alkyl chain length designed to properly match the
structure of Amp B
Amp B dissolved in
[C6NH3][OAc]
5 mg/mL
10 mg/mL
20 mg/mL
30 mg/mL
50 mg/mL
57
5/16/2015
IL solution is loaded into water
♦ For example, using 10 mg of Amp B/mL of
[C6NH3][OAc] stock solution, aliquots of the stock
solution are dissolved in water.
Concentration in mg Amp B per mL of
HexOAc
Concentration of mg Amp B in H2O
Enhanced solubility only observed by first dissolving Amp B in the IL.
Starting from 10 mg/mL
0.50 mg/mL
0.01 mg/mL
0.25 mg/mL
1 mg/mL
0.10 mg/mL
Not Soluble
Soluble!
Soluble for 1 min
58
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Ionic Liquids Are:
♦ Magic
Because they make you think
and allow you to dream….
Green Quest
Robin D. Rogers
Canada Excellence Research Chair in
Green Chemistry and Green Chemicals
Department of Chemistry
McGill University
59
5/16/2015
Tuscaloosa, AL USA to Montreal, Canada
2199.83 km / 22 h 1 min
Green Chemistry
Green Chemistry is more than
designing new chemical products
and processes that are
sustainable,
Green Chemistry represents new
business opportunities that are
sustainable.
60
5/16/2015
An Introduction to
George Washington Carver
•Tuscaloosa
Don’t be distracted from
special opportunities by
“Green Chemistry”
or by over emphasis on
“Reaction Media”!
61
5/16/2015
Utilizing Ionic Liquids and Green Chemistry for Sustainable
Technology Through Innovation
BIOMASS
MATERIALS
BIO-ACTIVE MATERIALS
The use of Ionic Liquids Technology as a basis for the
design, development, and delivery of biologically active
ingredients:
• Active Pharmaceutical Ingredients (APIs)
• Nutraceuticals
• Agrochemicals (pesticides, herbicides, fungicides)
SEPARATIONS
IONIC LIQUIDS
polymeric and composite materials
from biorenewable polymers
BIO-ACTIVE
MATERIALS
BIOMASS
Addressing a DOE Grand
Challenge through Ionic
Liquids Technology
ENERGETICS
Sustainability
tunable properties
by design and choice of ions
ACTINIDES
ENERGETICS
possible combinations for
dual functional Ionic Liquids
Use the tunability of Ionic Liquids to find safe synthetic routes to ILs
with high energy content and targeted physical and chemical
properties, to replace currently in use energetic materials.
Sustainability New TechnologyNew Companies International
Program
ANION
ACTINIDES
Use of Ionic Liquids to solve fundamental and applied
problems in f-element coordination chemistry and
separations.
Space ready propellants: Hypergolic
ionic liquids with exfoliated graphene
Rogers Group
RESEARCH IS A CONTINUUM
Where there is new knowledge, there can be innovation:
Top: Coordination of uraniumselective IL. Right: renewable
adsorbent fibers for extraction of
uranium from seawater.
CONTACT
INTERNATIONAL PROGRAM
Hosting international visitors
through collaborative projects
Institute of Process Engineering
Chinese Academy of Sciences
♦ New Knowledge
♦ New Technologies
China
Turkey
♦ Entrepreneurs
♦ New Companies
“new sustainable technologies based on the
unique attributes of Ionic Liquids”
Iran
Prof. Robin D. Rogers
rdrogers@as.ua.edu
http://bama.ua.edu/~rdrogers/
We will Choose Sustainability
Targets:
♦Energy
♦Water
♦Materials
♦Medicine
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5/16/2015
We will produce technologies that are
Environmentally Sustainable,
Economically Sustainable, and Socially
Sustainable, while developing:
♦ Entrepreneurs
♦ New Companies
♦ New Knowledge
We will Let Green
Chemistry Guide
Our Work, not
Define Us!
63
5/16/2015
Green Chemistry is
less about your tool
and more about
what you
accomplish!
The Future of Ionic Liquids?
OPPORTUNITY!
64