Computers and Chemical Engineering 34 (2010) 14761480

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Computers and Chemical Engineering
j our nal homepage: www. el sevi er . com/ l ocat e/ compchemeng
Design of ionic liquids via computational molecular design
Samantha E. McLeese, John C. Eslick, Nicholas J. Hoffmann, Aaron M. Scurto, Kyle V. Camarda

Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, KS 66045, United States
a r t i c l e i n f o
Article history:
Received 1 September 2009
Received in revised form 1 January 2010
Accepted 12 February 2010
Available online 20 February 2010
Keywords:
Molecular product design
Ionic liquids
Optimization
a b s t r a c t
Computational molecular design (CMD) is a methodology which applies optimization techniques to
develop novel lead compounds for a variety of applications. In this work, a CMD method is applied to the
design of ionic liquids (ILs), which are being considered for use as environmentally benign solvents. The
molecularly tunable nature of ILs yields an extraordinary number of possible cation and anion combi-
nations, the majority of which have never been synthesized. The product design framework developed
in this work seeks to accelerate the commonly used experimental trial-and-error approach by searching
through this large molecular space and providing a set of chemical structures likely to match a set of
desired property targets. To predict the physical and chemical properties of an ionic liquid in a specic
system, quantitative structureproperty relations (QSPRs) have been developed. In this work, correla-
tions were created for solubility, diffusivity, and melting temperature. The electronic structure of ionic
liquids is quantied using molecular connectivity indices, which describe bonding environments, charge
distribution, orbital hybridization and other interactions within and between ions. The resulting prop-
erty prediction model is then integrated within a computational molecular design framework, which
combines the QSPRs with structural feasibility constraints in a combinatorial optimization problem. The
problem is reformulated as an MILP after exact linearization of structural constraints. An example is
provided to test the formulation for the design of ionic liquids for use within a hydrouorocarbon (refrig-
erant) gas separation system. A second example compares a stochastic optimization algorithm, Tabu
Search, to a standard deterministic solver for the solution of a larger-scale refrigeration design problem.
The computational efciency and practical implementation of this product design methodology is also
discussed.
2010 Elsevier Ltd. All rights reserved.
1. Introduction
A large portion of the research currently performed today in the
chemical industries is devoted to product design, that is, the search
for new materials with specically tailored properties. One new
challenge withinproduct designis inthe designof environmentally
friendly refrigerants, solvents and mass separating agents. A class
of compounds which are currently being studied for such applica-
tions is ionic liquids: organic salts which are liquid at and around
room temperature. Ionic liquids usually possess negligible vapor
pressure, and thus do not contribute to air pollution (Ren, Scurto,
Shiett & Yokozeki, 2009). These compounds can be molecularly
engineered to match a set of target physio-chemical properties,
includingsolubility, diffusivityandacidity. It is estimated, however,
that as manyas 10
14
uniquecation/anioncombinations arepossible
for use as ionic liquids (Holbrey &Seddon, 1999). Thus the time and
expense required to perform a true search through this molecular
space to nd a novel ionic liquid is prohibitive. Furthermore, mix-

Corresponding author. Tel.: +1 785 864 4965; fax: +1 785 864 4967.
E-mail address: camarda@ku.edu (K.V. Camarda).
tures of ionic liquids should also be considered, and this certainly
makes a guess-and-test approach intractable. Currently, most new
designs for suchcompounds tendtohavesimilar structures tothose
previously used. In order to discover new ionic liquids which are
far different from those currently used, an efcient computational
screening procedure is required.
Such computational product design strategies are currently
being implementedinthe chemical andpharmaceutical industries;
a review of industrial applications of CMD is given in Hairston
(1998), and applications to other molecular systems are discussed
in Venkatasubramanian, Chan, and Caruthers (1994). Two major
challenges ariseinthedevelopment of suchacomputational molec-
ular design procedure: the ability to predict the physical and
chemical properties of a given molecule, and the ability to solve
the large optimization problem which is derived from the search
for the best molecule for a given application.
2. Physical property prediction
The simplest form of structureproperty relation links physi-
cal and chemical properties of interest to the number and type
of each functional group within a molecule. This group contribu-
0098-1354/$ see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.compchemeng.2010.02.017
S.E. McLeese et al. / Computers and Chemical Engineering 34 (2010) 14761480 1477
Table 1
Basic groups and their atomic and valence connectivity indices ( and
v
).

v

v
4 4 O 4 6
3 3 O 2 6
CH
2
2 2 F 1 7
CH
3
1 1 3 5
>C 3 4 N

2 1.333
4 2.667 O

1 7
tion approach is the basis for the well-known UNIFAC property
prediction system. Other structural descriptors take into account
not only the functional group types, but also the topology of those
groups. Bicerano(1996) correlateda large number of physical prop-
erties of polymers with topological indices, which are numerical
descriptors based on the electronic structure of the atoms within
a molecule, as well as on the interconnectivity of the atoms within
that molecule. Gonzalez, Abildskov, and Gani (2007) have used
these indices to ll in missing UNIFAC groups to predict physical
properties of small organics. Eike, Brennecke, and Maginn (2004)
have shown the feasibility of using connectivity indices for the pre-
diction of activity coefcients of ionic liquids. In this work, Randics
molecular connectivity indices (Randic, 1975) are used to generate
structureproperty correlations for ionic liquids. These descriptors
provide a quantitative assessment of the degree of branching of
molecules, and are based ona set of basic groups, whichare dened
as functional groups containing one non-hydrogen atom in a spe-
cic valence state and a given number of hydrogens. The nth order
simple and valence molecular connectivity indices are given by
n
x =

(i
0
,i
1
, ..., in) n
1

i
0
,
i
1
, ...,
in
(1)
n
x
v
=

(i
0
,i
1
, ..., in) n
1

v
i
0
,
v
i
1
, ...,
v
in
(2)
where
n
is the edge set of n consecutive bonds between basic
groups ina molecule, i
0
, i
1
, . . ., i
n
denote the n+1basic groups form-
ing the n consecutive bonds,
i
k
, k =0, . . ., n are the simple atomic
connectivity indices for those basic groups (the number of bonds
each group can form), and
v
i
k
, k =0, . . ., n are the atomic valency
connectivity indices, which are based on the electronic structure of
the basic group. Table 1 shows the basic groups employed in the
example in this paper, along with their atomic connectivity indices.
These topological indices can then be correlated with vari-
ous physical properties of molecules, given a consistent set of
experimental data for the properties of interest. In this work, six
properties important to the use of an ionic liquid within an absorp-
tionrefrigerationsystemarecorrelated: solubilityof thecompound
in the refrigerants R-32 and R-134A, diffusivity of the ionic liquid
in R-32 and R-134A, Henrys law constant, and melting point. Data
for these correlations was obtainedfromShiett, Harmer, Junk, and
Yokozeki, 2006 and Shiett and Yokozeki (2006). The correlations
used in this work (shown below) are preliminary based on 19 com-
mon ionic liquids, and further data is currently being obtained such
that thepredictivecapabilities of thecorrelations maybeexpanded.
Note that the examples given in this paper only allowthe introduc-
tion of functional groups present in the 19 ionic liquids evaluated
experimentally by the Shiett team referenced above. Thus the
example problems cannot design molecules outside of the range of
ionic liquids tested, and thus the application of these correlations
may be considered a form of interpolation in molecular space.
In the new correlations developed in this work, zeroth- and
rst-order connectivity indices of both the cation and anion are
applied. For thecorrelationof theHenrys lawconstant, dataat mul-
tiple temperatures was correlated together. Correlations were thus
created which are valid within a given range of temperature, but
since this parameter is assumed to be xed within a given design
implementation, it is not solvedfor withinthe formulation. The cor-
relations employed to predict the physical properties listed above
are as follows:
D
R32
= 14.57(P) +19.971(
0

cat
) +2.212(
0

v
cat
) +67.404(
1

cat
)
98.413(
1

v
cat
) 43.658(
0

an
) 3.143(
0

v
an
)
+107.237(
1

an
) 35.885(
1

v
an
) 92.735 (3)
D
R-134a
= 15.12(P) +3474.68(
0

cat
) +919.99(
0

v
cat
)
= 3622.20(
1

cat
) 1350(
0

an
) 27.07(
0

v
an
) +1961.14
(4)
100x
R-32
= 58.98(P) +967.05 (
0

cat
) 66.44(
0

v
cat
)
44.37(
1

cat
) +30.01(
0

an
) +15.23(
0

v
an
)
57.36(
1

an
) +29.68(
1

v
an
) 68.73 (5)
100x
R-134a
= 133.31(P)904.57(
0

cat
) +250.37(
0

v
cat
)
+926.35(
1

cat
)+10.27(
0

an
)15.38(
0

v
an
)+486.54
(6)
H = 0.01772(T) +0.22957(
0

cat
) 0.27367(
0

v
cat
)
0.01902(
0

an
) +3.67331 (7)
T
m
= 0.01772(T) 52.389 (
1

an
) +76.389(
0

v
an
) 3.934(
0

an
)
23.23(
1

v
an
) +69.001 (8)
where D is the diffusion coefcient (10
11
m
2
/s), P is the system
pressure, x is the solubility in (mol/L), His the Henrys lawconstant
1478 S.E. McLeese et al. / Computers and Chemical Engineering 34 (2010) 14761480
in MPa, and T
m
is the melting temperature (K). Note that the cor-
relations include topological information about both the anion and
cation, and also involve the operating pressure and temperature. A
larger set of data points froma set of structures whichspans a larger
molecular space would allowfor more exibility in the nal design,
but would not require a different optimization methodology.
3. Problem formulation
The correlations generated in the rst phase of this product
design methodology are then combined with structural constraints
to construct an optimization problem. The solution to this problem
is a candidate ionic liquid (both basic groups and bonds) which is
predicted to have properties matching a set of pre-specied target
values based on the application of interest. The objective function
seeks to minimize the scaled difference between the physical prop-
erty values of the candidate molecule and targets.
Along with the property prediction equations and the expres-
sions dening the molecular connectivity indices, structural
constraints are also included to ensure that a stable, connected
molecule is formed. These include valency and uniqueness con-
straints, which ensure that the valency of each atom is satised
and two groups may only bond with one type of bond (single or
double), charge constraints which insure that the cation and anion
have a charge of +1 or 1, as well as connectedness constraints,
which guarantee that all the basic groups within the molecule are
bonded into one coherent molecule (Camarda & Maranas, 1999;
Lin, Chavali, Camarda, & Miller, 2005).
In order to store the molecular candidates computationally, a
data structure is used which employs binary variables to dene
whether two basic groups i and j are bonded with a kth multi-
plicity bond. These binaries form a partitioned adjacency matrix
A which is structured such that the identity of each basic group
is known at each position within the molecule. This ensures that
the square root terms in the connectivity index Eqs. (1) and (2) are
all constants, and thus those equations are linear functions of the
unknown binary variables (Siddhaye, Camarda, Southard, & Topp,
2004). The objective function can be reformulated as a set of linear
functions, and all other constraints are formulated linearly as well.
Thus the problem is an MILP, which can be solved to optimality
using standard techniques. The overall formulation may be posed
as:
Min s =

m
1
P
scale
m

P
m
P
target
m

s.t. P
m
= f
m
()
= g
n
(a
ijk
, w
i
)
h
c
(a
ijk
, w
i
) 0
P
m
, continuous, a
ijk
, w
i
binary
where P
m
is the value of the mth physical of chemical property,
P
target
m
is a preselected target value for the mth property, P
scale
m
is a
scaling factor for the mth property, f
m
() are the m linear property
correlations whicharefunctions of theconnectivityindices , g
n
are
the (linear) dening equations for the connectivity indices which
are based on the data structure a
ijk
which is used to store bonding
andw
i
whichstores the identity of eachgroupi inthe molecule, and
h
c
(a
ijk
, w
i
) are structural constraints used to ensure that a stable,
connectedmolecule is designed. Note that ingeneral, f andg may be
nonlinear functions. However, for this and many other molecular
design formulations, the correlations are forced to be linear when
they are created, and the structural feasibility constraints may be
written as linear functions (since no connectivity indices of order
higher than one are employed). Thus the formulation considered
in this work is an MILP.
Table 2
Properties, target values and predicted values for the optimal solution to the rst
example problem.
Property Target value Best solution value
Sol. (10
2
mol/L) 0.80 5.34
D (10
11
m
2
/s) 20.00 20.09
Tm (K) 198.15 199.09
4. Solution methodology
Molecular design problems are often formulated as large MILP
or MINLP problems, and many optimization techniques have been
considered for their solution. When the problem is small or can
be formulated into a very specic form, then deterministic algo-
rithms (combined with integer cuts to obtain multiple solutions)
are often used. However, many molecular design problems, partic-
ularly those including highly nonlinear constraints or constraints
which cannot be written in a closed form, are not well-suited
to deterministic algorithms. In such cases, heuristic methods are
often useful. Heuristic methods are not guaranteed to nd the
global optimal solution; however, due to the limited accuracy of
the QSPRs used in molecular design, near-optimal solutions to the
optimization problem are often as useful as global optima in prac-
tice. For example, genetic algorithms have been used in the design
of straight-chain polymers using group contribution methods to
predict properties (Venkatasubramanian et al., 1994), while Tabu
Search has been applied in previous works by this research group
on molecular design (Eslick et al., 2009).
TabuSearchis aheuristic algorithmdevelopedbyGlover (1990a,
1990b). This methodkeeps arecordof recent solutions inaTabulist,
which prevents cycling near local optima and encourages explo-
ration of the entire search space. Tabu Search has been used in
chemical process optimization (Lin & Miller, 2004a, 2004b), plan-
ning and scheduling (Dowsland, 1998; Gendreau, Laporte, &Semet,
1998; Kimms, 1996), and molecular design (Chavali, Lin, Miller, &
Camarda, 2004; Eslick and Camarda, 2008; Lin et al., 2005; Zhao,
Ralston, Middaugh, & Camarda, 2004. In this work, Tabu Search
is compared to a deterministic branch-and-bound algorithm as
implemented in the CPLEX package within the GAMS optimization
suite.
5. Results
The methodologyis rst evaluatedusinganexample set of phys-
ical property targets, as shown in Table 2. The targets correspond to
values of solubility, diffusivity, and melting point which would be
reasonable for an ionic liquid used in conjunction with R-32 within
a refrigerant gas separation system. For this preliminary work,
the cation was xed to be 1-butyl-3-methylimidazolium (BMIM),
which has the structure shown in Fig. 1.
The structure of the anion was allowed to vary, but require-
ments were set on the number of total groups and on the existence
of one sulfate group, such that an organic salt would be formed.
The problemwas solved using GAMS/CPLEX, and required less than
300s to nd the optimal solution. The optimal structure found for
this example gave an objective function value of 0.90, which is the
percent scaled deviation from the target property values. While it
is easily possible to weight the importance of the various target
Fig. 1. Structure of 1-butyl-3-methylimidazolium.
S.E. McLeese et al. / Computers and Chemical Engineering 34 (2010) 14761480 1479
Fig. 2. Example ionic liquid designed using optimization methodology.
properties, all three properties in this example were given even
weighting. Properties can instead be given thresholds, which may
be included within the constraint set and require a given prop-
erty to be above or below a set value. The designed structure for
this example is shown in Fig. 2, which corresponds to the optimal
solution to the MILP, an ionic liquid which could now be synthe-
sizedandtested. Whilethesolubilityvaluefoundexceeds thetarget
substantially, this might be valuable for an application such as a
refrigerant gas mixture. However, if such a large deviation in that
property were unacceptable, thenthe solubility weighting could be
increased such that the objective function was skewed in favor of
that property. In that case, it is likely that a feasible solution would
exist corresponding to a lower solubility, but with diffusivity and
melting point deviating farther from the targets.
Asecondexample uses four property values, andseeks to design
an ionic liquid to be used in an absorbant refrigeration system
in conjunction with the common refrigerant R-134A. While the
important properties of the IL in this system are the same as those
in the previous example, the search space is expanded in this case
by the allowance of more groups in the anion. The cation is still
xed to be BMIM. The increased size of this problem provides an
opportunity to compare the stochastic algorithmTabu Search with
CPLEX. In this implementation of Tabu Search, we have dened
moves in terms of the replacement, addition or subtraction of a sin-
gle functional group, and apply graph isomorphism algorithms to
determine the similarity between two given solutions. These ideas
were developed previously in our research group, and details may
be found in Chavali et al. (2004), Lin et al. (2005), and more recently
Eslick et al. (2009). The target values for the four properties of inter-
est (solubility, diffusivity, melting point and Henrys lawconstant),
as well as values of these properties for the best candidate IL found
in each case are shown in Table 3.
As can be seen from the property values in the table, the two
optimization algorithms do not nd the same solution. Both solu-
tions are of about the same quality, as measured by the scaled
percent deviation(0.0317for TabuSearchas comparedwith0.0244
for CPLEX). Again, equal weighting was usedfor all properties, since
the focus is to compare the solution algorithms. Tabu Search pro-
vides a number of alternative solutions, all with similar objective
function values. The structures of the best solutions found via each
algorithm are shown in Fig. 3.
While the twomolecules presentedvaryinterms of whichprop-
erties deviate most strongly from the targets, the key difference
to be considered lies in the computational efciency of the two
algorithms. The Tabu Search implementation found the solution
presented in the table and numerous alternatives within 5s, while
CPLEX was run for 20min to nd the one solution presented. Con-
Table 3
Properties, target values and predicted values for the optimal solution to the second
example problem, when solved with Tabu Search and CPLEX.
Property Target value Tabu Search CPLEX
Sol. (10
2
mol/L) 55 39.1 29.3
D (10
11
m
2
/s) 30 117.0 59.5
Tm (K) 198.15 197.5 196.2
Henrys law constant (MPa) 2 2.05 2.06
Fig. 3. Example anions designed using Tabu Search and CPLEX, respectively.
sidering that the overall error in the property prediction equations
may be as high as 10%, one can conclude that the extra computa-
tional effort required to perform bounding calculations and prove
global optimality with a deterministic algorithm is not justied in
this case.
Note the methodology in its current form does not provide
information on how the new candidate structure is to be syn-
thesized, but it does give a researcher a short list of potential
compounds which are likely to match the desired physical prop-
erty targets. Property values may also be bounded (simultaneously
with being optimized) so that maximum and minimum values are
never exceeded for feasible solutions. This method may also be
used to improve a given ionic liquid pair. In this case, one simply
xes certain groups within the molecule, and uses the optimization
algorithm to suggest useful modications of a given structure. The
resulting optimization problems have fewer binary variables than
a full design problem, and thus a larger number of modications
may be considered.
6. Conclusions
In this paper, a molecular design problemfor the design of ionic
liquids for use within environmentally friendly refrigeration sys-
tems is considered. The product design problemhas been recast as
a mixed-integer linear program, and is solved to provide candidate
structures for synthesis and further testing. Examples are provided
whichshowthe utilityof the methodologyfor designing novel ionic
liquids for use within absorption refrigeration systems. The Tabu
Search algorithm is shown to be more efcient that a determinis-
tic algorithm for the purpose of generating near-optimal solutions
to this molecular design optimization formulation. Further work
will design both the anion and cation within the system, and will
integrate newexperimental data to correlate and then design con-
sidering a wider range of properties. Also, new experimental data
is being obtained for mixtures of ionic liquids, and this data will
later be used to develop property correlations for these systems.
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