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1868 Current Topics in Medicinal Chemistry, 2015, 15, 1868-1886

Nano-QSPR Modelling of Carbon-Based Nanomaterials Properties

Maryam Salahinejad*

Application Radiation Research School, NSTIR, Tehran, Iran

Abstract: Evaluation of chemical and physical properties of nanomaterials is of critical importance in a broad variety of
nanotechnology researches. There is an increasing interest in computational methods capable of predicting properties of
new and modified nanomaterials in the absence of time-consuming and costly experimental studies. Quantitative Struc-
ture-Property Relationship (QSPR) approaches are progressive tools in modelling and prediction of many physicochemi-
cal properties of nanomaterials, which are also known as nano-QSPR. This review provides insight into the concepts,
challenges and applications of QSPR modelling of carbon-based nanomaterials. First, we try to provide a general over-
view of QSPR implications, by focusing on the difficulties and limitations on each step of the QSPR modelling of nano-
materials. Then follows with the most significant achievements of QSPR methods in modelling of carbon-based nanoma-
terials properties and their recent applications to generate predictive models. This review specifically addresses the QSPR
modelling of physicochemical properties of carbon-based nanomaterials including fullerenes, single-walled carbon nano-
tube (SWNT), multi-walled carbon nanotube (MWNT) and graphene.
Keywords: Nano-QSPR, Physiochemical properties, Fullerenes, SWNTs, MWNTs, Graphene.

1. INTRODUCTION graphite with two-dimensional properties. The honeycomb

Carbon-based nanomaterials (CBNs) offer interesting
physical and chemical characteristic structures with superior
and unique thermal, mechanical, optical and electrical prop-
erties. Considering the aforementioned advantageous proper-
ties, carbon-based nanomaterials have found wide range ap-
plications in biomedical, technological and environmental
research. CBNs are important candidate for synthetic scaf-
folds in tissue engineering [1], drug delivery systems and
cancer therapy [2], cellular sensors and imaging agents [3].
Due to their potential applications in improving structural
strength of materials they have been identified as promising
nanomaterials in the field of electronics [4], cosmetics [5],
polymers [6] and energy [7]. In recent years, many environ-
mental researches have been done relying heavily on the
performance of CBNs with their increasing applications in
composite filters, high-flux membranes, antimicrobial
agents, nanoprobes and sensors [8].
Various types of CBNs such as fullerenes, graphene,
multi-walled carbon nanotubes (MWNT) and single-walled
carbon nanotubes (SWNT) are shown in Fig. (1). Fullerenes
are a class of cage-like molecules of carbon, Cn, with fairly
common structures of C60 and C70. Fullerene C60, consisting
of 60 sp2 hybridized carbon atoms arranged as 20 hexagonal
and 12 pentagonal rings, represents a special class of spheri-
cal quasi-aromatic systems [9]. The π -system of delocalized
electrons in fullerene structure make them like an electron
deficient alkene which reacts readily with electron rich spe-
cies [10]. Graphene is a single atomic layer of crystalline
*Address correspondence to this author at the Application Radiation Re-
search School, NSTIR, Tehran, Iran;
Tel: +989125253143; Fax: +982188221166;
E-mails: salahinejad@gmail.com; salahinejad@yahoo.com
lattice structure of graphene with a large delocalized π -
electron system gives rise to many interesting properties
[11]. Carbon nanotubes (CNTs), can be described as gra-
phene sheets rolled into a cylindrical tube. SWNTs are hol-
low cylindrical nanostructure tubes made from a wrapped
graphene sheet, while the MWNTs consist of multiple layers
of graphene sheets rolled up to form polymeric structures of
concentric tubes [10]. Based on the rolling vector of gra-
phene sheet which shows the arrangement of the sp2 carbon
hexagons, the tubes can have the shape of armchair, zigzag
and or chiral (Fig. 1D, 1E and 1F respectively). The chiral
vector (Ch) defined as Ch =na1 + ma2, where a1 and a2 are
graphene lattice vectors and n and m are integer numbers
characteristic for nanotube of any helicity [12, 13]. The
paired value of the integer numbers (n,m), which character-
ized the atomic structure of a nanotube, plays an important
role in many physical and chemical (physicochemical) prop-
erties of nanotubes. Due to different diameter, length, and
chirality during their growth, carbon nanostructures exhibit a
rich structural diversity, which has led to the discovery of
physicochemical properties of CBNs difficult and fascinating
as well.
Theoretical studies and computational methods of nanos-
tructured materials can help to obtain their structural infor-
mation and may result to a fast estimate of their properties or
activities in the absence of expensive experiments. Quantita-
tive Structure-Activity/Property Relationship (QSAR/QSPR)
approaches, as one of the major computational molecular
modeling methodologies act as an effective means to predict
and estimate of activities or properties of compounds based
on their structures [14]. Nano-QSAR or Quantitative Nanos-
tructure-Activity Relationships (QNAR), first introduced by
Puzyn et al. [15] refers to the application of QSAR methods

1873-5294/15 $58.00+.00 © 2015 Bentham Science Publishers

Nano-QSPR Modelling of Carbon-Based Nanomaterials Properties
A)
D)
Fig. (1). Carbon-based nano material structures. A) Fullerene C60, B) Geraphene, C) Multi-walled carbon nanotube (MWNT), and D) Arm-
chair, E) Zigzag and F) Chiral single-walled carbon nanotube (SWNT).
for construction of predictive models of biological activities
of nanomaterials. There are some recently published reviews
on QSAR modelling of nanomaterials, but most of those
manuscripts focus on toxicity or biological activity of nano-
materials especially nanoparticles [16-21]. The aim of this
review is to summarize the most significant achievements of
QSPR methods in modelling of carbon nanomaterials phys-
icochemical properties and their recent applications to gener-
ate predictive models.
2. GENERAL SCHEME OF QSPR
All physical, chemical, biological and technological
properties of a particular molecule depend on its molecular
structure and vary with it in a systematic way [22]. The es-
tablishment of correlations and quantitative prediction be-
tween diverse molecular properties and chemical structure is
known as quantitative structure-activity/property relationship
(QSAR/QSPR). QSAR methods are considered the most
popular theoretical method for chemical researches world-
wide, and are extensively applied in the fields of medicinal,
environmental, agricultural and technological aspects of life
[17, 23-25]. The major goal of the QSPR studies is to con-
struct a statistical model that relates the property of interest
and descriptive parameters (descriptors) derived from the
structure of the molecule. In QSPR methodology, a set of
descriptors (Xi) is connected to experimental property values
(Y) with a mathematical model (f), which defined as equa-
tion 1.
Y (property) =f (Xi) (1)
The construction of QSAR/QSPR model typically com-
prises of five main steps: collecting the experimental data
set; calculating descriptors from molecular structures; choos-
ing informative descriptors that are deemed to be important
for explaining the desired property or activity; generating
linear or non-linear relationships between selected descrip-
Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18 1869
B) C)
E) F)
tors and the property in question; and validating of reliabil-
ity, robustness and prediction capabilities of QSPR models.
The workflow of the QSAR/QSPR paradigm is shown in
Fig. (2).
Some comprehensive reviews [14, 22-24] provide the in-
depth representation of the main concepts involved in the
development of QSAR/QSPR models. Therefore, only a
summary of the important elements of the QSPR modelling
process, which used in modelling of carbon nanomaterials
properties, is provided here. Instead, the difficulties and
challenges on each step of building a nano-QSPR model will
be further investigated.
2.1. Data Collection
Data collection or selection of an appropriate training set
is a key step in developing a reliable QSPR model. Katritzky
et al. summarized some criteria which should be considered
in a data set selection [22]. Although, there is no direct and
simple answer to the size of the data set in constructing a
QSPR model, but it should utilize as many as possible com-
pounds. If the number of compounds in the training set is not
large enough, the data may not span the complete property
space, hence the QSPR production of new similar com-
pounds can't be reliable. The structural diversity and activ-
ity/property value distribution of compounds in a dataset are
very important for QSAR model development [26]. The
range of the property values should cover a range of at least
1 logarithmic unit. One challenges in developing nano-
QSAR models, is considering that the QSAR modelling has
been developed for structurally diverse small organic com-
pounds, but nanomaterials are not single discrete molecules
like small organic molecules, rather are often poorly defined
mixtures or distributions of materials. Hence, nanomaterials
have multiple dimensional physicochemical properties [27]
but have limited diversity in structure. In the case of carbon
1870 Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18
nanotubes the distribution of structures probably includes
different lengths, diameters, and numbers of layers in the
walls. Due to high structural complexity and the diversity of
nanomaterial properties it is difficult to develop quantitative
parameters capable of characterizing their structural and
chemical properties [28].
Fig. (2). Workflow of the QSAR/QSPR paradigm.
The reliability of the experimental property, as an impor-
tant issue, determines the prediction ability and accuracy of
QSPR models [22]. Unfortunately, the most nano-QSAR
models suffer from lack of high
quality experimental data
and sufficient data available for being able to build reliable
and predictive models. One important difficulty in extending
the traditional QSPR to nano-QSPR methodology would be
possibility to develop a reliable and predictive model based
on a limited number of experimental data on nanomaterials
[29].
2.2. Descriptors
The molecular descriptors are numerical value that char-
acterize various molecular properties, which can be meas-
ured physicochemical properties or theoretical indexes calcu-
Maryam Salahinejad
lated by mathematical formulas or computational algorithms
[30]. There are numerous programs that generally produce a
pool of different molecular descriptors involving: constitu-
tional, topological, geometric, electrostatic and quantum-
chemical, fragment-based and molecular fingerprint descrip-
tors for discrete, small organic molecules, not materials. Un-
fortunately, such packages which generate hundreds or thou-
sands of descriptors for small organic molecules, have not
yet developed for nanomaterials. As discussed above, due to
high structural complexity and the diversity of nanomaterial
properties, nano-specific descriptors or nanodescriptors are
needed to be developed to represent the physicochemical
properties of nanomaterials for developing reliable QSAR
models. Unlike small organic compounds, there is no sys-
tematic way to describe the physicochemical, geometrical
and structural features of nanomaterials. One important chal-
lenge in nano-QSPR modelling is to identify the relevant
features and develop quantitative parameters describing
unique molecular properties of nanomaterials for modelling
[15].
Different experimental and theoretical descriptors are
proposed and developed to describe the carbon nanomateri-
als. Theoretical descriptors were derived from physics-based
computational methodologies, such as molecular dynamics
(MD) simulations [31] and quantum chemistry [32]. The MD
simulation method is based on Newton’s second law and has
provided detailed information at the microscopic level, in-
cluding atomic positions and velocities [33]. Quantum chem-
istry methods are based on approximate solutions of the
Schrödinger equation and use quantum mechanics to deal
with chemical problems e.g. structure, molecular properties
and stability during reactions [34]. Chemical graph theory
have been also utilized to calculate some topological descrip-
tors including topological indices such as Wiener, Padmakar-
Ivan [35], Szeged indices [36], Simplified Molecular-Input
Line-Entry System (SMILES) and International Chemical
Identifier (InChI) descriptors of CNTs and fullerenes [37-
39]. Experimental descriptors derived from spectros-
copy/microscopy characterization results of nanomaterials
e.g. NMR spectroscopy [40], scanning tunneling microscopy
[41] and scan electron microscopy [42] also can be used as
descriptors. Borders et al. [31] defined and developed 20
descriptors for mechanical property prediction of carbon
nanotubes by MD simulations. Table 1 displays some theo-
retical descriptors derived from MD and DFT calculations or
graph theory for carbon nanotubes.
2.3. Variable Selection
The relevant descriptors only should be used in the
QSPR models to avoid overfitting and to improve predic-
tion ability of the models. A feature selection method
should completely eliminate uninformative and intercorre-
lated descriptors to avoid overfitting of QSPR model and
make easier interpretation of the model. Leaving unin-
formative descriptors in models can degrade the model sub-
stantially. As an acceptable guideline, “five or six data
points per descriptor”[43] is required to develop a QSPR
model. Considering this rule and the lack of sufficiently
large data sets for nanomaterials, some preliminary knowl-
edge or using a variable selection procedure is required to
select the best set of descriptors.
Nano-QSPR Modelling of Carbon-Based Nanomaterials Properties Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18 1871

Table 1. Theoretical descriptors for carbon nanotubes.

Descriptors Symbol Definition

Area A Cross-sectional area of nanotube (Å2)

Chiral angle CA Chiral angle (radians)

Average radius RA Average of first three end rings radii for relaxed CNT (Å)

Theoretical radius RT Theoretical radius of perfect nanotube (Å)

Aspect ratio AR Ratio of the length to the diameter

% Single defects %SD Percentage of single defects

% Double defects %DD Percentage of double defects

% Methyl groups %M Percentage of surface functionalized methyl

Number of Missing C’s CM Number of missing due to a vacancy defect

Number of Methyl groups MN Number of methyl functional groups

Number of Total C’s CT Total number of carbons in the test case

MN/CT MN/CT Ratio of methyl groups to total number of carbons

CM/CT CM/CT Ratio of missing carbons to total number of carbons

Number of Single defects #SD Number of single defect types

Number of Double defects #DD Number of double defect types

Number of Nonsp2 C’s CN2 Number of nonsp2 hybridized carbons

CN2/CT CN2/CT Ratio of nonsp2 hybridized carbons to total number of carbons

Surface area SP Total surface area of nanotube (uses average radius)

Defect surface area SD Surface area of defects

Ratio of SD/SP SD/SP Defect area to total surface area

HOMO HOMO Highest occupied molecular orbital

LUMO LUMO Lowest unoccupied molecular orbital

Energy gaps E Energy differences between HOMO and LUMO

Ionization potential IP Ionization potentian

Electrophilicity Index Ω Electrophilicity index

Chemical hardness η Chemical hardness

Electron affinity EA Electron affinity

Electronegativity Χ Electronegativity

Wiener index W Wiener index

Padmakar-Ivan index PI Padmakar-Ivan index

Szeged index Sz Szeged index

There are statistical techniques available for proper de-
scriptor selection based on filtering and wrapper techniques.
In filtering method, no model is built, and statistical proper-
ties of the features are evaluated using some criteria. Wrap-
per approaches, which are based on constructing and evaluat-
ing a series of models to select a subset of descriptors, in-
cludes sequential backward feature elimination, sequential
feature forward selection [44], genetic algorithm [45-47],
enhanced replacement method (ERM) [48, 49], successive
projection algorithm (SPA) [50] and fractional factorial de-
sign (FFD) [51]. Sparse feature selection methods as novel
mathematical techniques have been recently applied for find-
ing and extracting a small number of the most significant
features without overfitting the model [52, 53]. Sparse meth-
ods employed Bayesian statistics with a laplacian prior [54],
are efficient tool for supervised feature selection of descrip-
tors, specifically, when dealing with data sets with the large
number of features compared to small sample sizes [55]. For
more details, refer to the reviews published in variable re-
duction methods for QSAR [56-58].
1872 Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18
2.4. Model Construction
The main step of the QSPR methodology is to derive a
model that mapping between the property and the values of
the selected features. In many cases, linear models as the
basis of QSPR method from its beginning can generate good
models. Linear models are easily interpretable and suffi-
ciently accurate for small datasets of similar compounds
[24]. Linear multivariate statistical methods, such as multiple
linear regression (MLR), principal component regression
(PCR) [59] and partial least-squares regression (PLS) [60,
61] are widely used in QSPR model buildings. However, the
structure-property relationship, in some cases, may be non-
linear in nature and nonlinear approaches are required to
model properly such properties. Artificial Neural Networks
(ANN) [62, 63], the k-Nearest Neighbor (KNN) [64, 65] and
Support Vector Machines (SVM) [66, 67] are quite popular
nonlinear techniques in QSPR analysis. However, nonlinear
models seem to have the drawbacks of tendency to overfit
the data, more complicated estimation and interpretation in
ascertaining the descriptors which are most significant in the
resulting model [68]. Ridge regression for linear models and
Bayesian regularization for neural network models can be
employed to control the complexity (nonlinearity) of the
QSPR models. Bayesian regularized neural nets automati-
cally choose the optimum complexity of a QSAR model,
achieving the best balance between bias and variance [53,
54, 69].
2.5. Model Validation
Model validation, as an important and crucial step, is re-
quired to ensure reliability of the models developed in QSPR
analysis. Development and validation of nano-QSPR models
is a difficult task in the lack of high-quality and sufficient
quantity of experimental data for nanomaterials. Unfortu-
nately, some nano-QSPR reported using very small data sets
(less than 25 data), were validated insufficient according to
common QSPR modeling practices such as OECD principles
[70]. In the absence of enough data, the internal validation
methods are utilized more to validate the QSPR models.
Leave-one-out cross-validated squared correlation coeffi-
cient (Q2) as one of the most popular validation criteria [71],
N-fold cross-validation or leave-many-out [72], permutations
of the data (randomization test or scrambling) that represent
the model robustness [72] are common internal validation
methods. A reliable and predictive QSPR model should be
statistically significant and robust, be validated by making
accurate predictions for external data set that not used in the
model development and have a defined domain of applicabil-
ity [14, 71]. Models relying only on training and internal test
sets cannot reliably prove their robustness. Furthermore, the
separation of the external validation set should be independ-
ent of any modelling process. Validation of an external set is
one of the most widely used methods of correlation testing.
The purpose of the external validation is to evaluate how
well obtained model generalizes objects whose data have not
taken part in the process of model development [73, 74].
Standard error of calibration (SEC) and standard error of
prediction (SEP), as robust estimators, were used to assess
the predictive quality of the derived QSPR models since
these are independent on the number of parameters in the
model and size of the training set [75]. The root-mean-square
Maryam Salahinejad
error in calibration (RMSEC) and the root-mean-square error
in prediction (RMSEP) also used as alternative terms for
error in calibration and prediction sets respectively. The pre-
dictive power of the QSPR models is often quantified in
terms of predictive squared correlation coefficient (R2p) and
SEP [76]. A valid model with high generalization ability has
squared correlation coefficient of calibration (R2c) and SEC
values close to those of the model validation of R2p and SEP
respectively. Generally, higher values of Q2, R2c and R2p and
lower values of the SEC, RMSEC, SEP and RMSEP are de-
sired to develop a reliable QSAR model.
Besides of robustness, accuracy and predictive ability of
QSPR models, they should have a defined domain of appli-
cability. The applicability domain (AD) of a QSPR model is
a theoretical region of chemical space defined by the struc-
tural diversity of the compounds in the data set and the mod-
elled response, for which a given QSPR should make reliable
predictions [77]. The AD determines the boundaries of the
model developed to find how well it will work for new com-
pounds. Puzyn et al. argued that it was impossible to develop
a universal model for all nanosystems and that it is practi-
cally impossible to establish one QSPR model for a very
wide applicability domain in the case of classical chemicals.
The plot of the standardized residuals versus the leverage,
Williams plot, is often used to visualize the applicability
domain. Fig. (3) displayed the applicability domain of a
QSPR model of SWNTs dispersibility in different organic
solvents using a William plot [78].
3. NANO-QSPR MODELLING OF PHYSICOCHEMI-
CAL PROPERTIES OF CBNS
3.1. Fullerene’s Solubility
Solubility is an important physicochemical factor for
pharmaceutical, environmental, and industrial applications of
organic molecules [79]. Early knowledge of solubility is
crucial for estimating transport properties of organic mole-
cules in drug development [79, 80] and is also important for
environmental fate estimation, ecotoxicity and separation
science. Unfortunately, solubility is also one of the most
difficult molecular properties to predict using computational
models and a myriad of computational methods have been
used to estimate aqueous solubility directly from molecular
structures [80]. A number of QSPR approaches have been
reported to develop reliable models for accurate prediction of
solubility of different organic compounds [80-82].
Different QSPR approaches including linear solvation
energy relationship (LSER) [83-86], neural networks and
support vector machine [87-90], SMILES (simplified mo-
lecular input line entry system) and InChI based optimal
descriptors [37-39, 91], and others two dimensional (2D)
QSAR methods [92-96] have been applied to predict the
solubility of C60 in different organic solvents. Table 2 sum-
marizes the characteristics of QSPR approaches for C60 solu-
bility in different organic solvents.
Linear Solvation Energy Relationship (LSER), originally
developed by Kamlet and Taft [97], have been extensively
applied to study of nanomaterial properties prediction. LSER
methods are specific subclass of thermodynamic relation-
ships known as linear free energy relationships (LFERs),
Nano-QSPR Modelling of Carbon-Based Nanomaterials Properties
2.5
2.0
1.5
1.0
Studentized Residuals
0.5
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
0.00
Fig. (3). The Williams plot for QSPR model of SWNTs dispersibility in different organic solvents. Dotted lines represent ±2 studentized re-
sidual, dash line represents a warning leverage (h* ≈ 0.52).
which use solvatochromic parameters to describe the de-
pendency of physicochemical properties of a molecule to
solute-solvent interactions. LSER models typically express
in five main descriptors, including the solute size, polar-
ity/polarizability, hydrogen bond acidity, hydrogen bond
basicity and the excess molar refraction [98-100]. A most
common and widely accepted model of the LSER, repre-
sented by Abraham [101] is expressed as follows:
SP = = c + eE + sS + aA + bB + vV
where SP is any free energy related property, c is the regres-
sion constant, E is the excess molar refraction, S is the po-
larizability/dipolarity, A is the hydrogen bond donating abil-
ity, B is the hydrogen bond accepting ability, V is the mo-
lecular volume, and the e, s, a, b, and v are the regression
coefficients. Multiple linear regression analysis is often util-
ized to fit the coefficients and building the model. These
descriptors are determined using experimental techniques,
therefore LSER is an experiment-based QSAR/QSPR ap-
proach. These useful parameters are developed and exten-
sively used to obtain QSPR models and predict chemical
properties of nanomaterials.
LSER analysis was used extensively in the early reports
on fullerene solubility modelling. Sivaraman et al. reported
the first attempt to explain the trends in C60 solubility and
showed the correlation between experimental fullerene’s
solubility and calculated solubility parameter for 15 different
organic solvents at 303 K [86]. Ruoff et al. also investigated
C60 solubility trends in a larger data set of 47 organic sol-
vents, and examined the relation between C60 solubility and
various solvent properties such as index of refraction, dielec-
tric constant, molecular size, Hildebrand solubility parame-
ter, and H-bonding strength [102]. These studies showed no
systematic way to explain the C60 solubility with no predic-
tive model, indicated just certain trends in solubility.
The solubility of C60 were transformed into octanol-water
partition coefficient (log P) and gas-solvent partition coeffi-
cient or Ostwald solubility coefficient (logL) and used as
Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18 1873
Train set
Test set
0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60
Leverage
dependent variables by Abraham et al. [103]. Abraham sol-
vation equation, consisting of the solute excess molar refrac-
tivity, the solute dipolarity/polarisability, the overall or
summation hydrogen-bond acidity and basicity, and the
McGowan characteristic volume, showed a good correlation
with C60 solubility in 20 investigated solvents. It indicated
that C60 is not completely nonpolar, has no hydrogen bond
acidity but is a slightly stronger hydrogen basicity than com-
pounds such as acetophenone and behaves more like a poly-
(2) alkene than an aromatic system. Makitra et al. examined a
two-parameter equation to correlate the solubility of C60 in
47 organic solvents [104]. The required descriptor were the
solvent refractive index function, f(n)=(n2-1)/(n2-2) and the
solvent cohesive energy density, δ 2. This simple equation
gave an correlation coefficient of 0.95 and RMSEC of 0.48.
In the next study, they used a larger dataset of 89 solvents
and by adding another descriptor, the molar polarization
function f(ε)= (ε-1)/(ε+ 2), to the previous model and remov-
ing eight outliers, a correlation coefficient of 0.87 with and
RMSEC value of 0.47 were achieved [105]. They simply
concluded that the solubility of C60 increases with increasing
solvent polarizability and decreases with increasing solvent
polarity and cohesive energy density.
Marcus et al. regarded the solubility of C60 in various
solvents at two different temperatures of 298 and 303 K and
treated it by multivariate stepwise linear regression applied
as the linear solvation energy approach [106, 107]. They
constructed a four-variable in 55 solvents with R2c of 0.86
and SEC of 0.4 at of 298 K, and a three-variable model in 20
solvents with R2c of 0.72 and SEC of 0.52 at 303K [106].
The next study, they used larger data set of 113 and 32 solu-
bility data items for 298 K and 303 K respectively [107]. The
QSPR model with four variables and 95 data set (18 outliers)
showed R2c =0.99 with SEC of 0.41 at 298K. With three
variables, the results gave an R2c of 0.99 and SEC=0.39 at
303K, leaving seven outliers and 25 data set. It indicated that
increasing molar volume and solvent polarity diminished the
solubility of C60, whereas electron pair donation ability and
polarizability enhanced solubility.
1874 Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18 Maryam Salahinejad

Table 2. Summary of QSPR approaches for C60 solubility in different organic solvents.

Dataset Model Performance Descriptors Statistical Method Ref.

Nc=20 SEC=0.4 5 LSER [103]

Nc=47 R=0.95, RMSEC=0.48 2 MLR [104]

Nc=81 R=0.93, RMSEC=0.47 3 MLR [105]

2
Nc=55(298K) R c=0.86, SEC=0.4 4
LSER [106]
Nc=20(303K) R2c=0.87, SEC=0.52 3

Nc=120(298K) R2c=0.99, SEC=0.42 4

LSER [107]
Nc=25(303K) R2c=0.99, SEC=0.39 3

Nc=126 SEC =0.45 5 ANN [89]

Nc=76 RSMEC= 0.42, RMSEP=0.50 9 MLR

[87]
Np=20 RSMEC= 0.25, RMSEP=0.35 ANN

R2c=0.91, R2 p=0.91,
Nc=92 SVM
RSMEC= 0.10, RMSEP=0.15 5 [90]
Np=30 MLR
R2c=0.89, RSMEC= 0.13

Nc=100 R2c=0.91, Q2=0.89, RSMEC= 0.12 MLR

5 [88]
Np=24 R2c=0.94, Q2=0.94, RSMEC=0.07 ANN

Nc=45 (Aliphatics) R2c=0.91, SEC=0.26 4 MLR

[95]
Nc=25(Aromatics) R2c=0.94, SEC=0.21 5 MLR

Nc=29 R2c=0.87, Q2=0.79, RSMEC= 0.16

5 MLR [112]
Np=7 R2p=0.81, RSMEP= 0.22

Nc=25 R2c=0.81, SEC=3.6 a

1 MLR [96]
Np=11 R2p =0.79, SEC=4.67a

Nc=92 R2c=0.86, SEC=0.4, Q2=0.85

1 MLR [39]
Np=30 R2p =0.89, SEP=0.4

Nc=92 R2c=0.93, SEC=0.27, Q2=0.93

1 MLR [38]
Np=28 R2p =0.91, SEP =0.33,

Nc=92 R2c=0.95, SEC=0.25, Q2=0.94

1 MLR [37]
Np=30 R2p=0.93, SEP=0.26

Nc=92 R2c=0.86, SEC=0.41, Q2=0.84

4 MLR [94]
Np=30 R2p =0.9, SEP=0.35

R2c=0.88; Q2=0.72, SEC=0.39

5 SVM
Nc=92 R2p =0.87, SEP=0.43
[114]
Np=30 R2c=0.86; Q2=0.77, SEC=0.42 b
6 PLS
R2p =0.72, SEP=0.67

Nc=61 R2c=0.85; Q2=0.79, RSMEC=0.38

4 MLR [108]
Np=16 R2p =0.87, RMSEP=0.37

Nc=15 ( n-Heptane) R2c=0.90, RSMEC=0.18, Q2=0.84 3

MLR [93]
Nc=15 ( 1-octanol) R2c=0.7, RSMEC=0.08, Q2=0.93 3

Nc=18 R2c=0.76, SEC=17.6a, Q2=0.72

1 MLR [113]
Np=9 R2p =0.92, SEP=12.5a
a
S was used instead of logS, b: number of latent variable
Nc: number of data in training set, Np: number of data in prediction set, R: correlation coefficient, R2c: squared correlation coefficient of training set, R2p: squared correlation coeffi-
cient of prediction set, Q2: leave-one-out cross-validated squared correlation coefficient, SEC: standard error of calibration, SEP: standard error of prediction, RMSEC: root-mean-
square error in training, RMSEP: root-mean-square error in prediction.
Nano-QSPR Modelling of Carbon-Based Nanomaterials Properties
A LSER model, based on solvent empirical parameters
for the prediction and description of the C60 solubility in
various solvents was reported [108]. The authors collected
‘‘Equilibrium and Kinetic’’, ‘‘Multiparameter’’ and ‘‘Spec-
troscopic’’ parameters for 79 organic solvents from the lit-
erature and applied them to build a four-variable multilinear
QSPR model. The presented experimental-based QSPR
model yielded an R2c of 0.85 and SEC of 0.38, with remov-
ing two outliers outside the AD of the model. Besides the
problem that the empirical descriptors are restricted to those
solvents with available experimental data, the reported ex-
perimental-based QSPR model showed no improvement in
the statistical performance when compared to other reported
MLR models (Table 2).
Solubility parameter is an important quantity for predict-
ing solubility relations and have been widely used to select
proper solvent, predict the compatibility of materials and
characterize the surface interactions in industry or laboratory
applications. The Hildebrand solubility parameters and Han-
sen solubility parameters (HSP) are common empirical
methods for the prediction of solubility. The Hildebrand
solubility parameter is defined as the square root of the cohe-
sive energy density indicates the relative solvency behavior
of a specific solvent. The cohesive energy density of a liquid
is directly proportional to the heat of vaporization which is a
direct reflection of the degree of van der Waals forces hold-
ing the molecules of the liquid together [109]. Hansen pa-
rameters divide the total Hildebrand value into three differ-
ent components as equation 3:
()2=()2 + ()2+ ()2 (3)
where, δ t =total Hildebrand parameter; δ d =dispersion force
component, δ p=polar component and δ h=hydrogen bonding
parameter. Hansen solubility parameters are widely used to
correlate and predict the behavior of solvents.
Hansen and Smith [83] used Hansen solubility parame-
ters [110] to correlate the C60 solubility in a database of 89
organic solvents and 30 polymers. The Hansen solubility
parameters δd, δp, and δh, were estimated for C60 as 19.7, 2.9,
and 2.77 MPa1/2, respectively. These values were taken as a
three-dimensional coordinate system of the centre of the
sphere containing good solvents in the HSP space. A simple
composite affinity parameter, Relative Energy Difference
(RED), was defined to classify organic solvent. Good sol-
vents showed the RED value less than 1 and progressively
poorer solvents had higher RED values. It concluded that
both the good solvents and the compatible polymers for C60
solubility were polycyclic hydrocarbons and aromatic hydro-
carbons with halogen substitutions.
Huang explored the application of solution model of
Thomas and Eckert [111] with consideration of dispersion,
polar, acidity, and basicity interactions was used to correlate
the solubility of C60 in 54 solvents [84]. The author found
that fullerene had dispersion and polar components near
those that characterize aromatics, a small acidity, and a zero
basicity component and suggested that the model was able to
correlate solubility data ranging from alkanes to alcohols.
Kiss et al. applied artificial neural network (ANN) ap-
proach to introduce nonlinearity in QSPR model to predict
the solubility of C60 in 126 organic solvents [89]. Molar vol-
Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18 1875
ume, polarizability parameter, LUMO energy, saturated sur-
face, and average polarizability, calculated using semi em-
pirical quantum-chemical methods, were chosen as relevant
molecular properties and inputs of a back-propagation neural
network. Without model validation in the prediction of an
external or test set, and with excluding some outliers the
model showed the SEC of 0.45. The results showed that in a
large number of solvents the solubility of C60 decreases with
increasing molar volumes of the solvents and increases with
their polarizability and saturated surface areas.
Danauskas and Jurs developed ANN and MLR models
predicting fullerene solubility in 96 diverse solvents [87]
using four types of descriptors including: topological, elec-
tronic, geometric and geometric/electronic hybrids. The
feed-forward computational neural networks model consist-
ing of a 9-3-1 architecture, having RMSEC and RMSEP of
0.255 and 0.346 respectively. Randomization test was per-
formed to show the absence of chance correlations between
independent and dependent variables. As authors claimed,
the nonlinear ANN model, that yielded lower error, 15.3%
and 33.7% decrease in RMSEC and RMSEP respectively,
gave a good prediction for an external test set.
Least-squares support vector machine (LSSVM) was util-
ized to develop C60 solubility models in 128 diverse organic
solvents on the basis of CODESSA software consisting of
constitutional, topological, geometrical, electrostatic, and
quantum-chemical descriptors of compounds reported by Liu
et al. [90]. The data set was separated into a training set of
92 compounds and a test set of 30 compounds. Furthermore,
a process of leave-one-out cross-validation of the training set
was performed. Linear and nonlinear solubility generated
models gave satisfactory prediction results. The R2c was
0.892 and 0.903, and RMSEC was 0.126 and 0.116 for
LSSVM and MLR models respectively. LSSVM nonlinear
models produced slightly better models with good predictive
ability than did the linear regression. SVM techniques are a
powerful approach to modelling but they are quite complex
and required to optimize the kernel parameters.
Feed forward neural network (FFNN) approach was also
used to consider the nonlinear behavior of different molecu-
lar descriptors for prediction of solubility of C60 in 124 or-
ganic solvents. Genetic algorithm was used to extract the
statistically effective molecular descriptors. The proposed
FNN model consisting of a 5-6-1 structure, having an R2c of
0.94 and RMSEC of 0.267. The results of FNN were better
in comparison with the GA-MLR equation. Although the
data set divided to training and test set, no statistical results
reported for prediction ability of the model obtained [88].
Sivaraman et al. proposed several regression equations
for each individual class of solvents as well as for combina-
tions of these sets [95]. The models were based on topologi-
cal indices, polarizability parameter and indicator variables
denoting the structural details of the solvent molecules. The
values of R2c for individual subsets ranged between 0.91for
Alkans to 0.99 for Cycloalkanes with the corresponding val-
ues SEC from 0.04 (Cycloalkanes) to 0.22 (Alkyl halides).
Although, the models suggested for solvents subsets showed
good statistical performance and were better than the model
for the combined data set, they suffered from small numbers
of solvents and lack of an external validation set, therefore,
1876 Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18
they had limited application to particular families of sol-
vents. It indicated that the variation in neither polarizability
parameter nor structural parameters encodes the changes in
solvent-solute interaction due to changes in substituent, their
combination, and substitution pattern in the carbon skeleton.
Another study was reported the QSPR modeling of C60 solu-
bility for an individual class of solvents [112]. The authors
claimed that they developed the models in various organic
solvents, but the models were constructed only for 36 ben-
zene derivatives solvents. The presented models, with R2 c
and R2p less than 0.87 and 0.81 respectively, showed less
statistical performance compared to models obtained by
Sivaraman et al. [95] for C60 solubility in aromatic solvents
(Table 2).
Toropov and coworkers created some QSPR models of
the solubility of C60 in different organic solvent using
SMILES [38, 39, 96] and InChI [37] based optimal descrip-
tors. Optimal descriptors correlation weights (DCW) are
calculated from SMILES or InChI text-based descriptions of
a molecule. At the first attempt, they created a one-variable
QSPR model of C60 solubility using a DCW calculated from
rules of the SMILES fragments for a data set of 36 substi-
tuted benzene solvents [96]. DCW defined as the production
of SMILES fragments which optimized by Monte Carlo
method and expressed as:
DCW= k=1NCW(Sk)
where Sk is as a rule one character fragment of the SMILES
notation. The obtained model statistically characterized by
R2c=0.81 with SEC of 3.60, and for the training set and R2p
of 0.79 with SEP=4.67, without transformation the solubility
to log unit. They agin used the DCW to produce one-variable
QSPR model of C60 solubility in 122 different organic sol-
vents, while, here, the DCW defined as summation of
SMILES fragments optimized by Monte Carlo method [39].
Statistical characteristics of the model (Table 2), showed
slightly better than their previous work for a subclass of sol-
vents of substituted benzene. They also tried to build nonlin-
ear SMILES based models using the DCW2 or DCW0.5 but
the statistical quality of the models of the logS was not im-
proved. At the next attempt, they modified the DCW as
combinations of the SMILES attributes. The multiplicative
SMILES based optimal descriptors technique provided im-
provement over the previous models for predictions of
solubility of fullerene in organic solvents [38].
In the similar study, they used DCW (InChI) as the corre-
lation weight of the InChI attribute to construct QSPR mod-
els in various organic solvents [37] which defined as
DWCInChI=WIk, where the Ik was InChI attribute and W(Ik)
was the correlation weight for the Ik. It concluded that the
solubility model obtained from InChI-based optimal descrip-
tors are better than models based on optimal descriptors
which were calculating with SMILES-based descriptor [37].
The same research group utilized Ab initio quantum-
chemical descriptors to build QSPR model of C60 solubility
on the same data set of 122 organic solvents. Genetic algo-
rithm and multiple regression analysis (MLRA) was used to
construct one-, two-, three- four- and five-variable QSPR
models of C60 solubility [94]. The best performance was ac-
complished by the four-variable MLRA model with
Maryam Salahinejad
R2p=0.90. Their study revealed a correlation of HOMO en-
ergy (HOMO–LUMO gap), heteroatom fragments and geo-
metrical parameters with solubility of C60.
In contrast with the other papers, where the solubility of
C60 in different organic solvents was modelled, the last two
works of Table 2, represented QSPR models for C60 solu-
bility in one solvent. Two general QSPR models were de-
veloped by Martin et al. [93], describing the solubility of
14 polycyclic aromatic hydrocarbons (PAH) and C60 in two
different condensed media, an average polarity solvent with
an OH group (1-Octanol) and a nonpolar solvent (n-
Heptane). The CODESSA program descriptors [92], in-
cluding constitutional, topological and geometrical descrip-
tors and quantum chemical descriptors were calculated. The
proposed three-parameter QSPR models were derived with
Heuristic and best multilinear regression (BMLR) descrip-
tor forward selection approaches. The solubility QSPR
model in 1-octanol gave an R2 c and Q2 of 0.96 and o.93
respectively, while the solubility model in n-heptane
showed less statistical performance with an R2c of 0.9 and
Q2 of 0.83. The reliability of QSPR models was assessed
via leave-one-out and leave-50%-out methods and both
showed statistically good performance. However, the reli-
ability in predictions for C60 solubility has been questioned
by Puzyn et al. [15] due to structural difference between
(4) PAHs and the fullerene, as well as the large difference in
observed solubilities of fullerene compared to the poly-
cyclic aromatic compounds. The next one, reported by
Toropova's group, described the QSPR models between the
molecular structure of C60 and C70 fullerene derivatives and
their solubility in chlorobenzene [113]. The SMILES-based
optimal descriptors calculated using CORAL freeware [91]
gave a reasonable prediction of the solubility for both C60
and C70 fullerene derivatives.
All of the papers appeared in the literature used 2D-
QSPR modelling of solubility of C60 , and in our knowl-
edge, there is no publication in 3D-QSPR of C60 solubility
in various organic solvents. Recently, the 3D-QSPR model-
ling has been examined as an efficient tool for predicting
solubility of fullerene C60 [114] and dispersibility of
SWNTs [78] in different organic solvents. 3D-QSPR refers
to use of force field calculations to compute spatial proper-
ties of three-dimensional structure (3D) of compounds.
Molecular interaction fields (MIF) between chemical
probes and every atom of a molecule at surrounding points
of a predefined grid box [115, 116]. GRid-INdependent
Descriptors (GRIND) are alignment independent three di-
mensional descriptors derived from 3D maps of interaction
energies between the molecule and chemical probes based
on GRID molecular interaction fields (MIF) [117]. GRIND
descriptors are calculated as a function of the distance in-
stead of the position of each grid point and therefore insen-
sitive to the position and orientation of the molecular struc-
ture in the space to overcome the alignment problem. MIF
are generated around the molecule by probing different
chemical probes such as DRY, N1 , O, and TIP probes. The
DRY probe represents hydrophobic interactions, N1 (am-
ide) and O (carbonyl) probes represent hydrogen bond do-
nor and acceptor groups, respectively and the TIP probe
represents a shape-field.
Nano-QSPR Modelling of Carbon-Based Nanomaterials Properties
The VolSurf approach generates 3D maps of molecular
interaction field (MIF) based on probing the grid around a
target molecule with different chemical probes, and converts
the calculated MIFs to simple and interoperable molecular
descriptors [118]. By using various probes such as hydrogen
bonding interactions, hydrophobic interactions or donor
group with specific cutoff values for energy were utilized to
produce different molecular properties. These descriptors
quantify the polarity, shape, size and hydrophobicity of
molecules, including molecular volume and surface, hydro-
philic and hydrophobic regions.
GRIND and VolSurf descriptors were successfully em-
ployed to develop predictive 3D-QSPR model of C60 solubil-
ity in 132 different organic solvents [114]. Two variable se-
lection techniques namely successive projections algorithm
(SPA) [119] and genetic algorithm (GA) [120] were used to
extract the more informative Volsurf descriptors and build
more predictive models.
The data set divided into three different sets of training,
test and external sets. Four solvents with indistinctive value
of C60 solubility (log S<−8), also considered as second ex-
ternal set. SVM and PLS were used to construct several
QSPR models. The SVM model based on Volsurf descrip-
tors extracted using the SPA method showed the best statis-
tical performance in C60 solubility modelling. The SPA-
(A)
Fig. (4). VolSurf GRID fields from A) OH2 probe and (B) DRY probe at energy level of -1kcal/mol of 1-Phenylnaphthalene as a strong sol-
vent for C60 (log S= -1.9).
(A)
Fig. (5). VolSurf GRID fields from A) OH2 probe, (B) DRY and (C) N1 probe at energy level of -1kcal/mol of Tetrahydrofuran as a very
weak solvent for C60 (log S<-8).
Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18 1877
SVM analysis resulted in a model with five latent variables
and an R2c=0.88; Q2=0.72 and R2p=0.87. The SEC and SEP
of SPA-SVM model were 0.39 and 0.43, respectively.
The five most significant VolSurf descriptors selected
by SPA procedure were: critical packing parameter (CP),
that represents the concentration of hydrophobic interac-
tions on the molecular surface, polarizability (POL), flexi-
bility parameter (Flex), capacity factor (CD1), which repre-
sents the ratio of the hydrophobic volume over the total
molecular surface, and intrinsic solubility (SOLY) which
calculated from thermodynamic solubility model and de-
fined as aqueous solubility in Mol/liter at 25o C. Fig. (4)
showed the VolSurf GRID fields obtained with OH2 and
DRY probes for a strong solvent, 1-Phenylnaphthalene.
Fig. (5) displayed the VolSurf GRID fields obtained with
OH2 , DRY and N1 probes for Tetrahydrofuran as a very
weak solvent for C60 . As concluded from Figs. (4 and 5),
the VolSurf GRID fields from DRY probe had no expres-
sion for the Tetrahydrofuran (Fig. 5B), while a large hy-
drophobic region located around 1-Phenylnaphthalene as a
strong solvent for C60 (Fig. 4B). GRID fields obtained with
N1 probe had a large area on Tetrahydrofuran but its not
any region around 1-Phenylnaphthalene, indicating the in-
significant role of hydrogen bond donor of solvent in C60
solubility.
(B)
(B) (C)
1878 Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18
The GRIND descriptors were related to C60 solubility in
different organic solvents by means of PLS analysis with six
latent variables. The GIND model with the FFD variable
selection method gave an R2c =0.86; Q2=0.77 and R2p=0.72
with the SEC and SEP of 0.42 and 0.67 respectively. Fig. (6)
depicted the PLS coefficient plot of chemical descriptors,
which were directly or inversely correlate to the C60 solubil-
ity. The largest peaks of PLS coefficients were related to
DRY and TIP probes, which represent hydrophobicity, shape
and size of the molecules, whereas N and O probes showed
no significant peaks. A deeper inspection of PLS plot re-
vealed that the variable of DRY-TIP: distance 7.2-7.6 Å,
explained a positive and the largest impact on C60 solubility
and variable of DRY-TIP at distance of 2.8-3.2 Å, showed
an inverse relationship between this variable and C60 solubil-
ity. This indicated that adjacent of hydrophobic groups, in
the distance about 3 Å, could reduce the interaction between
the solvent molecules and fullerene with spherical surface
area. The next two important GRIND descriptors related to
DRY-DRY blocks at distance of 1.6-2Å and 6-6.4Å respec-
tively. It is well known that DRY probe interacts with differ-
ent types of π systems (aromatic or vinyl type) but have not
high affinity to aliphatic moieties. Thus, variables related to
DRY probe had small region in the weak solvent for C60
solubility (Fig. 5B). Validation, reliability and robustness of
models obtained checked by the prediction of external test
sets, leave-one-out Q2 and progressive scrambling approach.
The results obtained from Volsurf and GRIND 3D-QSPR
methods confirmed that the hydrophobicity and the shape
parameters (steric effects) of solvent molecules had an effec-
tive impact on C60 solubility in different organic solvents.
3.2. CNTs Dispersion
Geckeler and Premkumar recommended to use the dis-
persion term when dealing with carbon nanotubes [121], due
to ability of CNTs in formation of colloids with respect to
their diameters and lengths. However, both solubilization
and dispersion processes strongly depend on the magnitude
Fig. (6). PLS coefficient plot of GRIND descriptors of organic solvents for C60 solubility.
Maryam Salahinejad
and sign of the enthalpy of mixing (ΔHmix) as discussed in
details elsewhere [122-124]. The interactions between sol-
vent molecules and CNTs are very important to successfully
disperse a nanotube in a solvent. There is not numerous and
sufficient experimental data on dispersion of carbon nano-
tube in organic solvents, hence a few QSPR models reported
on the dispersibility modeling of carbon nanotubes. Most
studies explored the dependency of solubility parameters and
CNTs dispersibility.
Ham et al. explored the dispersions of SWNTs in various
organic solvents and aqueous surfactant emulsions and man-
aged to correlate the degree of dispersion state with Hansen
solubility parameters [125]. It concluded that organic sol-
vents with certain dispersive component (δd) values dis-
persed SWNTs better compared to solvents with high polar
component (δp) values or hydrogen-bonding component (δh)
values. The dispersion states of the nanotubes in various or-
ganic solvents were classified into three groups as “dis-
persed,” “swollen,” and “sedimented”. Nanotubes were pre-
cipitated in the solvents with high polar component (δp) val-
ues or hydrogen-bonding component (δh) values. Surfactants
dispersed SWNTs if they had hydrophobic alkyl chains equal
to and longer than a decyl group, regardless of their func-
tionality or their hydrophilic heads. Application of the Han-
sen solubility parameters theory to several types of carbon
nanotubes in common organic solvents was studied by
Detriche et al. [126]. The top four solvents for CNTs dis-
persibility had 19<δd<24 MPa1/2, 5<δp<8 MPa1/2, and 3<δh<5
MPa1/2. They showed that the mixture of two good solvents
can give better dispersibility than a single solvent.
Bergin et al. measured the dispersibility of single-walled
carbon nanotubes in a range of organic solvents and explored
the nanotube dispersibility as a function of the Hansen solu-
bility parameters of the solvents [127]. A new set of solubil-
ity parameters was suggested, based on the surface energies
of nanotubes and solvent. They claimed the level of SWNTs
dispersibility was more sensitive to the dispersive Hansen
parameter than the polar or H-bonding Hansen parameter.
Nano-QSPR Modelling of Carbon-Based Nanomaterials Properties
However, they mentioned that the role of polar and H-
bonding solubility parameters on the dispersion of SWNTs
could not be neglected.
Cheng et al. reported a systematic study of the effect of a
series of organic solvents on the dispersion of as-produced
SWNTs. The dispersibility of SWNTs in different solvents
was quantitatively assessed in terms of the absorption and
scattering parameters. Their correlation with the Hildebrand
solubility parameters and three-dimensional Hansen solubil-
ity parameters was investigated with the aim of establishing
structure-property relationships governing the solubilizing
process [128]. Interestingly, in contrast to the Ham and co-
workers, Cheng et al. concluded that the dispersion compo-
nent (δd) seems not to be the dominant factor for dispersing
SWNTs, while polar component (δp) and hydrogen-bonding
component (δh) are important factors for obtaining SWNT
dispersions. In a follow-up study, they explored the correla-
tions between the dispersion limit of SWNTs and solvent
solubility parameters, including the Hildebrand solubility
parameter and three-dimensional Hansen solubility parame-
ters [129]. It was identified that degree of SWNTs dispersion
depends critically on sample preparation conditions and in
particular sonication time. It was found that SWNTs easily
dispersed in solvents with Hildebrand solubility parameter
ranged from 22-24 MPa1/2 and Hansen polarity component
(δp)12-14 MPa1/2 and no clear correlation between disper-
sion limits and the dispersion force (δd) or hydrogen bonding
force (δh) were evident. One limitation of the aforementioned
studies is that the models are not well-represented and there-
fore cannot be reproduced to predict dispersibility of CNTs
for new organic solvents.
Some studies to investigate the relationship between
chiral vectors and the water solubility (logS) and partition
coefficient (logP) of SWNTS were reported by Torrens [130,
131]. Toropova et al. performed a QSPR study on the data
reported by Torrens and represented a simple two-variable
models of water solubility and octanol water partition coeffi-
cient of SWNTs based on chiral vectors of nanotubes as
structural descriptors [132]. The models obtained showed a
great performance. Unfortunately, in these models in addi-
tion to use very small data sets (eight training and eight pre-
diction set), the water solubility and partition coefficient
which were derived from computational models, was used to
build models actually building a model of a model [17] not a
model of experimental data.
We applied GRIND methodology for modeling of
SWNTs dispersibility in a series of 29 different organic sol-
vents [78] which their experimental values were reported by
Bergin et al. [122]. Log-transformed of maximum concentra-
tion of SWNTs in organic solvents (logCmax) was used in the
following QSPR modellings. The data set split into a training
of 22 solvents and a prediction set of 7 solvents. Five vari-
able selection techniques including fractional factorial design
(FFD) [51], stepwise multiple linear regression [133],
successive projection algorithm (SPA) [50], genetic algo-
rithm (GA) [47] and enhanced replacement method (ERM)
[48] were used to extract the more informative factors from
GRIND descriptors and generate more predictive models.
Various PLS models were constructed based on selected
variables. ERM-PLS model, with six latent variable, gave
Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18 1879
the best statistical performance with R2c = 0.99, Q2 = 0.93,
RMSEC of 0.072. The ERM-PLS model satisfied a set of
rigorous validation criteria and performed well in the predic-
tion of an external test set with an R2P of 0.98 and RMSEP=
0.072. Table 3 shows the most important GRIND descriptors
involved in ERM-PLS modelling of SWNTs dispersibility in
different organic solvents with their PLS coefficients. The
DRY-N1 at 6.4-6.8 Å had the highest coefficient with posi-
tive correlation on SWNTs dispersibility. This variable is
strongly expressed in solvents with donating groups in aro-
matic backbone and shows week value in aliphatic backbone.
This concludes that a distance of about 6.6Å between hydro-
phobic moieties and hydrogen donor groups of solvent's
structure has the most favorable influence on the SWNTs
dispersibility. Fig. (7) shows the graphical display of GRIND
variable DRY-N1: distance 6.4-6.8Å for a good solvent (N-
Cyclohexyl-pyrrolidinone) and a weak solvent (benzyl alco-
hol) in the dispersion of SWNTs. The TIP probe, which indi-
cate the shape and size of the molecules, comprised four
variables having significant impact on the model, whereas
the O probe representing hydrogen bond acceptor showed no
important peaks. The N1-TIP variables indicate the favorable
position of a hydrogen bond donor site or a polar group with
respect to the size and shape of a molecule. Remarkably, this
variable showed an inverse effect at short distance of ap-
proximately 3.6Å and but had a positive effect on distance
longer than 11 Å, on SWNTs dispersibility (Table 3). The
inverse effect of DRY-TIP variable at distance: 7.6-8 Å, in-
dicated that adjacent of a π system (aromatic backbone) and
a bulky group in the distance about 7.8 Å, could reduce the
interaction between the solvent molecules and SWNTs. It
concluded that, the hydrophobic interactions in the small
solvent molecule with polar or bulky groups were restricted
and caused a reduction of the SWNTs dispersibility in the
solvent. Although the GRIND variables defined as distances
between molecular features, but the importance of TIP, DRY
and N1 probes, in a preliminary analysis, suggested that the
presence and orientation of hydrophobic and polar groups
(hydrogen bond donor group) as well as the size and shape
of the solvent molecules were crucial for the SWNTs dis-
persibility. The analysis of the applicability domain of the
ERM-PLS model based on GRIND descriptors is displayed
in Fig. (3). All the training and validation compounds were
within the chemical domain, indicating that there was no
chemical outlier or structure influential compound outliers
and the predictivity of the model was reliable.
Table 3. Most important GRIND descriptors involved in
ERM-PLS modelling of SWNTs dispersibility in dif-
ferent organic solvents.
Variable Distance (Å) PLS-Coefficient
DRY-N1 6.4-6.8 0.91
N1-TIP 10.8-11.2 0.62
TIP-TIP 2.4-2.8 -0.32
DRY-TIP 7.6-8 -0.49
N1-TIP 3.6-4 -0.60
1880 Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18
Fig. (7). Graphical display of GRIND variable DRY-N1: distance 6.4-6.8 Å for A: a good solvent (N-Cyclohexyl-pyrrolidinone) and B: a
weak solvent (benzyl alcohol) in dispersion of SWNTs.
In another study, we developed some QSPR models, able
to correlate and predict the dispersibility of SWNTs at the
same organic solvents data set based on different kind of 2D
descriptors [134]. Three new amidine solvents reported by
Barman et al. [135] were used as an external set. A feed for-
ward neural network trained by back-propagation algorithm
and MLR were applied to model constructions. The best
model with four-variable MLR model was defined as fol-
lows:
log(Cmax) = 2.861+0.402(GCUT_SLOGP_3)-
2.785(AM1_Eele)-3.283(diameter)+0.685(b_rotR)
2 2
R c = 0.88, RMSEC= 0.14, Q =0.82, R2P=0.07, RMSEP=0.08
GCUT_SLOGP calculates log P based on atomic contri-
butions and a modified graph distance [136], b_rotR and
AM1_Eele variables were a fraction of rotatable bonds and
electronic energy respectively. The model obtained eluci-
dated the contributions of steric (diameter), polarizability
(GCUT_SLOGP), molecular flexibility (b_rotR) and electro-
static (AM1_Eele) interactions to the dispersibility of
SWNTs in organic solvents. The ANN models taking into
accounts both linearity and non-linearity in model construc-
tion, yielded a slightly more predictive models than MLR
analysis.
3.3. Graphene Dispersion
Graphenes are supplied in granular form, while the avail-
ability of processable graphene in single-layer sheets are a
prerequisite for exploiting their optimal properties in most
applications. Micromechanical synthesis of mono layer gra-
phene is extremely low yielded techniques and not applica-
ble for large scales [137], hence the exfoliate graphite into
monolayer sheets in liquid phase directly or disperse gra-
phene powder in aqueous solution or organic solvents [138]
are of particular importance.
Hernandez et al. measured the dispersibility of graphene
in 40 various organic solvents [139]. They also explored the
Maryam Salahinejad
relationship between Hildebrand solubility parameter, Han-
sen solubility parameters and surface tension and graphene
dispersibility. It concluded the good solvents for graphene
should had Hansen parameters of δd=18.0, δ P=9.3 and δ h=7.7
MPa1/2, and by a Hildebrand solubility parameter of δ t23
MPa1/2. The authors suggested that the level of dispersibility
of graphene was more sensitive to the dispersive Hansen
solubility parameter, but surprisingly, nonzero values of the
polar and H-bonding Hansen parameters are required for a
solvent to disperse graphene.
(5) The only QSPR study on graphene dispersion in different
solvents has been reported by Yousefinejad and Hem-
mateenejad [140]. They used the data reported by Hernandez
et al. [139] and performed MLR analysis with stepwise se-
lection of variables to construct two linear QSPR models. In
the first model, a three-variable MLR model, based on sol-
vent empirical parameters, gave an R2c=0.85 with SEC=0.17
and with seven solvents collected as prediction set the model
yilded R2p=0.9. The solvent polarity/polarizability, the
maximum absorption band of copper(II) N,N,N',N'-
tetramethylethylenediamine acetylacetonate complex in pure
solvent and 19
F-NMR shielding of para-Nitro
f1uorobenzenes as a shielding probe in a solvent, extracted
from the literature, were included in MLR model. The sec-
ond model with four theoretical descriptors, derived from
Dragon software and DFT calculations, yielded an R2c 0f
0.81with SEC of 0.18 and R2p of 0.76. Although the model
based on the solvent empirical scales showed better results in
comparison to the model based on the theoretical structural
parameters, but both models confirmed the significant role of
dispersive interactions compared to H-bonding and polar
interactions on the dispersibility of graphene in organic sol-
vents.
3.4. Adsorption onto CNTs
Adsorption is a surface phenomenon in which a sub-
stance, in gas or liquid phase, accumulates on a solid surface.
Nano-QSPR Modelling of Carbon-Based Nanomaterials Properties
The large surface area and chemical properties of CNTs
make them as a strong adsorption capacity for a variety of
synthetic organic contaminants. Adsorption mechanisms
mainly govern by the effects of properties of both CNTs and
organic chemicals along with environmental conditions and
it is also influenced by CNTs suspendability, which strongly
affects their mobility, exposure and risk in the environment
[141]. Therefore, understanding the adsorption phenomena
of organic contaminants to CNTs is of great importance for
environmental applications of CNTs as special adsorbents
and assessment of the fate and transport of toxic chemicals
and organic contaminants with CNTs in the environment.
The adsorption of some polar and nonpolar organic com-
pounds with varied physical-chemical properties to graph-
eme, one SWNT and two MWNTs was evaluated [142].
Three adsorbents groups, including: nitro aromatics (polar
group), nonpolar aromatics (benzene, methylated, and chlo-
rinated benzenes) and nonpolar aliphatics (cyclohexane) ex-
hibited different adsorption affinity on CBNs. The adsorp-
tion affinity was correlated poorly with hydrophobicity but
increased in the order of nonpolar aliphatic<nonpolar aro-
matics<nitro aromatics, and within the group of nitro aro-
matics, the adsorption affinity increased with the number of
nitro functional groups. The strong adsorptive interaction
between carbon nanotubes and nitro aromatics was due to
the π-π electron-donor-acceptor (EDA) interaction between
nitro aromatic molecules (electron acceptors), while the
strong π-electron-dependent polarizable interactions between
CNTs and nonpolar aromatics and cyclohexane might have
contributed to the adsorption of nonpolar aromatics to carbon
nanotubes.
Yang et al. reported the first systematic study on poly-
cyclic aromatic hydrocarbons (PAHs) sorption by various
carbon nanomaterials [143]. They investigated the adsorp-
tion of naphthalene, phenanthrene and pyrene onto six car-
bon nanomaterials, including fullerenes, SWNTs and
MWNTs. They presented a single parameter linear relation-
ship between the adsorbed volume capacity and the specific
surface area. The next study by the same authors, the aque-
ous adsorption of a series of 13 phenols and anilines by
MWNTs were examined and employed LSER to investigate
the adsorptive behaviors of nondissociated species [144]. A
single variable linear model based on the chemical hydro-
gen-bonding donor parameter (Rm) values of organic chemi-
cals was presented. They concluded that besides the van der
Waals force, H-bonding interactions from solutes as hydro-
gen bonding donors and followed by π-electron polarizabil-
ity, may play important roles on the adsorption of phenols
and anilines by CNTs in the aqueous environment.
Xia et al. successfully applied LSER approach in predict-
ing a mixture of 28 aromatics, to depict relative contributions
of molecular interactions on CNT adsorption [145].
logk = −1.33 + 0.043R + 1.75P − 0.37A− 2.78B+ 4.18V (5)
n=28, R2c=0.93, F=63, Q2 =0.89, R2p=0.78
External validation was conducted using 12 different
compounds, suggesting satisfactory prediction for the exter-
nal validation compounds. According to their LSER equation
(5), hydrophobicity had the strongest contribution to adsorp-
tion, represented by the V term. Hydrogen bond donating
Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18 1881
ability was the second most predominant factor with a nega-
tive correlation which indicates that the sorbent surface has a
weaker tendency to donate protons than water at the liquid-
solid interface.
QSPR and LSER techniques were used to develop pre-
dictive models for adsorption of organic contaminants onto
MWNTs, reported by Abul et al. [146]. Adsorption data for
29 of low molecular weight aromatics by MWCNTs with
less than 5% oxygen content were used as training set to
generate MLR models. QSPR model with three molecular
connectivity indices gave an R2 of 0.88 and LSER equation
with four solvatochromic descriptors yielded an R2 of 0.83.
The validities of the developed QSPR and LSER equations
were evaluated using 30 aromatics of the data reported by
Xia et al. [145]. The higher error value the LSER model in-
dicated that the QSPR approach has the stronger prediction
ability than LSER approach. The combination of training
and validation data for all 59 compounds which were used to
obtain a combined LSER equation gave an R2 of 0.84. They
also generated LSER equations at different concentrations
(infinite concentrations, 1% and 10% of adsorbate aqueous
solubility). In the next study, Apul et al. conducted three
different learning approaches, MLR, ANN and SVM, to de-
velop QSPR models for adsorption data for 39 aromatic
compounds onto MWCNTs [147]. The same validation set
of 30 aromatics was used. In the model development proc-
ess, for eliminating the surface area effect of MWCNTs the
adsorption coefficients were normalized by specific surface
area and the log unit of surface area normalized adsorption
coefficients (log KSA) was used. The number of nitrogen and
oxygen atoms in rings, Kow (with positive correlation), the
dipole moment of the molecule and the number of hydrogen
bonds (negative correlation) are the dominant variables in
QSPR modelling of adsorption coefficient of aromatics onto
MWNTs. A five-variable MLR model yielded an R2c of 0.76
and R2p of 0.59. ANN and SVM models resulted in better
agreement between predicted and measured values with R2 of
0.83 and 0.78 respectively, showed the nonlinear relation
between logKSA and physicochemical properties.
In a recently published paper, Zhao et al. introduced a
modified model of concentration-dependent polyparameter
linear free energy relationships (pp-LFERs) model to de-
scribe the compound-CNTs interactions and to predict sorp-
tion behavior of chemicals on CNTs in a wide range of con-
centrations [148]. This modified model combines LFERs
parameters with aqueous equilibrium concentrations of com-
pounds in a wide range of concentrations, from -5 to 0 of log
Ce/Cs, where Ce represents the equilibrium concentration and
Cs is the solubility of the compounds, in MWCNT15. A new
model was therefore obtained as follows:
logki=f1+ f2Ri + f3Pi + f4 Ai+ f5Bi+ f6Vi i=1,2,3,…n (6)
Where f1, f2, f3, f4, f5, and f6 are the quadratic functions of
log(Ce/Cs) and describe the relative contribution of interac-
tion strength from molecular force of lone-pair electrons,
dipolarity/polarizability, hydrogen-bond acidity, hydrogen-
bond basicity and hydrophobic interactions, respectively.
The LFER equations were represented at various concentra-
tions for MWCNT resulted in models with R2>0.8, RMSEC<
0.5 and Q2>0.7. They concluded that at low Ce
(<0.000753mg/L) π-π stacking interaction was the most sig-
1882 Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18
nificant and the hydrogen-bond basicity interaction as the
less dominant interaction while at Ce>0.000753mg/L, hydro-
phobic interaction became the most dominant interaction.
Xia et al. proposed a biological surface adsorption index
(BSAI) to characterize surface adsorption energy of nanoma-
terials [27]. It is assumed that the adsorption properties of
nanomaterials are governed by five fundamental forces of
molecular interactions in biological processes, including
Coulomb force (charged particles), London dispersion (hy-
drophobic interactions), hydrogen-bond acidity and basicity,
dipolarity/polarizability and the lone-pair electrons. A set of
small molecule probes was allowed to competitively adsorb
onto a set of nanoparticles and the adsorption coefficients of
the probe molecules were measured and used to create a set
of nanodescriptors representing the contributions and relative
strengths of each molecular interaction. This method suc-
cessfully predicted the adsorption of coefficients set of 28
simple benzene derivatives, as molecule probes, onto the
MWCNTs. Abraham descriptors were used to demonstrate
the BSAI approach and an LSER equation was developed
with R2=0.93 and Q2 of 0.89. The nanodescriptors of
MWCNTs representing the relative contributions of the four
types of molecular interactions. The lipophilicity is a strong
contributor with positive impact on adsorption coefficients
and Hydrogen-bond basicity is the second most significant
factor with negative impact, suggests that the sorbent surface
has a weaker tendency to donate protons (to the probe com-
pounds) than water at the liquid–solid interface. External
validation was conducted using 12 different compounds,
given a R2p of 0.78. In a follow-up study, the authors deter-
mined the surface adsorption forces of 16 different nanoma-
terials including SWNTs, C60, MWCNT-OH, l-MWCNT,
MWCNT8nm-COOH, MWCNT15nm-COOH, MWCNT-
40nm-COOH, carbon hollow sphere and graphene oxide
[27]. The same probe compounds of 28 benzene derivatives
were used. The R2 of MLR analysis ranged from 0.84 for
nC60(OH)20 to 0.95 for MWCNT40nm-COOH. When the
five-dimensional information of the nanodescriptors was
reduced to two dimensions, the 16 nanomaterials were clas-
sified roughly into three clusters according to their surface
adsorption properties. The studied nanomaterials roughly
clustered as strong adsorption nanomaterials including car-
bon hollow spheres, carbon nanotubes and their derivatives,
medium adsorption nanomaterials including C60 (powder),
polar derivative of fullerenes and graphene oxides, and weak
adsorption nanomaterials such as oxide and metal nanoparti-
cles.
In a recently research, Liu et al. employed QSPR model-
ing and DFT simulations to explore the structure-dynamics-
adsorption relationship of simple benzene derivatives with
CNTs [149]. The same data set of Xia et al. [145] and their
adsorption activities were used to QSPR model construction.
Eight selected descriptors, through the stepwise method, was
used to generate the MLR-based QSAR model. The QSAR
model exhibits a R2c of 0.986, Q2 of 0.968 with SE of 0.109.
With eight descriptors involved in MLR model of 25 data,
the proposed MLR-QSPR model constructed with almost
three data points per descriptor without any validation of
prediction set and tests on chance correlations. Q2 is not the
sufficient criteria to examine the model validation and the
high value of Q2 can not guarantee the high predict ability of
Maryam Salahinejad
a model [71]. As mentioned earlier, the model with three or
four data points per variable encountes a meaningless chance
correlations [43]. When too many variables are involved in
MLR analysis, the model complexity problem are occurred
and the model is susceptible to overfitting. Overfitted models
generally perform poorly when are used to make predictions,
although they have shown low error in training set [150].
DFT simulations are carried out to determine preferential
interaction modes, binding conformations, and underlying
driving forces of the molecule-SWCN systems. They re-
sulted the preference of the bridge configuration in mole-
cule-SWCN interaction mode and the main effect of π–π
stacking in the adsorption of simple benzene derivatives on
SWNTs, while the substituent play a secondary effect on the
adsorption process. The predicted DFT energies do not show
a strictly positive or negative correlation with experimental
adsorptions.
3.4. Mechanical Properties of CNTs
The extraordinary mechanical properties of CNTs, e.g.
high elastic modulus and tensile strength make them an ideal
choice for mechanical reinforcement of polymers, metal ma-
trices, and ceramic for improved stiffness and strength [151].
Numerous experimental studies have been performed to de-
termine the mechanical properties of CNTs, but experimental
measurements is a tedious task which shows highly different
results due to differences in the experimental methods used.
Hence the simulating CNTs with quantum mechanics are
widely used to predict their mechanical properties at infinite
length [151]. A number of QSPR studies were reported on
computed physicochemical properties of CBNs. The proper-
ties derived from computational methods, usually quantum
mechanical (QM) techniques, were used as independent
variable to build QSPR models, in fact building a model of a
model not a model of experimental data. However the ob-
tained QSPR models based on these purely computational
data set, in the absence of reliable experimental data set, can
give primary estimation on desired property and would be
straightforward by adding experimental data and recreating
the mathematical models.
Young’s modulus (Y) is a measure of stiffness and de-
fined as the ratio of axial stress to axial strain over ranges of
stress in which Hooke’s law holds true. The Possion's ratio is
the ratio of the lateral contraction strain to longitudinal ex-
tension strain when a material is stretched elastically uniaxi-
ally [152].
Borders et al. developed 20 descriptors from molecular
dynamics (MD) simulations to build QSPR for Young’s
modulus and Poisson’s ratio in two separate analyses: va-
cancy only and vacancy plus methyl functionalization [31].
The data set contained 78 SWNTs covering a 10×range of
radii, all three chiralities, surface vacancies, surface func-
tionalization, and multiple chiral angles. Many QSPR mod-
els were presented with different descriptors and at different
SWNTs sizes. Each model was trained with 80% of the data
and 20% used as an external test. For vacancy only test cases
CN2/CT (number of non-sp2 hybridized carbons per the total
carbons) and chiral angle was identified as critical descrip-
tors for both Young’s modulus and Poisson’s ratio. The two
variable QSPR model gave R2c values of 0.92 and 0.87 for
Nano-QSPR Modelling of Carbon-Based Nanomaterials Properties
Young’s modulus, and Poisson’s ratio respectively. Further
analysis and literature findings indicated the effect of chiral
angle is negligible at larger CNT radii for both properties. In
the analysis of vacancy plus methyl functionalization, the
critical descriptors were CN2/CT, chiral angle, and MN/CT
(number of methyl groups per total carbons). The 3-
descriptor models showed R2c values of 0.92 and R2P of 0.93
for Young’s modulus and R2c values of 0.91 and R2P of 0.81
for Poisson’s ratio. The computational model was qualified
and quantified against three separate sets of experimental
data.
Mohammadinasab and Goodarzi performed density func-
tional theory (DFT) study to calculate the energy and elec-
tronic properties of zigzag carbon nanotubes. The relation-
ship between some of the topological indices such as Wie-
ner, Padmakar-Ivan and Szeged in contrast to the electric
moments and energy (kJmol−1) and quantum chemical de-
scriptors such as HOMO, LUMO, the most positive net
atomic charges (q+) and the most negative net atomic charges
(q-) of CNTs were presented [153]. Taherpour used a four
data set of properties derived from MD calculations, to es-
tablish one variable linear and nonlinear models between the
number of carbon atoms of the fullerenes (n) with the struc-
tural mechanical properties. The relationship between n with
diameter, volume, molecular energy, endurance load and
compressive stiffness of empty fullerenes (n = 20, 60, 80,
and 180) were constructed and the equations obtained were
extended for other twenty fullerenes (Cn, n from 24 to 300)
[154]. In a similar study, the relationship between Cn index
and fullerenes polarizabilities on the basis of monopole-
dipole interactions theorem were presented [155].
Unfortunately, the aforementioned studies in this section
used the properties derived from computational methods to
build QSPR models. Although such computational models
are good for qualitative explanations, but experimental data
are required for evaluating and verifying these models to
provide a quantitatively accurate prediction.
CONCLUSION
This paper reviewed the applicability of the QSPR meth-
odologies for the prediction of the diverse properties of car-
bon-based nanomaterials. Different steps in the construction
of QSPR models along with the important challenges in ex-
tending the traditional QSPR to nano-QSPR methodology
was described. Then the most significant achievements of
QSPR methods in modelling of carbon-based nanomaterials
properties and their recent applications to generate predictive
models were presented. There is an increasing interest in the
use of well-established nano-QSPR models, providing suc-
cessful results in a rapid and accurate prediction of nanoma-
terials properties reducing the time and cost of the experi-
mental work. However, the future progress of nano-QSPR
requires the development of adequate and relevant quantita-
tive parameters describing unique molecular properties of
nanomaterials. For most nanomaterials properties, no suffi-
cient data to develop reliable QSPR models are available.
Nano-QSPR models obtained from a small data set may suf-
fer from the impossibility of making accurate predictions for
external data set, regardless of their good performance in
internal validations. However, nano-QSAR, with properly
Current Topics in Medicinal Chemistry, 2015, Vol. 15, No. 18 1883
executed modelling will continue to be a promising and in-
deed a valuable tool in the most areas of nano research.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
Declared none.
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