Ind. Eng. Chem. Res.

2004, 43, 6253-6261 6253

A Group-Contribution Method for Predicting Pure Component

Properties of Biochemical and Safety Interest
Emmanuel Stefanis, Leonidas Constantinou, and Costas Panayiotou*,
Department of Chemical Engineering, Aristotle University of Thessaloniki, GR 54124, Thessaloniki, Greece
and Frederick Research Center, P.O. Box 24729, Nicosia, Cyprus

A simple, yet quite accurate method for predicting properties of organic compounds of
environmental and nutraceutical interest is presented. It is an extension of a previous successful
group-contribution method (Constantinou, L.; Gani, R. AIChE J. 1994, 40, 1697) and uses two
kinds of groups: first-order groups that describe the basic molecular structure of the compounds
and second-order groups, which are based on conjugation theory and improve the accuracy of
the predictions. Twenty-six new first-order groups have been defined to ensure that the molecular
structures of any compound of biochemical interest, including complex aromatic, multiring, and
heterocyclic compounds, can be easily described. Furthermore, 12 new second-order groups have
been defined to enhance the reliability of the predictions and the applicability of the method.
The three properties that have been estimated by the new method are the octanol-water partition
coefficient (logKow), the total (Hildebrand) solubility parameters at 25 C, and the flash point.
These properties have many applications in the chemical, pharmaceutical, and food industries,
as well as in the protection of the environment.

Introduction of functional groups: first-order groups (UNIFAC groups)

Computer-aided molecular design is a very important
process and tool that is used for the prediction of
properties of organic compounds when reliable experi-
mental data are not available, for checking questionable
values of already measured properties, and especially
for the selection of compounds with desired properties.
In the past several decades, many group-contribution
methods have been widely used for the prediction of
physicochemical properties of pure organic compounds.
One of the first widely used group-contribution methods
was the UNIFAC method,1 where the value of each
property was obtained as the sum of contributions of
simple first-order groups. The methods of Joback and
Reid2 and of Horvath3 are also methods of this kind.
More recently, a new class of group-contribution meth-
ods has been proposed. In this kind of method,4,5 second-
order groups are defined to provide more structural
information, to distinguish isomers, and to afford more
accurate predictions. Second-order groups have a strong
physicochemical meaning and can significantly improve
the accuracy of property predictions. The definition of
second-order groups is based on the theory of conjuga-
tion operators.5,6 Marrero and Gani7 introduced a higher
level of approximation by defining third-order groups
to provide more structural information about systems
of fused aromatic and nonaromatic rings.
The Existing Constantinou-Gani Model
One of the most accurate group-contribution methods
is the model proposed by Constantinou and Gani.4
According to this model, the molecular structure of each
organic compound can be described by using two kinds
* To whom correspondence should be addressed. Fax:
+302310996222. E-mail: cpanayio@auth.gr.
Aristotle University of Thessaloniki.
Frederick Research Center.
10.1021/ie0497184 CCC: $27.50 2004 American Chemical Society
Published on Web 07/29/2004
and second-order groups that are based on conjugation
theory. The second-order groups give a physical mean-
ing to the method, and this is an advantage compared
to the other group-contribution methods. These groups
improve the accuracy of the predictions significantly.
The definition of second-order groups is based on the
ABC framework.5 According to this framework, each
compound is represented as a hybrid of many conjugate
forms. Every conjugate form is considered as a structure
with integer-order localized bonds and integer charges
on atoms. The purely covalent conjugate form is the
dominant conjugate, and the ionic forms are the reces-
sive conjugates, which are generated by using a conju-
gate operator. When a conjugate operator is applied to
a dominant conjugate, it can generate a series of
recessive conjugates. Conjugate operators consist of
subchains with two or three bonds, such as OdC-C or
C-C-C-H. In this theory, the properties of each
compound are estimated by combining the correspond-
ing properties of its conjugate forms. The properties of
the conjugate forms are estimated through conjugation
operators. Each operator has a fixed contribution, which
is determined through regression and reflects the
contribution of a whole series of conjugate forms.
The basic property in the ABC framework is the
standard enthalpy of formation at 298 K. For the
estimation of this property, the contributions of the
conjugate forms can be expressed in terms of their
physical significance rather than adjustable parameters.
Therefore, the most important conjugate forms, i.e., the
forms that exert the strongest influence on the standard
enthalpy of formation (and also on the other properties
to be estimated), can be distinguished. The conjugation
operators that are related to the most important con-
jugate forms make the largest contributions.6 It is
possible to identify the classes of conjugate forms with
the highest conjugation activity by examining the
contributions of their operators. The identification of
6254 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004

Table 1. First-Order Group Contributions for logKow, Total Solubility Parameter (25 C), and Flash Point
contributions
total solubility flash sample group assignment
group logKow parameter point (occurrences)
-CH3 0.6998 -2308.6 0.6 propane (2)
-CH2 0.4707 -277.1 10.8 butane (2)
-CH< 0.0405 -355.5 12.2 isobutane (1)
>C< -0.4723 -176.2 12.4 neopentane (1)
CH2dCH- 0.9737 -2766.2 10.3 propylene (1)
-CHdCH- 0.6749 -381.9 19.1 cis-2-butene (1)
CH2dC< 0.8361 -980.2 19.1 isobutene (1)
-CHdC< 0.1234 1887.1 37.9 2-methyl-2-butene (1)
>CdC< 2.6256 1601.8 - 2,3-dimethyl-2-butene (1)
CH2dCdCH- - -3745.0 - 1,2-butadiene (1)
CHEC- 0.2159 -975.5 21.8 propyne (1)
CEC 0.1597 2169.3 24.5 2-butyne (1)
ACH 0.3633 -6.4 11.5 benzene (6)
AC 0.2497 684.3 20.5 naphthalene (2)
ACCH3 0.7748 -221.8 23.8 toluene (1)
ACCH2- 0.4036 1023.4 31.5 m-ethyltoluene (1)
ACCH< 0.1910 605.5 36.4 sec-butylbenzene (1)
CH3CO -0.5433 3269.1 47.4 methyl ethyl ketone (1)
CH2CO -0.9379 7274.2 69.7 cyclopentanone (1)
CHO -0.3524 5398.2 35.5 1-butanal (1)
COOH -0.5994 9477.8 97.3 vinyl acid (1)
CH3COO -0.3164 1865.1 53.0 ethyl acetate (1)
CH2COO -0.7454 5194.2 61.9 methyl propionate (1)
HCOO -0.9078 1716.0 38.4 n-propyl formate (1)
COO -0.8772 3671.8 54.1 ethyl acrylate (1)
OH -1.0577 12228.9 60.3 2-propanol (1)
ACOH -0.2851 8456.1 68.5 phenol (1)
CH3O -0.3088 -480.8 22.4 methyl ethyl ether (1)
CH2O -0.8032 -206.7 29.8 ethyl vinyl ether (1)
CHO -0.5994 1229.1 28.8 diisopropyl ether (1)
C2H5O2 -1.5767 - 91.9 2-methoxyethanol (1)
CH2O (cyclic) -0.4673 3733.9 28.1 1,4-dioxane (2)
CH2NH2 -0.9178 3650.7 39.4 1-amino-2-propanol (1)
CHNH2 -2.0541 560.4 33.6 isopropylamine (1)
CH3NH -0.7114 8616.2 - n-methylaniline (1)
CH2NH -1.1628 4183.8 44.4 di-n-propylamine (1)
CHNH -1.5361 3381.8 41.3 diisopropylamine (1)
CH3N -0.7715 2166.5 51.4 trimethylamine (1)
CH2N -1.1007 -2662.6 34.1 triethylamine (1)
ACNH2 -0.7834 9228.4 87.4 aniline (1)
CONH2 - 14930.1 - 2-methacrylamide (1)
CONHCH3 -1.8463 27386.9 - n-methylacetamide (1)
CONHCH2 - - 150.1 n-butylacetamide (1)
CON(CH3)2 -1.5663 12770.8 126.3 n,n-dimethylacetamide (1)
CON(CH2)2 -1.8559 - - n,n-diethylacetamide (1)
C5H4N 0.3803 4686.3 104.3 2-methylpyridine (1)
C5H3N - 6574.7 - 2,6-dimethylpyridine (1)
CH2SH 0.5426 2191.2 46.1 n-butyl mercaptan (1)
CH3S 0.2730 1271.1 - methyl ethyl sulfide (1)
CH2S -0.0200 3585.2 63.8 diethyl sulfide (1)
CHS -0.0961 - - diisopropyl sulfide (1)
I 1.0874 3183.8 - isopropyl iodide (1)
BR 0.7195 2163.8 44.2 2-bromopropane (1)
CH2Cl 0.7601 1923.3 37.6 n-butyl chloride (1)
CHCl 0.4039 426.3 37.8 isopropyl chloride (1)
CCl -0.3759 -1415.6 - tert-butyl chloride (1)
CHCl2 - 1164.0 - 1,1-dichloropropane (1)
CCl3 - -1208.7 105.8 benzotrichloride (1)
ACCl 0.9738 1332.2 40.7 m-dichlorobenzene (2)
ACF 0.4075 -701.5 -15.7 fluorobenzene (1)
Cl-(CdC) -0.0890 -473.5 7.6 2,3-dichloropropene (1)
CF3 0.8115 -5199.5 -6.2 perfluorohexane (2)
CH2NO2 -0.3970 10030.7 81.5 1-nitropropane (1)
CHNO2 -0.6961 12706.7 - 2-nitropropane (1)
ACNO2 0.0451 6303.5 96.5 nitrobenzene (1)
CH2CN -0.6326 9359.8 69.7 n-butyronitrile (1)
CF2 - -3464.4 - perfluoromethylcyclohexane (5)
C4H3S 1.5387 4722.7 - 2-methylthiophene (1)
F (except as above) - -2965.3 - 2-fluoropropane (1)
CH2dCdC< - -2326.1 - 3-methyl-1,2-butadiene (1)
CHdCdCH- - -795.6 - 2,3-pentadiene (1)
CHCO -1.0761 7805.8 - diisopropyl ketone (1)
O (except as above) -0.0431 2467.6 6.7 divinyl ether (1)
Cl (except as above) 0.2919 636.3 47.6 hexachlorocyclopentadiene (2)
NH2 (except as above) 0.0088 -841.5 - melamine (3)
>CdN- -0.5341 3380.7 - 2,4,6-trimethylpyridine (1)
 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004 6255

Table 1 (Continued)
contributions
total solubility flash sample group assignment
group logKow parameter point (occurrences)
-CHdN- -0.5597 5026.4 38.8 isoquinoline (1)
NH (except as above) -0.5432 3459.4 - dibenzopyrrole (1)
NdN- -0.0403 -7339.6 - p-aminoazobenzene (1)
CN (except as above) -0.8772 10253.0 60.1 cis-crotonitrile (1)
NO2 (except as above) - 1655.1 - nitroglycerine (3)
OdCdN- - 2694.6 42.3 n-butyl isocyanate (1)
CHSH - 1234.8 45.9 cyclohexyl mercaptan (1)
CSH - 2230.2 - tert-butyl mercaptan (1)
SH (except as above) 0.5157 - - 2-mercaptobenzothiazole (1)
S (except as above) 0.3793 4770.2 17.8 thiophene (1)
SO2 -2.7494 14215.0 190.7 sulfolene (1)
>CdS - 26271.8 - n-methylthiopyrrolidone (1)
OdP< -3.4646 - - bis-2-chloroethyl-2-chloroethyl phosphonate (1)
>P- -0.6046 -1643.4 2.7 triphenylphosphine (1)
>CdO (except as above) -0.5028 - - anthraquinone (2)
NHCO -1.0134 - - phenylurea (1)
-NdO -0.1526 - - nitrosobenzene (1)
N (except as above) -0.5546 - - triphenylamine (1)

second-order groups is based on the operators with
much higher contributions than the others. The struc-
ture of a second-order group should incorporate a
subchain with at least one important conjugate opera-
tor. Because of a possible structural similarity of the
operators, a second-order group can contain more than
one conjugate operators. For example, the second-order
group CH3COCH2 contains the following operators:
OdC-C, OdC-C-H, and C-C-C-H. The structure
of a second-order group should be built with first-order
groups and should be as small as possible.
The methodology that is followed for the identification
of second-order groups is as follows:8 (a) identification
of all first-order groups present in the syntactic type of
a given compound; (b) definition of all possible substruc-
tures of two or three adjacent first-order groups; (c)
identification of all two-bond and three-bond conjugation
operators in the substructures; (d) estimation of the
conjugation operator energy of all substructures by
addition of the energies of all of the conjugation opera-
tors; and (e) identification of substructures with much
higher conjugation energies than the others. These
substructures are the second-order groups.
The basic equation that gives the value of each
property according to the molecular structure is
f(p) ) i niFi + j mjSj (1)
where Fi is the contribution of the first-order group of
type i that appears ni times in the compound and Sj is
the contribution of the second-order group of type j that
appears mj times in the compound. f(p) is a single
equation for the property under consideration, p, and
is selected after a thorough study of the physicochemical
and thermodynamic behavior of the property. The
determination of the contributions is made by a two-
step regression analysis.
In the first step of the regression, the aim is to
determine the contributions of the first-order groups
only (that is, the Fi). In the second step, using the Fi
contributions, the second-order groups are activated,
and the second-order group contributions (Sj) are cal-
culated through regression. These contributions act as
a correction to the first-order approximation.
Ten properties have been estimated so far by the
Constantinou-Gani method. These are the critical
temperature, Tc; critical pressure, Pc; critical volume,
Vc; melting point, Tm; normal boiling point, Tb; standard
Gibbs energy at 298 K, Gf; standard enthalpy of
vaporization at 298 K, Hvap; standard enthalpy of
formation at 298 K, Hf;4 acentric factor, ; and liquid
molar volume at 298 K, Vl.9
Recently,10 the method has been extended to the
prediction of polymer properties, such as the glass
transition temperature, Tg, through the estimation of
three scaling constants, namely, T*, P*, and F*, of the
lattice fluid (LF) model of Sanchez and Lacombe.11 The
first- and second-order group contributions of each
scaling constant were estimated through regression.
Proposed Model
The model of Constantinou-Gani, even though it is
one of the most accurate group-contribution methods,12
cannot be applied to all homologous series of organic
compounds because the 78 first-order groups (UNIFAC
groups) that it uses cannot describe the molecular
structure of complex compounds. Compounds of complex
multiring, heterocyclic, and aromatic structures are of
significant importance in the chemical, biochemical,
pharmaceutical, and food industries, as well as for the
environmental protection.
The first target of the present work was to introduce
a new, accurate model that can predict the properties
of both simple- and complex-structured compounds. This
was achieved by adding 26 new first-order groups to the
78 already existing UNIFAC groups. The new, simple
groups ensure that any molecular structure can be
described at an initial, basic level. Thus, the model is
able to provide a basic description of each of the
compounds that occur in the DIPPR database of ther-
mophysical properties. Twelve new second-order groups
were also added to the existing second-order groups of
the Constantinou-Gani method to provide more details
about the molecular structure of the recently introduced
complex compounds, such as fused aromatic and mul-
tiring structures. These groups lead to more accurate
results, and in some cases, they allow isomers to be
distinguished.
The second target was to apply the new model to the
prediction of important properties of chemical, biochemi-
cal, and safety interest. These are (a) octanol-water
partition coefficients (logKow), (b) total (Hildebrand)
solubility parameters at 25 C, and (c) flash points.
6256 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004
The octanol-water partition coefficient (logKow) is
defined as the common logarithm (base 10) of the ratio
of a compounds concentration in n-octanol to its con-
centration in water in a two-phase system in equilibri-
um. The logKow of n-octanol is equal to 3.00. This
means that the concentration of n-octanol that is diluted
in the n-octanol of the two-phase system is considered
to be 1000 times greater than that in water (log 1000 )
3).
The total (Hildebrand) solubility parameter is defined
as the square root of the cohesive energy density, where
the cohesive energy density is the ratio of the cohesive
energy (Ecoh) to the molar volume (V) of a compound.
Cohesive energy is equal to Hvap - RT, where Hvap
is the standard enthalpy of vaporization, R is the
universal gas constant, and T is the temperature. Thus
x x
Ecoh Hvap - RT
) ) (2)
V V
The flash point is the minimum temperature at which
the vapor pressure of a liquid is sufficient to form an
ignitable mixture with air near the surface of the liquid.
The sources of reliable experimental data were the
handbook Exploring QSARsHydrophobic, Electronic
and Steric Constants by Hansch, Leo, and Hoekman for
the octanol-water partition coefficients (logKow), the
DIPPR database of thermophysical properties14 for the
total (Hildebrand) solubility parameters at 25 C; and
Fire Protection Guide to Hazardous Materials (National
Fire Protection Association)15 for the flash points of
organic compounds.
A least-squares analysis was carried out to estimate
the first-order and second-order contributions for all
properties. The modified Levenberg approach was used
to minimize the total sum of squared errors between
the experimental and predicted values of the properties.
This was the criterion for the selection of the most
appropriate equation to fit the experimental data. The
model is applicable to organic compounds with three or
more carbon atoms excluding the atom of the charac-
teristic group (e.g., -COOH or -CHO).
In Table 1, the first-order group contributions for the
three previously mentioned properties are presented.
Table 2 lists the second-order group contributions for
the same properties. (Dashes indicate that the contribu-
tions of the group in the specific property are not
available.)
The equations selected for the estimation of each
property are as follows:
Octanol-water partition coefficient (logKow)
logKow ) i niFi + j mjSj + 0.097 (3)
Total solubility parameter (25 C) [(kJ/m3)(1/2)]
solubility parameter ) ( i niFi + j mjSj +
75954.1)0.383837 - 56.14 (4)
Flash point (K)
flash point ) i niFi + j mjSj + 216 (5)
The quantity mjSj is considered to be zero for com-
pounds that do not have second-order groups.
Table 3 illustrates the overall improvement of the
estimations of the three properties that was achieved
after the introduction of second-order groups in the
regression. The following three parameters are used to
measure the accuracy of the estimations:
(Xest - Xexp)2
standard deviation (SD) ) x N
1
average absolute error (AAE) ) |Xest - Xexp|
N
average absolute percent error (AAPE) )
1 |Xest - Xexp|
N Xexp
100%
where N is the number of data points, Xest is the
estimated value of the property, and Xexp is the experi-
mental value.
Scatter plots of estimated vs experimental values for
the three properties are presented in Figures 1-3.
In Table 4, the statistical logKow values of the
proposed method are compared with the values of
similar existing methods of logKow estimation, accord-
ing to the standard deviations, average absolute errors,
and the correlation coefficient r2
r2 )
(Xest - Xexp)2
(Xexp - Xexp)2
In Table 5, the standard deviation and the average
absolute error of the method of Marrero and Gani18 for
logKow estimation and that of the present new method
are compared at each level of approximation.
Discussion
The proposed model features many advantages over
existing similar models. First, it is able to describe the
basic molecular structure of organic compounds, both
simple and complex, with a relatively small set of first-
order groups. In addition, the set of second-order groups,
which can provide more accurate results, is probably
the only set of functional groups in the literature that
has a sound physical meaning because it is based on
conjugation theory. The application of the model is
simple, and the accuracy is exceptional compared to
other existing methods.
Concerning the octanol-water partition coefficients
(logKow), this model seems to be more accurate than
other existing models by Meylan and Howard16 (Kow-
Win software17 is based on this theory) and Marrero and
Gani.18 In Tables 4 and 5, one can see that the proposed
method has smaller standard deviations, smaller aver-
age percent errors, and higher correlation coefficients
(r2) between the experimental and estimated values.
The other models for estimating logKow16-18 use
larger sets of experimental data but also hundreds of
groups to describe the molecular structures. These
groups have little physical meaning, whereas the second-
order groups of the proposed new method are based on
conjugation theory. On the other hand, even though the
proposed method employs a significantly smaller num-
ber of first- and second-order groups, it still can describe
most of the existing molecular structures of organic
 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004 6257

Table 2. Second-Order Group Contributions for logKow, Total Solubility Parameter, and Flash Point
contributions
total solubility flash sample group assignment
group logKow parameter point (occurrences)
(CH3)2-CH- 0.0341 142.1 2.7 isobutane (1)
(CH3)3-C- 0.3415 592.3 0.6 neopentane (1)
-CH(CH3)-CH(CH3)- 0.4434 1581.2 -6.8 2,3-dimethylbutane (1)
-CH(CH3)-C(CH3)2- - 2678.4 - 2,2,3-trimethylbutane (1)
-C(CH3)2-C(CH3)2- - 5677.6 - 2,2,3,3-tetramethylpentane (1)
ring of 5 carbons 0.3986 -2637.7 -24.6 cyclopentane (1)
ring of 6 carbons 0.3436 -524.2 -9.6 cyclohexane (1)
-CdC-CdC- -0.1577 -426.8 -22.8 1,3-butadiene (1)
CH3-Cd 0.0020 11.9 -4.3 isobutene (2)
-CH2-Cd 0.1639 -762.7 10.2 1-butene (1)
>C{H or C}-Cd - -1257.2 20.2 3-methyl-1-butene (1)
string in cyclic - 626.1 23.9 ethylcyclohexane (1)
>CHCHO - -1634.4 -3.7 2-methylpropanal (1)
CH3(CO)CH2- -0.2217 142.0 1.1 methyl ethyl ketone (1)
C(cyclic)dO -0.1947 -3745.0 -7.6 cyclopentanone (1)
ACCOOH 0.4878 -3076.5 9.1 benzoic acid (1)
>C{H or C}-COOH -0.2086 511.1 2.2 isobutyric acid (1)
CH3(CO)OC{H or C}< 0.0749 134.4 3.5 isopropyl acetate (1)
(CO)C{H2}COO 0.0339 1060.5 8.4 ethyl acetoacetate (1)
(CO)O(CO) - -2875.9 -17.0 acetic anhydride (1)
ACHO 0.0229 3315.0 6.4 benzaldehyde (1)
>CHOH -0.0238 -359.5 -1.4 2-propanol (1)
>C<OH -0.2811 -23.4 -2.8 tert-butanol (1)
-C(OH)C(OH)- 0.0293 5020.6 5.9 1,2-propanediol (1)
-C(OH)C(N) 0.1716 3306.4 21.4 1-amino-2-propanol (1)
C(in cyclic)-OH -0.2029 4022.7 -1.7 cyclohexanol (1)
C-O-CdC 0.0732 -228.5 -14.4 ethyl vinyl ether (1)
AC-O-C 0.4087 2493.0 2.8 methyl phenyl ether (1)
>N{H or C}(in cyclic) 0.2166 -492.7 -0.5 cyclopentimine (1)
-S-(in cyclic) - 2389.4 - tetrahydrothiophene (1)
ACBr 0.1263 337.4 -3.6 bromobenzene (1)
ACI 0.0000 1267.1 - iodobenzene (1)
CH3(CO)CH< -0.2375 -437.1 - methyl isopropyl ketone (1)
ring of 3 carbons 0.2113 -9764.5 - cyclopropane (1)
ring of 4 carbons - -3673.4 - cyclobutane (1)
ring of 7 carbons 0.6085 -1486.4 - cycloheptane (1)
ACCOO -0.0047 -83.5 -9.4 methyl benzoate (1)
AC(ACHm)2AC(ACHn)2 -0.0814 -69.8 3.2 naphthalene (1)
Ocyclic-CcyclicdO -0.9326 9215.6 64.8 diketene (1)
AC-O-AC 0.0930 -4646.5 6.1 diphenyl ether (1)
CcycHmdNcyc-CcycHndCcycHp -0.0582 2348.2 0.0 2,6-dimethylpyridine (1)
NHm-CHn-COOH -1.0851 -7854.3 - ethylenediaminetetraacetic acid (4)
CHn-O-OH - 2002.5 - ethylbenzene hydroperoxide (1)
CHm-O-O-CHn - -2029.1 - di-tert-butyl peroxide (1)
NcycHm-CcycdO 0.2315 11489.1 49.3 2-pyrrolidone (1)
Ocyc-CcycHmdNcyc -0.0487 -8721.6 - oxazole (1)
-O-CHm-O-CHn- 0.2923 -620.3 -2.3 methylal (1)
AC-NH-AC 0.2617 2.8 - dibenzopyrrole (1)
C(dO)-C-C(dO) 0.9193 -3668.9 -14.7 2,4-pentanedione (1)

Table 3. Comparison of the First- and Second-Order can be seen in the Appendix, the estimated value of the
Approximations of the Proposed Method present new method is 3.03 (absolute error ) 1%). The
SD AAE AAPE (%) estimated value for n-octanol obtained by the Marrero
data first second first second first second and Gani method18 is 2.85 (absolute error ) 4.8%), and
property points order order order order order order the logKow value that the KowWin software17 estimates
logKow 422 0.315 0.267 0.226 0.188 - - is 2.81 (absolute error ) 6.3%).
total solubility 1017 1.468 1.308 0.996 0.901 5.15 4.67 The group-contribution methods by van Krevelen and
parameter
flash point 418 16.530 14.733 11.898 10.689 3.66 3.27 Hoftyser20 and Fedors21 have been used widely for
decades for predicting the cohesive energy, liquid molar
compounds. Introduction of a third-order approximation volume, and solubility parameters of polymers. Fedors
level18 makes the method rather inconvenient for sci- contributions can also give satisfactory results for the
entists to use and also complex for the needs of total solubility parameters of pure compounds. In fact,
computer-aided design. In addition, this third-order for relatively simple molecules, Fedors method is
approximation does not seem to exceed the accuracy of comparable to and sometimes better than ours. How-
the second-order approximation of the proposed method ever, for complex molecules, as are most of the molecules
(see Tables 4 and 5). of biochemical interest, Fedors method appears rather
The key compound that can provide an indication on inappropriate. We demonstrate this fact by means of
the accuracy of each logKow method is the n-octanol. examples in the Appendix. The proposed model has an
Theoretically, the logKow value of n-octanol is 3.00. This error of -0.5% for salicylic acid, whereas the Fedors
is also the experimental value for this compound. As method give a result for the total solubility parameter
6258 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004
Figure 1. Scatter plot of estimated vs experimental logKow
values.
Figure 2. Scatter plot of estimated vs experimental total solubil-
ity parameters.
Figure 3. Scatter plot of estimated vs experimental flash points.
of this compound with an error of 29.5%. In the example
of 2-cyclohexyl cyclohexanone, the errors were 0.1% and
8.8% for our method and for Fedors method, respec-
tively. In general, the differences in accuracy are
probably due to the extensive use of second-order groups
that can provide a more detailed description of molec-
ular structures in multiring, heterocyclic, or aromatic
compounds of biochemical interest, which was one of the
most important scopes of this new method.
Table 4. Comparison of the Accuracy of Existing
Methods for logKow Estimation
KowWin software Marrero, new
version 1.6617 Gani18 method
standard deviation (SD) 0.44 0.34 0.27
absolute average error (AAE) 0.32 0.24 0.19
correlation coefficient (r2) 0.95 0.97 0.99
Table 5. Comparison of the Marrero and Gani18 Method
and the New Method for the logKow Estimation
first-order second-order third-order
approximation approximation approximation
standard deviation (SD)
Marrero, Gani 0.42 0.38 0.34
new method 0.31 0.27
absolute average error (AAE)
Marrero, Gani 0.35 0.27 0.24
new method 0.23 0.19
In the literature, there are no relevant group-
contribution methods for estimating the flash point
exclusively from the molecular structure and without
any other data, so there cannot be any direct compari-
sons with our method. In the flash point estimation, the
mean error is only 3.27% (Table 3), and the average
error of the absolute values about 10 K. In some cases,
an accuracy of 10 K would not be appropriate for safety
purposes, but it could act as a warning when the actual
temperature reaches the estimated flash point -10 K.
This warning is very important for the safety of the
personnel in both laboratories and industries, especially
in cases of presence of substances without any experi-
mental data available or in the production of new
compounds with completely unknown flammability
behavior.
Conclusion
With the group contributions and model equations
that were presented in this work, crucial environmental
and safety properties of organic compounds can be
predicted easily and with satisfactory accuracy. By
adding the results for the octanol-water partition
coefficients (logKow), the total solubility parameters at
25 C, and the flash points to the other 10 properties
previously predicted by Constantinou et al.,4,8 the total
set of properties of this method is much more complete.
In addition, the experimental database of the method
now includes a larger number of compounds that cover
homologous series with multiring, aromatic, or hetero-
cyclic structures and have special applications in the
chemical, pharmaceutical, or food industries.
The present method is currently being extended to
temperature-dependent properties, such as surface ten-
sion, through its combination with the QCHB model.19
Acknowledgment
The authors express their appreciation to the Cyprus
Research Promotion Foundation for the partial financial
support of the project.
List of Symbols
AAE ) average absolute error
AAPE ) average absolute percentage error
C ) universal constant of the model
f(p) ) equation of property p
Fi ) contribution of a first-order group of type i
logKow ) octanol-water partition coefficient
 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004 6259

mj ) number of occurrences of a second-order group of type First-order Approximation:

j in the compound
ni ) number of occurrences of a first-order group of type i
in the compound occurrences, contribution,
N ) number of data points first-order group ni Fi niFi
Pc ) critical pressure -CH3 1 0.6998 0.6998
R ) universal gas constant C5H4N 1 0.3803 0.3803
r2 ) correlation coefficient niFi 1.0801
SD ) standard deviation universal constant, C 0.097
Sj ) contribution of a second-order group of type j
T ) temperature First-order approximation value
Tb ) normal boiling point
Tc ) critical temperature
Tm ) melting point
logKow ) i niFi + 0.097 ) 1.1771
V ) molar volume
Vc ) critical volume First-order approximation error ) (1.18-1.11)/1.11 )
Vl ) liquid molar volume 6.3%
Xest ) estimated value of a property Second-Order Approximation:
Xexp ) experimental value of a property
) total (Hildebrand) solubility parameter
Gf ) standard Gibbs energy occurrences, contributions,
Hf ) standard enthalpy of formation second-order group mj Sj mj S j
Hvap ) standard enthalpy of vaporization CcycHmdNcyc- 1 -0.0582 -0.0582
) acentric factor CcycHndCcycHp
mjSj -0.0582
Appendix
Second-order approximation value
Examples of Predictions of the Octanol-Water
Partition Coefficients (logKow). Example 1: 1-Oc-
tanol. logKow ) i niFi + i mjSj + 0.097 ) 1.1189
Estimated logKow ) 1.12
Experimental logKow ) 1.11
Percentage error ) (1.12-1.11)/1.11 ) 0.9%
Other Methods of Estimation
Marrero, Gani: Estimated logKow ) 1.40. Error )
(1.40-1.11)/1.11 ) 26.1%
KowWin version 1.66: Estimated logKow ) 1.35.
Error ) (1.35-1.11)/1.11 ) -21.6%
occurrences, contribution, Examples of Predictions of Total Solubility
first-order group ni Fi niFi Parameters. Example 1: Salicylic Acid.
-CH3 1 0.6998 0.6998
-CH2 7 0.4707 3.2949
-OH 1 -1.0577 -1.0577
niFi 2.9370
universal constant, C 0.097

No second-order groups are involved. First-order ap-

proximation value
First-Order Approximation:
logKow ) i niFi + 0.097 ) 3.034
occurrences, contribution,
first-order group ni Fi niFi
Estimated logKow ) 3.03
Experimental logKow ) 3.00 ACH 4 -6.4 -25.6
AC 1 684.3 684.3
Percentage error ) (3.03-3.00)/3.00 ) 1% COOH 1 9477.8 9477.8
Other Methods of Estimation ACOH 1 8456.1 8456.1
Marrero, Gani: Estimated logKow ) 2.85. Error ) niFi 18592.6
(2.85-3.00)/3.00 ) -4.8% universal constant, C 75954.1
KowWin version 1.66: Estimated logKow ) 2.81.
Error ) (2.81-3.00)/3.00 ) -6.3% First-order approximation value
Example 2: 2-Methylpyridine.
solubility parameter ) ( i niFi + C)0.383837 - 56.14
) (94546.7)0.383837 - 56.14 ) 25.11 (kJ/m3)1/2

First-order approximation error ) (25.11-24.21)/

24.21 ) 3.7%
6260 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004

Second-Order Approximation: Percentage error ) (18.79-18.77)/18.77 ) 0.1%

Other Method of Estimation
Fedors: Estimated solubility parameter ) 20.42.
occurrences, contributions,
second-order group mj Sj mj S j Error ) (20.42-18.77)/18.77 ) 8.8%
Examples of Predictions of Flash Point. Ex-
ACCOOH 1 -3076.5 -3076.5 ample 1: Naphthalene.
mjSj -3076.5

Second-order approximation value

solubility parameter ) ( i niFi + i mjSj +

C)0.383837 - 56.14
) (91470.2)0.383837 - 56.14 ) 24.09 (kJ/m3)1/2

Estimated solubility parameter ) 24.09 (kJ/m3)1/2 First-Order Approximation:

Experimental solubility parameter ) 24.21 (kJ/m3)1/2
Percentage error ) (24.09-24.21)/24.21 ) -0.5%
Other Method of Estimation occurrences, contribution,
Fedors: Estimated solubility parameter ) 31.36. first-order group ni Fi niFi
Error ) (31.36-24.21)/24.21 ) 29.5% ACH 8 11.5 92
Example 2: 2-Cyclohexyl Cyclohexanone. AC 2 20.5 41
niFi 1 7274.2 133
universal constant, C 216

First-order approximation value

flash point ) i niFi + 216 ) 349 K

First-order approximation error ) (349 - 352)/352 )
0.9%
First-order approximation: Second-Order Approximation:

occurrences, contribution, occurrences, contributions,

first-order group ni Fi niFi second-order group mj Sj mj S j
-CH2 8 -277.1 -2216.8 AC(ACHm)2AC(ACHn)2 1 3.2 3.2
-CH 2 -355.5 -711 mjSj 3.2
CH2CO- 1 7274.2 7274.2
niFi 4346.4
universal constant, C 75954.1 Second-order approximation value

First-order approximation value flash point ) i niFi + j mjSj + 216 ) 352.2 K

solubility parameter ) ( i niFi + C) 0.383837
- 56.14
Estimated flash point ) 352.2 K
Experimental flash point ) 352 K
) (80300.5.)0.383837 - 56.14 ) 20.18 (kJ/m3)1/2
Percentage error ) (352.2 - 352)/352 ) 0.02%
First-order approximation error ) (20.18-18.77)/ Example 2: D-Limonene [Cyclohexene, 1-Meth-
18.77 ) 7.5% yl-4-(1-methylethenyl)-, (R)-].
Second-Order Approximation:

occurrences, contributions,
second-order group mj Sj mj S j
C(cyclic)dO 1 -3745 -3745
mjSj -3745
First-Order Approximation:
Second-order approximation value

solubility parameter ) ( i niFi + i mjSj + first-order group

occurrences,
ni
contribution,
Fi niFi
0.383837 -CH3 2 0.6 1.2
C) - 56.14 -CH2 3 10.8 32.4
-CH 1 12.2 12.2
) (76555.5)0.383837 - 56.14 ) 18.79 (kJ/m3)1/2 CH2dC< 1 19.1 19.1
-CHdC< 1 37.9 37.9
Estimated solubility parameter ) 18.79 (kJ/m3)1/2 niFi 102.8
Experimental solubility parameter ) 18.77 (kJ/m3)1/2 universal constant, C 216
 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004 6261

No second-order groups are involved. First-order ap- (2) Joback, K. G.; Reid, R. C. Estimation of Pure-Component
proximation value Properties from Group Contributions. Chem. Eng. Commun. 1983,
57, 233.
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1992.
(4) Constantinou, L.; Gani, R. New Group Contribution Method
for Estimating Properties of Pure Compounds. AIChE J. 1994, 40,
Estimated flash point ) 318.8 K 1697.
Experimental flash point ) 318 K (5) Mavrovouniotis, M. L. Estimation of Properties from Con-
Percentage error ) (318.8 - 318)/318 ) 0.25% jugate Forms of Molecular Structures. Ind. Eng. Chem. Res. 1990,
Example 3: Camphor (Bicyclo-2.2.1-heptan-2- 32, 1734.
one, 1,7,7-Trimethyl-). (6) Constantinou, L.; Prickett, S. E.; Mavrovouniotis, M. L.
Estimation of Thermodynamic and Physical Properties of Acyclic
Hydrocarbons Using the ABC Approach and Conjugation Opera-
tors. Ind. Eng. Chem. Res. 1993, 32 (8), 1734.
(7) Marrero, J.; Gani, R. Group Contribution Based Estimation
of Pure Component Properties. Fluid Phase Equilib. 2001, 183-
184, 183-208.
(8) Constantinou, L. Property Estimation Method for Accurate
Process Design. Petroleum Technology Quarterly 2001, 6/2, 103-
109.
First-order approximation: (9) Constantinou, L.; Gani, R.; OConnell, J. Estimation of the
Acentric Factor and the Liquid Molar Volume at 298 K Using a
New Group Contribution Method. Fluid Phase Equilibr. 1995, 103,
occurrences, contribution, 11-22.
first-order group ni Fi niFi (10) Boudouris, D.; Constantinou, L.; Panayiotou, C. Prediction
-CH3 3 0.6 1.8 of Volumetric Behavior and Glass Transition Temperature of
-CH2 2 10.8 21.6 Polymers: A Group-Contribution Approach. Fluid Phase Equilib.
-CH 1 12.2 12.2 2001, 167, 1-19.
-C 2 12.4 24.8 (11) Sanchez, I. C.; Lacombe, R. Statistical Thermodynamics
CH2CO 1 69.7 69.7 of Polymer Solutions. Macromolecules 1978, 11, 1145.
niFi 130.1 (12) Poling, B. E.; Prausnitz, J. M.; OConnel, J. P. The
universal constant, C 216 Properties of Gases and Liquids; McGraw-Hill: New York, 2000.
(13) Hansch, C.; Leo, A.; Hoekman, D. Exploring QSARs
First-order approximation value Hydrophobic, Electronic and Steric Constants; ACS Professional
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(14) Daubert, T. E.; Danner, R. P. Physical and Thermodynamic
Properties of Pure Compounds: Data Compilation; Hemisphere:
New York, 1989.
First-order approximation error: ) (346.1 - 339)/339 (15) Fire Protection Guide to Hazardous Materials, 11th ed.;
) 2.1% National Fire Protection Association: Quincy, MA, 1994.
Second-order Approximation: (16) Meylan, W.; Howard, P. Atom/Fragment Contribution
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Pharm. Sci. 1995, 84, 83.
occurrences, contributions, (17) KowWin; U.S. Environmental Protection Agency: Wash-
second-order group mj Sj mj S j ington, DC, 2000 (free distribution at www.epa.gov/oppt/exposure/
C(cyclic)dO 1 -7.6 -7.6 docs/episuite.htm).
mjSj -7.6 (18) Marrero, J.; Gani, R. Group-Contribution-Based Estima-
tion of Octanol/Water Partition Coefficient and Aqueous Solubility.
Second-order approximation value Ind. Eng. Chem. Res. 2002, 41, 6623.
(19) Panayiotou, C. The QHCB model of fluids and their
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(20) Van Krevelen, D. W.; Hoftyzer, P. J. Properties of Polymers,
Their Estimation and Correlation with Chemical Structure; 2nd
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Estimated flash point ) 338.5 K
(21) Fedors, R. F. Method for estimating both the solubility
Experimental flash point ) 339 K parameters and molar volumes of liquids. Polym. Eng. Sci. 1974,
Percentage error ) (338.5 - 339)/339 ) -0.15% 14, 147.

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