Full Papers

Design of Discovery Libraries for Solids Based on QSAR Models

D. Farrussenga, C. Klannerb, L. Baumesa, M. Lengliza, C. Mirodatosa, F. Sch
thb*
a
Institut de Recherches sur la Catalyse – CNRS – 2, Av. A. Einstein, F-69626 Villeurbanne, France
b
MPI f
r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 M
lheim, Germany, E-mail: schueth@lcofo.mpg.de

Keywords: Combinatorial chemistry, High-throughput screening, Material library design, Virtual

screening, Descriptor, Data mining, Heterogeneous catalysis

Received: 17. 09. 2004; Accepted: 27. 10. 2004

Abstract
A method is described which is used to construct a descriptor vector of solid catalysts in
the oxidation of propene. Different methods are described which allow one to construct a
correlation between characteristics of the catalysts and their performance in propene
oxidation. Successful descriptor vectors are generated which predict catalytic performance
substantially better than statistically expected. These descriptor vectors do not contain
explicit information on the elemental composition of the catalysts any more, but only
parameters that are either derived from the elemental composition, such as the enthalpy
of oxide formation, or are related to the synthetic method. The general concept can
probably be extended to the development of descriptors for solids to be used in other
applications as well.

1 Introduction the atomic level, can be encoded as fingerprints that ena-

Over only a few years, the Quantitative Structure – Activi-
ty Relationship (QSAR) approach has substantially
changed the process of drug discovery, because it enables
one to select an adapted and – as opposed to a random se-
lection – improved subset of experiments among an infin-
ite number of candidate molecules by applying virtual
screening techniques. In addition, the number of com-
pounds that can be taken into consideration is increased
by orders of magnitude with respect to a conventional
strategy. This helps to increase the chance of discoveries
while saving experiments by discarding compounds before
they have to be synthesized. Depending on whether the
goal is to design discovery or targeted libraries, different
criteria for library design are applied. For a discovery li-
brary, samples that constitute the subset should be as di-
verse as possible and the set should cover the whole search
space. For a targeted library, on the other hand, one seeks
drug candidates that are similar to a lead structure. Thus,
the diversity profiling of drugs/molecules is the key con-
cept in the design of libraries of molecules. It relies on the
“similar property principle”, that is, the assumption that
structurally similar molecules should have similar biologi-
cal activities. The similarity/diversity of two molecules can
be assessed by measuring a “distance” between them ac-
cording to different methods, such as, for instance, Euclidi-
an metrics or Tanimoto indices. It is clear that the distance
calculation depends strongly on the coordinates of the two
molecules, which in turn rely on the way they have been
encoded. Molecules and drugs, which can be described at
ble their molecular features or molecular characteristics to
be captured through the so-called “descriptors”. These de-
scriptors form a vector of variables, so that a library of
compounds can be described by a tabular array where a
row represents a molecule and the columns the different
descriptors. Molecules can be described by a vast number
of descriptors that are related to structural features or mo-
lecular properties. Commonly, property descriptors are
sub-divided into one-, two-, and three-dimensional (1D,
2D, and 3D, respectively) descriptors, indicating the re-
quired type of structural representation of a molecule for
its calculation. 1D descriptors include bulk properties and
physiochemical parameters, for instance, molecular
weight. Properties that can be computed from a 2D-struc-
ture representation include, for example, defined structur-
al fragments and connectivity indices. 3D properties are,
for instance, the solvent-accessible surface area, molecular
volumes, or spatial pharmacophores. After selection of the
relevant descriptors, the diversity of any two molecules
can be assessed by computing the distance between them,
based on the descriptors.
The combinatorial approach has recently been extended
from drug discovery to materials science and catalysis [1 –
6]. Unfortunately, the QSAR approach cannot be equally
well transferred to the discovery of materials, because (i)
solids can hardly be characterized at the atomic scale,
which is a serious obstacle for fingerprint encoding, as
mentioned above for molecules, and (ii) the similar prop-
erty principle is not generally applicable to solids in mate-
rials science [7]. Hence, truly QSAR and virtual screening

78 QSAR Comb. Sci. 2005, 24 DOI: 10.1002/qsar.200420066  2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Design of Discovery Libraries for Solids Based on QSAR Models
methods based on descriptors have not been applied to
catalysts so far, even if data-mining methods have been re-
cently used [8 – 13]. Therefore, there is no method today
for the library design of solids that can guarantee that the
properties of the solids will be diverse. It is the high com-
plexity of solids, as compared to molecules or drugs, which
makes the design of libraries a serious challenge [14]. One
of the main hurdles is the description of a solid, especially,
if the solid has not been synthesized in reality and, there-
fore, no characterization results are available.
The motivation of this work is to demonstrate for the
first time an implementation strategy for the building of a
QSAR analogue model for solids. Since the solids are not
represented as structures, in the following, the term QPAR
(Quantitative Property – Activity Relationship) will be
used. The methodology to generate and select relevant de-
scriptors is described. Different QPAR models are com-
pared and discussed with respect to previous knowledge
and the available literature. A short account on some as-
pects of this work has been given recently [15].
2 Materials and Methods
2.1 Workflow Overview
Figure 1 gives a general description of the workflow used
in this study, which, however, is generic and should be ap-
plicable to other problems as well. The data-processing
steps to generate the catalyst descriptors are shown on the
left side in Figure 1, while the workflow to assess and clas-
Figure 1. General workflow for the development of descriptors for solid catalysts; for explanation, see text.
QSAR Comb. Sci. 2005, 24  2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
sify the catalytic behavior experimentally is depicted on
the right side. The whole process consists of the following
stages: (1) collection and synthesis of a diverse library of
solids, in which the selection is based upon experience and
chemical intuition; (2) description of these solids by nu-
merous attributes; (3) selection of a subset of relevant and
uncorrelated attributes to create a first possible descriptor
vector; (4) high-throughput (HT) testing of the whole li-
brary of solids in a catalytic reaction and classification of
the catalysts in distinct classes of performance, resulting in
clusters containing solids which exhibit similar catalytic
properties; and (5) computing QPAR models between de-
scriptor vectors and catalytic performances, where in this
process the descriptor vectors are further modified. De-
tails of each step are reported in the following sections.
2.2 Sample Collection and HT Synthesis
For the first stage, we collected approximately 500 differ-
ent solids with the aim to cover a wide chemical space.
Hence, samples had to be as diverse as possible with re-
spect to the elements, the material types, and the synthesis
procedures, which also means that compounds were in-
cluded in the study for which it was clear that they were es-
sentially inactive in the target reaction, such as silica. This
initial diverse library was created based on a priori knowl-
edge and intuition. A first selection of 367 catalysts was
carried out among solids already available in our laborato-
ries. Then, 100 additional solids were synthesized by means
of HT equipment in order to expand the chemical space
with respect to the element and support representation.
79
Full Papers
Thus, we ensure that most of the elements of the periodic
table (excluding exotics) were represented, and that the
occurrence of each element was well distributed over the
library. As it is far beyond the scope of this work, the prep-
aration method of each solid catalyst will not be discussed
in detail. However, synthetic methods include impregna-
tion, ion exchange, precipitation, co-precipitation, deposi-
tion – precipitation, the activated-carbon route [16], sol-gel
synthesis, and others.
2.3 Computation of Catalyst Attributes
A Microsoft Access database was implemented to record
the description of the catalyst synthesis and to perform in
an automatic manner the calculation of thousands of at-
tributes (also called meta data) for each catalyst. A variety
of different information is recorded in the database, name-
ly, (1) synthesis parameters of the catalysts, (2) elemental
composition of the catalysts, (3) properties of constituent
elements, (4) properties of constituent-element oxides, and
(5) properties of constituent-element ions (Figure 2). The
entries concerning the properties of elements, element ox-
ides, and element ions were collected from the Handbook
of Chemistry and Physics [17] and other sources of physi-
co-chemical data. The workflow that describes the combi-
natorial generation of the attributes is shown in Figure 3.
By combining the elemental composition of a catalyst and
the respective properties of the elements, ions, or oxides,
3100 attributes were computed in a combinatorial manner
using operators such as the average of a certain property
for the constituents of the catalyst, the maximum, the min-
imum, weighted averages, and so on. For instance, from
the enthalpies of formation of the element oxides, one can
compute the average enthalpy of formation, or the spread
between the highest and the lowest enthalpy of formation.
Such values should, in some complex way, be related to
the availability of oxygen at the surface of a solid catalyst,
and thus to the performance in an oxidation reaction. The
motivation to generate a vast number of attributes is the
fact that relevant and discriminative attributes are a priori
not known, and obviously the relationship between prop-
erties of a catalyst and its performance is not simple.
Finally, different types of attribute sets were generated:
X1 accounted for the composition of all catalysts (60 in to-
tal), X2 consists of parameters calculated on the basis of
X1 and physical data (3100 in total), and X3 contains syn-
thesis parameters of the solid catalysts. The last attribute
set consists of 19 categorical (mostly binary) variables
which provide information on the last synthesis step,
namely main synthesis parameters, precursor types, addi-
tive types, etc.
2.4 Search Space Reduction – the Descriptor Vector
The number of attributes must be reduced since there are
no modeling techniques available which are able to deal
80  2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
D. Farrusseng et al.
with 3000 attributes. We assumed that a set of around 75
attributes would be a maximum with respect to the num-
ber of catalysts (467), otherwise the risk of self learning
would be too high. The task thus consists of selecting dis-
criminative attributes that are not strongly correlated be-
tween each others. A ranking of the 3119 attributes (X2
and X3 attribute sets), based on their discriminative pow-
er, was carried out using the Relief algorithm [18]. Then,
56 attributes were selected from the 3100 X2 attributes
with respect to their ranking and in order to map different
properties (Table 1). This ensemble of 56 X2 attributes
plus the 19 X3 attributes form a first descriptor vector
which is used as input for the QPAR model (and which
was further reduced during the model building). Note that
this descriptor vector does not contain information on the
elemental composition any more. This only enters the vec-
tor via the computed values that are correlated to the ele-
ments present in the catalyst.
2.5 HT Testing and Clustering of Catalytic Performance
The library of solids has been tested in the gas-phase oxi-
dation reaction of propene with oxygen. This reaction of-
fers the advantage to provide a wide spectrum of possible
products from C1 to C6 including a number of alkenes and
oxygenates. A complete list is given in Table 2. Data analy-
sis serves to classify the performances of all catalysts into a
small number of distinct classes that are representative of
typical catalytic behavior. An automated HT set-up has
been used to evaluate the performance of each catalyst. It
consists of a set of mass-flow controllers for oxygen, pro-
pene, and nitrogen, which feed the reagents via a common
line into a 16-fold plug flow reactor. The principle set-up
of this system corresponds to the one described in Ref.
[19]. A gas chromatograph equipped with a capillary col-
umn and flame-ionization detector in combination with a
methanizer has been used for analysis. Catalytic tests were
carried out with a gas consisting of 1% propene, 5% oxy-
gen (slightly over-stoichiometric for full oxidation to water
and carbon dioxide), and nitrogen as balance, at a space
velocity of 225 mL h
1 (gcat)
1 at five different tempera-
tures (200, 250, 300, 400, and 500 8C). Catalyst was used as
grains of between 250 and 500 mm in size. Propylene con-
version and the selectivity to 27 products were determined
for each catalyst. Each test was repeated twice. Each full
cycle to analyze 16 catalysts needs 8 h. This means that the
catalysts were not analyzed at the same time on stream.
However, the activation or deactivation information was
also taken into account to some extent by calculating the
difference between the propene conversion of the first and
the second measurement. Using this procedure, the per-
formance of the 467 catalysts was described by 120 varia-
bles: propene conversion, 21 selectivities, deactivation be-
havior, and mass balance (a measure for possible coking
or residue formation on the catalysts) at five different tem-
peratures. Because of obvious strong correlations in prod-
QSAR Comb. Sci. 2005, 24
Design of Discovery Libraries for Solids Based on QSAR Models

Figure 2. Simplified scheme of the database for solid catalysts.

uct selectivities accompanied with low variance, some
composite variables were constructed by the combination
of variables to reduce the complexity of the problem: The
variables mass balance at all temperatures and temporal
behavior at 200 8C, 250 8C, and 300 8C have been discarded,
as their information content was extremely low. It is ex-
pected, that this will be different for other reaction condi-
tions under net reducing conditions, where coke formation
can be a serious problem. 17 variables with high informa-
tion content have been taken directly for analysis: conver-
sion, selectivity to CO and to CO2 at all five temperatures,
and temporal behavior at 400 8C and 500 8C. Four variables

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Full Papers D. Farrusseng et al.

Figure 3. Scheme for the generation of the attribute set X2. For the elements only one operation was necessary, for oxides and ions
two steps were needed; first the different states for one element had to be taken into account and in the second step the different
constituents in the catalyst were generated. (SD ¼ standard deriation).

with medium information content were taken into ac-
count by summing up the respective variable for all five
temperatures giving formaldehydeall temperatures, acetalde-
hydeall temperatures, acroleinall temperatures, and benzeneall temperatures.
Variables that were assumed to be important from a chem-
ical point of view, but had a low variance, were taken into
account by grouping products with similar chemical func-
tion or chemical structure The values of the respective
groups for all temperatures were summed up, giving
S C3H6Oall temperatures (propionaldehyde and acetone), S
acidsall temperatures (acetic acid and acrylic acid), S alkanesall
temperatures (ethane, butane, and pentane), S C4 hydro-
carbonsall temperatures (1-butene, 2-butene, and 2-methylpro-
pene), S C5 hydrocarbonsall temperatures (2-methyl-1-butene, 2-
methyl-2-butene, and pentenes), and S C6 hydro-
carbonsall temperatures (S C6H12). Then, a principal component
analysis (PCA) was carried out to decrease the dimension-
ality and to orthogonalize the dataset. From the scores on
the PCs axis, distinct catalytic classes were generated by
means of hierachical clustering (Wards distance) and the
k-means technique as implemented in Statistica 6.1.
2.6 QPAR Model
The task here consists of modeling the correlation between
the descriptors (56 þ 19) and the performance clusters,
which represent typical catalytic behavior. In other words,
we seek classification models that enable us to assign a cat-

82  2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim QSAR Comb. Sci. 2005, 24
Design of Discovery Libraries for Solids Based on QSAR Models

Table 1. A list of the 56 attributes from the attribute set X2 used for the correlation. 1 – 24 are element properties and 25 – 56 are ox-
ide properties. Since often more than one oxide exists, an additional operation to calculate the value for an element is necessary, for
instance, the mean of the densities of different oxides for one element.
Number Code Property Calculation for cata-
lyst
1 meanbc_1ie first ionization energy mean all metals and semi-metals
2 meanbc_ar atomic radius mean all metals and semi-metals
3 difec_ar difference from highest to lowest value
4 meanbc_bseo bond strength element – oxygen mean all metals and semi-metals
5 difec_bseo difference from highest to lowest value
6 meanbc_bsee bond strength element – element mean all metals and semi-metals
7 difec_bsee difference from highest to lowest value
8 meanec_ea electron affinity mean all elements
9 meanbc_ea mean all metals and semi-metals
10 difec_ea difference from highest to lowest value
11 meanec_pe Pauling electronegativity mean all elements
12 meanbc_pe mean all metals and semi-metals
13 difec_pe difference from highest to lowest value
14 minec_nffefmsmo normalized formation free-enthalpy for most stable minimum value all elements
metal oxide
15 maxec_nffefmsmo maximum value all elements
16 minec_sedmsmoom smallest formation free-enthalpydifference from minimum value
the most stable metal oxide to another metal oxide
17 maxec_sedmsmoom maximum value all elements
18 wmec_ms molar mass weighted mean all elements
19 meanec_ms mean all elements
20 meanbc_ms mean all metals and semi-metals
21 wmbc_no number of element oxides weighted mean all metals and half metals
22 minec_no minimum value all elements
23 maxec_no maximum value all elements
24 nvec number of elements in catalyst number all elements

Number Code Property Calculation for ele- Calculation for cata-

ment lyst
25 meanec_moe_d density of oxides mean mean all elements
26 meanec_moe_dc dielectric constant of oxides mean mean all elements
27 meanec_meanvho- formation free-enthalpy of oxides mean value for the mean all elements
soe_ffe highest oxidation state
28 meanec_difoe_ffe difference highest to mean all elements
lowest value
29 meanec_moe_ffe mean mean all elements
30 meanec_meanvho- melting point of oxides mean value for the mean all elements
soe_mp highest oxidation state
31 meanec_moe_mp mean mean all elements
32 meanec_difoe_mp difference highest to mean all elements
lowest value
33 meanec_nvoe_os oxidation states of oxides number mean all elements
34 sumec_nvoe_os number sum all elements
35 meanbc_mie_cn coordination number of ions mean mean all metals and
semi-metals
36 meanbc_difie_cn difference highest to mean all metals and
lowest value semi-metals
37 meanec_mie_cn mean mean all elements
38 meanec_difie_cn difference highest to mean all elements
lowest value
39 meanbc_mie_icp ionic covalency parameter of ions mean mean all metals and
semi-metals
40 meanbc_difie_icp difference highest to mean all metals and
lowest value semi-metals
41 meanec_mie_icp mean mean all elements
42 meanec_difie_icp difference highest to mean all elements
lowest value

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Table 1. (cont.)

Number Code Property Calculation for ele- Calculation for cata-

ment lyst
43 meanbc_mie_ir ionic radius of ions mean mean all metals and
semi-metals
44 meanbc_difie_ir difference highest to mean all metals and
lowest value semi-metals
45 meanec_mie_ir mean mean all elements
46 meanec_difie_ir difference highest to mean all elements
lowest value
47 meanbc_mie_l optical basicity of ions mean mean all metals and
semi-metals
48 meanbc_difie_l difference highest to mean all metals and
lowest value semi-metals
49 meanec_mie_l mean mean all elements
50 meanec_difie_l difference highest to mean all elements
lowest value
51 meanec_maxvhosie_os oxidation states of Ions maximum value for mean all elements
the highest oxidation
state
52 meanec_difie_os difference highest to mean all elements
lowest value
53 sumec_sumie_os sum sum all elements
54 sumec_nvie_os number sum all elements
55 sumec_minvhosie_os minimum value for sum all elements
the highest oxidation
state
56 sumec_maxvhosie_os maximum value for sum all elements
the highest oxidation
state

Table 2. Products of the reaction clearly identified by gas chromatography.

C1 methane C3 propene C4 butane C6 hexane
formaldehyde allyl alcohol 2-methylpropene cyclohexane
carbon monoxide propylene oxide 1-butene benzene
carbon dioxide acetone 2-butene
propionaldehyde
C2 ethane acrolein C5 pentane
acetaldehyde acrylic acid 2-methyl-1-butene
acetic acid 2-methyl-2-butene

alyst to a specific cluster. The model quality is assessed by
means of prediction-rate criteria. Two classification tech-
niques were used: Artificial Neural Networks (ANN) and
Classification tree as implemented in Statistica 6.1.
In the search for appropriate ANN models, both Multi-
Layer Perceptron (MLP) and Probabilistic Neural Net-
works (PNN) were applied using the Intelligent Solver of
Statistica. In order to get robust models, we have enabled
the solver to discard attributes during the screening of the
neural networks. In addition, after models were built, a
pruning was performed for discarding irrelevant variables.
Pruning refers to a sensitivity analysis, e.g., a ranking of
variables based on their discriminative power. The dataset
of 467 catalysts was randomly divided into three subsets.
The learning step was performed on one half of the whole
dataset, the verification step on one quarter, and the inde-
pendent testing step on the remaining quarter.
For the Classification tree models, we used the C&RT
method with the Gini criteria as splitting conditions and
FACT-style direct stopping as pruning rule (Statistica 6.1).
Cross-validation was carried out on one third of the data-
set to ensure that models were not prone to overlearning.

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Design of Discovery Libraries for Solids Based on QSAR Models

2.7 Quality Assessment of QPAR Models the variance, which indicates the high dimensionality of
the search space (Figure 4). In addition, the loading plots
The assessment was performed by comparing the predic- PC1 vs. PC2 and PC3 versus PC4 enable us to visualize the
tions made by the model with our observations. The results fairly good covering of the variable search space for the at-
are reported in a so-called confusion matrix. This table re- tributes which contain most information (Figures 5a and
veals the number of correctly classified catalysts, how
many catalysts were misclassified, and for which classes
the misclassification occurred. The prediction rate is de-
rived from the confusion matrix to estimate the quality of
the prediction. It accounts for the correctly classified cases
in the respective predicted class and can be considered as
statistical benchmark for the quality of the prediction,
since it can directly be compared to the “ratio” given in
the confusion matrix. This ratio gives the statistical distri-
bution probabilities into the respective classes for the orig-
inal dataset. Hence, a model becomes meaningful when
the prediction rates are higher than the corresponding ra-
tios.

3 Results

3.1 Feature Selection – Descriptor Vector

In order to assess the relevance of the different attributes,
the Relief algorithm was used, which indicates the discrim-
inative power of the attributes with respect to the different
classes of catalytic behavior. Among the 3119 attributes, 5
attributes describing the synthesis procedure are by far the
most relevant and 11 attributes related to the synthesis are
in the top 50. Therefore, all 19 synthesis attributes from at-
tribute set X3 were selected, as their influence on the cata-
lytic performance was estimated to be very strong. This
also corresponds to experience in the field of catalysis,
where it is known that the synthesis method to create a
catalyst is of paramount importance in determining the
performance. On the other hand, clear trends of the rele-
vance of the continuous attributes from the attribute set
X2 can hardly be identified. Nevertheless, it was noticea-
ble that attributes calculated with simple operators such as
the minimum of a set of values for a given catalyst, the
maximum, or the average have more discriminative power
than other, more complex operators such as standard devi-
ation. Attributes generated by the complex operators
where thus discarded. In order to reduce the number of at-
tributes, strongly correlated attributes (e.g., melting point
and boiling point of elements) and attributes based on
properties that were only accessible for few elements (for
instance, heat capacity of element oxides) were discarded.
Finally, among the rest we decided to pick 56 attributes
from the X2 attribute set according to their ranking, in or-
der to map all defined properties. The list of continuous
descriptors is reported in Table 1. A PCA analysis on the
56 continuous attributes was carried out in order to get in-
sights on the features of the dataset. The Eigenvalue plot
shows that up to eight PCs are required to explain 75% of
Figure 4. Eigenvalue plot and the corresponding percentage of
variance for each principal component.
5b). From the distribution study of the attributes one can
extract that most of them follow a normal distribution, as
shown for the example of the attribute meanecmie_l (#49)
reported in Figure 6a. This is in contrast with the attribute
set X1, which accounts for the elemental compositions
(Figure 6b). Indeed, the box and whisker plot indicates
that the median and quartiles for most of the variables re-
garding the elemental compositions are equal to zero. This
results from the fact that a catalyst contains typically be-
tween three and eight elements, which implies that all oth-
er elements are assigned the value 0. Therefore, in addi-
tion to higher information content of the attributes, gener-
ating the X2 attribute set enables us to obtain normally
distributed attributes, which is beneficial with respect to
the QPAR modeling task. In conclusion, this ensemble of
56 X2 attributes plus the 19 attributes from the X3 form
the initial descriptor vector that is used as input for the
QPAR model.
3.2 Data Analysis and Clustering of Catalytic
Performance
Catalytic performance for 467 very different catalytic ma-
terials in a reaction such as propene oxidation is highly
complex. Altogether 120 variables fully describe the cata-
lytic performance. As already explained in the methods
section, various variables among the 120 have been group-
ed since they were obviously very strongly correlated re-

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Full Papers D. Farrusseng et al.

Figure 5. Loading plots for the PCA analysis of the selected

56 continuous attributes from the attribute set X2. Projection of
all variables on the PC1/PC2 plane (a) and the PC3/PC4 plane
(b).

sulting in a reduced dataset of 27. In order to make the da-

taset orthogonal for allowing proper clustering, a subse-
quent PCA step was carried out. Taking the first eight PCs
79.4% of the variance based information is retained. Most
of the variables are represented above 75%, except the
variables accounting for the selectivities to formaldehyde
and acetaldehyde (35 and 45%, respectively). The first
PCs are closely correlated with specific catalytic behavior.
High PC1 levels mean high conversion at low temperature
and high CO2 selectivity, whereas low PC1 levels mean
high CO selectivity. High PC2 values, one the other hand,
are related with high selectivity for alkane and alkene for-
mation. Some obvious trends concerning the variables
conversion, CO, and CO2 at all temperatures can also be
distinguished in the PC1 – PC2 and PC1 – PC3 loading
plots (Figures 7a and 7b). All conversion variables and all
CO2 variables are directly correlated and both inversely
with all CO variables. It can also be observed that all other
variables are independent (orthogonal) of propene conver-
sion, CO, and CO2. The variables benzene, S acids, S alka-
nes, S C4 hydrocarbons, S C5 hydrocarbons, and S C6 hy-
drocarbons are strongly correlated and orthogonal to all
remaining variables.
Different clustering methods were applied to classify
the catalytic behavior of the 467 catalysts. The clustering
was performed on the PCA scores (coordinates of catalysts
in the space defined by the first 8 PCs axis). The selection
criteria were (1) to generate a minimum number of classes

Figure 6. a) Typical distribution of normalized values shown for the example of the attribute meanecmie (#49). b) Box and whisker
plot for the distribution of the elements in the catalysts. Since most catalysts only contain few elements, most values for a given cata-
lyst are zero. Since most materials are oxides, only the median for oxygen differs substantially from zero. Quartiles significantly differ-
ing from zero are only observed for silicon and aluminium, which occur frequently in the supports.

86  2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim QSAR Comb. Sci. 2005, 24
Design of Discovery Libraries for Solids Based on QSAR Models
Figure 7. Loading plots for the PCA analysis of the catalytic
performance data. Projection of all variables on the PC1/PC2
plane (a) and the PC1/PC3 plane (b).
which represent the different obvious catalytic behavior
(coverage), (2) to avoid that a class is represented by less
than 15 catalysts of the whole population (representative-
ness), and (3) to get classes as distinct as possible. Addi-
tionally, the goal of the clustering was to identify each clus-
ter with distinct chemical behavior. With respect to these
criteria, the hierarchical clustering indicates that four dis-
tinct classes can be generated when cutting at a linkage
distance of 150 (Figure 8). On the other hand, k-means
clustering enables us to generate five distinct classes with a
higher degree of discrimination. The distribution of the
467 catalysts in the five clusters is shown in Figure 9. It re-
veals that four classes encompass about 100 catalysts,
whereas the last class contains only 17 catalysts, which rep-
resent about 4% of the whole dataset. The results of the k-
means clustering are shown on the PCA score plot (Fig-
ure 10). For further analysis, these five clusters were inves-
tigated, since they fulfill all our requirements. In addition
QSAR Comb. Sci. 2005, 24  2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 8. Hierarchical tree plot for all 467 catalysts. Cutting
between 100 and 200 generates four well-separated clusters.
Figure 9. Number of cases in each cluster for k-means cluster
analysis based on eight principal components.
it is possible to assign a specific catalytic behavior to each
class. The chemical significance of each of the clusters is:
cluster #1: low conversion, high selectivity to CO2,
cluster #2: medium conversion, high selectivity to CO2,
cluster #3: low conversion, high selectivity to CO, partial
oxidation products,
cluster #4: low selectivity to (CO2 þ CO), hydrocarbons,
and
cluster #5: high conversion, high selectivity to CO2.
3.3 QPAR Model
After the selection of the 56 (X2) plus 19 (X3) attributes
and the identification of five distinct classes of catalytic be-
havior, a model was built in order to establish Quantitative
Property – Activity Relationships between the attributes
and the classes. In addition, because models can highlight
the most discriminative attributes, a last selection of attrib-
87
Full Papers D. Farrusseng et al.

Table 3. Contingency table for the ANN analysis, reporting the

predictions for the training (top), verification (middle) and test-
ing (bottom) datasets. ANN: Probabilistic Neural Network
(PNN) with 51 input nodes: 119 nodes in the first layer and
240 nodes in the second layer.
training 1 2 3 4 5 sum ratio pred. rate sensibility
1 predicted 54 0 2 1 0 57 0.24 0.95 9,83
2 predicted 1 69 1 0 2 73 0.30 0.95 0.96
3 predicted 3 1 67 0 0 61 0.25 0.93 0.95
4 predicted 0 0 0 7 0 7 0.03 1.00 0.86
5 predicted 0 2 0 0 40 42 0.18 0.95 0.95
sum/mean 68 72 80 8 42 240 0.96 0.93

verification 1 2 3 4 5 sum ratio pred. rate sensibility

1 predicted 14 2 5 2 2 25 0.27 0.56 0.45
2 predicted 10 18 1 0 7 36 0.26 0.50 0.62
3 predicted 7 2 22 0 0 31 0.25 0.71 0.79
4 predicted 0 0 0 1 1 2 0.03 0.50 0.33
5 predicted 0 7 0 0 18 20 0.20 0.65 0.57
sum/mean 31 29 28 3 23 114 0.59 0.55

test 1 2 3 4 5 sum ratio pred. rate sensibility

1 predicted 14 3 7 1 1 26 0.25 0.54 0.50
2 predicted 4 14 3 0 13 34 0.25 0.41 0.50
3 predicted 9 5 12 0 1 27 0.21 0.44 0.50
4 predicted 0 0 1 5 0 6 0.05 0.83 0.83
5 predicted 1 6 1 0 12 20 0.24 0.60 0.44
sum/mean 28 28 24 6 27 113 0.57 0.56

Figure 10. Score plots showing the results of k-means cluster

analysis based on eight principal components.
utes was performed, yielding the final descriptor that has
the most robust predictive power. Two different classifica-
tion tools were used to build the QPAR model, namely
ANN and Classification tree techniques.
Both MLP and PNN neural networks with two hidden
layers gave high overall prediction rates. The best PNN
network found is characterized by 51 nodes in the input
layer, and 119 and 240 in the first and second hidden lay-
ers, respectively. For this model, the results of the predic-
tions for the training, verification and testing datasets, re-
spectively, are reported in the contingency table (Table 3).
Values reported on the diagonal correspond to correct
classifications while the other entries account for misclassi-
fications. For example, in the quality assessment for the
training dataset, 54 catalysts were correctly classified in
cluster #1, whereas one was misclassified in cluster #2, and
3 misclassified in cluster #3. Prediction rates (number of
correctly classified catalysts divided by the number of all
catalysts assigned to this class) have been calculated for
each catalyst class. The tables reveal very good learning
performance with prediction rates above 93% for all
classes. The prediction rates for the verification and the
test datasets at about 57% indicate that over learning did
not take place, i.e., the model can perform predictions
with a high confidence level on “new catalysts”. It has to
be pointed out that the PNN model enables good predic-
tions to be performed on cluster #4 when considering the
very low number of catalysts used in the learning step
(eight and three catalysts for learning and verification, re-
spectively). The lowest prediction performance is associat-
ed with cluster #2. This results from the fact that catalysts
belonging to cluster #5 are misclassified in cluster #2 and
vice versa. These misclassifications originate from the jux-
taposition of the two clusters which can be seen in the
PCA plots. Chemically, the performance of the catalysts in
these two clusters is related (differing only with respect to
the level of conversion), so that this misclassification is
less severe than, for instance, misclassification into cluster
#3 or #4.
Applying the pruning method, the number of attributes
was reduced from 75 to 51 resulting in the generation of a
descriptor vector with more condensed information con-
tent. Similar results were obtained with MLP neural net-
works. The best architecture found consists of 45 nodes in
the input layers, and 144 and 27 in the first and second hid-
den layers, respectively.
The Classification tree analysis was based on a further
reduced attribute set of 42 attributes based on a weight
analysis by ANN. A loss matrix had to be used to achieve
discriminative models. A loss matrix consists of a square
matrix of coefficients (Table 4) multiplied by a vector of
class probabilities to form a vector of cost estimates. The

88  2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim QSAR Comb. Sci. 2005, 24
Design of Discovery Libraries for Solids Based on QSAR Models

diagonal of a loss matrix is always equal to zero, because a ed in Figure 11 as example. The bar chart on top of the
correct classification has zero costs. The value 1 indicates tree presents the distribution of the catalysts in the five
no adjusted preference, while all values > 1 induce a pref- clusters as already shown in Figure 9. The whole dataset is
erence for certain classifications. With the loss matrix as firstly divided into two smaller datasets according to the
set, it becomes more “costly” to misclassify cases from most discriminative splitting rule i.e. whether catalysts
show values for maxec_nffefmsmo (#15) higher or lower
than 153.1. Then, successive splitting conditions are used
Table 4. Loss matrix for the Classification tree analysis which in-
dicates the “costs” for misclassification of catalysts in the re- to generate nodes that are aimed at creating clusters which
spective classes. are clearly separated from each other. At the end of each
branch, the terminal nodes contain the results of the pre-
Loss matrix 1 2 3 4 5
dictions. For example, when all splitting conditions which
1-predicted 0 1 4 5 1 define the terminal node * are fulfilled, the prediction rate
2-predicted 3 0 1.2 5 3 is 84% with respect to cluster #1 whereas the initial proba-
3-predicted 1.1 1 0 1.5 1 bility of cluster #1 is 25% (node 1). The results of the ter-
4-predicted 1 1 1 0 1 minal nodes are gathered by cluster prediction and then
5-predicted 1 1.5 1.1 1.1 0
reported in the confusion matrix (Table 5) which shows
the prediction rates for all catalyst classes and for the
small clusters than from large clusters. In other words, us- learning and cross-validation datasets, respectively.
ing a loss matrix enables to improve the prediction rates Judging from the prediction performance, it is obvious
on smaller classes. This is desirable, because these small that the learning has proceeded rather well since the mod-
clusters contain the catalysts producing partial oxidation el can predict all five clusters satisfactorily, with an overall
products or hydrocarbons, which are more valuable prod- prediction rate of 0.68. In order to validate the model, a
ucts than CO2 and CO. The search for best combinations prediction test was carried out with independent catalysts
of misclassification costs was carried out by trial and error (one third of the dataset). Also here, the prediction rates
to obtain high prediction rates in all five classes. for each class are well above the distribution probabilities
The best classification tree yielded a model based on although the prediction performance is significantly inferi-
only 23 attributes, 33 split nodes, and 34 terminal nodes or with respect to the training set. In addition, also the
(leaves). Because the large size of the classification trees good prediction for the catalytic behavior #4 has to be
results in a complex scheme, a complete graph represent- pointed out. Indeed, the model allows us to predict, with a
ing the tree structure cannot be shown here. However, the confidence rate at around 40%, that a catalyst would be-
first nodes and a few leaves of a simpler model are depict- long to the class of partial oxidation catalysts. In contrast,

Figure 11. Schematic representation of the first nodes and leaves of the classification tree. The numbers in the boxes and the bars
represent the number of cases left in each class after application of the corresponding splitting rule.

QSAR Comb. Sci. 2005, 24  2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 89
Full Papers D. Farrusseng et al.

Table 5. Contingency table for the Classification tree analysis often is as important as the chemical composition with re-
which reports the predictions for the training and testing data- spect to the catalytic performance. Great care therefore
sets. has to be taken to capture the essentials of the synthetic
training 1 2 3 4 5 sum ratio pred. rate sensibility procedure.
In general, all solids have been synthesized in several
1 predicted 42 14 13 0 4 80 0.25 0.61 0.64
steps. However the number of steps is a matter of defini-
2 predicted 5 58 0 0 7 70 0.28 0.83 0.67
3 predicted 16 1 54 1 1 73 0.24 0.74 0.74 tion. For example, Cu/MCM-41 (MCM-41: mesoporous
4 predicted 6 5 5 10 1 27 0.04 0.37 0.91 silica as discovered by scientists of Mobil Oil Corporation
5 predicted 1 8 1 0 49 59 0.20 0.83 0.79 [20]) would intuitively be classified as a two-step reaction
sum/mean 77 86 73 11 62 309 0.68 0.75 (preparation of the support, which is not commercially
test 1 2 3 4 5 sum ratio pred. rate sensibility
available and has to be synthesized, and subsequent im-
pregnation), while Cu/SiO2 made by impregnation of a
1 predicted 18 7 14 0 7 46 0.25 0.39 0.45 commercial SiO2 support would normally be assumed to
2 predicted 6 19 10 1 9 45 0.27 0.42 0.44 be a one-step reaction. However, although the support
3 predicted 11 2 12 0 0 25 0.25 0.48 0.31
was bought from a supplier, its synthesis, for instance via
4 predicted 2 3 2 5 0 12 0.04 0.42 0.83
5 predicted 3 12 1 0 14 30 0.19 0.47 0.47 flame pyrolysis, should also be considered as a synthetic
sum/mean 40 43 39 6 30 158 0.44 0.50 step, resulting, altogether, in a two-step reaction. Consid-
ering an ion-exchange reaction, it is also a matter of defini-
tion whether each exchange step counts as a reaction step
or whether the whole exchange procedure is considered as
with random selection, one would only have a 4% chance a single step. This creates a problem in coding the syn-
of classifying such a catalyst. thesis procedure: the more steps that are defined and the
From the tree structure and splitting conditions, 34 rules more precisely each single step is described, the more en-
are derived yielding an explicit model. A prediction rule tries that are equal to zero and therefore without informa-
corresponds to the ensemble of splitting conditions from tion are obtained. This results from the fact that each cata-
the top node to a terminal node. The collection of all path- lyst has to be described with the same attributes in order
ways to each terminal node in text form results in a “rec- to allow meaningful correlation in the model-building
ipe” which enables us to predict straightforwardly the cat- step. For example, assuming that each catalyst should be
alytic behavior of a new catalyst, in contrast to ANN. As described by four synthesis steps and that each step con-
an example, some of the 34 rules are reported in Table 6. sists of 15 parameters (altogether 60 parameters), the en-
try for a catalyst synthesized in a single step (for instance
by precipitation) would contain at least 45 variables with-
4 Discussion out any information. Hence, the goal was to find a good
compromise between a precise description and a suffi-
In the course of the work on this project, several issues ciently simple coding, by either discarding or regrouping
were encountered which are important and which shall be information to avoid the above-mentioned problem. For
addressed in this section, together with the discussion of this study, it was decided to restrict the information only to
the results and the wider implications this work may have. the last synthetic step which was encoded by 19 different
categorical attributes: coding the type of the synthesis re-
action (such as ion-exchange or impregnation), solvents,
4.1 Synthesis Coding
precursors, and the presence of supports and additives,
Appropriate encoding of the synthesis procedure, even in such as chlorine, alkali metal, or others.
a simplified form, is a very difficult task, if one deals with In a more advanced stage of this technology and on a
solid catalysts. On the other hand, the synthesis protocol broader data basis of catalysts, one can – and should – cer-

Table 6. Example for rules that allow the prediction of the performance cluster into which a catalyst falls. Explanation of symbols:
see in Table 1. Both sets of rules predominantly sort catalysts into cluster #1.
Cluster 1 2 3 4 5 1 2 3 4 5
Terminal node 14 Terminal node 26
Cases 10 3 0 0 0 13 0 3 0 0
Rule 1 maxec_nffefmsmo 
153.1 maxec_nffefmsmo 
153.1
Rule 2 meanbc_bseo  185.3 meanbc_bseo  185.3
Rule 3 meanec_ea  0.75 meanec_ea > 0.75
Rule 4 meanbc_difie_l  0.09 meanec_difie_l > 0.11
Rule 5 sumec_minvhosie_os  7

90  2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim QSAR Comb. Sci. 2005, 24
Design of Discovery Libraries for Solids Based on QSAR Models

tainly encode the synthesis of the solids in more detail.

However, on the basis of less than 500 catalysts, this did
not seem to be appropriate.

4.2 Design of Relevant Descriptors

Software-based methods alone were not sufficient to re-
duce the more than 3000 attributes to the significant ones
that could be used to construct suitable descriptor vectors.
Chemical knowledge and intuition has thus been used to
design possibly useful elements of the descriptor vector.
This shall be illustrated for some examples: Two properties
were introduced to account for the stability of oxides and
their ability to change oxidation states. These properties
were assumed to be correlated to the availability of oxygen
atoms for an oxidation reaction, such as the propene oxi-
dation. A normalized formation free enthalpy of forma-
tion of element oxides has been introduced (calculation is
performed by dividing formation free enthalpy by the
number of metal atoms in the formula unit). The oxide
with the lowest value of all possible oxides in the catalyst
is referred to as the most stable oxide. Additionally, the
difference between the most stable oxide and the second-
most stable oxide has been taken into account. Consider-
ing another attribute based on element oxide characteris-
tics, the sum of all accessible oxidation states in oxides of
all elements in the catalyst was expected to correlate with
the reduction and oxidation properties of the catalyst. In-
Figure 12. Prediction rates for each cluster in comparison to
tuitively, one would expect that oxidation and reduction the statistical probability of a catalyst to belong to the cluster.
steps would be easier if many oxidation states are accessi- a) ANN of the MLP type based on 45 attributes. b) Decision
ble under ambient conditions tree C&RT based on 23 attributes

4.3 QPAR Models

The comparison of prediction performance based on the
whole dataset for ANN and Classification tree models is
shown in Figure 12. The prediction rates are compared to
the initial probability for a catalyst to belong to a given
cluster. The gap between the prediction rate and respec-
tive initial probability reveals how well the model can pre-
dict performance. From the bar chart it is obvious that
classification trees performed less well than ANN. On the
other hand, the simplicity/readability of Classification tree
models is a major advantage since much information can
be gained on the most relevant descriptors and guidelines,
as will be discussed in the following section. It should also
be pointed out that many more catalysts should be
screened to allow a fully reliable comparison between the
two modeling techniques, especially since a significant part
of the different datasets were reserved either for verifica-
tions or cross-validations.
When complex catalytic reactions are analyzed, such as
the partial oxidation of hydrocarbons, it is obvious that a
very limited number of catalyst types will have the desired
performance, compared to the infinite number of potential
candidates. From a statistical point of view, it follows that
the most interesting catalytic behavior corresponds to the
class that contains the smallest number of catalysts. This is
an issue for the modeling task, because the learning on
limited numbers of cases cannot be optimal, and because
the construction of the models is usually biased by the dis-
tribution of the classes, i.e., models tend to learn better on
larger classes than on smaller ones. For the latter problem,
the bias can be corrected by using cost-misclassification
systems that allow the learning on targeted classes to be
forced. The design of the cost matrix is not straightforward
and is usually carried out by trial-and-error processes.
4.4 Descriptor Vector
The goal of this study was the evaluation of a descriptor
vector that consists of relevant attributes. This descriptor
vector should allow the correlation of properties of solid
catalysts with the respective performance of the catalysts,
and would thereby enable the design of libraries suitable
for HT testing. On the other hand, however, from the in-
spection of classification rules or attributes selected for
the descriptor vector by ANN, one may learn more about

QSAR Comb. Sci. 2005, 24  2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 91
Full Papers
the decisive factors that influence the catalytic behavior of
solids in certain catalytic reactions.
For the different types of ANN that were tested in this
study, certain attributes were consistently selected as input
variables by many ANN. If one analyzes these attributes,
one can identify certain trends. Considering the attributes
related to properties of the elements, variables based on
the atomic radius (ar, #2, 3), the electron affinity (ea #8, 9,
10), the normalized formation free-enthalpy of the most
stable metal oxide (nffefmsmo, #14, 15), and the smallest
energy difference between the most stable metal oxide
and another metal oxide (sedmsmoom, #16, 17) seemed to
be of major importance. The number of elements in a cata-
lyst (nvec, #24) was also significant. When examining the
attributes related to the element oxides, only two attrib-
utes based on the melting point (mp, #31, 32) seemed to
have any significance. When analyzing the attributes relat-
ed to element ions, the ionic radius (ir), coordination num-
ber (cn, #35 – 38), and ionic covalent parameter (icp, #39 –
42) seemed to be the most important variables. The list of
synthesis attributes contains the highest number of attrib-
utes (eight) that were selected as input variables in all net-
works. This is reasonable from a chemical point of view, as
synthesis parameters refer directly to the experimentally
tested solid catalyst.
All types of analysis revealed that the stability of oxides
has a strong impact on the performance of catalysts in the
oxidation of propene. This is a result that chemical intu-
ition would also have given. However, in the framework of
this study this conclusion was discovered without addition-
al interference by a chemist, and one could therefore, with
some justification, say that the methodology used in the
framework of this investigation has implemented chemical
intuition on a basic level in a software program.
5 Conclusions
We have described the implementation of a methodology
that is the basis for a virtual screening of complex solids
with respect to their catalytic properties. These solids are
generated at random from available elements via a set of
different synthetic procedures. Screening in-silico then al-
lows one to identify those samples which should be experi-
mentally investigated. Since the coding is set up in a man-
ner that corresponds relatively closely to a synthetic proce-
dure, there is a high probability that the suggested samples
can indeed be synthesized.
This approach could be very valuable, especially in reac-
tions where no good lead is available as yet, since for such
reaction thousands of samples may have to be tested be-
fore some activity is discovered at all. Prescreening to re-
duce the number of tests to be performed is therefore al-
most mandatory. Moreover, if descriptors with high pre-
dictive power are discovered, one may be able to extract
92  2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
D. Farrusseng et al.
information on the relevant properties that a catalyst
should have for a specific reaction.
At this point it is not clear just how general descriptor
vectors for catalytic reactions will be, i.e., whether a de-
scriptor for propene oxidation catalysts, such as developed
in this study, will also be valid for other alkenes or even
for hydrocarbon oxidation reactions. The establishment of
a much broader database is necessary to verify and further
develop the descriptor concepts for catalysts. It is expected
that there will be an intimate interplay between the refine-
ment of descriptors and the testing of new solids in catalyt-
ic reactions. The broader the experimental database be-
comes, the more discriminative will be the descriptors de-
veloped on this basis, which in turn allows more focused
catalytic testing.
In addition, the concept seems to be more broadly appli-
cable. Any field in which the correlation between proper-
ties of solids and performance in a given application is
complex and development is, to a large extent, empirically
governed, may benefit from the possibility of virtual
screening as the first stage of a high-throughput program.
It will be interesting to see how fast these methods will
find their way into the laboratories active in this field.
Acknowledgements
We thank the Marie Curie Fellowship Association and re-
gion Rhône-Alpes (Programme EuroDoc) for having sup-
ported the students mobility and training. In addition, we
would like to thank the Leibniz program of the DFG and
the FCI who provided funding in addition to the basic
funding by the Max-Planck-Gesellschaft and the CNRS.
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