The Role of the Frontier Orbitals

in Acid–Base Chemistry of Organic

Amines Probed by Ab Initio and
Chemometric Techniques
FELIPE A. LA PORTA, REGIS T. SANTIAGO,
TEODORICO C. RAMALHO, MATHEUS P. FREITAS,
ELAINE F. F. DA CUNHA
Department of Chemistry, Federal University of Lavras, Campus Universitário, CP 3037,
37200-000 Lavras-MG, Brazil

Received 23 October 2009; accepted 15 February 2010

Published online 21 April 2010 in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/qua.22676

ABSTRACT: The Frontier effective-for-reaction molecular orbital (FERMO) concept

emerges as a powerful and innovative implement to investigate the role of molecular
orbitals (MOs) applied in the description of breakage and formation of chemical bonds.
In this work, theoretical calculations were carried out for conjugated acids of 18 amines
and their acid–base behavior was analyzed using MO energies. We observed that
highest occupied MO (HOMO) energies are inadequate to describe the acid–base
behavior of these compounds. By using the FERMO concept, the reactions that are
driven by HOMO, and those that are not, can be better explained, independent of the
calculation method used, as independent of the calculation method used, both HF and
Kohn–Sham methodologies lead to the same FERMO. V C 2010 Wiley Periodicals, Inc. Int J

Quantum Chem 110: 2015–2023, 2010

Key words: FERMO; amines; pKb; molecular orbital

molecules. Consequently, a precise knowledge

1. Introduction about the acidity and basicity of organic com-
pounds in various solvents is fundamental for the

P roton transfer is one of the most important

processes in the transformations of organic
Correspondence to: T. C. Ramalho; e-mail: teo@dqi.ufla.br
Contract grant sponsors: FAPEMIG, CNPq.
Additional supporting information may be found in the online
version of this article.
study of mechanistic organic chemistry [1, 2].
Among the several compound classes, amines
play an important role in organic chemistry.
Amines are relatively weak bases, one of the most
common organic bases [2], their biological impor-
tance is undeniable, because of their appearance

International Journal of Quantum Chemistry, Vol. 110, 2015–2023 (2010)

V
C 2010 Wiley Periodicals, Inc.
LA PORTA ET AL.
in many substances. Another usual way is to clas-
sify them as aliphatic, aromatic, and heterocyclic
amines. A basic strength of amines may be con-
veniently provided by means of the basicity con-
stants (pKb) of their acid conjugates [3]. Evidently,
basicity is one of the important factors to tune the
reactivity of such transformations. The basicity of
these compounds is related to the lone pair avail-
ability [2].
Molecular orbitals (MOs) and their properties,
such as energies and symmetries, are very useful
for chemists. According to Fukui, the MO proper-
ties have used the Frontier electron density for
predicting the most reactive position in p-electron
systems. Hoffmann and Woodward set out orbital
symmetry rules to explain several types of reac-
tions in conjugated systems, and the Frontier
MOs gained importance for the better under-
standing of chemical reactions. The concept of
Frontier orbital, introduced by Fukui around
1952, relates reactivity with the properties of two
MOs: highest occupied MO (HOMO) and lowest
unoccupied MO (LUMO). One application of the
HOMO–LUMO argument is the description of the
acid–base behavior of compounds [4–7].
The calculation of gas-phase acid–base parame-
ters is a well-established methodology. However,
the theoretical calculation of acid–base parame-
ters, especially in solution, is a great challenge for
quantum chemists [8]. Turning to gas phase, the
proton affinity (PA) is the most useful acid–base
parameter and many works have shown how PA
values correlate with quantum descriptors [9–13].
The PA of a molecule is a measure of its gas-phase
basicity. Thus, the higher the PA, the stronger the
base and the weaker the conjugate acid in the gas
phase. In other words, proton affinities illustrate
the role of hydration in aqueous-phase Brønsted
acidity. Consequently, all acid–base reactions
involve proton transfers between combined pairs.
Some studies in the literature show that the
energy of HOMO is directly related to the acid–
base behavior of some compounds. However,
HOMO is not the effective Frontier MO at least
for many compounds; in these cases, the energy
of HOMO does not describe correctly the acid–
base behavior [4, 14, 15].
Thus, given the limitations of HOMO–LUMO
argument and the new approaches proposed in
the literature to understand the chemical reactiv-
ity, one must move forward the role of MOs in
chemistry, giving rise to a new idea: the Frontier
effective-for-reaction MO (FERMO) [9, 16–25].
2016 INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY
The FERMO concept comes from a dose of
intuition, together with the criteria for the compo-
sition and location to correctly determine the reac-
tant MO. This concept can be understood as a
complement to the HOMO–LUMO argument.
Another important feature in FERMO is that both
HF and Kohn–Sham orbitals make the same con-
clusions about reactivity [21–24]. A careful study
is necessary to understand when the use of
HOMO energy works or not. Moreover, there is a
lack of studies concerning the most common and
important base compounds in organic chemistry,
the amines, and the relationship of their acid–
base behavior with their MO energies. For this
reason, our primary goal in this work was to
investigate, which is the best MO for describing
the acid or base character for a set of 18 amines.
Additionally, this work aims to apply the FERMO
concept to describe the acid–base behavior (pKb)
of a series of amines.
2. Computational Methods
In recent years, theoretical methods based on
the density functional theory (DFT) have emerged
as an alternative to traditional ab initio methods
in the study of structure and reactivity of chemi-
cal systems [26, 27]. All calculations were carried
out with the Gaussian 98 package [28]. Each con-
jugated base of all 18 compounds was fully opti-
mized by using DFT with the B3LYP functional
[29, 30] using the 6-31G(d,p) basis set. No sym-
metry constraint was imposed during the opti-
mization process. Those optimized geometries
were used in all subsequent calculations. This
theoretical level was also used for the frequency
calculations. Furthermore, ab initio HF energy
calculations were computed using the 6-31G(d,p)
basis set.
To account for solvent effects (water), single-
point energy calculations were performed using
the polarizable continuum model [31, 32] at both
the DFT, with the B3LYP functional, and MP2 lev-
els, using the 6-31G basis set.
The orbital energies obtained from these calcu-
lations were fit to a linear model with experimen-
tal pKb values and the determination coefficients
(r2) were analyzed. The MO figures were pre-
pared using the Gauss View 2.1 package [28] with
a contour value of 0.020.
DOI 10.1002/qua VOL. 110, NO. 11
 ROLE OF THE FRONTIER ORBITALS

TABLE I
Organic amines and their pKb values.

Class Compound Amines pKb Ref.

Aromatic 1 Aniline 9.13 33

2 Benzylamine 4.66 33
3 2-methylaniline 9.55 33
4 3-methylamine 9.29 33
5 4-methylaniline 8.92 33
6 N-methylamine 9.15 33
Heterocyclic 7 2-ethylpyridine 8.11 33
8 2,3-dimethylpyridine 7.43 33
9 2,4-dimethylpyridine 7.01 33
10 2,5-dimethylpyridine 7.60 33
11 2,6-dimethylpyridine 6.65 33
12 3,4-dimethylpyridine 7.54 33
13 3,5-dimethylpyridine 7.85 33
Aliphatic 14 Ethylamine 3.35 34
15 Diethylamine 3.16 34
16 Triethylamine 3.25 34
17 Isobutylamine 3.52 34
18 tert-butylamine 3.30 34

lengths, have to be included in multiple linear

3. Results and Discussion
3.1. HOMO AND CHEMICAL REACTIVITY
Eighteen compounds, classified as aromatic
(1–6), heterocyclic (7–13), and aliphatic (14–18)
amines, were used in this study, and their experi-
mental pKb values in water are depicted in Table I.
Theoretical calculations of acid–base parame-
ters, especially in solution, are a great challenge
for quantum chemists. Then, preliminary to deter-
mining the solution-phase pKb of an amine, it is
important to estimate its gas-phase basicity. These
results may be used to evaluate the solvent effect
on basicity parameters using theoretical calcula-
tions of orbital energies.
Numerous works have shown how well pKb
values correlate with quantum descriptors; the
average local ionization potential [35, 36], atomic
charges and interatomic distances [14, 37], and
the HOMO energy [10, 13, 15] are the most com-
mon quantum descriptors used.
The relationships between HOMO energies and
pKa/pKb are often displayed for families of
compounds, such as phenols [14] and azines [15].
However, for a number of other compounds,
HOMO energies do not show good correlation
with acid/base parameter values, and other quan-
tum parameters, such as dipole moments, bond
orders, atomic charges on hydrogen, and bond
regression analysis to improve the correlation [10–
15]. This procedure weakens the familiar idea that
donor-acceptor reactions are driven by Frontier
orbital energies.
In line with this, this study is intended to res-
cue the role of the Frontier orbitals in acid–base
chemistry of organic amines. Thus, the HOMO
energy values were correlated with the corre-
sponding amine pKb values. From the relation-
ships, we can observe that different amine classes
(aromatic, heterocyclic, and aliphatic) provided
different linear models [r2 ¼ 0.918 (aromatic);
0.099 (heterocyclic); 0.4538 (aliphatic)]. Heterocy-
clic amines exhibited higher deviations from the
ideal linear model and a very poor linear model
between HOMO and pKb values.
With those correlations, it was not possible to
distinguish, which is the best orbital to describe
the acid/base chemical reaction. In addition, from
these data, two questions appear: (1) Can the
amine groups be correlated together? and (2)
Would HOMO be the best orbital to describe the
reaction? To find the answer for these questions,
we have used a new chemically intuitive FERMO
concept to describe the acid/base behavior [21–
25]. It has been shown elsewhere that the FERMO
idea may be an alternative way to explain chemi-
cal phenomena when HOMO–LUMO arguments
fail or cannot be applied.

VOL. 110, NO. 11 DOI 10.1002/qua INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY 2017
LA PORTA ET AL.
FIGURE 1. Representation of the Frontier molecular orbital of amines 1, 13, and 14. [Color figure can be viewed in
the online issue, which is available at www.interscience.wiley.com.]
Thus, based on the FERMO idea, we expanded
the correlations to other Frontier orbitals, namely
HOMO-1, HOMO-2, and HOMO-3 (see Fig. 1).
Furthermore, using the FERMO concept, MO
composition and shape are taken into account to
identify the MO, which will actually be involved
in a given reaction.
On the basis of the orbital composition and
localization, it is possible to get insights about the
orbital that mainly governs the acid/base reac-
tion. The orbital composition is also an important
indicator for discovering the adequate orbital [21,
22]. The MO shape and the atomic composition
are very important parameters for analyzing
FERMO [23, 24]. The percentage of nitrogen char-
acter in some of the occupied (canonical) MOs in
the studied compounds was calculated from a full
population analysis, using Eq. (1):
P 2
/
% nitrogen character ¼ P 2N (1)
/all
2018 INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY
PN 2
where i¼1 /i (i ¼ N or all) is the sum of the
squares of the eigenvalues associated with the
nitrogen atomic orbital (AO) and all of the AOs in
a particular MO, respectively. This calculation
was performed on each of the seven HOMOs that
had significant nitrogen character and these val-
ues were then average.
When the solvent effects are considered, the
MO energy positions relative to the one observed
in the vacuum are interchanged (see Supporting
Information for complete results). This is also
observed when different basis sets are used. On
the other hand, the solvent effects were neglected
in other works correlating MO energies with
acid/base parameters values [10, 14]. That
approximation seems valid for some aromatic sys-
tems previously studied (anilines [10], phenols
[12], and azines [15]), in which sizes and geome-
tries do not vary strongly. For these reasons, the
entropy term may be roughly the same along
each of these compound families and the solvent
effects will also be considered.
DOI 10.1002/qua VOL. 110, NO. 11
 ROLE OF THE FRONTIER ORBITALS

TABLE II LUMOþn (n ¼ 0–4) were taken from the HF calcu-

Nitrogen contribution (%) and orbital energy for lations and matrixed as m rows (amines) by n col-
studied amines using Hartree–Fock approach. umns (energy of the Frontier MOs).
PCA [38] creates p latent variables (Y) as linear
Compound Contribution (%) Fermo (Hartree)
combinations of the original p variables (X), in
1 39.24
0.44053 such a way that new orthogonal axes are built to
2 6.69
0.39392 explain the maximum variance possible in just a
3 37.20
0.43862 few dimensions [Eq. (2)].
4 38.53
0.43220
5 38.35
0.43011 Y i ¼ ei T X (2)
6 44.80
0.41761
7 74.85
0.40465 where the unknown vector ei establishes the ith
8 73.81
0.40178 linear combination, for i ¼ 1,…,p.
9 75.94
0.40249 The PCA allowed clustering the three amine
10 74.05
0.40190 types, namely aliphatic, aromatic, and heterocyclic
11 74.75
0.40028
amines, by using the two first principal compo-
12 73.76
0.40415
13 73.62
0.40313
nents (PC1 and PC2). Compound 2, an aliphatic
14 7.50
0.38174 amine containing an aromatic ring, did not fit in
15 86.49
0.36192 any other group. PC1 was capable of separating
16 88.44
0.34371 aliphatic amines from the aromatic ring-contain-
17 83.44
0.38340 ing amines, whereas PC2 differentiated the heter-
18 80.11
0.37651 ocyclic amines from the aromatic ones [Fig. 2(a)].
This may be rationalized in terms of the higher
energy of the nonresonant lone pair contribution
Upon analyzing orbital localization and compo-
of nitrogen in aliphatic amines to the HOMO-type
sition more deeply, it can be observed that there
orbitals, and to the lower energies of the LUMO-
is a MO with energy quite close to the HOMO
type orbitals in the aromatic compounds (p* con-
energy value and with large nitrogen contribution
tribution). From the loadings analysis, the four
(Table II). Thus, it is supposed that this orbital
MOs contributing importantly for the groups sep-
could describe the acid/base behavior better than
aration in PC1 were HOMO
1 > LUMOþ1 >
HOMO. Moreover, it also does not fit our orbital
LUMO > HOMO, whereas HOMO
2 exhibited
choice criterion, because it is not common to all
high weight for the separation of heterocyclic
studied compounds and is not mainly located
amines in PC2 [Fig. 2(b)]. The energies of the five
where the reaction takes place, in the nitrogen
most weighted orbitals in PC1 and PC2 were
atom. The HOMO problem arises from the influ-
regressed against the pKb values using multiple
ence of the aromatic p-electrons, and the solution
linear and PLS regressions. The best PLS model
would be finding an MO that does not have this
was found using two latent variables, which
influence. From this point of view, other concepts
explain 96% of data variance, and the calibration
of chemical reactivity could be useful to under-
squared correlation coefficient (r2) was 0.814 (root
stand reactions that were not driven by HOMO–
mean square error of calibration, RMSEC ¼ 1.009),
LUMO properties.
with a leave-one-out cross-validation squared cor-
relation coefficient (q2) of 0.799 (root mean square
3.2. FRONTIERS ORBITAL AND error of validation, RMSEV ¼ 1.05); r2 and q2 are
CHEMOMETRIC TECHNIQUES
improved to 0.877 (RMSEC ¼ 0.826) and 0.954
To understand the reactivity of amines and es- (RMSEV ¼ 0.504) after removing compound 2, an
tablish a relationship with MOs, the amine sets, outlier. The MLR model for the whole series of
namely those aliphatic, aromatic, and heterocyclic, compounds was highly predictive, with an r2 of
were classified according to their Frontier MOs, 0.926 and the following MLR equation [Eq. (3)]:
which were subsequently correlated with the cor-
responding pKb values. In addition, principal com- pKb ¼12:83
34:67  EHOMO
2
4:01  EHOMO
1
ponent analysis (PCA) and partial least squares
þ 44:54  EHOMO
57:74  ELUMO
(PLS) were used as explorative and regression
tools, respectively. The energies of HOMO
n and þ 6:53 LUMOþ1 ð3Þ

VOL. 110, NO. 11 DOI 10.1002/qua INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY 2019
LA PORTA ET AL.

FIGURE 2. (a) Scores in PC1 and PC2. (b) Loadings in PC1 and PC2.

From the Lewis definition of acid–base reactions,
which is a further generalization that encom-
passes the Brønsted–Lowry definition and the sol-
vent-system definitions [2]. The Lewis defines a
base (referred to as a Lewis base) to be a com-
pound that can donate an electron pair, and an
acid (a Lewis acid) to be a compound that can
receive this electron pair [2]. So, the basicity is
mainly related to occupied MOs in accordance
with the chemical intuition.
In this point, it is important to mention that the
HOMO
2 and HOMO exhibited higher weight in
the correlation with pKb for occupided MOs. In
line with this, we can then notice that the contri-
butions from the HOMO
2 and HOMO might
determine the acid–base chemistry of organic
amines.
The MLR model may be simplified by remov-
ing collinear descriptors, that is, those MOs with
highly correlated energies (Table III). In this way,
only HOMO
1 and LUMOþ1 were selected to
derive the MLR-based model. The MLR squared
correlation coefficient using HOMO
1 and
LUMOþ1 as independent variables was 0.783,
and the following model was obtained [Eq. (4)]:
pKb ¼ 20:81 þ 34:87  EHOMO
1
5:61  ELUMOþ1
(4)
Despite the nice correlation obtained using both
regression methods PLS and MLR (see Fig. 3).
The MLR model is based on contributions of
some MOs apparently not related to basicity,
according to the chemical intuition (e.g., as is the
nitrogen lone pair), making physicochemical inter-
pretation difficult; simple and strongly correlative
models may be derived by using the FERMO con-
cept and chemometric techniques, which are

TABLE III
Correlation matrix of selected orbital energies (r2 depicted).

HOMO
4 HOMO
3 HOMO
2 HOMO
1 HOMO LUMO LUMOþ1 LUMOþ2 LUMOþ3 LUMOþ4

HOMO
4 1.000
HOMO
3 0.476 1.000
HOMO
2 0.329 0.022 1.000
HOMO
1 0.300 0.086 0.501 1.000
HOMO 0.309 0.070 0.253 0.839 1.000
LUMO 0.132 0.002 0.783 0.692 0.434 1.000
LUMOþ1 0.232 0.003 0.846 0.748 0.493 0.966 1.000
LUMOþ2 0.343 0.050 0.490 0.869 0.824 0.629 0.711 1.000
LUMOþ3 0.449 0.073 0.584 0.865 0.824 0.648 0.750 0.943 1.000
LUMOþ4 0.416 0.097 0.582 0.872 0.806 0.661 0.736 0.870 0.865 1.000

2020 INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY DOI 10.1002/qua VOL. 110, NO. 11

FIGURE 3. MLR and PLS modeling of pKb using HOMO
2, HOMO
1, HOMO, LUMO, and LUMOþ1 energies.
referred to as those MOs with higher contribution
of nitrogen AOs (intuitively related to the amines
basicity).
Thus, motivated by this expectation, a closer
examination in Table III reveals that HOMO
2
and HOMO are MOs with highly correlated ener-
gies. This means that HOMO
2 and HOMO
could, in principle, have similar properties, such
as symmetry and ionization potential. In addition,
it is certainly worth noticing those orbitals also
show a high nitrogen contribution.
Furthermore, it is important to note that the
FERMO concept leads to same conclusions about
chemical reactivity for both HF and Kohn–Sham
approaches [21–24]. Nowadays, it is well-known
that the Kohn–Sham DFT is a leading method for
electronic structure calculations in chemistry
mainly due to its high efficiency and relatively
low computational cost [19, 33].
Nevertheless, despite the recent improvements
in DFT, there are still difficulties in using DFT to
properly describe intermolecular interactions, espe-
cially van der Waals forces (dispersion) and charge
transfer excitations due to lack of exact Hartree–
Fock exchange in some functionals [39–42].
Currently, the development of new DFT meth-
ods designed to overcome this problem, by altera-
tions to the functional or by the inclusion of addi-
tive terms is a very important research topic.
Particularly, the hybrid functionals, such as the
B3LYP functional used in this work, yields unsatis-
factory atomization energies [39–41]. For instance,
for metals, the error is almost larger than 25%,
and for transition and noble metals, it may
increase to 40%.[39, 40] Probably, a larger fraction
of the error is related to the LYP correlation func-
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ROLE OF THE FRONTIER ORBITALS
tional, because the LYP correlation functional sig-
nificantly underestimates the correlation energy of
the homogeneous electron gas [39].
On the other hand, for large gap systems, with
well-localized electrons, the agreement with
experiment and conventional functionals is rea-
sonable [39, 43]. In line with that our theoretical
results using B3LYP combined with the FERMO
concept could be justified. In these cases, the re-
spective errors for the constituents of the reaction
cancel, as electrons are localized for all reactants
and the product [21–25].
3.3. FERMO AND STATISTICAL
CORRELATIONS
A molecule can have as many FERMOs as it
has reaction sites, and it could be the HOMO or
any other Frontier MO [22]. Reactions involving
electron donation and acceptance are related to
MO energies, as electrons are occupying and will
occupy a MO and a Frontier orbital, as stated by
Fukui [4–6]. A criterion has been established in
this study to determine the FERMO. In this con-
cept, FERMO provides the adequate orbital shape
and composition to correlate with reactive indexes.
The FERMO for aromatic and aliphatic amines
is the HOMO, whereas HOMO
2 is the invoked
FERMO for heterocyclic amines. Thus, when
HOMO fails in describing the reactivity parame-
ter, another Frontier MO would be responsible for
the phenomenon. Using this modification, the cor-
relation between the orbital energies and pKb val-
ues for the heterocyclic amines enhanced from
0.099 to 0.631. Based on the MO location and
composition, the FERMOs shown in Figure 4
LA PORTA ET AL.
FIGURE 4. Surface plots for FERMO at the HF level
for the aromatic (A), heterocyclic (B), and aliphatic (C)
amines. [Color figure can be viewed in the online issue,
which is available at www.interscience.wiley.com.]
could be found for the aromatic (A), heterocyclic
(B), and aliphatic (C) amines.
From Figure 1, it is clear that the HOMO is
formed mainly by the AO in the ‘Z’ axis of the
nitrogen, whereas the FERMO has a high contri-
bution of the AO of nitrogen in the ‘XY’ plan
(plan of the aromatic ring) of the amine group.
A direct consequence of the different composi-
tions of these orbitals is the position of their node
plains in relation to the plan formed by nitrogen
atom. Thus, the statistical results from chemomet-
ric methods reinforce our rationalization: FERMO
could in principle be the orbital to better describe
the acid–base chemistry of organic amines.
The previous results take us to a key question:
why are FERMO energies better quantum descrip-
tors for pKb values than HOMO energies? The an-
swer to this question resides in the shape of those
MOs. It is well known that organic amine moi-
eties from these bases have a specific geometry
[1–7] because of the lone pair distribution. We
should keep in mind that acid/base reactions are
localized and the basicity of these compounds is
related to the lone pair availability [2].
Upon analyzing the localization and the com-
position of the orbitals more deeply, it can be
observed that there is an MO with energy quite
close to the HOMO energy value, with highly cor-
related energies (Table III), and with large nitro-
gen contribution (Table II).
It is well known that in the MO theory, the
electrons in a molecule are in the delocalized orbi-
tals generated from linear combination of AOs.
Nevertheless, sometimes these delocalized orbitals
are quite diffuse leading to a difficult rationaliza-
tion of the chemical reactivity. In contrast, some
chemical reactions, such as acid–base reaction, take
2022 INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY
place in specific regions of the molecule. Therefore,
currently, the need for inexpensive computational
techniques capable of reliably contributing to the
prediction of the chemical reactivity based on
chemical intuition is emerging. We believe that the
FERMO idea could, in combination with other
approaches, offer contributions in this sense.
Thus, we may notice that the FERMO idea is to
use the MO calculations with a valence bond
theory (VB) interpretation. In MO theory, the elec-
trons in a molecule occupy delocalized orbitals
made from linear combination of AOs. However,
it should be kept in mind that the VB approaches
are quite useful in analyzing enzymatic reactivity
[44, 45], photochemistry [46–45], chemical dynam-
ics [46], and theories of conductivity, where the
localized representation seemed indispensable.
In fact, it is well known that the VB methods
allow generating new ideas on chemical bonding.
Recently, there has been an intense surge of con-
cepts related to localized representation, for exam-
ple, multiple bonding between transition metals
[50, 51] and the development of natural resonance
theory [52].
4. Conclusions
Overall, the FERMO concept has been success-
fully applied to describe the acid–base behavior
of the series of amines studied, presenting better
correlation with pKb than HOMO. Thus, the
FERMO concept may be useful to explain acid–
base reactions in a wide range of applications.
Amine types were clustered using PCA and the
more weighted MOs were accurately regressed
against the pKb values using MLR and PLS, dem-
onstrating that different MOs other than HOMO
may be applied to explain the basicity-based reac-
tions of amines. Nevertheless, it is the FERMO
concept (the shape of the reactant orbital) that
really provided chemical insight about which is
the MO related to acid–base reactions. It should
be kept in mind that understanding the behavior
of the MO is crucial to understanding the chemis-
try. Therefore, these investigations lead to new
perspectives and ideas about the reactivity, and
may be expanded to solve other problems. For
example, the principle of hardness and enervation
of Pearson may invoke the FERMO concept. The
hardness of a molecule is defined as the differ-
ence in energy between HOMO and LUMO; thus,
DOI 10.1002/qua VOL. 110, NO. 11

according to that definition, only a single value of
hardness would exist for a given molecule. But as
we know, many molecules have soft and hard
sites and the HOMO–LUMO energy difference is
not enough to describe this type of behavior. Our
results clearly reveal the fundamental relation-
ships between the nature of chemical bonding
and the acid–base chemistry of organic amines.
ACKNOWLEDGMENT
We thank the Brazilian agency FAPEMIG,
CNPq for funding part of this work. CNPq is also
gratefully acknowledged for the fellowships (to TCR
and MPF) and CENAPAD-SP for the computational
facilities.
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