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Studies of regioselectivity of large molecular

systems using DFT based reactivity descriptors
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Ram Kinkar Roy* and Soumen Saha

DOI: 10.1039/b811052m

This report describes the recent works on Conceptual Density Functional

Theory (DFT) based reactivity descriptors used to predict the regioselectivity
of large systems, biomolecular systems, in particular. The challenges of
bio-systems, the large number of atoms and high structural flexibility, made
the way to a routine application of DFT more laborious. To cope with
extended systems, fragmentation based method is developed recently (given
the name ‘One-into-Many’ model) for a reliable determination of the
regioselectivity of biomolecular systems. Thus, our main motivation to
embark on the endeavor of this report is to provide a brief introduction of
Conceptual DFT and fragmentation approaches based on these reactivity
descriptors for predicting the regioselectivity of large biomolecular systems.

1. Introduction
An important chemical concept prevalent in chemistry (organic chemistry, in
particular) is regioselectivity. Regioselectivity1,2 is defined as the preference of a
chemical bond making or breaking in one direction over all other possible ones.
Understanding the regioselectivity of a reaction between two chemical species is
crucial not only for predicting the corresponding reaction mechanism but also for
designing desired products. Last few decades several electronic parameters, viz,
Frontier Molecular Orbital (FMO),3–6 Electron Localized Function (ELF),7,8
Molecular electrostatic Potential (MEP)9–17 etc., were proposed and extensively
used to explain the regioselectivity of a wide variety of reactions. Similarly, empirical
principles, such as the hard and soft acids and bases (HSAB),18–22 Electronegativity
equalization method (EEM),23–28 etc. have been developed to rationalize chemical
behaviours. However, most of these principles remained empirical until a branch of
density functional theory (DFT),29–41 called ‘‘Conceptual DFT’’ or ‘‘Chemical
Reactivity Theory’’, has been initiated by its protagonist, R. G. Parr. Based on
the idea that the electron density is the fundamental quantity for describing atomic
and molecular ground states, Parr and co-workers, and later on a large community
of theoretical chemists provided the theoretical basis to formal definitions of
empirical concepts.42–52 Conceptual DFT was even successful to propose a new
quantitative principle, the ‘principle of maximum hardness’ (PMH),53–64 which can
predict the most stable state of a chemical species.
Although, DFT provided a sound basis for the development of computational
strategies for obtaining information about molecules at much lower cost than the
conventional ab initio65 wave function techniques, these methods are still not

Department of Chemistry, Birla Institute of Technology and Science, Pilani-333031, Rajasthan,

India. E-mail: rkroy2@rediffmail.com

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routinely feasible for large systems such as biological molecules and molecular systems
with hundreds or thousands of atoms, due to the steep increase of their computational
cost with increasing molecular size. To extend quantum chemical calculations or DFT
calculations to macromolecules, theoretical chemists have come up with a variety of
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approaches, which allow HF, DFT or post-HF calculations to achieve linear scaling.
Linear-scaling methods are primarily based on the principle of quantum locality66 or
‘‘near-sighted-ness’’,67 that the properties of a certain observation region of only one
or a few atoms are only weakly influenced by factors that are spatially far away from
this observation region. This can be achieved by limiting to a local region of space the
physical span of the electronic degrees of freedom.46 Careful consideration of such
underlying physics and improved mathematical methods have led to linear scaling in,
inter alia, the calculations of the Coulomb68–74 and exchange75,76 integrals, and in
alternative approaches to the direct diagonalization of the Fock matrix.77–85 These
rigorous algorithms treat the molecule as a whole, being ‘‘black-box’’. Nevertheless,
these algorithms begin to exhibit linear scaling only for quite large molecules, say, with
several hundreds of atoms.
In addition to this category of linear-scaling algorithms that are aimed to
calculate the whole system at once, there also exists a category of fragment-based
approaches86–113 which are capable of reproducing ab initio HF or post-HF results of
large molecules quite accurately but with much lower computational costs. The basic
idea shared by the fragment-based approaches is to divide a large molecule into a series
of fragments (rather than treating the whole system at once), and then obtain the energy
or molecular properties of this molecule from conventional quantum chemical calcula-
tions on a series of subsystems, each of which is constructed by connecting a fragment
with its local surroundings. These methods not only offer a very considerable reduction
of the computational costs but also allude to the chemical building blocks in larger
systems, such as residues taken as fragments, and provide details of the interaction and
other properties of these fragments-in-molecules. Furthermore, molecular fragmenta-
tion approaches are of two main types. One is the density matrix-based fragmentation
approach,86,87,90,92,95,97,100,105,108 in which the density matrix of the target molecule is
obtained by assembling the density matrices or localized molecular orbitals from
various subsystems, and then this density matrix is employed to calculate the total
energy or some properties of the target molecule. Another type can be named as the
energy-based fragmentation (EBF) approach.91,93,96,99,101,102,104 In this approach, the
total energy of a molecule is approximately estimated as linear combinations of
the energies of its various subsystems, like, energy or heat of formation of a molecule
can be approximated as a sum of bond energies or enthalpies. In comparison with
those density matrix-based approaches, energy-based approaches have one main
advantage. Within energy-based approaches, the energy derivatives or other molecular
properties of the target system can be computed as combinations of the corresponding
quantities from various subsystems while no such simple algorithms exist within
density matrix-based approaches.93,96,98,109
However, for predicting the regioselectivity of large molecular systems, a simple
fragment-based approach, named as ‘‘One-into-Many’’ model, was proposed by
us.114,115 In this model a large system is proposed to be broken into different smaller
fragments and in that way an intra-molecular problem of a large system can be
re-casted into an inter-molecular problem of individual fragments, thus helping the
prediction of regioselectivity of the large system.
In this report, we will present some advancement achieved in last few years to
predict the regioselectivity of the large bio-molecular systems using Conceptual DFT

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(or chemical reactivity theory) based reactivity descriptors with some review of its
basic aspects. We would like to highlight how an intra-molecular problem of a large
system can be re-casted into an inter-molecular problem of individual fragments.
The limitations of the present approach in predicting the regioselectivity of target
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systems (e.g., large chemical and biological molecules) as well as likely developments
over the next few years will also be discussed. In the first part of our presentation, the
Conceptual DFT is described briefly, which provides the theoretical foundations of
different reactivity descriptors. The second part takes care of more recent develop-
ments enabling evaluations of the regioselectivity for a number of large biological
systems using these reactivity descriptors. Finally, in the last part of our presentation
we have summarized the whole report.

2. Theoretical background
A Foundations
In 1964, Pierre Hohenberg and Walter Kohn29 proved that for molecules with a
nondegenerate ground state, the ground state molecular energy, wave function and
all other molecular electronic properties are uniquely determined by the ground state
electron density r(x,y,z). One says that the ground state electronic energy E is a
functional of r and writes

E = E [ r] (1)

where the square brackets denote a functional relation. Density Functional Theory
(DFT) attempts to calculate E and other ground state molecular properties from the
ground state electron density, r.
The total electronic energy is given by116
R
E [ r] = F [ r] + v(r)r(
r)d
r (2)

where the functional F [ r], so-called Hohenberg-Kohn functional,29 is the sum of the
kinetic energy functional T [ r] and the electron–electron repulsion energy functional
Vee[ r]; v(r) is the external potential (i.e., the potential acting on an electron at
position r due to the presence of nuclei plus any other external field, if present). To
turn from a formal relation to a practical tool, we need a second theorem also proved
by Hohenberg and Kohn,29 and a practical approach of it’s evaluation was
developed by Kohn and Sham.30 In this second theorem, a variational principle is
formulated, stating that the ground state density is that density that minimizes the
energy of the system for a fixed number of electrons
R
d(E [ r]  m r(r)d
r) = 0 (3)
R
where m is a Lagrange multiplier arising from normalization constant r( r)d
r = N;
here, N is the total number of electrons in the ground state of the system. Otherwise
dF
m ¼ vðrÞ þ ¼ constant ð4Þ
rÞ
drð
Kohn and Sham rewrote eqn (4) as an orbital equation having the form30
 Z 
1 rðr0 Þ 0
 r2 þ vðrÞ þ vxc ðrÞ þ 0
r ci ¼ ei ci
d ð5Þ
2 jr  r j

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where vxc(
r) is the exchange-correlation potential, the functional derivative of the
exchange-correlation energy functional Exc, i.e.,
dExc
vxc ðrÞ ¼ ð6Þ
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drðrÞ

In eqn (5), ci’s are the Kohn-Sham orbitals, the squares of which must sum up to the
total electron density of the system
X
rðrÞ ¼ jci j2 ð7Þ
i

In recent years, many accurate forms of the exchange correlation functional were
derived.117–120 However, a great strength of the density functional language is its
appropriateness for defining and elucidating important universal concepts of molecular
structure and molecular reactivity. It has become clear in recent years that there is also
a very important ‘‘noncomputational’’ or conceptual side to DFT.43,45,46,49,51 In this
aspect of the theory, the central quantities are the so-called response functions.44,47,50,52
As such, they are reactivity descriptors (or reactivity indicators) for the molecule under
consideration: these terms measure the response of the chemical system to perturba-
tions in its number of electrons, N, and/or the external potential, v( r). The reactivity
descriptors allow one to predict what sorts of perturbations stabilize the molecule the
most (or, alternatively, destabilize the molecule the least). This, in turn, allows one to
predict toward what sorts of reagents the molecule will be most reactive. It also allows
one to predict the regioselectivity of the reactions with those reagents.

B Reactivity descriptors
The response functions can be split into three groups: global, local, and nonlocal
reactivity indices. The associated reactivity descriptors that arise from differentiation
with respect to N (but not the external potential v( r)) are called global reactivity
descriptors: they are associated with the overall reactivity of the molecule and do not
contain any information about regioselectivity. Coefficients that contain exactly one
differentiation with respect to the external potential v(r) are said to be local reactivity
descriptors because they vary locally from one position to another in a molecule.
Local reactivity descriptors provide key information about the relative reactivity of
different sites in a molecule. So the local reactivity descriptors are key in making
predictions about regioselectivity. Coefficients that contain exactly two or more
differentiations with respect to the external potential are called nonlocal reactivity
descriptors or reactivity kernels. Nonlocal reactivity descriptors either measure a
molecule’s polarization with respect to its environment or the change in polarization
associated with electron transfer. All these descriptors provide us a status to
understand experimental observations in an elegant way. The important aspect of
this presentation is to verify and interpret the correlation of these descriptors with
the experimental studies at macromolecular level. Hence, it is very essential to know
which parameters represent molecular structure and reactivity, and which represent
the tendency of a given molecule to undergo a certain class of reactions.

(i) Global reactivity descriptors. Global reactivity descriptors measure the overall
reactivity of a molecule. These reactivity descriptors can be considered as response
functions describing the system’s response to perturbations in the number of
electrons N at constant v(r).

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After the introduction of DFT, advancement in the chemical reactivity was

observed by concentrating on the interpretation of the Lagrangian multiplier m in
eqn (4). It has been Parr’s impressive contribution42 to identify this abstract multiplier
as the partial derivative of the systems energy with respect to the number of electrons
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at constant external potential, v(r) (i.e., identical nuclear charges and positions)
 
@E
m¼ ð8Þ
@N vðrÞ

The physical meaning of chemical potential in DFT is to measure the escaping

tendency of an electron cloud. It is constant in three dimensional space for the ground
state of an atom, molecule or solid and equals the slope of E versus N curve at constant
external
 @E  potential. Assuming continuity and differentiability of E, the quantity
 @N vðrÞ
is easily seen to be a measure of the electronegativity, w, of the atom. Thus,
it is now pertinent to note that the chemical potential (m) is exactly identical with the
definition of one of the important concepts, electronegativity (w), for which a number of
definitions are available starting from Pauling’s work.121,122 Interestingly, Iczkowski
and Margrave,123 in an important contribution to the literature of electronegativity
have defined the electronegativity (w) of a system by the following,
 
@E
w¼ ð9Þ
@N
Mulliken’s124 definition of electronegativity is given as the arithmetic average of two
experimentally measurable quantities, i.e., ionization potential (IP) and electron affinity
(EA):
IP þ EA
w¼ ð10Þ
2
 dE 
The expression is just the finite difference approximation to the term,  dN . However,
42
now within the framework of DFT, Parr and his collaborators have provided the
theoretically justified definition of the electronegativity, w, to minus the chemical
potential, m in a natural way:  
@E
w ¼ m ¼  ð11Þ
@N vðrÞ

The idea that electronegativity is a chemical potential originates with Gyftopoulos and
Hatsopoulos.125
The operational definition of m and w are provided by the finite difference 
approximation20 from E(N) vs. N curve, in which the first derivative @N @E
, m is
calculated as the average of the left- and right-hand side derivatives. The left
derivative is obtained as the finite difference of energy of cation, N  1, and neutral,
N, (usually neutral, but may be charged) electrons. This is simply equal to negative
of IP. Similarly, the right derivative is obtained as difference of neutral (N) and
anion (N + 1) electrons. This is equal to the negative of EA.

EðN  1Þ  EðNÞ
m ¼ ¼ IP ð12Þ
1
m+ = E(N + 1)  E(N) =  EA (13)
 
@E 1 1
¼ m ¼ ðmþ þ m Þ ¼  ðIP þ EAÞ ð14Þ
@N vðrÞ 2 2

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Thus, from eqn (11) electronegativity (w) can be written as

w = m = 12(IP + EA) (15)
The expression of w originated from here is similar to that of Mulliken (i.e.,
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eqn (11)).124 As an approximation to eqn (15), one can relate chemical potential
(m) to the frontier orbital energies. This can be obtained through the Koopmanns’
approximation126,127 within the molecular orbital theory wherein IP and EA can be
replaced by frontier orbital energies (i.e., HOMO and LUMO energy, in conven-
tional notation LUMO represents the lowest unoccupied molecular orbital in the
species in question, and HOMO the highest occupied molecular orbital) as,53,128–133
EHOMO = IP (16)
ELUMO = EA (17)
Therefore, using Koopmanns’ theorem,126 we can write
ELUMO þ EHOMO
m ¼ w ¼ ð18Þ
2
The physical significance is that the negative of w represents a horizontal line at
the energy midpoint between HOMO and LUMO. This approximation might be
of some use when large systems are considered as it requires a single calculation
(i.e., only for neutral system), whereas the evaluation of eqn (15) necessitates three
calculations (i.e., for cationic and anionic system along with the neutral one), which
is computationally expensive and sometimes very complicated to compute. Also, in
the case of systems leading to metastable N + 1 electron systems (typically anion),
the problem of negative electron affinities is sometime avoided via eqn (18).134–136
Moreover, theoretical justification was provided for Sanderson’s principle of
electronegativity equalization23,26,137,138 which states that when two or more atoms
come together to form a molecule, their electronegativities become adjusted to the
same intermediate value. Electronegativity, being synonymous with chemical
potential, the correctness of Sanderson’s principle immediately follows from the
fact that the chemical potential of DFT is a property of an equilibrium state. The
chemical potential (electronegativity) is expected to be sensitive to the external
potential and may not be necessarily easy to calculate, but it is a concept securely
rooted in DFT. Semiempirical electronegativity equalization methods now are
widely used.28
E versus N plots are not straight lines but generally convex upward. Their
curvatures define another property of substantial importance, the chemical
hardness (Z)20
 2   
@ E @m
Z¼ ¼ ð19Þ
@N 2 vðrÞ @N vðrÞ

The chemical hardness is introduced by Pearson in the framework of his classifica-

tion of Lewis acids and bases, leading to the introduction of the hard and soft acids
and bases principle (HSAB).18,19,54,139–142 This principle states that hard acids prefer
to bond to hard bases and soft acids to soft bases. A factor of two, included in the
original definition of Z, is omitted now as Parr himself recommended.143,144 Again,
using a finite difference approximation and a quadratic E = E(N) curve, this
equation reduces to
Z = IP  EA (20)

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which, after using Koopmans approximation,126 becomes

Z = eLUMO  eHOMO (21)
For an insulator or semiconductor, hardness is the band gap. When the gap is large
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(other things being equal), one expects high stability and low reactivity. When it is
small, one expects low stability and high reactivity. These predictions are well borne
out in the good correlation that exists between HOMO–LUMO gap and the organic
chemists’ concept of aromaticity.145 This finding is nicely captured in the maximum
hardness principle also, proposed by Pearson,53 which states that ‘‘molecules will
arrange themselves to be as hard as possible’’. Parr and Chattaraj provided a
rigorous proof for this principle based on a combination of statistical mechanics and
the fluctuation-dissipation theorem.55,146–149
The inverse of the global hardness is called the global softness143,140
 
1 @N
S¼ ¼ ð22Þ
Z @m vðrÞ

which was empirically shown to be proportional to the polarizability of the

system.149–155 The hardness can be thought of as a resistance to charge transfer,
while the softness measures the ease of transfer.
Drawing analogy from classical thermodynamics, Parr and Pearson20 developed the
formalism for energy lowering i.e., the stabilization energy (SE), due to electron transfer
between two chemical species A and B. If chemical potentials of the two species are moA and
moB respectively, and moB > moA (i.e., A is more electronegative than B) then electrons flow
from B to A in the formation of AB. Assuming there are no other complicating factors it
can be shown from the definition of m and Z that when electron transfer (DN) is small,
EA = EoA + moA(NA  NoA) + 12ZA(NA  NoA)2 +   (23a)
EB = EoB + moB(NB  NoB) + 12ZB(NB  NoB)2 +   (23b)

[here, terms from third order onwards are neglected and it is assumed that
@2 E
@N 2
¼ Z]. Now ignoring all other effects, the total energy can be written as,
vðrÞ
EA + EB = EoA + EoB + (moA  moB)DN + 12(ZA + ZB)(DN)2 +  
or
(EA + EB)  (EoA + EoB) = DEA + DEB = D(EA + EB) = (moA  moB)DN
+ 12(ZA + ZB)(DN)2 +   (24)
where,
DN = NoB  NB = NA  NoA (25)
Thus, when moB
> moA;
a positive DN i.e., a flow of electron from B to A, will stabilize
the system (particularly for small DN). Now electron transfer will be stopped when,
DðEA þEB Þ
DN ¼ 0. Hence, from eqn (24) one can write,
DðEA þ EB Þ
¼ 0 ¼ ðm0A  m0B Þ þ ðZA þ ZB ÞDN
DN
or
(moA + ZADN)  (moB + ZBDN) = 0
or
mA = mB (26)

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where,
 
@EA
mA ¼ ¼ moA þ ZA DN ð27aÞ
@NA rÞ
vð
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@EB
mB ¼ ¼ moB þ ZB DN ð27bÞ
@NB rÞ
vð

Hence, from eqn (26), (27a) and (27b), we can write,

moB  moA
DN ¼ ð28Þ
ðZA þ ZB Þ

Substituting the values of DN from eqn (28) in eqn (24), we can write,
 o 
moB  moA 1 mB  moA 2
ðEA  EAo Þ þ ðEB  EBo Þ ¼ ðmoA  moB Þ þ ðZA þ ZB Þ
ðZA þ ZB Þ 2 ðZA þ ZB Þ

Or

ðmoB  moA Þ2 ðmoB  moA Þ2 ðmo  moA Þ2

DESE ¼ DEA þ DEB ¼ DðEA þ EB Þ ¼  þ ¼ B
ðZA þ ZB Þ 2ðZA þ ZB Þ 2ðZA þ ZB Þ

ðmoB  moA Þ2
DESE ¼ DEA þ DEB ¼  ð29Þ
2ðZA þ ZB Þ

Here, eqn (29) represents the stabilization energy due to transfer of DN amount of
electron from B to A (from eqn (29) it is obvious that DESE is negative i.e., energy is
lowered due to charge transfer).20,156
Another global reactivity descriptor is global electrophilicity (w), also proposed by
Parr et al.157 while tried to validate the experimental findings of Maynard et al.158 A
model was used according to which, when electrophilic system (atom, molecule, or
ion) immersed in an idealized zero-temperature free electron sea of zero chemical
potential (e.g., a protein or a DNA coil), there would be an electron flow of amount
DN from the sea to the system until the chemical potential of the system becomes
zero. The change in the electronic energy as a function of the change in the number
of electrons, DN up to second order, at constant external potential v( r) is

DN 2
DE ¼ mDN þ Z ð30Þ
2

The saturation situation by soaking up the maximum amount of electrons, DNmax, of

the system can be characterized by putting

DE
¼0 ð31Þ
DN

implying
m
DNmax ¼  ð32Þ
Z

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which yields stabilization energy,

m2
DE ¼  ð33Þ
2Z
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In eqn (33), the numerator (m2) is quadratic and, hence, positive and the
denominator (2Z) is positive due to the convexity of the energy vs. N curve and
hence, DE is negative: charge transfer is an
 energetically favorable process. In view of
2
the analogy between classical electricity power  W ¼ VR , Parr et al.157 defined
w = DE as a measure of electrophilicity of the system (atom, molecule, or ion). The
resulting equation is
m2
w¼ ð34Þ
2Z

This quantity w is called the ‘‘electrophilicity index’’. Kinetic and thermodynamic

aspects of w was investigated by Chattaraj and collaborators159 by correlating it
with the relative experimental rates of different types of reactions. However, a
thorough discussion, aided by analytical reasoning, on the thermodynamic and
kinetic aspects of w were reported by Bagaria and Roy.160 The ‘thermodynamic’
aspect helps to explain, qualitatively, favourable product formation. This aspect
 of w
DE
is established from the condition of maximal flow of electrons, i.e., when DN v
¼ 0,
2
DE  w ¼ m2Z. As Z > 0, DE o 0, i.e., charge transfer is an energetically favorable
process. The ‘kinetic’ aspect is used to describe the rate of the reaction. This can be
realized from the expression of w (i.e., of eqn (34)) in terms of first vertical IP and
first vertical EA as (by using eqn (14) and (20)),

m2 ½ðIP þ EAÞ=22 ðIP þ EAÞ2

w¼ ¼ ¼ ð35Þ
2Z 2ðIP  EAÞ 8ðIP  EAÞ

In a chemical reaction, where the substrate acts as an electron acceptor, it is expected

that a substrate with higher EA value will enhance the rate of the reaction than that
with a lower EA. Therefore, the rate of the reaction can be correlated with EA and
hence with global electrophilicity (w) value. If the substrate is an electron acceptor
then higher w value will favor the reaction and for electron donor substrate naturally
the lower w value will favor the reaction leading to the lower activation energy (Ea),
or free energy of activation (DG#).
It also was reasoned160 that the above correlation of global electrophilicity (w)
with the activation energy is not justified for all types of reactions. Only for single-
step reactions, it is safe to carry out such correlation. For multi-step reactions the
overall rate depends on the rate-determining step in which the substrate may not be
directly involved.
More recently, Bagaria et al.161 extended the use of global electrophilicity
descriptor, as proposed by Parr et al.,157 to the system where the donor is not a
perfect one and the acceptor is of comparable size to that of the donor (viz, when
both are ordinary organic molecules). It was then proposed that the energy
fragments (generated after decomposing the stabilization energy, i.e., |DEA(B)| and
|DEB(A)|) together with the global electrophilicity descriptor of the acceptor (wA),
could explain the rate determining step of a multistep chemical reaction.161 They also
showed that eqn (33) is a special case of eqn (29), when both m0B and ZB are assumed
to be zero in case of a idealized donor (normally very large biological systems, e.g.,
DNA-coil, protein).

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Several other global reactivity descriptors e.g., nucleophilicity,162–166 electro-

fugality and nucleofugality,167–169 potentialphilicity and potentialphobicity,170 charge-
philicity and chargephobicity171 are also proposed recently, which are all conceptually
related to w.
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(ii) Local reactivity descriptor. Parallel to the development of global reactivity

descriptors, some local reactivity descriptors have also been proposed which have
potential use in predicting local (site) reactivity (selectivity) of a chemical species.
Local properties may vary from point to point in space and are one-point ( r)
functions. So, local reactivity descriptors are the key to determining which places in a
molecule are most reactive.
If a change from one ground state to another is considered then one finds the
fundamental equation for the change in E[N,v(r)] as,
  Z 
@E dE
dE ¼ dN þ rÞd
dvð r
@N vðrÞ dvðrÞ N

or,
Z 
dE
dE ¼ mdN þ rÞd
dvð r ð36Þ
dvðrÞ N

thus, one has the most fundamental local reactivity descriptor, the ground state
r)31,172–178
electron density r(
 
dE
rÞ ¼
rð ð37Þ
dvðrÞ N

Similarly, the change in chemical potential associated with a change in N and/or v(
r)
is given by the formula
  Z 
@m dm
dm ¼ dN þ rÞd
dvð r ð38aÞ
@N vðrÞ rÞ N
dvð

@m
Or, introducing the symbol Z ¼ @N
rÞ
vð
Z 
dm
dm ¼ ZdN þ rÞd
dvð r ð38bÞ
dvðrÞ N

and we arrive at another important space-dependent (local) derivative of chemical

potential,
   
dm rÞ
@rð
f ðrÞ ¼ ¼ ð39Þ
dvðrÞ N @N vðrÞ

143,179–181
which isR known as Fukui Function (FF). This quantity integrates to
unity, f( r)dr = 1. The second formula for f( r) in eqn (39) is a ‘‘Maxwell
relation’’182 following from the fact that dE is an exact differential. There is a
discontinuity179,183,184 in the derivative of the Fukui function just as there is for
chemical potential.185 When an electron is being added, one has f+( r); when it is
being subtracted one has f(r); one also has the average f 0(
r). Parr and Yang179 have
defined the left [f(r)], right [f+(r)] and central [f 0(r)] derivatives of eqn (39).

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These three Fukui functions can be written by applying a finite difference

approximation and the frontier-orbital theory3–6 of reactivity as,
f(r) D rN(
r)  rN1(r) E rHOMO(
r) measures reactivity toward an
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electrophilic (El+) reagent (derivative as N increases from N  d - N), (40)

f (r) D rN+1(
+
r)  rN(r) E rLUMO(r) measures reactivity toward a
nucleophilic (Nu ) reagent (derivative as N increases from N - N + d),

(41)

and
f 0(r) = 12[f+( r)] D 12[rN+1(
r) + f( r)  rN1(r)] E 12[rHOMO(
r) + rLUMO(
r)]
measures reactivity toward an innocuous (radical) reagent (mean of left and
right derivatives) (42)

where, rN(r), rN1(

r) and rN+1(r) represent the electron density at a point r for the
N, N  1 and N + 1 electron system, respectively.
As chemists are interested with reactivities of atomic sites in reactions involving
neutral systems and their monopositive and mononegative ions (i.e., when the electron
number is changing by 1, instead of an infinitesimally small amount, d), it would be
more useful, albeit approximate, if f(r) indices of an atom in a molecule could be
evaluated. Yang and Mortier186 proposed such approximate atomic f( r) indices
(or condensed-to-atom Fukui functions) applying finite difference approximation to
the condensed electronic population on any atom (say for atom k) as
f(k) D PN(k)  PN1(k) (43)
f (k) D PN+1(k)  PN(k)
+
(44)

and
f 0(k) D 12[PN+1(k)  PN1(k)] (45)

where P(k) denotes the electronic population on atom k. Parr and Yang179 proposed
that larger value of Fukui function indicates more reactivity. Hence, greater the
value of the condensed Fukui function, the more reactive is the particular atomic
center in the molecule.
Moreover, one of the often-cited problems with Fukui function is that of its
negative values.187–202 A negative Fukui function value means that when adding an
electron to the molecule, in some spots the electron density is reduced (i.e., for
nucleophilic attack). Alternatively when removing an electron from the molecule, in
some spots the electron density grows larger (i.e., for electrophilic attack). If Fukui
function indices are expected to be positive values, then the above equalities should
not occur, which is unreasonable and also has yet not been formally shown whether
such behavior is physically correct or not. But it has been emphasized that Fukui
function should be normalized,45 i.e., they should sum to one.
To treat the problem regarding the negative Fukui function, Hirshfeld population
analysis (HPA)203 (also known as stockholders charge-partitioning technique), as
proposed by Hirshfeld is used and shown that HPA yields only positive Fukui
functions.59,162,187,191,192,194,204 Also, it was shown that electronic population derived
on the basis of HPA produces more reliable intramolecular reactivity trends when
compared to those obtained from Mulliken population analysis (MPA),205 natural
bond orbital (NBO) analysis,206–209 and molecular electrostatic potential (MESP)
based methods.9 Even though it is difficult to evaluate the superiority of one method

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to the others, studies by Roy et al.187,191,192 clearly demonstrated that HPA is

superior to other charge-partitioning schemes. Subsequently, there are quite a
number of studies in this area,189,194,210 which have also analytically shown that
HPA is a superior charge-partitioning scheme because it suffers from minimum
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missing information when atoms form a molecule.188–190,193–196,198–202,204,211,212 But

in this HPA technique also, there is no formal prescription for evaluating atomic
charges (i.e., qk) in the corresponding ionic species. Also, what would be the weight
factors ‘wk(r)’ for the atoms in the corresponding ionic species is not clearly outlined.
In the first study in this series Roy et al.,187 have shown that condensed Fukui
function can be positive only when same weight factor for the neutral, cationic and
anionic species is considered. It is true that such an approximation is crude one and
not a generalized method.
In order to mitigate the problems associated with the above Hirshfeld scheme,
recently in 2007, Bultinck et al.213 have proposed an alternative, iterative version of
the Hirshfeld partitioning procedure, known as ‘‘Hirshfeld-I’’ method. They have
verified this method on the test set of 168 molecules containing C, H, N, O, F and Cl
atoms. On the basis of this study, they ensure that this iterative scheme eliminates
arbitrariness in the choice of the promolecule, so the atomic populations are
determined solely by the molecular electron density, increases the magnitudes of
the charges, and also treats open shell species without problem. But right now, it is
difficult to comment on its universal validity, as this method has yet not been
used much by other researchers working in this area. However, it has been
recognized that HPA is trustworthy214 as long as small atoms (especially hydrogen
atoms) are not embedded in regions with substantial negative or positive deformation
densities. It also seems that HPA is rather trustworthy when ‘‘large’’ changes
in atomic charge (on the order of a tenth of the charge on the electron) are of
interest and less trustworthy when small nuances are being studied. For systems that
fail to meet these criteria, alternative population analysis schemes should be considered.
If negative Fukui function indices even occur at equilibrium geometries, then
the molecule would be expected to have very interesting magnetic and redox
properties.215–217 This is important in view of the fact that although the problem
of negative Fukui function indices has been looked upon in detail, no definitive
answers has been given yet to the question whether negative values are physically
acceptable or are artifacts. Thus, the occurrence of negative Fukui function has
remained a puzzle for a long time. And according to some computational studies, it
is truly impossible to exclude negative Fukui function.189,218–221 It has been pointed
out that the possibility of negative atom condensed Fukui function values depend
critically on the properties of the hardness matrix.195,204,215,222
In any case f( r) is established as an index of considerable importance for under-
standing molecular behaviour—the natural reactivity index of density functional theory.
Note that f(r) is defined independently of any model, while the concepts of classical
frontier theories are framed in the language of the independent-particle model.
The Fukui function is a powerful local reactivity indicator for regioselectivity but
it is not expected to provide an accurate indication of the overall reactivity of a
molecule. When a reactivity indicator that reflects overall reactivity is needed,
workers in Conceptual DFT usually work in the grand canonical ensemble.223
Reactivity descriptors in the grand canonical ensemble are obtained by replacing
derivatives with respect to the number of electrons, N, with derivatives with respect
to the electronic chemical potential, m (the electronic chemical potential measures
the intrinsic strength of Lewis acids and bases, so reactivity descriptors in the

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grand canonical ensemble represent how a molecule’s reactivity changes as its

electron-withdrawing power or electronegativity decreases). In the grand canonical
ensemble, the Fukui function, f( r)143
r), is replaced by the local softness, s(
     
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@rðrÞ rÞ
@rð @N
rÞ ¼
sð ¼ ¼ f ð
rÞS ð46Þ
@m vðrÞ @N vðrÞ @m vðrÞ

where S is global softness (vide eqn (22)).

Thus local softness in such a reactivity parameter which describes the response of any
particular site of a chemical species (in terms of change in electron density r(
r)) to any
global change in its chemical potential values. The parameter s( r) obeys the condition,
R
r)d
s( r=S (47)

The Fukui function in eqn (46) can be identified with the Fukui function from
above (eqn (40)), the Fukui function from below (eqn (41)), or from the average of
the two (eqn (42)). Similarly, the three approximate atomic f( r) indices (from
eqn (43)–(45)), when multiplied by S, provide three different local softnesses for
any particular atom (k). These can be written as
s(k) D [PN(k)  PN1(k)]S (suited for studies of electrophilic attack) (48)
s (k) D [PN+1(k)  PN(k)]S (suited for studies of nucleophilic attack)
+
(49)
and
s0(k) D 12[PN+1(k)  PN1(k)]S (suited for studies of radical attack) (50)

From eqn (46) it is obvious that local softness contains the same information as
Fukui function plus additional information about the total molecular softness. The
Fukui function may be thought of as a normalized local softness.143 Therefore, either
the Fukui function or local softness can be used in the studies of intramolecular
reactivity sequences (i.e., relative site reactivity in a molecule).224 But only s( r) (and
not f(r)) should be a better descriptor of the global reactivity with respect to a
reaction partner having a given hardness (or softness), as stated in the HSAB
principle.18
There is an interesting fluctuation formula for this quantity in finite-temperature
DFT, where the averages are over all members of a grand ensemble at temperature T.143
This formula and other similar DFT fluctuation formulae225,226 may provide a basis for
fluctuation theories of catalysis. s(r) is measurable using scanning tunnel microscopy.
For an infinite system, s(
r) is approximately the local density of states at the Fermi level
and S the total density of states at the Fermi level.143,227

It has been argued that the individual values of s+ k and sk are strongly influenced
by the basis set or correlation effects. But the ratio of sk and s
+
k , involving two
differences of electron densities of the same system differing by one in their number
of electrons, at constant nuclear framework, are expected to be less sensitive to the
basis set and correlation effects. Based on this argument, Roy et al.228 introduced
two new reactivity descriptors to find out the preferable reactive sites. These are
  +
defined as relative electrophilicity (s+ k /sk ) and relative nucleophilicity (sk /sk ) of any
particular atom k, and helps to locate the preferable site (or atom) in a molecule for
nucleophilic and electrophilic attack on it, respectively. That is, relative nucleo-
philicity is the nucleophilicity of any site as compared to its own electrophilicity and
relative electrophilicity is the electrophilicity of any site as compared to its own
nucleophilicity.

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There is no unique simple inverse of s(r). Berkowitz and Parr229 have given a
derivation of local softness that reveals its relation to its reciprocal property, local
hardness.230–232
Substitution of eqn (4) into eqn (2) follows, for a ground state
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Z 
dF½r
E½r ¼Nm  rðrÞd
r  F½r
drðrÞ ð51Þ
¼Nm  H½r

where the hardness functional H[ r] is defined by the formula233

Z
dF½r
H½r ¼ rðrÞdr  F½r ð52Þ
drðrÞ
H[ r] is what must be added to E to give Nm. Note that a leading term in H[ r] is J[ r],
is the classical part of Vee[ r].
The total differential of eqn (51), associated with a change of the system of
interest, is simply
dE [ r] = Ndm + mdN  dH[ r] (53)
Comparing this with eqn (36), one can obtain the equation
R
Ndm =dH[ r] + r(r)dv( r)d
r (54)
42
The differential of H[ r] has a surprisingly simple form. From eqn (52) one has
Z  Z Z
dF½r dF½r dF½r
dH½r ¼  dF½r þ d rðrÞdr ¼  rÞd
drð rþ rÞd
drð r
drðrÞ drðrÞ rÞ
drð
Z    ZZ
dF½r d2 F½r
þ d rðrÞdr ¼ r0 Þrð
drð rÞd r0
rd
drð rÞ drðrÞdrðr0 Þ
ð55Þ
So, from eqn (53),
ZZ
d2 F½r
dðE½r  NmÞ ¼  r0 Þrð
drð rÞd r0
rd ð56Þ
r0 Þ
drðrÞdrð
This is where the local hardness comes in. Following Ghosh and Berkowitz,231 local
r) is defined as:230
hardness Z(
Z
1 d2 F
ZðrÞ ¼ r0 Þd
rð r0 ð57Þ
N drð r0 ÞdrðrÞ
One can find accurate to all orders,
dH½r
¼ NZð
rÞ ¼ hð
rÞ ð58Þ
rÞ
drð
Parr and Gázquez called h(r) the hardness potential for the system.233
Introducing the symbol of Z( r), one can rewrite eqn (56) as
R
d(E [ r]  Nm) = N Z( r)dr(r)d
r (59)
Eliminating dE from eqn (36) and (59), was obtained
Z Z
1
dm ¼ ZðrÞdrð rÞd
rþ rÞdvð
rð rÞd
r ð60Þ
N

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This is the local counterpart of eqn (38) in the sense of Nalewajski,44 in which it now
appears the local hardness in place of the global hardness.
From eqn (60) one can find another formula for Z( r),230
 
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dm
rÞ ¼
Zð ð61Þ
drðrÞ vðrÞ

Eqn (61) is an example of an ambiguous ‘‘constrained functional derivative’’.225,230,234–251

The functional derivative is ambiguous because of the interdependence of r( r).225
r) and v(
It is interesting to note that the local hardness also appears in a natural way when the
chain rule is applied to the global hardness:
 2   
@ E @m
Z¼ ¼
@N 2 vðrÞ @N vðrÞ
Z    Z ð62Þ
dm drðrÞ
¼ dr ¼ ZðrÞf ð
rÞd
r
drðrÞ vðrÞ dN vðrÞ

An explicit expression for Z(r) can be deduced from eqn (57) and the definition of Fukui
function (eqn (39))234
Z
d2 F
ZðrÞ ¼ r0 Þd
f ð r0 ð63Þ
r0 Þdrð
drð rÞ
Local hardness and local softness are reciprocals in the sense that
R
Z(r)s(
r)d
r=1 (64)
One can simplify the definitions of local hardness by writing236
  Z
dm 1 d2 F
Zl ð
rÞ ¼ ¼ r0 Þd
l½rð r0 ð65Þ
rÞ vðrÞ N drð
drð r0 Þdrð
rÞ

where, l[r(r 0 )]225 is a composite function that integrates to N (i.e., total number of
electrons of the system),
R
r 0 )]dr = N
l[r( (66)
Two important choices of the composite function r 0 )]
l[r( are
r(r 0 )114,115,231,236,245,246,248,249,252 and Nf( r 0 ),234,237,239,241,243,247,250,251 when the following
possibilities emerge:
Z
1 d2 F
l½rðr0 Þ ¼ rð r0 Þ yielding ~ZD ð rÞ ¼ rðr0 Þd
r0 ð67Þ
N drð r0 ÞdrðrÞ
and
Z
d2 F
l½rðr0 Þ ¼ Nf ð
r0 Þ yielding ~ZF ð
rÞ ¼ r0 Þd
f ð r0 ð68Þ
r0 Þdrð
drð rÞ

But Z~F(r) is shown to be equal to the global hardness Z at every point of space,225
when the exact functional F [ r] is used253 in eqn (68)
    Z  
@m @ dF½r d2 F½r r0 Þ
@rð
Z¼ ¼ ¼ r0
d
@N vðrÞ @N drðrÞ drð rÞdrðr0 Þ @N
Z ð69Þ
d2 F½r 0 0
¼ f ðr Þdr ¼ ~ ZF ð
rÞ
drðrÞdrðr0 Þ

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At first sight this form seems to be less appropriate, as ‘‘unlike the chemical
potential there is nothing in the concept of hardness which prevents it from having
different values in different parts of the molecule’’.140
Based on the global electrophilicity index w (eqn (34)) as defined by Parr et al.,157
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Pérez et al.254 introduced an useful expression for the local electrophilicity index w(k)
in terms of the electrophilic Fukui function and local softness. From eqn (34) and
using the inverse relationship between global hardness and global softness143
(eqn (22)) one may obtain
m2 m2 m2 X þ X
w¼ ¼ S¼ s ðkÞ ¼ wðkÞ ð70Þ
2Z 2 2 k k

Afterward, Chattaraj et al. proposed a broader and general local reactivity descriptor
by using the resolution of identity.255 This is named as the ‘‘philicity’’ index w(
r),255–258
which encompasses all types of reactions (i.e., electrophilic, nucleophilic, and radical
reactions). This local philicity w(r) is promised to be a more powerful quantity than
global reactivity descriptors because the former contains the information of the latter
in addition to the site selectivity of a molecule toward electrophilic, nucleophilic, and
radical attacks. Also, according to the argument of the authors, ‘‘because the global
electrophiliciy of two different molecules are different, best sites of two different
molecules for a given reaction can be explained only in terms of the ‘philicity’ and not
Fukui function’’. So, they proposed the existence of a local electrophilicity index (w( r))
that varies from point to point in an atom, molecule, ion or solid and is defined as
R
w = w( r)dr (71)
R
By using the resolution of identity as represented by f( r)d
r = 1, the best choice of
w(r) was proposed to be
R R R
w = w f(r)dr = wf(r)dr = w( r)dr (72)
where
r) = wf(
w( r) (73)
To take care of all types of reactions three different forms of w(
r) was defined as
wa(r) = wf a(r) (74)
where a = +, , and 0 for attacks by a nucleophile, electrophile, and radical,
respectively. It is obvious that eqn (73), when integrated, generates w, i.e., the global
electrophilicity. This is true for a = +, , and 0. However, in the presence of a
physicochemical perturbation, some particular atom (or atoms) is (are) better
equipped toward electrophilic (or nucleophilic) attack on it. As wa( r) takes care of
all types of reactions, it is claimed to be more general and is called the local philicity
index. The corresponding condensed-to-atom forms of the philicity index for atom k
is written as
wa(k) = wf a(k) (75)
259
In a study by Roy, it has been shown that the philicity index w( r) and the local
softness s(r) generate identical intramolecular reactivity (or site selectivity) trends.
This is because w( r) and s(r) are analytically related as follows:
m2
rÞ ¼ wf ðrÞ ¼
wð rÞ ¼ m2 Sf ð
f ð rÞ ¼ m2 sð
rÞ ð76Þ
2Z

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That is, w(r) can be obtained after multiplying the s( r) by m2 which is constant for a
particular system but varies from system to system. Therefore, it has been concluded
that w( r) will not provide any extra information than that of s( r) or f(r) on
intramolecular reactivity trends. It may be noted that Chattaraj himself also later on
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mentioned that for intramolecular reactivity, philicity, local softness and FF furnished
the same trend.260 Roy et al.,261 in one interesting study made a significant revelation
regarding the correlation between global and local reactivity descriptors. It was argued
that the claim [i.e., global trend of electrophilicity (or nucleophilicity) originates from
the local behavior of the molecules, or precisely of that atomic site which is most prone
to electrophilic (or nucleophilic) attack] is logical for systems having only one distinctly
strong site (electrophilic or nucleophilic) but does not hold true for systems having
more than one site of comparable strength. For the justification of this argument, a
thorough study was carried out by Roy et al.,261,262 using numerical demonstrations
and analytical reasoning. Finally, it was concluded that reliable intermolecular
reactivity trend can be generated by global electrophilicity (or may be local hardness)
and that is possible with local electrophilicity only for the systems having one distinctly
strong site. In another interesting article Ayers et al.,223 have discussed the ‘extensive’,
‘intensive’ and ‘subintensive’ nature of DFT based reactivity descriptors.

(iii) Nonlocal reactivity descriptors. These are reactivity descriptors which depend
on two or more spatial positions, r, r 0 , etc. Interest on these reactivity descriptors
originates from the fact that local descriptors are defined as responses to a global
perturbation, whereas the chemical reaction is typically local. In the detailed con-
sideration of a change of any chemical system from one ground state to another, or in
the determination of a ground state by any trial and error process in which r is guessed
repeatedly, it has been recognized that nonlocal quantities play an important role.229
If we consider the ground state of a system of interest which changes only from
one ground state to another, r( r) determines everything by the original Hohenberg-
Kohn theorems29 including m and v( r). It therefore determines the modified potential
u(r) as (eqn (4)),
dF½r
rÞ ¼ vðrÞ  m ¼ 
uð ð77Þ
drðrÞ

where, u( r) is also a functional of r(r). The functional derivative of u( r) with respect
to r(r 0 ) therefore exists. This defines the hardness kernel, Z( r 0 )44,143,227,229,263
r,
r0 Þ
duð duðrÞ d2 FE
r; r0 Þ  
Zð ¼ ¼ ð78Þ
drðrÞ drðr0 Þ drð
r0 Þdrð
rÞ

the last equality coming from eqn (77). Recall the first definition of local hardness,
Z(r) (eqn (57)), by introducing the symbol of Z(r,r 0 ), one can find
Z
1
rÞ 
Zð r; r0 Þrð
Zð r0 Þdr0 ð79Þ
N

Similarly, another fact is that u(

r) determines all properties- not only v( r) but also
N, and hence r(r). The functional derivative of r( r) with respect to u(
r) therefore
exists. This defines the softness kernel s( r 0 )44,143,227,229,263
r,

drðr0 Þ rÞ
drð
sðr; r0 Þ   ¼ ð80Þ
duðrÞ r0 Þ
duð

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and the local softness s(

r)
R
r,r 0 )dr 0
s(r)  s( (81)
Moreover, since both the functional derivatives exist,
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Z
drðrÞ duðr0 Þ 0
r00  rÞ
dr ¼ dð ð82Þ
duðr0 Þ drðr00 Þ
so that
R
s(r,r 0 )Z(r 0 ,
r00 )dr 0 = d(r00  r) (83)
The hardness and softness kernels are true inverses.
r00 ) then integrating over 
Multiplying eqn (83) by r( r00 and making use of eqn (79)
one can write,
Z
rÞ
rð
r; r0 ÞZð
sð r0 Þd
r0 ¼ ð84Þ
N
Integrate this over r, and employing eqn (81), gives previous eqn (64)
R
Z(r)s(
r)d
r=1 (64)

To achieve eqn (46), writing

Z
drð rÞ
rÞ ¼
drð duð r0 Þd
r0
duðr0 Þ
Z
¼  sð r; r0 Þduðr0 Þd
r0 ðby using eqn ð80ÞÞ
Z ð85Þ
¼ r; r0 Þ½dvðr0 Þ  dmdr0 ðapplying eqn ð77ÞÞ
sð
Z  Z
0 0
¼ r; r Þd
sð r; r0 Þdvð
r dm  sð r0 Þd
r0

R
r 0 )dr 0 from eqn (38b) and (39) we get,
r)  s(r,
utilizing s(
R
dm = ZdN + f(r 0 )dv(r 0 )d
r0 (38c)
generating
R R
dr = s( r 0 )dv(
r)ZdN + s(r)f( r 0 )dr 0  s( r 0 )dv(
r, r 0 )d
r0
or,
R
dr(r) = s( r,r 0 )+ s(r)f(
r)ZdN + [s( r 0 )]dv(
r 0 )d
r0 (86)
Also, r = r[N,v] implies
Z  
drðrÞ
drðrÞ ¼ f ð
rÞdN þ r0 Þd
dvð r0 ð87Þ
r0 Þ
dvð N

N and v(r) being independent, coefficients of dN and dv(

r) in eqn (86) and (87) must
be equal. Consequently, we have

     
f ð
rÞ @rðrÞ @N rÞ
@rð
sðrÞ ¼ ¼ f ðrÞS ¼ ¼ ð46Þ
Z @N vðrÞ @m vðrÞ @m vðrÞ

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h i
rÞ
drð
The derivative dvð r0 Þ N is the conventional linear response function, denoted by
w(r,r 0 ).264,265 It is connected to the local softness, global softness and the softness
kernel via an exact formula229
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drðrÞ r0 Þ
rÞsð
sð
r; r0 Þ ¼
wð ¼ sðr; r0 Þ þ ð88Þ
dvðr0 Þ N S

Eqn (88) shows that the chemical reactivity, as measured by the softness kernel, is
the sum of two contributions:47 (i) the nonlocal response function of the system that
contains contributions of all the MOs to the reactivity; and (ii) the electronic
reactivity contained in the local softness, which is dominated by the frontier orbitals.
This shows that the polarization changes in the electronic distribution (response to
the external potential displacements) can be determined from the softness properties
calculated for the fixed nuclear geometry (external potential).

C Other developments
Apart from the above developments of global, local and nonlocal reactivity
descriptors in Conceptual DFT, some other parallel developments in the area are
worth mentioning.
The defined reactivity and selectivity descriptors are inadequate to study the
reactions which involve changes in spin multiplicity. For this purpose, the conceptual
spin-polarized density functional theory (SP-DFT) was introduced by Galvan, Vela,
and Gazquez.266 This fact derives from the explicit consideration of the electron
density and spin density (i.e., r(
r) and rS(
r)), respectively, written in terms of the spin-up
ra(r) and spin-down rb(r) components as
r(r) = ra(
r) + rb(r) (89)

and
r)  rb(r)
rS(r) = ra( (90)

which integrates to the electron number, N, and spin number, NS, respectively.
R
N = Na + Nb = r( r)dr (91)
R
NS = Na  Nb = rS(r)d r (92)

Spin-polarized DFT allows one to get some insight into the chemical properties
related to the change in spin number. In recent years, many studies have appeared on
the basis of which one can say that in some cases spin-polarization plays an
important role.266–295
Here, so far we have put emphasis on the effects of change of N and change of v( r)
on the electron density. The other elementary extension is shifts in the nuclear
positions which must be incorporated in a complete theory.226,227,296–305
In the light of the above discussion on DFT based reactivity descriptors we will try
to analyze the regioselectivity criteria of large molecular systems in the next section.
Although these reactivity indices have become very useful in predicting the regio-
selectivity of chemical reactions, for tracing the proper reactivity descriptor to explain
the intermolecular reactivity trend the argument still continues. Therefore, in the next
section, first we will explore the suitable reactivity descriptor for describing the
intermolecular reactivity trend as well as its feasibility for computing large systems.

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After carrying out the above task we will contemplate the regioselectivity for a number
of large biological systems.

3. Regioselectivity of large system in the context of conceptual DFT

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A On the way of detecting suitable intermolecular reactivity index

In 1968, G. Klopman306 attempted to quantify Pearson’s HSAB principle18 using
polyelectronic perturbation theory and for that he defined two types of inter-
action namely, orbital-controlled (i.e., soft–soft interaction) and charge-controlled
(i.e., hard–hard interaction). Later on, with the development of Conceptual DFT
based reactivity descriptors, it is realized that orbital-controlled reactivity descrip-
tors include Fukui function index [f( r) or f(k)],143,179,181,307 local softness [s(
r) or
143 255 
s(k)], philicity [w(k)], ‘relative electrophilicity’ (s+k /sk ) and ‘relative nucleo-
philicity’ indices (s + 228
k /sk ), whereas local hardness, Z(r)230–232 (when evaluated through
Thomas-Fermi-Dirac (TFD) approach308–310), is an example of predominantly charge-
controlled reactivity descriptors.
As regioselectivity is a local phenomenon, explaining the regioselectivity of any
system by local reactivity descriptors are promised to be more reliable than the
corresponding global reactivity descriptors. As we intend to search for suitable
‘intermolecular’ local reactivity index we have to look on to those orbital-controlled
as well as charge-controlled reactivity descriptors.
The most useful orbital-controlled descriptor is Fukui function. Because of the
R PN
normalization condition of Fukui function (i.e., f( r)dr = 1 or f ðkÞ ¼ 1)45 it is
k
applicable for explaining intramolecular reactivity (site-selectivity) trends and
becomes less applicable for the study of intermolecular processes.
The most demanding local reactivity descriptor, which is believed to be a
sustainable index for intermolecular reactivity trends, is local softness [s( r) or s(k)].
The reasoning behind this demand is that local softness is such a reactivity parameter
which describes the response of any particular site of a chemical species (in terms of
change in electron density r(r)) to any global change in its chemical potential values.
Furthermore, as s( r) = f( r)S (eqn (46)) local softness seems to be a much more
potential index as it contains local as well as global information. However, local

softness (particularly individual values of s+k and sk ) is strongly influenced by the basis
set or correlation effects and because of the ‘intensive’ nature223 of Fukui function [f( r)]
the local softness parameter remains ‘subintensive’ (i.e., becomes smaller and smaller as
the size of the system increases). For these two reasons local softness is a dubious choice
as an intermolecular reactivity index.
Another reactivity descriptor which is partially orbital-controlled is philicity index
[w(r) or w(k)]255 and is believed to be a reliable intra as well as intermolecular local
reactivity index. However, w(r) will not provide any extra information than that by
s(r) or f(r) as far as intramolecular reactivity is concerned.259 Even though,
individually this descriptor is ‘extensive’ (i.e., does not go to zero in the thermo-
dynamic limit) in nature, here also ‘intensive’ nature of f( r) or f(k) makes philicity
[w(r) or w(k)] indices applicable to limited cases160,259,261,262,311,312 of intermolecular
reactivities.
In Conceptual DFT the predominantly charge-controlled reactivity descriptors is
local-hardness. The applicability of local hardness, [Z( r)] as an intermolecular
reactivity descriptor originates from the fact that it contains electronic part of the
molecular electrostatic potential. However, before going into details of the

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usefulness of local hardness, [Z(r)], as an intermolecular descriptor a brief discussion

on the derivations of working equations of Z(r) seems to be justified.
From eqn (67) and (68) it is obvious that prescription of any routine calculation
scheme for Z(r) is difficult, since the exact functional form for Hohenberg-Kohn
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functional F [ r]29 is unknown. It can be done by using the approximated F [ r]. These
approximations are based on the Thomas-Fermi-Dirac (TFD)308–310 approach to
DFT. If we keep in mind that the nucleus-electron attraction is not contained in
r)], the following equation is obtained from the general form of the energy
F[r(
functional ETFD[r(r)],45 without further approximations:
Z Z Z Z
1 rðrÞrðr0 Þ 0
FETFD ½rð
rÞ ¼ CF rÞ5=3 d
rð rþ d r  CX
r d rÞ4=3 d
rð r ð93Þ
2 r  r0 j
j

3
2  1
Here, CF ¼ 10 ð3p2 Þ3 ¼ 2:8712 and CX ¼ 34 p3 2 ¼ 0:7386 are the coefficients of the
kinetic energy and exchange-energy functionals, respectively.45
r 0 )) Ghosh et al.231
Inserting eqn (93) in eqn (67) (where l[r(r 0 )] is replaced by r(
derived the expression of local hardness as,

10 1 4
ZTFD
~D ðrÞ ¼ rÞ2=3  V el ðrÞ 
CF rð rÞ1=3
CX rð ð94Þ
9N N 9N

Starting from eqn (93) and taking into account the exponential falloff of the density
0
in the outer regions of the system, the local hardness ~ZTFD
D ð
rÞ was approximated
230
as,

0 1 el
~ZTFD
D ð
rÞ ¼  V ð
rÞ ð95Þ
N

here, N is the total number of electrons of the system and Vel( r) is the electronic part
of the molecular electrostatic potential. However, eqn (95) can be derived by
approximating just the coulombic contribution (i.e., only the middle term of
eqn (93)).230,237 It was shown that this approximated form of local hardness,
(i.e., Vel(
r)/N) can be used as a reliable parameter for comparison of intermolecular
reactivity sequences of any particular site in a series of molecules.114,115,236,247,252,313
There are also some recent studies by Geerlings and his collaborators on the relative
contributions of different energetic components to the global and local hardness
values.232,247,314
In a very recent study, Saha and Roy252 critically illustrated the limitation250,251 of
Z(r) (evaluated from two composite functions i.e., l[r( r 0 )] = r(
r 0 ) eqn (67), (i.e., total
local hardness)114,115,231,236,245,246,248,249,252 and l[r( r 0 )] = Nf( r 0 ) eqn (68), i.e.,
234,237,239,241,243,247,250,251
frontier local hardness) ) when used for comparison of
intermolecular reactivity trends between systems of different sizes but having
common reactive centers. After a careful analysis they revealed that as the number
of electrons increases with the size of the system, the N1 factor alters the expected
0
trends of Z~TFD
D r) or ~ZTFD
( D ð
rÞ values. So, the broader applicability of Z( r) as a reliable
intermolecular reactivity descriptor necessitates the removal of its N1 dependence.
This is because the comparison of intermolecular reactivity trends is mainly based on
the local hardness values of those particular sites (or atoms in the condensed form),
electronic or any other effects exerted by the rest of the system already incorporated.
But the N1 factor creates an impression as if the whole system does equally con-
tribute to the reactivity of that particular site or atom. In reality, parts (or moieties)

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of the system, far from the site of interest, may have very little or no effect on the
reactivity of that particular site. Geerlings and collaborators also raised a similar
argument in some of their earlier studies.315 Therefore, the best way to incorpo-
rate the electronic (or any other) effects of the rest of the system, without over-
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emphasizing N1 factor, is to consider only the active site (or atoms or group) for which
the number of electrons is same. Thus the modified form of eqn (94) and (95) can be
written as
10 4
~ZTFD
D ðrÞ ¼ CF rðrÞ2=3  V el ð rÞ1=3
rÞ  CX rð ð96Þ
9 9
0
~ZTFD
D rÞ ¼ V el ð
ð rÞ ð97Þ

For example they have shown that if only CQO moiety is considered (N will be
same, i.e., N = 14, for all the chosen carbonyl systems) one can use the modified
‘condensed-to-atom’ form of eqn (96) and (97) as,
10 4
~ZTFD
D ðkÞ ¼ CF PðkÞ2=3  V el ðkÞ  CX PðkÞ1=3 ð98Þ
9 9
0
~ZTFD
D ðkÞ ¼ V el ðkÞ ð99Þ

From the preceding justification it is clear that local hardness is conducive to

explain intermolecular properties. However, for predicting the overall reactivity
sequence it will be more rational to consider both the charge-controlled as well as
orbital-controlled contributions i.e., the descriptor should be dual in nature.236,316
The argument in favour of the dual nature of the desired reactivity descriptor
originates from the fact that during an electrophile–nucleophile interaction process,
at the initial stage of a reaction, when two reactants approach each other, charge will
play a major role in determining the reactivity. Because electrostatic force operates
from large distance any hardness based (or charge-controlled) reactivity descriptors
will be more suitable for explaining the reactivity at this stage (i.e., intermolecular
reactivity sequence).230 Once the reaction starts, frontier orbitals play the major role
in determining the reactivity of a particular site (or atom). This is because when an
electrophile or a nucleophile approaches the substrate the preferable site of attack
depends on the frontier orbitals of the substrate. Hence, one can argue that any
r) or s(k)],143
softness based (orbital-controlled) reactivity descriptors (e.g., local softness [s(
143,179,181,307 255
Fukui function index [f( r) or f(k)], philicity [w(k)] ) will be more
suitable to describe the intramolecular reactivity. The findings by Klopman306 also
support this argument.

B On the way of predicting the regioselectivity of large molecular systems within the
framework of conceptual DFT
The bottleneck in predicting the intramolecular reactivity trends of large chemical
and biological systems lie in the fact that the calculation for the whole system is
needed to be performed. This is because of the incorporation of the global softness
part in the expression of local softness (i.e., sa(r) = f a(
r)S where a = +,  and 0).143
Thus, larger and larger the system becomes, lower and lower level of calculation we
have to opt for. Although the regioselectivity plays an important role to understand
a reaction, because of this bottleneck, very little conceptual DFT based works have
been done involving large biological systems. However, one way to avoid this

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difficulty is to use molecular fragmentation approach. It is worthwhile to point out

here that for predicting the regioselectivity of large molecular systems in the
framework of Conceptual DFT, a simple fragmentation approach was first proposed
by Saha and Roy.114,115 They proposed a model, named as ‘One-into-Many’ model,
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in which one can break the larger system into different smaller ones, each having at
least one reactive site, and then to study the reactivity of the required active sites in
the individual fragments using hardness-based reactivity descriptors (e.g., local
hardness). As argued in the previous sub-section [3 A], local hardness is mainly a
charge-controlled descriptor when evaluated using eqn (96) and (97) (or eqn (98) and
(99)). Since it can take care of the long-range reactivity (i.e., intermolecular
reactivity), one can recast the intramolecular problem of a large system into an
intermolecular problem of its smaller fragments and then predict the regioselectivity
of the original large system. Thus, while the technique to be adopted is similar to the
divide-and-conquer (DC) approach formulated by Yang,86 the local quantities (e.g.,
electron density, electronic contribution to the electrostatic potential) of the
individual fragments are not extended to the original large system. Because,
the regioselectivity (or site selectivity) is a local phenomenon, it is assumed that
the contribution to the local reactivity descriptor (e.g., ‘local hardness’, evaluated on
the basis of Thomas-Fermi-Dirac (TFD)308–310 approach of density functional
theory) from the distant atoms or moieties are less significant and thus can be
neglected. However, contribution from close atoms or environment can be taken
care of by careful fragmentation process. This is to be achieved, even if not fully, by
keeping some ‘buffer zone’ on both sides of the reactive site. Here, ‘buffer zone’
refers to the moiety of the chemical system, which is common to two adjacent
reactive sites (local hardness values of which are to be evaluated).
To implement the ‘One-into-Many’ model,114,115 Saha and Roy has chosen right-
handed B-DNA (PDB ID: 1BNA)317 as a model system. The structure of the DNA is
shown in Fig. 1. In this model system there are 12 base-pairs with the sequence
d(CpGpCpGpApApTpTpCpGpCpG).317 Detail literature study on adduct
formation indicates that the majority of known carcinogens react with DNA
through N2 and N7 positions of guanine.318–322 Those positions are the most
reactive sites towards electrophilic attack in double-stranded DNA. Apart from
these positions, it is also reported that the exocyclic oxygen of guanine (O6)323,324
and the exocyclic oxygen of thymine (O2)324,325 residues are the reactive sites for
0
electrophilic attack. Saha and Roy calculated Z~TFD D (k) (eqn (98)) and ~ ZTFD
D ðkÞ
(eqn (99)) values of those reactive sites by considering one of the GC base-pair
and one of the AT base-pair (given the name ‘Single-Base-Pair Systems’) of DNA
molecule (Fig. 2). The geometries associated with these two base-pairs are taken
from 1BNA317 without any modification. However, to generate more reliable data a
buffer zone around each reactive site is required. So, three base-pairs were chosen at
a time (named as ‘Triple-Base-Pair Systems’) and evaluated the Z~TFD D (k) and also
0
~ZTFD
D ðkÞ values of the reactive sites in the middle base-pair. Here the base-pairs,
which are on either side of the central base-pair, create the buffer zone i.e., try to
mimic the environment of the 1BNA.317 Although, in reality, some contribution
from base-pairs which are next to the adjacent base pairs are also expected, for
computational limitation the calculation has been restricted to the ‘Triple-Base-Pair
Systems’ only. All possible combinations of ‘Triple-Base-Pair Systems’ (Fig. 3) are
also taken from 1BNA317 and the geometrical parameters are generated326 without
any geometrical changes in the study. Relevant calculations have been performed
using Gaussian suite of programs.327

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Fig. 1 Fragmentation of Watson-Crick double-stranded B-DNA (PDB ID: 1BNA)317 into

Triple-Base-Pair Systems (Reprinted with permission from ref. 114. Copyright 2010 American
Chemical Society).

As the total number of electrons in GC base-pair is equal to the total number of
electrons in AT base-pair, the number of electrons (i.e., N) is equal in all the base-pairs
(whether Single or Triple). So, for DNA one can directly apply the modified form of
eqn (96) and (97), i.e., eqn (98) and (98).114,115
Saha and Roy114,115 concluded that the trends of atomic hardness values
generated by the proposed model are as expected for exocyclic NH2-groups and
for ring N-atoms of the DNA base-pair systems. In the case of exocyclic nitrogen,
0
Z~TFD
D (k) and ~ZTFD
D ðkÞ values of N2 position of G is found to be the highest among all
the exocyclic nitrogen’s present in DNA, which agrees with the previous experi-
mental results.318,320,321 While comparing the N7 position for Single-Base-Pair
0
Systems and Triple-Base-Pair Systems, highest Z~TFD D (k) and ~ZTFD
D ðkÞ values belong
115
to that of G. Only for exocyclic O-atom in DNA base-pairs, the method proposed
by Saha and Roy114,115 fails to generate expected trends of hardness values (~ ZTFD
D (k)
0 TFD 0
TFD
and ~ZD ðkÞ). They have reported that (both from Z~D (k) and ~ ZD ðkÞ values) O2
TFD

position of C is the most reactive sites even though Singer324 has observed that O6 of
G and O2 of T are the two significant reactive sites towards electrophilic attack in the
double helical DNA. This failure of Saha and Roy114,115 is attributed to their
inability (due to lack of computational facilities) to (i) take care of the dielectric
effect of the biological medium and (ii) include polarization and diffuse functions in
the basis set for Triple-Base-Pair Systems. It is worth mentioning here that Fan et al.,
in one interesting study,328 suggested a general guideline for the computation of large

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Fig. 2 Two different Single-Base-Pair Systems (a) Cytosine-Guanine and (b) Thymine-
Adenine (Reprinted with permission from ref. 114. Copyright 2010 American Chemical
Society).

biological systems with considerably high accuracy and low computational expense.
By using DFT based reactivity indices (namely, chemical potential, hardness,
softness and electrophilicity index) of the nucleic acids base pairs they concluded
that (i) the A-T base pair has a larger hardness (Z) than the G-C pair, indicating
that in gas phase the former should be more stable than the latter, and (ii) the G-C
base pair possesses a bigger electrophilicity index (w), indicating that it has better
capability to accept electrons than the other pair, in agreement with the experimental
finding.328 However, in their study they confined into the Single-Base-Pair
Systems only.
In a very recent study, Barrientos-Salcedo et al.,329 successfully reproduced
experimental findings of reactivity segment as well as the reactive atomic sites of
TP53 using DFT based reactivity descriptors. Therein, PNC-27 peptide derived
amino acid sequence PPLSQETFSDLWKLL (aa 12-26)330 was analyzed in three
fragments: PPLSQ, ETFS, and DLWKLL (with carboxyl terminal ends in all cases).
The chemical structure of the amino acids 12–26 (1Q2F, DOI: 10.2210/pdb1q2f/pdb)330
was taken from the Protein Data Bank. The chemical structures of the three fragments
studied in this work are shown in Fig. 4, while the convention of atom-numbering for
heavy atoms in this study is shown in Fig. 5. They revealed329 that PPLSQ, ETFS, and
DLWKLL fragments studied, have important electrophilic sites such as Q16 (C71),
D21 (C12), E17 (C17), P13 (C19), L26 (C103), S15 (C52), S20 (C53), L14 (C33), T18
(C18) and L25 (C82), suggesting that these amino acids are exposed to nucleophilic
attacks on these atoms. Also, from the negative charge on nitrogen atoms such as Q16
(N76 and N59), K24 (N80), E17 (N1), D21 (N1), S20 (N42), and W23 (N23) and
oxygen atoms S20 (O57), T18 (O24), S15 (O56), D21 (O15 and O16), and Q16 (O75),

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Fig. 3 Ten different Triple-Base-Pair Systems of B-DNA (PDB ID: 1BNA)317 (Reprinted with
permission from ref. 114. Copyright 2010 American Chemical Society).

respectively, they observed329 that these have larger negative charges as compared with
the remainder of the atoms; therefore, electrophilic attacks might occur on these sites
as well. These results are consistent with the experimental result of Kanovsky et al.,331

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Fig. 4 Images showing (A) TP53 protein, (B) amino acids 12–26 of TP53 protein (shaded
circle) and penetratin and (C) fragments analyzed in ref. 329 (ball and stick model) (Reprinted
with permission from ref. 329. Copyright 2010 American Chemical Society).

and reinforce the proposal that the segment (17–20, ETFS) is essential for the
biological effect.
From the global reactivity descriptors values for the fragments, such as ionization
20 157
potential (IP), hardness (Z) (i.e., Z ¼ IPEA
2 ), electrophilicity index (w)(eqn (34)),
2
and the spatial extent measured though the hR i, Barrientos-Salcedo et al.
observed329 that the ETFS fragment exhibits a larger value for ionization potential,
which might be related with the greater global chemical stability of these fragments,
i.e., larger ionization potential values may indicate smaller oxidative effects, and they
observed that PPLSQ and DLWKLL show a decreasing potential order. Moreover
from the hydrogen atom charges, they concluded that these atoms might be forming
hydrogen bonds (i.e., intramolecular interactions), which might contribute in
increasing the stability of these (i.e., PPLSQ and DLWKLL) peptides structures.
Furthermore, results of the frontier molecular orbitals (HOMO–LUMO) and
electrostatic potential surfaces revealed329 the possible reactive sites of the amino
acid fragment.
Until now, attention was focused only on the fragment-based approach. On the
basis of an energy perturbation method, Li and Evans332,333 presented a slightly
different formulation, indicating that, for a hard reaction, the site of minimal Fukui
function143,179,181,307,334,335 is preferred, whereas for a soft reaction, the site of
maximal Fukui function is preferred. In a contribution, Li and Evans quantified
the chemical reactivity of C3 of phosphoenolpyruvate (PEP).333 PEP is involved in a
number of important enzymatic reactions, i.e., 5-enolpyru-vylshikimate 3-phosphate
(EPSP) synthase, an enzyme of the shikimate pathway in plants; 3-deoxy-D-manno-
2-octu-losonate-8-phosphate (KDO8P) synthase, an enzyme of the glycolysis;
2-dehydro-3-deoxyphosphoheptonate aldolase (DAHP, also referred to as
DHAP).336–342 During the reaction catalyzed by EPSP synthase339,340 (Fig. 6, path I),
C3 of PEP is protonated during initiation of the reaction, which implies, that
this carbon is a hard base (because a proton is believed to be a hard acid). In
contrast to the EPSP synthase-catalyzed reaction, in the KD08P synthase-catalyzed
reaction341,342 (Fig. 6, path II), this same carbon acts as a soft base and is used to

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Fig. 5 Convention used in numbering heavy atoms of atomic charges in ref. 329 (ball and stick
model) (Reprinted with permission from ref. 329. Copyright 2010 American Chemical Society).

attack an aldehyde carbon, which is believed to be a soft base, of the cosubstrate of the
enzyme. As in the KD08P synthase catalyzed reaction, a soft base at C3 is needed for
the reaction catalyzed by DAHP synthase to attack the carbonyl carbon336–338 (Fig. 6,
path III). Conceptual DFT leads to hypothesis that this dual nature of C3 of PEP
depends on the ionization state of PEP and on the conformation of the dihedral angle
between the carboxylate and the C2–C3 double bond. The charge and f( r)
(the Fukui function is approximated by HOMO density divided by two307) of the
C3 atom change when the conformation of the molecule varies.
The gas-phase proton affinity of the amino acids was investigated by Baeten
et al.,343 where electronegativities and hardnesses were determined for artificially
constructed amino acid groups, in both the a-helix and b-sheet conformations.
Group hardness344–351 (by using Z ¼ IPEA 2 ) was found to play the dominant role,
whereas group electronegativity (by using eqn (10)) only had a minor influence on
the sequence.343
As an example of how the Conceptual DFT have predicted reactivity of ligands for
the NCp7 Zn fingers, Rice and co-workers studied,158,352 via f(r) (eqn (43))143,179,181,307
 143
and s (r) (eqn (48)), the regional reactivity of the two retroviral zinc fingers of
the HIV-1 nucleocapsid p7 (NCp7) protein, representing antiviral targets. Regional
reactivity is displayed spectrally on the solvent-accessible surface of the Zn fingers
(Fig. 7). The reactivity spectrum corresponds to the Fukui function which probes the
regions of the Zn fingers most able to donate electron density and thus participate in

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Fig. 6 Schematic representation of three enzymatic reactions that use the enolpyruvyl moiety
of PEP. The arrow in the structure of PEP indicates the rotation of the carboxylate group of the
molecule around the single bond. Structures in parentheses indicate intermediates observed
experimentally; structures in brackets indicate intermediates proposed here that are not yet
observed. Path I is the 5-enolpyruvyl-shikimate-3-phosphate (EPSP) synthase catalyzed reac-
tion; path II is that 3-deoxy-D-manno-2-octulosonate-8-phosphate (KD08P) synthase catalyzed
reaction; and path III is the 3-deoxy-D-arabinoheptulosonate-7-phosphate (DAHP) synthase
catalyzed reaction (Reproduced from ref. 333 with permission. Copyright 2010 National
Academy of Sciences, U.S.A.).

Fig. 7 NCp7-ligand docking arrangements. Ligand atom coloring: (A) Finger 1 (B) Finger 2
orientations (Reproduced from ref. 158 with permission. Copyright 2010 National Academy of
Sciences, U.S.A.).

covalent bond formation. The regions of both Zn fingers prove that the Cys thiolates
dominate the reactivity profile of NCp7. The reactive sites of finger 2 form a more
contiguous reactive surface in comparison to finger 1, where they appear more
isolated. On the basis of the sum of the thiolate Fukui indices, the reactivity of finger
2 was predicted to be greater than that of finger 1. The thiolate of Cys 49 in the
carboxyl terminal finger 2 turns out to be the most susceptible to electrophilic attack,

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providing a rationale for experimental evidence for antiviral agents that selectively
target retroviral nucleocapsid protein Zn fingers.
In the catalytic reaction of serine proteases the basicity of a histidine and
the nucleophilicity of a serine together with an aspartate residue belonging to the
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‘‘catalytic triad’’ (Asp32-His64-Ser221 for subtilisin), are of great importance. The

influence of amino acid substitution on the basicity and the nucleophilicity of these
important amino acids was investigated by Baeten et al.353 In the proteolysis of
peptides by serine proteases, a nucleophilic attack by the hydroxyl oxygen (Og) of
Ser221 at the carbon atom of the scissile peptide bond occurs when simultaneously
the hydroxyl proton of the catalytic Ser221 is transferred to the Ne2 atom of His64
[Fig. 8, X-ray Structure of subtilisin BPN (PDB code: 2ST1)354–357]. As a possible
reactivity index for the serine nucleophilicity both local softness143 and local
hardness230–232 were looked at.353 They found that local softness (eqn (48)) is not
suitable for describing the nucleophilicity of Ser221. Local hardness, approximated
by the minimum of the MEP, V(R)  min, and the atomic charge q(k) for the serine
hydroxyl oxygen (Og), however performs very well. The basicity of the histidine was
studied using the charge (q) on the basic nitrogen atom (i.e., Ne2) and the
‘‘protonation energy’’ DE (the difference between the energy of the model system
with the histidine protonated on the Ne2 atom and the energy of the model system
having an unprotonated histidine). The diminished basicity of histidine in the
aspartate mutants also was reflected in decreased q of Ne2and DE values.
Mignon et al.358 also used local hardness230–232 approximated by atomic charge
(i.e., Mulliken charge) for explaining nucleophilicity of the 2 0 -hydroxyl in the Active
Sites of RNase A (bovine pancreatic ribonuclease A) (EC 3.1.27.5)359 and RNase
T1 (EC 3.1.27.3).360,361 They have shown that the negative charge build up on the

Fig. 8 Schematic drawing of subtilisin, side chains of the residues of importance in ref. 353 are
shown (X-ray Structure of subtilisin BPN (PDB code: 2ST1))354 (Reprinted from ref. 353.
Copyright 2010, with permission from Elsevier Publications.).

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2 0 -oxygen atoms upon substrate binding. The increased nucleophilicity results from
stronger hydrogen bonding to the catalytic base, which is mediated by a hydrogen
bond from the charged donor.
On the basis of the group softness (sum of the local softness143 of the involved
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atomic centers),344,346,349,362 conceptual DFT studies by Rivas et al. have led to the
suggestion of a direct hydride transfer between the reactive regions in nicotinamide
and lumiflavine.363,364 Different atomic centers of lumiflavine and nicotinamide were
tested, but the smallest difference in group softness was found between the C3, Ht,
and C5 atoms of nicotinamide and the C4a, N1, and N5 atoms of lumiflavine,
supporting the hydride transfer365–371 between these regions (Fig. 9)363 In the
lumiflavine molecule, the local electrophilicity255 (i.e., w+(k); eqn (75)) of the N5
atom is higher than the local electrophilicity of the N1 and C4a atoms. So, the N5
atom will most likely receive the hydride ion. When N1 is protonated, the local
electrophilicity of N5 increases almost 4-fold, while, when N5 is protonated, the
electrophilicity of C4a increases 10 times. As such, protonation of N1 leads to
hydride transfer to C4a via N5.
In the series of subsequent papers, Roos et al.364,372–375 scrutinizes the experi-
mental findings of the enzymatic reaction mechanism of Staphylococcus aureus
arsenate reductase (ArsC) within the Conceptual DFT framework. The ArsC gene
product from Staphylococcus aureus pI258 plasmid, has a low-molecular-weight
phosphatase (LMW PTPase) anion-binding motif376 known as the P-loop. The
amino acid sequence of this ligand-binding loop in pI258 ArsC is Cys10–Thr11–
Gly12–Asn13–Ser14–Cys15–Arg16–Ser17.376 The first step in the multistep catalytic
mechanism of ArsC consists of a nucleophilic displacement reaction carried out by Cys10
on arsenate, by which a covalent Cys10–arseno adduct is formed (Fig. 10, step 1).377 In
the second step, another nucleophile, Cys82, attacks the covalent Cys10–arseno
adduct, thereby leading to the release of arsenite and the formation of a
Cys10–Cys82 disulfide bridge (Fig. 10, step 2).376,378–380 After the second reaction
step (Fig. 10, step 2), when the Cys10–Cys82 disulfide intermediate has been formed,
the conformation of the redox helix is changed into a transitional conformation

Fig. 9 Hydride transfer reaction between lumiflavine and 1-methylnicotinamide (NH) (Reprinted
from ref. 363. Copyright 2010, with permission from Elsevier Publications. Reprinted with
permission from ref. 364. Copyright 2010 American Chemical Society).

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Fig. 10 Scheme of the reaction mechanism of PI258 ArC. (1) The reaction starts with the
nucleophilic attack of Cys10 on arsenate leading to a covalent enzyme-arseno intermediate. (2)
Arsenite is released after the nucleophilic attack of the thiol of Cys82. A Cys10–Cys82
intermediate is formed, and the redox helix partially unfolds. (3) At the end of the reduction
cycle, Cys89 attacks Cys82, forming a Cys82–Cys89 disulde. The redox helix is looped out and
presents the disulde bridge at the surface of the enzyme to thioredoxin. (4) Thioredoxin
(Trx) regenerates the reduced form of arsenate reductase for a subsequent catalytic cycle.
(Reproduced from ref. 386 with permission. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.
And reprinted with permission from ref. 364. Copyright 2010 American Chemical Society).

between a helix and a loop (Fig. 10).379,380 The subsequent third reaction step (Fig. 10,
step 3) consists of the nucleophilic attack of Cys89 on the Cys10–Cys82 disulfide, a
process resulting in the formation of the Cys82–Cys89 disulfide and the reduction of
Cys10.381 Thioredoxin (Trx) converts oxidized ArsC back to its initial reduced state382
(Fig. 10, step 4) through a subsequent catalytic cycle (Fig. 11). Thioredoxins are
proteins that act as antioxidants by facilitating the reduction of other proteins by
cysteine thiol-disulfide exchange.382 All thioredoxins have a similar three-dimensional
fold comprising a central core of four b-strands surrounded by three a-helices.383
They also feature a conserved active-site loop containing two redoxactive cysteine
residues in the sequence Trp–Cys–Gly–Pro–Cys384 numbered as Trp28 to Cys32 in both
Bacillus subtilis (Bs_Trx) and S. aureus (Sa_Trx) Trx.364,372–375 Cys29Trx nucleophilically
attacks Cys89ArsC of the Cys82ArsC–Cys89ArsC disulfide, leading to the reduction of
Cys82ArsC and the formation of the Trx–ArsC mixed disulfide intermediate complex
between Cys29Trx and Cys89ArsC (Fig. 10 and 11A).382,385 In this complex, Cys32Trx
performs a nucleophilic attack on Cys29Trx of the Cys29Trx–Cys89ArsC disulfide

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Fig. 11 Bs_Trx reduces Bs_ArsC via an intermediate Trx–ArsC complex. (A) Cys29Trx of
reduced Bs_Trx nucleophilically attacks Cys89ArsC of the Cys82ArsC–Cys89ArsC disulfide of
oxidized Bs_ArsC, leading to the formation of the mixed Cys29Trx–Cys89ArsC disulfide. (B and C)
Cys32Trx performs a nucleophilic attack on Cys29Trx, leading to the release of reduced Bs_ArsC
and oxidized Bs_Trx (Reproduced from ref. 375).

(Fig. 11B). Accordingly, the Trx–ArsC complex dissociates, releasing reduced ArsC and
oxidized Trx (Fig. 11C).
To implement the Conceptual DFT for describing pI258 ArsC enzyme, one needs
an adequate model, combining accuracy with computational tractability. Ross et al. in
their studies applied an interesting modeling technique.372–375 For electrophile, the
model system of choice was constructed starting from the X-ray structure of the
Cys15Ala mutant of ArsC complexed with arsenite (product of the first reaction step,
PDB 1LJU).379 Their model included the complete conserved catalytic sequence motif,
Cys10-X-X-Asn13-X-X-Arg16-Ser17, since the backbone amides of this substrate
binding loop form hydrogen bonds with the oxygen atoms of the substrate. Amino
acids 10 and 17 were terminated respectively with –NH2 and –CONH2. The side
chains of residues 11, 12, 14, and 15 were terminated on a Ca, since they are positioned

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Fig. 12 Reduction of the X-ray structure of ArsC (PDB: 1LJU)379 to the WT model.
Partitioning of the WT model system of ArsC into two layers: high level represented in ‘‘Ball
& Stick’’; low level in ‘‘Tube’’. A similar division is made for the Asn13Ala and the Arg16Ala
mutants. Color code: hydrogen, white; nitrogen, blue; carbon, gray; oxygen, red; sulfur, yellow;
arsenic, purple (Reprinted with permission from ref. 373. Copyright 2010 American Chemical
Society).

at the periphery of the substrate binding loop where no interaction with the substrate
occurs. The three well positioned water molecules present in the active site of the PDB
structure 1LJU were incorporated. Dianionic arsenate was taken as substrate. The
resulting model is called ‘‘wild type (WT)’’ 372–375 (Fig. 12). The Ser17Ala Arg16Ala
and the Asn13Ala mutants were built ‘‘in silico’’,158 starting from the coordinates of
the WT model. The enzymatic environment of the Cys82 nucleophile was built by
using the coordinates from free wild-type ArsC (PDB file1LJL).379 Thr11 was
modelled by HOCH3 and the a-helix at residues 82–89 was taken as a whole and
was terminated on both sides with CONH2. For the Cys89 nucleophile, the
coordinates of the partially unfolded residue 82–89 helix were taken from the
Cys89Leu mutant (A chain in PDB file 1LK0).379 In both structures, hydrogen
atoms were placed and optimized.
The Conceptual DFT is used to assess the nucleophilic attack of Cys10 on arsenate
(Fig. 10 step 1). The difference in local softness (i.e., Ds(k) = |s(k)  s+(k)|) between
the attacking nucleophilic sulfur atom of Cys10 and the receiving electrophilic arsenic
atom of arsenate is minimal when dianionic arsenate was considered.372 In addition,
calculation of the binding energy showed that the binding of dianionic arsenate in
ArsC turned out to be more favorable than that of monoanionic arsenate.373
Moreover, in an another study Roos et al. demonstrated that both the Conceptual
DFT-based reactivity analysis and the calculated thermodynamics point to a
monoanionic Cys10–arseno adduct in ArsC prior to the nucleophilic attack by
Cys82.364,386 Conceptual DFT analysis indicates Ser17 to be the major activator
of the electrophilic Cys10–arseno adduct. Calculation of the nucleofugality (i.e.,
2
DEnucleofuge ¼ ðIP3EAÞ
8ðIPEAÞ )
167–169
indicates that the enzyme increases the leaving-group
capacity of OH (first reaction step) and of HAsO2 3 (second reaction step). Further,
on the basis of the correlation between the natural population analysis (NPA) charge
on the sulfur of the thiolate compound and the pKa of Cys82 and Cys89, Roos et al.
were able to explain why the presence of arsenate in the active site of ArsC brings
Arg16 within hydrogen bonding distance to Cys82, leading to an additional pKa
decrease of 0.95 pKa.374 Thus, the substrate itself contributes to the nucleophilic

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character of Cys82. Prior to the third reaction step, Cys89 is kept in the nonactive high
pKa form by the presence of the Cys82–Cys89 redox helix. This helix partially unfolds
when the Cys10–Cys82 disulfide is formed, thereby favouring the thiolate form of
Cys89 and enabling the third reaction step.386
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In a most recent study Roos et al.364,375 provided fresh insight into the mechanism
behind the dissociation of the mixed disulfide complexes between thioredoxin
(Trx)382 and its substrates. As a key model, the complex between Trx and its
endogenous substrate, arsenate reductase (ArsC), was used (Fig. 11).375 In this
structure, a Cys29Trx–Cys89ArsC intermediate disulfide is formed by the
nucleophilic attack of Cys29Trx on the exposed Cys82ArsC–Cys89ArsC in
oxidized ArsC. With DFT-based reactivity analysis, molecular dynamics
simulations, and biochemical complex formation experiments with Cys-mutants,
Trx mixed disulfide dissociation was studied by Roos et al.364,375 Information
regarding the selectivity of the nucleophilic attack was obtained from a DFT
based reactivity analysis.375 In the Trx–ArsC complex, four possible reactions
between the attacking nucleophilic cysteines (Cys32Trx and Cys82Trx) and
the accepting electrophilic disulde (Cys29Trx–Cys89ArsC) can be considered. The
minimal local softness143 difference (i.e., Ds(k) = |s(k)  s+(k)|) of the interacting
sulfur atoms favors the nucleophilic attack of Cys32Trx on Cys29Trx.375 By
228
studying the s+ k /sk of the sulfur atoms of the nucleophilic Cysteines in the
Bs_Trx–ArsC complex they found that the Cys29Trx –Cys89ArsC disulde is less
soft than Cys32Trx and Cys82ArsC, and Cys32Trx is softer than Cys82ArsC.375
The high reactivity of Cys32Trx toward the Cys29Trx–Cys89ArsC disulde is
consistent with the lower softness of Cys32Trx compared to Cys82Trx. On the
basis of the fk+/fk, it was found that Cys29Trx was more susceptible to nucleophilic
attack than Cys89ArsC.375

4. Conclusion
The study of regioselectivity remains a very important topic in the chemical
literature. Thousand of papers have appeared in this topic, and interest in it is
accelerating. Furthermore, not only are the methodologies for experimentation
steadily improving, but also the content of the theory is still evolving. In DFT,
the big advantage is that the electron number, N, has a central place in the theory. A
great strength of the density functional language-augured Conceptual DFT—is its
appropriateness for defining and elucidating important universal concepts of
molecular structure and molecular reactivity. By now there is powerful evidence
that the Conceptual DFT here used, and here extended, provides not only a correct
quantitative description of molecular electronic structure but also a description
generally in full agreement with a lot of previous work in the chemical literature.
Accurate prediction of regioselectivity of large chemical and biological systems
has its bottleneck in the computational limitation (because the computation is to be
performed on the molecule as a whole). Although the world has witnessed a
manifold rise in computational power, a direct calculation of the properties of a
middle-sized protein from a good wave function is still considered to be almost
impossible, at least in the foreseeable future, unless new methodologies are developed.
Thus, detailed physical descriptions of large and complicated biological molecules for
the purpose of understanding and modulating their biological functions require more
intensive efforts than ever.

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Motivated by its potential importance and guided by the insights (as described in
section 2) of the present report, the authors have given one simple fragmentation
(One-into-Many model114,115) approach. This model may be considered as the first
one, which describes how Conceptual DFT based reactivity descriptor can be used to
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systematically address the regioselectivity problem of large chemical and biological

systems. The reactivity descriptor, used in this model as a key tool, is local hardness
[Z(r)] because it’s predominant component is electronic contribution to the molecular
electrostatic potential (MEP). MEP has a long distance effect, thus making it
suitable for predicting intermolecular reactivity and so fitting the proposed model.
However, Z( r) (or better it’s condensed form, Z(k)) suffers from one severe limitation
and that is it’s N-dependence problem.252 In case of studying the regioselectivity
(using One-into-Many model) of DNA systems114,115 N-dependence problem was
solved automatically as the number of electrons in all base-pairs (whether it is ‘single’
or ‘triple’ or higher base-pair systems) are same (may be nature has created base
pairs like this!!!). To, solve this N-dependence problem the present authors have
suggested to consider only those moieties in different systems for which the number
of electrons is same (e.g., CQO moiety, when intermolecular reactivity of carbonyl
compounds are studied).252 But, this is not a general solution, applicable to all kinds
of systems. So, to make One-into-Many model widely applicable, it should be based
on a descriptor, which has the essential quality of taking care of intermolecular
reactivity aspects and at the same time N-dependence problem removed analytically.
The present authors are working on it and hope to find such a descriptor soon.

Acknowledgements
The authors are extremely grateful to B. M. Deb, D. Mukherjee, S. Pal, K. Hirao,
P. Geerlings and P. W. Ayers. This goal would not have been attainable without the
intellectual support and the fruitful exchange of ideas of numerous teachers,
colleagues, coworkers, theoreticians as well as experimentalists, from the BITS-
Pilani, India, as well as from numerous other countries. R.K.R. wish to express his
deepest sense of gratitude and sincere thanks to them: P. Bultinck, P. Bagaria, A. K.
Chandra, K. R. S. Chandrakumar, P. K. Chattaraj, R. Ch. Deka, M. Durga Prasad,
S. R. Gadre, S. K. Ghosh, M. K. Harbola, E. D. Jemmis, S. Krishnamurty,
A. Kumar, D. Kumar, W. Langenaeker, B. K. Patel, J. Paulovič, F. de Proft,
P. Purkayastha, P. U. Manohar, G. Narahari Sastry, N. Tajima, V. Usha and
N. Vaval. S.S. acknowledges R. Goswami, Md. S. Alam and T. K. Roy for their
helping hand. R.K.R. is greatly indebted to Prof. G. Webb for requesting him to
write this article. Finally, the senior author gratefully acknowledges research support
to DST (Project Ref. No. SR/S1/PC-41/2008) and Departmental Research Support
under University Grants Commission (UGC) Special Assistance Programme (SAP)
[Project Ref. No. F. 540/14/DRS/2007 (SAP-I)], Government of India. S. S. thanks
CSIR, New Delhi, India for granting him Senior Research Fellowships.

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