Accepted Article

Title: Electrostatics and Polarization in σ- and π-Hole Noncovalent

Interactions: An Overview

Authors: Peter Politzer and Jane S. Murray

This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.

To be cited as: ChemPhysChem 10.1002/cphc.201900968

Link to VoR: http://dx.doi.org/10.1002/cphc.201900968

A Journal of

www.chemphyschem.org
ChemPhysChem 10.1002/cphc.201900968

Electrostatics and Polarization in σ- and π-Hole Noncovalent Interactions: An Overview

Peter Politzer and Jane S. Murray

Department of Chemistry
University of New Orleans
New Orleans, LA, 70148, U.S.A.

Accepted Manuscript
Abstract

The energetics of σ- and π-hole interactions can be described very well in terms of
electrostatics and polarization, consistent with their Coulombic natures. When both of these
components are taken into account, very good correlations with quantum-chemically computed
interaction energies are obtained. If polarization is only minor, as when the interactions are quite
weak, then electrostatics can suffice, as represented by the most positive electrostatic potential
associated with the σ- or π-hole. For stronger interactions, the combination of electrostatics plus
polarization is very effective even for interaction energies considerably greater in magnitude than
what is normally considered noncovalent bonding. Several procedures for treating polarization
are summarized, including the use of point charges and the direct inclusion of electric fields.

Keywords:
Electrostatic potentials, polarization, noncovalent interactions, σ-hole interactions, π-hole
interactions.

E-mail: ppolitze@uno.edu

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

1. The Molecular Electrostatic Potential

In the context of molecular recognition, a particularly important property of a molecule is the
electrostatic potential V(r) that its nuclei and electrons create at every point r in the surrounding
space. V(r) is given rigorously by eq. (1),

ZA ρ(r)dr
V(r)    (1)
RA  r r  r

Accepted Manuscript
A

in which ZA is the charge on nucleus A, located at RA, and ρ(r) is the molecule’s electronic
density.
The sign of V(r) at any r depends upon whether the positive contribution of the nuclei or the
negative one of the electrons is dominant there. The significance of the electrostatic potential is
in relation to interaction energy. For instance, if a point charge Q is placed at the position r, then
the energy of interaction ΔE between the molecule’s static charge distribution and Q is ΔE =
QV(r). If Q and V(r) have opposite signs, then ΔE is negative and the interaction is favorable; if
they have the same sign, ΔE is positive and the interaction is unfavorable.
The negative gradient of V(r) is the molecule’s electric field ε(r): ε(r )  V(r ) . The
significance of the electric field is in relation to the force F(r) that the molecule exerts upon Q:
F(r )  Qε(r )  QV(r) . Both ε(r) and F(r) are vectors. If the interaction is favorable, then
the force exerted upon Q by the molecule is attractive. All of these relationships are simply
forms of Coulomb’s Law.
It follows that when two molecules approach each other, there will be a general tendency
for the regions of positive V(r) on each molecule to be attracted to those of negative V(r) on the
other. The molecules will “recognize” that this will lead to favorable interactions.
Two features of molecular electrostatic potentials need to be emphasized:
(1) The electrostatic potential is a real physical property, an observable. It can be
determined experimentally, using diffraction techniques,[1-3] as well as computationally.
The electrostatic potential should not be confused with atomic charges, which have no
physical basis and are arbitrarily defined in various ways.[4]
(2) As eq. (1) shows, while the contributions of the nuclei and electrons to V(r) increase as
they are closer to r, V(r) does reflect all of the nuclear and electronic charge in the entire
molecule.[5-9] One consequence of this is that the sign and magnitude of V(r) in a
particular region do not necessarily correlate with just the electronic density in that
region; e.g. “electron-rich” does not always imply negative V(r). The nuclear
contribution must also be considered. For example, the internuclear regions of covalent
bonds typically have buildups of electronic density,[3,10] but the electrostatic potentials in
these regions are usually positive,[1,5,11] due to the nearby nuclei.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

2. Noncovalent Interactions: σ-Holes and π-Holes

The use of computed electrostatic potentials in analyzing molecular reactive behavior was
pioneered by Scrocco, Tomasi and their colleagues.[12-15] The relevance to understanding
noncovalent interactions was recognized very early. Already in 1975, referring to hydrogen
bonding, Kollman et al concluded that “the electrostatic potential is a powerful tool in

Accepted Manuscript
understanding H bonds.” [16] In the years to follow, applications to noncovalent interactions,
especially in biological systems, increased dramatically, as reviewed elsewhere.[2,11,17-19]
A unifying pattern to many of these interactions eventually emerged through the concepts of
σ-holes and π-holes. These terms refer to the fact that covalently-bonded atoms tend to have
anisotropic electronic densities, with regions of higher and lower density.[20-27]
An isolated free atom has, on the average, a spherically-symmetrical electronic density[28]
that decreases monotonically with distance from the nucleus.[29] The electrostatic potential that
is created by its nucleus and electrons is positive everywhere (dominated by the nucleus) and
also decreases monotonically from the nucleus.[30]
When atoms interact to form covalent bonds, however, they lose their spherical symmetry;
their electronic densities become higher in some regions, lower in others.[20-27] For example,
there is typically lower electronic density on the side of an atom opposite to one of its covalent
bonds, on the extension of that bond. Evidence of this is that the radius of the atom in that
direction is less than its radius to a lateral side.
Such a region of lower electronic density on the extension of a bond has been labeled a
σ-hole.[31] Atoms that are involved in more than one covalent bond may have a σ-hole on the
extension of each. There is also frequently a lower electronic density above and below a planar
portion of a molecule, such as a trigonally-bonded atom or an aromatic ring with strongly
electron-withdrawing substituents. This is called a π-hole.[32]
There are often (not always) positive electrostatic potentials associated with σ- and π-holes,
which can lead to attractive Coulombic interactions with negative sites, such as lone pairs, π-
electrons and anions. These are known as σ-hole and π-hole interactions, even though the actual
interactions are not with the σ- or π-holes but rather with the resulting positive electrostatic
potentials.
Such noncovalent interactions have been known for many years, long before σ-holes and π-
holes were identified, and they are of considerable importance in areas ranging from crystal
engineering to pharmacology to molecular biology. Numerous reviews discuss the interactions
and their applications.[9,20,33-42]

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

3. σ-Hole and π-Hole Electrostatic Potentials

In using electrostatic potentials to analyze noncovalent interactions, it is now customary to
compute V(r) on the “surfaces” of the molecules, taking these to be outer contours of their
electronic densities as suggested by Bader et al.[43] These surfaces have the advantage that they
are specific to the particular molecules, and reflect features such as lone pairs, π-electrons and
atomic anisotropies. The 0.001 au contour is commonly used to define molecular surfaces,
although other outer contours, e.g. the 0.0015 or 0.002 au, would show the same trends.[44] The
0.001 au surfaces are typically beyond the van der Waals radii of the atoms in the molecules,[45]

Accepted Manuscript
and the electrostatic potentials on these surfaces are accordingly representative of what an
approaching molecule “sees.”
When V(r) is computed on the 0.001 au surface, it is labeled VS(r). Its local maxima and
minima, i.e. its most positive and most negative values, are designated by Vs,max and VS,min,
respectively. There may be several of each.
It should be kept in mind that the VS,max and VS,min are local maxima and minima only on the
0.001 au contour; they are not spatial maxima and minima. It was shown by Pathak and Gadre
that there are no spatial maxima of V(r) other than by the nuclei.[46] Spatial local minima, on the
other hand, are not precluded but they are not normally on the 0.001 au contour; they are usually
within this contour (although sometimes external to it for regions of π electrons[47]).
Examples of molecular surface electrostatic potentials are shown in Figures 1-3. These were
computed at the density functional B3PW91/6-31G(d,p) level, using Gaussian 09[48] and the
WFA-SAS code.[49]
In Figure 1 is V(r) for F2C(H)Br, 1. It shows the positive potentials associated with the
bromine and hydrogen σ-holes, on the extensions of the C-Br and C-H bonds. It is through these
positive regions that the hydrogen and bromine can interact with negative sites. In this example,
the hydrogen is expected to interact more strongly, because the potential due to its σ-hole is more
positive; its VS,max is 32.2 kcal/mol, vs 16.5 kcal/mol for the bromine.

Hydrogen bonding is a σ-hole interaction.[39,50-53] However since the one electron of the
hydrogen is primarily involved in its bond, the positive region on the hydrogen is essentially
hemispherical, Figure 1, in contrast to the more focused positive region on the bromine. Thus
the σ-hole interaction of bromine with a negative site Y, C-Br---Y, is likely to be more linear
than the hydrogen bond C-H---Y. Furthermore, the bromine can also interact favorably with a
positive site, through its negative lateral sides.[54-56]

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

In Figure 2 is V(r) for Se(Cl)CN, 2. There are two VS,max on the selenium, with magnitudes
of 43.2 and 37.8 kcal/mol, corresponding to the σ-holes on the extensions of the Cl-Se and
NC-Se bonds, respectively. There is also a weaker VS,max, 15.8 kcal/mol, on the chlorine, due to
the Se-Cl bond.
Atoms in heterocyclic rings can also have positive σ-hole potentials.[42,57,58] If the atoms are
adjacent to each other, their positive regions may overlap with the result that there is just a single
VS,max, at a point intermediate between the two atoms. What is particularly notable is that
interactions with negative sites are through this positive potential, not with either of the two

Accepted Manuscript
atoms.
Figure 3 displays VS(r) for the planar molecule Cl2C=O, 3. There is a π-hole above and
below the carbon, resulting in VS,max of 22.7 kcal/mol. The chlorines also have VS,max, 18.9
kcal/mol, arising from the σ-holes on the extensions of the C-Cl bonds.
π-Holes are also frequently associated with aromatic and other cyclic structures that have
strongly electron-withdrawing substituents.[38,40,57-59] If such a structure has more than one
π-hole, the positive regions may again overlap, producing a single VS,max through which
interactions with negative sites then occur.[58,60]

4. Polarization
Eq. (1) gives the exact electrostatic potential of a molecule for a fixed nuclear configuration
and for the static electronic density corresponding to ρ(r). These are typically taken to be the
nuclear configuration and electronic density of the free molecule in its equilibrium ground state,
prior to interaction.
However as two molecules approach and interact to form a noncovalent complex, the
electric field of each molecule increasingly polarizes the charge distribution of the other. Thus
the V(r) computed for the free molecules gradually become somewhat less meaningful as the
molecules approach each other. Polarization is an intrinsic, stabilizing part of a Coulombic
interaction, along with electrostatics.[8,32,39,51,52,61-67] The degree to which each molecule
undergoes polarization depends upon its polarizability and upon the strength of the electric field
to which it is subjected. In many instances, the extent of polarization is relatively minor.
However it can also be quite significant. An external electric field can cause a σ-hole potential to
become more positive or more negative, and can even induce a positive potential.[51,62]
Accordingly, an interaction that would be unfavorable in terms of the electrostatics of the
free unperturbed molecules may actually be favorable when polarization is taken into account.
Two examples are the σ-hole interactions of H3CCl and H3P. The electrostatic potentials
associated with the σ-holes of the chlorine in H3CCl and the phosphorus in H3P are actually near-
neutral or even slightly negative (depending upon the computational procedure) and accordingly
would not be expected to interact attractively with negative sites. Nevertheless the complexes
H3CCl---O=CH2[68] and H3P---NSH[69] have both been found computationally to have favorable

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

interaction energies. The electric fields of O=CH2 and NSH evidently induce positive σ-hole
potentials on the chlorine and phosphorus.
Further examples are counterintuitive attractive positive/positive or negative/negative
interactions.[7,70 ] For instance, 1,4-difluorobenzene, 4, has a negative potential above and below
the ring, yet it interacts favorably with the nitrogen lone pair of HCN.[7] 1,3,5-trifluorobenzene,
5, has a positive potential above and below the ring but interacts favorably with the hydrogen of
HCN. The electric fields of the negative and positive ends of HCN induce ring potentials of the
opposite signs.

Accepted Manuscript
The effects of polarization can be seen by plotting the “density difference” Δρ(r), i.e. the
difference between the electronic density of the complex and the sum of the superposed
electronic densities of the free molecules at the same separation as in the complex:[61,71,72]
Δρ(r) = ρ(r)A---B – [ρ(r)A + ρ(r)B] (2)
Δρ(r) shows how the free molecule electronic densities were changed by polarization as they
formed the complex.
Another approach to showing polarization was taken by Tomasi et al[17,73] and later Alkorta
et al.[74,75] Invoking the fact that V(r) is equal in magnitude to the energy of interaction of a unit
positive point charge at r with the static (unpolarized) electronic distribution of the molecule,
and taking the total interaction energy ΔE to be the sum of the electrostatic and polarization
contributions, they expressed the polarization energy P(r) at any point r as,
P(r) = ΔE(r) – V(r) (3)
By using some quantum chemical procedure to compute V(r) for the isolated free molecule and
ΔE(r) for its total interaction energy with a unit positive point charge at any point r, it possible to
evaluate and map P(r).[17,73-75] Tomasi et al also presented an approximate formulation of P(r)
based upon dividing the molecule into fragments.[17,73]
Polarization energy can be determined directly by applying second-order perturbation
theory.[76-79] Francl showed that including the polarization contribution can allow prediction of
sites for nucleophilic as well as electrophilic attack,[78] whereas V(r) alone is generally effective
only for the latter.[80]

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

In related work, Bartlett and Weinstein used double perturbation theory to show how the
polarization of a molecule resulting from its interaction with a point charge Q at one site affects
the molecule’s reactivity toward a second charge Q’ at another site.[81] This was subsequently
extended to interactions with molecules.[82,83] A detailed analysis of the early (but still relevant)
efforts to take polarization into account via perturbation theory was given by Politzer and
Daiker.[11]

5. Interaction Energies and Electrostatic Potentials

Accepted Manuscript
The total interaction energy ΔE for molecules A and B forming a complex A---B is given in
terms of the respective energies by eq. (4):
ΔE = E(A---B) – [E(A) + E(B)] (4)
The more negative is ΔE, the stronger is the interaction.
The electrostatic potentials associated with σ- and π-holes are typically positive and have
local maxima VS,max, although there are exceptions,[8,36,42] as mentioned above. For instance, the
σ- and π-holes of covalently-bonded C, N, O and F atoms sometimes have negative potentials
(although less negative than the surrounding surface regions). A second-row atom, such as
phosphorus or chlorine, may have a near-zero σ- or π-hole potential if the remainder of the
molecule is not sufficiently electron-withdrawing. Positive σ- or π-hole potentials in close
proximity may overlap, resulting in just one VS,max located at an intermediate point.
In most instances, however, the regions of positive electrostatic potential due to σ- and
π-holes do have individual VS,max. One can therefore pose the question: Can the interaction
energies for a series of σ- or π-hole interactions with the same negative site be correlated with the
VS,max associated with the σ- or π-holes? Alternatively, can the interaction energies for a series
of negative sites with the same σ- or π-hole be correlated with the VS,min of the negative sites?
In principle the answer should be no, since the VS,max and VS,min are normally computed for
the free molecules in their equilibrium states, prior to interaction, and accordingly do not reflect
polarization. Furthermore, the interactions are not just with single points (the VS,max or the
VS,min); they can involve other parts of the molecules as well. There may be significant
secondary interactions that the VS,max and VS,min do not reflect.[32,84,85] For instance, consider the
σ-hole interactions of the bromines in 6 and 7 with the oxygen of acetone. Before the
interactions, the bromine VS,max is more positive in 6 than in 7, yet the interaction is stronger for
7.[84] This is because of the attraction between the negative potentials of the cyano nitrogens in 7
and the positive potentials of the acetone hydrogens, which complements the Br---O σ-hole
interaction.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

Accepted Manuscript
Nevertheless, quite good correlations have sometimes been obtained between ΔE and
VS,max,[35,36,40,84,86,87] or between ΔE and VS,min.[17,40] This is particularly likely when the
interactions are relatively weak, suggesting that the effects of polarization are minor.
A variation on this procedure that proved to be very effective was tested for the σ-hole
interactions of the hydrogens and bromines in HCN, BrCN, HCF3 and BrCF3 with the nitrogen
lone pairs of NH3 and HCN,[50] e.g. NCBr---NH3. Different C-H-N and C-Br-N angles were
considered. Instead of using the σ-hole VS,max on the 0.001 au surfaces, the potentials of the
unperturbed σ-hole molecules were computed at the positions R of the NH3 or HCN nitrogens in
the complexes at each angle. It was hoped that this V(R) would more accurately reflect what the
negative site actually “saw.” Excellent correlations were found between the computed
interaction energies and the V(R) at the positions of the nitrogens.[50] For 18 interactions with
NH3, the R2 was 0.986. For 32 with HCN, R2 = 0.990.
Brinck and Borrfors used the same approach for the σ-hole interactions of 20 organic
bromides with a Br- anion.[64] When the interaction energies were plotted against the potentials
of the unperturbed σ-hole molecules at the positions of the Br- anions in the complexes, the R2
was a very good 0.973.
Could the restriction to a constant negative site or a constant σ- or π-hole be dropped by
including both the VS,max and the VS,min? This has had some success, for weak interactions. For
a series of hydrogen bonds between different proton donors and acceptors, ΔE correlated with
the product (VS,max)(VS,min) with R2 = 0.931.[53] For two series of σ-hole interactions involving
various negative sites, double regression analyses using ΔE = c1VS,max + c2VS,min + c3 were found
to reproduce the computed ΔE with R2 of 0.94[36] and 0.91.[52] (The constants c1, c2 and c3 were
determined by the regression analysis.)
However sometimes, especially for stronger interactions, polarization is not insignificant
and electrostatics alone – specifically the VS,max and/or VS,min on the 0.001 au surface – is not
sufficient to explain the trends in the ΔE values. An example is the group of complexes
X3C-I---Cl- between trihalomethyliodide and a chloride ion.88,89 The interactions were found to
become stronger as the VS,max on the iodine became less positive in going from X = F to X = I.
This is exactly the opposite of what would be anticipated on the basis of electrostatics alone, and
it was argued that this demonstrates the incompleteness of the σ-hole explanation. What it
actually demonstrates, as shall be seen below, is the need to take the polarization of the X3C-I
into account; this should not be surprising, given that the negative site is an ion.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

Polarization in σ- and π-hole interactions has two components: They are due, respectively,
to the effect of the electric field of the σ- or π-hole molecule upon the negative site and the effect
of the electric field of the negative site upon the σ- or π-hole molecule. While both are typically
present in a σ- or π-hole interaction, their effects upon the electrostatic potentials of the σ- or π-
hole molecule and the negative site are obscured by the overlapping of the respective electronic
densities, as can be seen in Figure 4 for the π-hole complex between Cl2C=O and NH3.
Figure 4 shows that the electrostatic potential in the region between the π-hole and the
negative site is close to neutral. However the polarization of electronic density from the nitrogen

Accepted Manuscript
lone pair to the Cl2C=O is clearly evident from the changes in the VS,max on the surfaces of the
two molecules. The VS,max of the ammonia hydrogens become more positive, going from 25.5
kcal/mol in free ammonia to 28.8 kcal/mol in the complex. The VS,max of the carbon π-holes in
Cl2C=O are 22.8 kcal/mol; the VS,max of the non-interacting π-hole of the carbon in the complex
in Figure 4 is 13.6 kcal/mol. The VS,max of the chlorines also become less positive as electronic
density shifts from the nitrogen lone pair to the Cl2C=O, from 18.9 to 12.0 kcal/mol. In the next
two sections, we will discuss recent approaches to accounting for each of the two components of
polarization.

6. Polarizing Effect of the Negative Site

A very direct way of demonstrating the polarization induced by a negative site is to replace
that site by a negative point charge Q and repeat the quantum chemical calculation of the
electrostatic potential of the σ- or π-hole molecule. It was shown in this manner that a σ-hole
VS,max can be made significantly more or less positive by varying the magnitude of Q.[51,62] It was
also found that the presence of Q produces a change (increase or decrease) in the stretching
frequency of the bond to the atom with the σ-hole. Such blue shifts and red shifts have been
observed both experimentally and computationally.[90-93] Formalisms developed by
Hermansson[94] and by Qian and Krimm[95] allow them to be explained and predicted in terms of
the electric field of the negative site and the permanent and induced dipole moments of the
σ-hole molecule.[92,93] The effect of the point charge Q is consistent with this.
Clark and Hesselmann[65] used the point charge approach to address the apparent X3C-I---Cl-
contradiction mentioned above, that the interactions become stronger as the VS,max on the iodine
of the unperturbed X3C-I becomes less positive. In place of the chloride anion, they put a
negative point charge at the position of the anion in the complex and repeated the quantum
chemical calculation of the X3C-I electrostatic potential. This produced a polarized VS,max on the
iodine that was much more positive than that on the unperturbed free X3C-I molecule. (There is
no problem of overlapping electronic densities since a point charge has no electronic density.)
Clark and Hesselmann carried out this procedure for X = F, Cl, Br and I, and for each halide ion,
F-, Cl-, Br- and I-. When the computed interaction energies of all 16 actual complexes were
plotted against the polarized VS,max, an excellent correlation was obtained: R2 = 0.994. The
range of interaction energies was -19.0 to -49.8 kcal/mol. Clark and Hesselmann concluded that
“the Coulombic σ-hole concept is fully satisfactory for describing the interactions in these

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

10

complexes,” even when they are relatively strong.[65] It was simply necessary for the VS,max to
reflect polarization.
A similar procedure was applied to the interactions XY---Z- of dihalogen molecules XY with
halide anions Z- to give trihalide anions XYZ-.[66] The relationship between the computed
interaction energies and the VS,max on the Y atoms of the free unperturbed XY molecules was
very poor, as would be anticipated since it ignores the strong polarization induced by the anions;
the R2 was 0.35. However when the Z- anions were replaced by unit negative point charges and
the XY electrostatic potentials re-computed, the correlation between the interaction energies and

Accepted Manuscript
the polarized VS,max was much better, R2 = 0.958. The interaction energies were in the range -
11.7 to -62.7 kcal/mol.
Brinck and Borrfors undertook a more ambitious project, for 20 σ-hole interactions between
organic bromides and a Br- anion.[64] They sought not just a correlation with the computed
interaction energies but to actually reproduce them, by combining estimated electrostatic and
polarization contributions. The anion was treated as a negative point charge.
The results were remarkable. The relationship of the quantum chemically computed ΔE and
the sums of the approximated electrostatic and polarization contributions had R2 = 0.9995. It
passed through the origin and had a slope of 0.88; a slope of 1.00 would have meant exact
agreement. Brinck and Borrfors pointed out that they had not included the energies involved in
geometry changes in the σ-hole molecules, which averaged 0.6 kcal/mol; if these were included,
R2 would be 0.9990 and the slope would increase to 0.92.[64]
This study was particularly important because it confirmed that the interactions can be fully
described by electrostatics and polarization. Charge transfer from the negative site to the σ-hole
molecule, which is frequently invoked,[20,40,73,88,89,91,96,97] is not possible since a point charge has
no electrons to transfer.

7. Polarizing Effect of the σ- or π-Hole Molecule

As was discussed in section 5, good correlations have sometimes been found between
computed interaction energies and the VS,max of the free, unperturbed σ- or π-hole
molecules.[35,36,40,84,86,87] This implies that there is only minor polarization, and is particularly
likely when the interactions are relatively weak.
We have recently investigated the possibility of taking some account of at least the
polarization of the negative sites by including in these relationships not only the VS,max of the
unperturbed σ- or π-hole molecules but also their electric fields and the polarizabilities of the
negative sites.[87] An expanded version of that data base is in Tables 1-3.
In Table 1 are 20 complexes between five different molecules having σ-holes and the lone
pairs of four nitrogen bases that served as the negative sites. In Table 2 are eleven π-hole
complexes in which the nitrogen lone pair of HCN is the negative site, and in Table 3 are ten
more involving the nitrogen lone pair of NH3. Geometry optimizations and interaction energies

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

11

were obtained with Gaussian 09[48] at the MP2/aug-cc-pVDZ level; electrostatic potentials and
electric fields were computed with the B3PW91/6-31G(d,p) procedure, which has been shown to
be effective for these purposes.[98-100] The WFA-SAS code[49] was used for the surface
properties.
With the data in Tables 1-3, we tested triple regression relationships of the form of eq. (5):
ΔE = c1[VS,max] + c2[ε(R)2] + c3[α] + c4 (5)
In eq. (5), VS,max is the maximum potential associated with the σ- or π-hole on the 0.001 au

Accepted Manuscript
surface prior to interaction and ε(r) is the electric field produced by the σ- or π-hole molecule at
the position R of the negative site. The electric field is raised to the second power because the
energy of an induced dipole is given by -0.5αε2.[101] The quantity α is the average polarizability
of the negative site. For the four negative sites in Tables 1-3, the values of α, in Å 3, are: HCN,
2.593; NH3, 2.103; H3CNH2, 3.754 and (H3C)2NH, 5.447.[102]
The results obtained with eq (5) were quite encouraging.[87] For the 20 σ-hole interactions in
Table 1, the correlation between ΔE predicted with eq. (5) and computed ΔE had R2 = 0.959 and
a root mean square error of 1.0 kcal/mol. The computed ΔE ranged from -3.6 to -22.0 kcal/mol.
For the 21 π-hole interactions in Tables 2 and 3, involving HCN and NH3 as the negative
sites, the correlation between predicted and computed ΔE had R2 = 0.952 and the root mean
square error was 2.7 kcal/mol. The range of the computed ΔE was from -4.0 to -42.4 kcal/mol,
twice as great as for the σ-hole interactions.
In these complexes, the electronic densities of the negative sites are being polarized toward
the σ- or π-hole molecules. In the stronger interactions, this tends to be accompanied by marked
changes in their geometries. The lengths of the bonds to the σ-hole atoms increase, while the
π-hole atoms go from trigonal to quasi-tetrahedral configurations. As has been pointed
out,[32,35,36,103] these interactions can be viewed as developing some degree of “dative” or
“coordinate covalent” character.
In these analyses, it must be kept in mind that the predicted ΔE reflect only the polarization
of the negative sites and just the primary σ- or π-hole interactions. In contrast, the computed ΔE
also take into account the polarization of the σ- or π-hole molecules as well as any secondary
interactions that may be occurring. The latter may be significant,[32,84,85] as was pointed out in
section 5 in relation to the dicyanobromobenzenes 6 and 7. They are particularly likely in π-hole
complexes, since more atoms in the interacting molecules are relatively close to each other.
Another example will be given below.
Also to be noted are the uncertainties associated with experimental polarizabilities.[104,105]
Furthermore, only average polarizabilities are usually available, whereas it is the components
parallel to the external electric fields that are actually needed.[105]
Could a third regression relationship of the form of eq. (5) encompass all of the interactions,
both σ-hole and π-hole? The answer is yes, but not as well as when they are treated separately.
The R2 for the correlation between predicted and computed ΔE was 0.888 and the root mean

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

12

square error was 3.1 kcal/mol. We view this as satisfactory, given that the relationship
encompasses 41 interactions, both σ-hole and π-hole, involving 20 molecules of different types.
We have also considered a modified version of the procedures just described. In eq. (5),
VS,max pertains to the 0.001 au surface of the unperturbed σ- or π-hole molecule, whereas ε(R)2
refers to the electric field of the unperturbed molecule at the position of the negative site. Would
it be better to be consistent and replace VS,max by the potential V(R) of the σ- or π-hole molecule
at the position R of the negative site?
The V(R) values are included in Tables 1-3. They are normally smaller in magnitude than

Accepted Manuscript
the VS,max because the negative site is usually beyond the 0.001 au contour of the free σ- or
π-hole molecule. A notable exception is the π-hole interaction Cl3B---NH3, for which the V(R)
of the boron is considerably greater than the VS,max of the boron in free BCl3, 41.9 vs. 24.0
kcal/mol. This is because the negative site is well within the 0.001 au contour of free BCl3; the
B---N separation in Cl3B---NH3 is 1.62 Å while the distance from the boron nucleus to the VS,max
on the 0.001 au surface is 1.92 Å .
Why is the B---N separation so short in Cl3B---NH3? We believe that it is because of the
secondary attractive interactions between the chlorines and the hydrogens. Consistent with this
are the Cl---H distances, 2.90 Å , which are less than the sum of the chlorine and hydrogen van
der Waals radii, 3.02 Å .[106]
To investigate the effects of using V(R), we developed new triple regression relationships
of the form of eq. (5) with V(R) in place of VS,max. The results for the σ-hole and π-hole
interactions separately, shown in Figures 5 and 6, were very much the same as before: For the σ-
hole, R2 = 0.950 and the root mean square error was 1.1 kcal/mol. For the π-hole, R2 = 0.951
and the root mean square error was 2.7 kcal/mol. However for the σ- and π-hole interactions
taken together, Figure 7, there was a small improvement: R2 = 0.904 and root mean square error
= 2.8 kcal/mol.
The most prominent outlier in Figure 7 is for the π-hole complex between F2Si=O and
HCN, in which the π-hole interaction is Si---N. The predicted ΔE is -31.8 kcal/mol, much more
negative than the computed -22.6 kcal/mol. We believe that this is due to the secondary F---N
and O---N repulsive interactions. The F---N and O---N separations are 2.66 Å and 2.87 Å ,
respectively, considerably less than the sums of the van der Waals radii, 3.12 Å and 3.16 Å .[106]
In the π-hole complex between F2Si=O and NH3, on the other hand, the F---N and O---N
repulsions are approximately balanced by the F---H and O---H attractions.

8. Discussion and Summary

The forces that hold molecular complexes together are Coulombic. This follows from the
rigorous Hellmann-Feynman theorem,[107,108] and more fundamentally from the fact that the
potential energy terms in the Hamiltonian – which determine the forces – are purely Coulombic.
But this does not mean that electrostatics involving the free, unperturbed molecules is adequate
for describing the complex. The nuclei and electrons of any molecule create an electric field that

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

13

polarizes to some extent the charge distribution of any other molecule in its vicinity. This
polarization is an integral part of the Coulombic interaction.
Electrostatics alone is never sufficient to describe with full accuracy an intermolecular
interaction; polarization must be taken into account. This was recognized by Scrocco and
Tomasi,[17,73] who pioneered the analysis of molecular electrostatic potentials, and it has been
pointed out and discussed in detail numerous times since then.[8,32,39,51,52,61-67] Nevertheless, the
insufficiency of electrostatics alone continues to be “rediscovered” and cited, incorrectly, as
indicating the inadequacy of σ- and π-hole interpretations of noncovalent interactions.

Accepted Manuscript
The work that has been described in sections 5-7 of this overview demonstrates that the
electrostatic and polarization contributions to σ- and π-hole interactions, taken together, correlate
very well with their quantum-chemical energetics. This is consistent with the Coulombic
interpretation of these interactions (which encompasses dispersion, as shown by Feynman[108]).
As Levine put it, in the context of molecules, “…there are no ‘mysterious quantum-mechanical
forces’…”.[109]
In some cases, especially for very weak interactions, the polarization component is quite
minor and electrostatics alone can provide a good approximate description of the energetics. The
maximum positive potential VS,max arising from the σ- or π-hole has been found to be effective
for this purpose. However in many instances, especially relatively strong interactions,
polarization does need to be taken into account. Several approaches for doing this have been
summarized, with particular emphasis upon the use of point charges and the explicit introduction
of electric fields. The fact that negative point charges have been shown to represent very well
the polarizing effects of negative sites demonstrates that the widely invoked charge transfer is
not occurring, since point charges have no electronic density to transfer.
It is noteworthy that the combined electrostatics/polarization treatments that have been
described are able to include even interactions that are much stronger than is normally associated
with noncovalent bonding. No new factors or types of bonding need to be invoked to understand
such interactions; they usually simply reflect greater degrees of polarization. They could be
viewed as having varying degrees of “dative” or “coordinate covalent” character. The gradation
in interaction energies that is observed is in accord with the concept that chemical bonding is a
continuum of forms, ranging from weak to strong.[32,103,110-113]
Finally, we want to point out that the value of the electrostatics/polarization relationships
that have been discussed is primarily conceptual rather than predictive. They serve the very
important purpose of providing strong support for the Coulombic description of σ- and π-hole
interactions. However they cannot, in their present forms, be used to predict interaction energies
because evaluating the polarization contributions, whether via point charges or electric fields,
requires knowledge of the position of the negative site in the complex – which currently is
determined by a quantum chemical calculation. Overcoming this limitation, at least partially, is
one of our objectives.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

14

References
[1] R. F. Stewart, Chem. Phys. Lett. 1979, 65, 335-342.
[2] Chemical Applications of Atomic and Molecular Electrostatic Potentials (Eds: P. Politzer, D.
G. Truhlar), Plenum, New York, 1981.
[3] C. L. Klein, E. D. Stevens, in: Structure and Reactivity (Eds: J. F. Liebman, A. Greenberg)
VCH, New York, 1988, chap. 2, pp. 25-64.

Accepted Manuscript
[4] J. S. Murray, P. Politzer, WIREs Comput. Mol. Sci. 2011, 1, 153-163.
[5] P. Politzer, J. S. Murray, in: Reviews in Computational Chemistry, Vol. 2 (Eds: K. B.
Lipkowitz, D. B. Boyd) VCH Publishers, New York, 1991, pp. 273-312.
[6] S. E. Wheeler, K. N. Houk, J. Chem. Theory Comput. 2009, 5, 2301-2312.
[7] J. S. Murray, Z. P.-I. Shields, P. G. Seybold, P. Politzer, J. Comput. Sci. 2015, 10, 209-216.
[8] J. S. Murray, P. Politzer, WIREs Comput. Mol. Sci. 2017, 7, e1326.
[9] P. Politzer, J. S. Murray, Crystals 2017, 7, 212(1-14).
[10] P. Coppens, Angew. Chem. Int. Ed. 1977, 16, 32-40.
[11] P. Politzer, K. C. Daiker in The Force Concept in Chemistry (Ed: B. M. Deb), Van
Nostrand Reinhold, New York, 1981, chap. 6, pp. 294-387.
[12] R. Bonaccorsi, E. Scrocco, J. Tomasi, J. Chem. Phys. 1970, 52, 5270-5284.
[13] R. Bonaccorsi, A. Pullman, E. Scrocco, J. Tomasi, Theoret. Chim. Acta 1972, 24, 51-60.
[14] E. Scrocco, J. Tomasi, Topics Curr. Chem. 1973, 42, 95-170.
[15] E. Scrocco, J. Tomasi, Adv. Quantum Chem. 1978, 11, 115-193.
[16] P. Kollman, J. McKelvey, A. Johansson, S. Rothenberg, J. Am. Chem. Soc. 1975, 97, 955-
965.
[17] J. Tomasi in Chemical Applications of Atomic and Molecular Electrostatic Potentials (Eds:
P. Politzer, D. G. Truhlar) Plenum, New York, 1981, pp. 257-294.
[18] P. Politzer, P. R. Laurence, K. Jayasuriya, Environ. Health Perspect. 1985, 61, 191-202.
[19] Molecular Electrostatic Potentials: Concepts and Applications (Eds: J. S. Murray, K. Sen)
Elsevier, Amsterdam, 1996.
[20] H. A. Bent, Chem. Rev. 1968, 68, 587-648.
[21] E. D. Stevens, Mol. Phys. 1979, 37, 27-45.
[22] T. N. Guru Row, R. Parthasarathy, J. Am. Chem. Soc. 1981, 103, 477-479.
[23] S. C. Nyburg, C. H. Faerman, Acta Cryst B 1985, 41, 274-279.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

15

[24] N. Ramasubbu, R. Parthasarathy, Phosphorus Sulfur, 1987, 31, 221-229.

[25] V. G. Tsirelson, P. F. Zou, T.-H. Tang, R. F. W. Bader, Acta Cryst A 1995, 51, 143-153.
[26] S. S. Batsanov, Struct. Chem. 2000, 11, 177-183.
[27] H. Eramian, Y.-H. Tian, Z. Fox, H. Z. Beneberu, M. Kertesz, J. Phys. Chem. A 2013, 117,
14184-14190.
[28] G. Delgado-Barrio, R. F. Prat, Phys. Rev. A 1975, 12, 2288-2297.

Accepted Manuscript
[29] H. Weinstein, P. Politzer, S. Srebrenik, Theoret. Chim. Acta 1975, 38, 159-163.
[30] K. D. Sen, P. Politzer, J. Chem. Phys. 1989, 90, 4370-4372.
[31] T. Clark, M. Hennemann, J. S. Murray, P. Politzer, J. Mol. Model. 2007, 13, 291-296.
[32] J. S. Murray, P. Lane, T. Clark, K. E. Riley, P. Politzer, J. Mol. Model. 2012, 18, 541-548.
[33] P. Metrangolo, G. Resnati, Chem. Eur. J. 2001, 7, 2511-2519.
[34] P. Metrangolo, H Neukirch, T. Pilati G. Resnati, Acc. Chem. Res. 2005, 38, 386-395.
[35] P. Politzer, J. S. Murray, ChemPhysChem 2013, 14, 278-294.
[36] P. Politzer, J. S. Murray, T. Clark, Phys. Chem. Chem. Phys. 2013, 15, 11178-11189.
[37] P. Politzer, J. S. Murray, G. V. Janjić, S. D. Zarić, Crystals, 2014, 4, 12-31.
[38] A. Bauzá, T. J. Mooibroek, A. Frontera, ChemPhysChem 2015, 16, 2496-2517.
[39] P. Politzer, J. S. Murray, T. Clark, Topics Curr. Chem. 2015, 358, 19-42.
[40] H. Wang, W. Wang, W. H. Jin, Chem. Rev. 2016, 116, 5072-5104.
[41] M. H. Kolář, P Hobza, Chem. Rev. 2016, 116, 5155-5187.
[42] P. Politzer, J. S. Murray, T. Clark, G. Resnati, Phys. Chem. Chem. Phys. 2017, 19, 32166-
32178.
[43] R. F. W. Bader, M. T. Carroll, J. R. Cheeseman, C. Chang, J. Am. Chem. Soc. 1987, 109,
7968-7979.
[44] J. S. Murray, T. Brinck, M. E. Grice, P. Politzer, J. Mol. Struct. (Theochem), 1992, 256, 29-
45.
[45] J. S. Murray, P. Politzer, Croatica Chim. Acta 2009, 82, 267-275.
[46] R. K. Pathak, S. R. Gadre, J. Chem. Phys. 1990, 93, 1770-1773.
[47] J. S. Murray, F. Abu-Awwad, P. Politzer, J. Phys. Chem. A 1999, 103, 1853-1856.
[48] M J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, et al, Gaussian 09, Revision A.1,
Gaussian, Inc., Wallingford, CT, 2009.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

16

[49] F. A. Bulat, A. Toro-Labbé, T. Brinck, J. S. Murray, P. Politzer, J. Mol. Model. 2010, 16,
1679-1691.
[50] ZP-I Shields, J. S. Murray, P. Politzer, Internat. J. Quantum Chem. 2010, 110, 2823-2832.
[51] M. Hennemann, J. S. Murray, P. Politzer, K. E. Riley, T. Clark, J. Mol. Model. 2012, 18,
2461-2469.
[52] P. Politzer, J. S. Murray in Noncovalent Forces (Ed: S. Scheiner) Springer, Heidelberg,
2015, chap. 10, pp. 291-321.

Accepted Manuscript
[53] J. S. Murray, P. Politzer, J. Indian Inst. Sci., 2019, DOI: 10.1007.s41745-019-00139-3
[54] N. Ramasubbu, R. Parthasarathy, P. Murray-Rust, J. Am. Chem. Soc. 1986, 108, 4308-
4314.
[55] P. Politzer, J. S Murray, M. C. Concha, J. Mol. Model. 2008, 14, 659-665.
[56] P. Politzer, J. S. Murray, T. Clark, Phys. Chem. Chem. Phys. 2010, 12, 7748-7757.
[57] P. Politzer, J. S Murray, J. Comput. Chem. 2018, 39, 464-471.
[58] J. S. Murray, G. Resnati, P. Politzer, Faraday Discuss. 2017, 203, 113-130.
[59] C. R. Martinez, B. L. Iverson, Chem. Sci. 2012, 3, 2191-2201.
[60] S. Benz, J. López-Andarias, J. Mareda, N. Sakai, S. Matile, Angew. Chem. Int. Ed. 2017,
56, 812-815.
[61] P. Politzer, K. E. Riley, F. A. Bulat, J. S. Murray, Comput. Theoret. Chem. 2012, 998, 2-8.
[62] P. Politzer, J. S. Murray, T. Clark, J. Mol. Model. 2015, 21, 52(1-10).
[63] D. J. R. Duarte, G. L. Sosa, N. M. Peruchena, I. Alkorta, Phys. Chem. Chem. Phys. 2016,
18, 7300-7309.
[64] T. Brinck, A. N. Borrfors, J. Mol. Model. 2019, 25, 125(1-9).
[65] T. Clark, A. Hesselmann, Phys. Chem. Chem. Phys. 2018, 20, 22849-22855.
[66] T. Clark, J. S. Murray, P. Politzer, ChemPhysChem 2018, 19, 3044-3049.
[67] T. Clark, J. S. Murray, P. Politzer, Phys. Chem. Chem. Phys. 2018, 20, 30076-30082.
[68] K. E. Riley, P. Hobza, J. Chem. Theory Comput. 2008, 4, 232-242.
[69] M. Solimannejad, M. Gharabaghi, S. Scheiner, J. Chem. Phys. 2011, 134, 24312(1-6).
[70] I. Geronimo, N. J. Singh, K. S. Kim, J. Chem. Theory Comput. 2011, 7, 825-829.
[71] M. Solimannejad, M. Malekani, I. Alkorta, J. Phys. Chem. A 2010, 114, 12106-12111.
[72] S. Scheiner, J. Chem. Phys. 2011, 134, 164313(1-9).

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

17

[73] R. Bonaccorsi, E. Scrocco, J. Tomasi, Theoret. Chim. Acta 1976, 43, 63-73.
[74] I. Alkorta, H. O. Villar, J. J. Perez, J. Phys. Chem. 1993, 97, 9113-9119.
[75] I. Alkorta, J. J. Perez, H. O. Villar, J. Mol. Graph. 1994, 12, 3-13.
[76] J. Bertran, E. Silla, J. I. Fernández-Alonso, Tetrahedron 1975, 31, 1093-1096.
[77] A. D. Haymet, D. W. Oxtoby, J. Chem. Phys. 1982, 77, 2466-2474.

Accepted Manuscript
[78] M. M. Francl, J. Phys. Chem. 1985, 89, 428-433.
[79] M. Orozco, F. J. Luque in Molecular Electrostatic Potentials: Concepts and Applications
(Eds: J. S. Murray, K. Sen) Elsevier, Amsterdam, 1996, chap. 4, pp. 181-218.
[80] P. Politzer, S. J. Landry, T. Wärnhelm, J. Phys. Chem. 1982, 86, 4767-4771.
[81] R. J. Bartlett, H. Weinstein, Chem. Phys. Lett. 1975, 30, 441-447.
[82] S.-Y. Chang, H. Weinstein, D. Chou, Chem. Phys Lett. 1976, 42, 145-150.
[83] S.-Y. Chang, H. Weinstein, Int. J. Quantum Chem. 1978, 14, 801-813.
[84] K. E. Riley, J. S. Murray, P. Politzer, M. C. Concha, P. Hobza, J. Chem. Theory Comput.
2009, 5, 155-163.
[85] P. Metrangolo, J. S. Murray, T. Pilati, P. Politzer, G. Resnati, Cryst. Growth Des. 2011, 11,
4328-4246.
[86] A. Bundhun, P. Ramasami, J. S. Murray, P. Politzer, J. Mol. Model. 2013, 19, 2739-2746.
[87] P. Politzer, J. S. Murray, T. Clark, J. Phys. Chem. A. 2019, DOI: 10.1021/acs.jpca.9b08750
[88] S. M. Huber, E. Jimenez-Izal, J. M. Ugalde, I. Infante, Chem. Commun. 2012, 48, 7708-
7710.
[89] J. Thirman, E. Engelage, S. M. Huber, M. Head-Gordon, Phys. Chem. Chem. Phys. 2018,
20, 905-915.
[90] P. Hobza, Z. Havlas, Chem. Rev. 2000, 100, 4253-4264.
[91] E. Arunan, G. R. Desiraju, R. A. Klein, J. Sadlej, S. Scheiner, I. Alkorta, D. C. Clary, R. H.
Crabtree, J. J. Dannenberg, P. Hobza, H. G. Kjaergaard, A. C. Legon, B. Mennucci, D. J.
Nesbitt, Pure Appl. Chem. 2011, 83, 1619-1636.
[92] W. Wang, N. B. Wang, W. Zheng, A. Tian, J. Phys. Chem. A 2004, 108, 1799-1805.
[93] J. S. Murray, M. C. Concha, P. Lane, P. Hobza, P. Politzer, J. Mol. Model. 2008, 14, 699-
704.
[94] K. Hermansson, J. Phys. Chem. A. 2002, 106, 4695-4702.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

18

[95] W. Qian, S. Krimm, J. Phys. Chem. A, 2002, 106, 6628-6636.

[96] C. L. Mustoe, M. Gunabalasingam, D. Yu, B. O. Patrick, Faraday Discuss. 2017, 203, 79-
91.
[97] S. V. Rosokha, Faraday Discuss. 2017, 203, 315-332.
[98] F. De Proft, J. M. L. Martin, P. Geerlings, Chem. Phys. Lett. 1996, 256, 400-408.
[99] R. Soliva, M. Orozco, F. J. Luque, J. Comput. Chem. 1997, 18, 980-991.

Accepted Manuscript
[100] K. E. Riley, K. Tran, P. Lane, J. S. Murray, P. Politzer, J. Comput. Sci. 2016, 17, 273-284.
[101] J. O. Hirschfelder, C. F. Curtiss, R. B. Bird, Molecular Theory of Gases and Liquids,
Wiley, New York, 1954, p. 852.
[102] NIST Computational Chemistry Comparison and Benchmark Data Base (Ed: R. D.
Johnson, III), NIST Standard Reference Database No. 101, 19 April 2018, http://cccbdb.nist.gov/
[103] P. Politzer, J. S. Murray, Theor. Chem. Acc. 2012, 131, 1114(1-10).
[104] P. Fuentealba, Y. Simón-Manso, J. Phys. Chem. A 1997, 101, 4231-4235.
[105] V. W. Couling, B. W. Halliburton, R. I. Keir, G. L. D. Ritchie, J. Phys. Chem. A 2001,
105, 4365-4370.
[106] S. Alvarez, Dalton Trans. 2013, 42, 8617-8636.
[107] H. Hellmann, Einführung in die Quantenchemie, Deuticke, Leipzig, 1937.
[108] R. P. Feynman, Phys. Rev. 1939, 56, 340-343.
[109] I. N. Levine, Quantum Chemistry, 5th Ed., Prentice-Hall, Upper Saddle River, NJ, 2000.
[110] J. C. Slater, J. Chem. Phys. 1972, 57, 2389-2396.
[111] R. F. W. Bader, J. Phys. Chem. A 2009, 113, 10391-10396.
[112] M. Rahm, R. Hoffmann, J. Am. Chem. Soc. 2016, 138, 3731-3744.
[113 ] P. Politzer, J. S. Murray, Struct. Chem. 2019, 30, 1153-1157.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

19

Table 1. Computed properties for σ-hole interactions. The atom having the σ-hole is indicated
in bold. VS,max is the most positive potential of the σ-hole prior to interaction; V(R) is the
potential at the position R of the negative site after interaction. ΔE is the interaction energy, eq.
(4). ε(R) is the magnitude of the electric field of the σ-hole molecule at R.

σ-Hole VS,maxa V(R) ΔEa ε(R)a

molecule (kcal/mol) (kcal/mol) (kcal/mol) (au)

HC≡CH---NCH 30.7 9.1 -3.58 0.006834

Accepted Manuscript
F2(NC)P---NCH 36.5 12.0 -4.60 0.007417
H3(F)Si---NCH 34.1 12.2 -4.67 0.008482
HC≡CH---NH3 30.7 9.5 -4.71 0.007218
HC≡CH---NH2CH3 30.7 10.3 -5.51 0.008089
FCl---NCH 40.3 15.4 -5.96 0.01256
HC≡CH---NH(CH3)2 30.7 11.1 -6.26 0.009099
(NC)2S---NCH 43.8 17.0 -6.65 0.01033
F2(NC)P---NH3 36.5 14.7 -6.98 0.01032
H3(F)Si---NH3 34.1 16.8 -7.26 0.01416
(NC)2S---NH3 43.8 17.8 -8.56 0.01104
F2(NC)P---NH2CH3 36.5 16.9 -9.45 0.01305
(NC)2S---NH2CH3 43.8 19.5 -10.10 0.01267
H3(F)Si---NH2CH3 34.1 21.1 -10.35 0.02059
FCl---NH3 40.3 21.8 -12.18 0.02138
F2(NC)P---NH(CH3)2 36.5 20.0 -12.26 0.01713
(NC)2S---NH(CH3)2 43.8 20.7 -12.39 0.01393
H3(F)Si---NH(CH3)2 34.1 23.0 -13.22 0.02358
F-Cl---NH2CH3 40.3 25.3 -17.28 0.02697
F-Cl---NH(CH3)2 40.3 27.4 -21.96 0.03012
a
Ref. 87.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

20

Table 2. Computed properties for π-hole interactions with the nitrogen lone pair of HCN. The
atom having the π-hole is indicated in bold. VS,max is the most positive potential of the π-hole
prior to interaction; V(R) is the potential at the position R of the nitrogen lone pair after
interaction. ΔE is the interaction energy, eq. (4). ε(R) is the magnitude of the electric field of
the π-hole molecule at R.
______________________________________________________________________________
π-Hole VS,maxa V(R) ΔEa ε(R)b
molecule (kcal/mol) (kcal/mol) (kcal/mol) (au)

Accepted Manuscript
Cl2C=O 22.8 5.2 -3.99 0.005042
SO2 32.9 10.2 -4.04 0.007796
SeO2 35.4 11.6 -4.14 0.008652
FNO2 32.8 8.5 -4.38 0.007202
Cl3B 24.0 6.7 -4.46 0.006555
F2C=O 40.9 9.0 -4.58 0.007798
F3B 48.8 17.9 -6.94 0.01836
H3CPO2 47.6 14.8 -7.59 0.01361
H2Si=O 43.4 30.7 -11.55 0.03635
FPO2 58.4 36.3 -11.88 0.03868
F2Si=O 66.7 53.4 -22.58 0.06293

a
Ref. 32.
b
Ref. 87.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

21

Table 3. Computed properties for π-hole interactions with the nitrogen lone pair of NH3. The
atom having the π-hole is indicated in bold. VS,max is the most positive potential of the π-hole
prior to interaction; V(R) is the potential at the position R of the nitrogen lone pair after
interaction. ΔE is the interaction energy, eq. (4). ε(R) is the magnitude of the electric field of
the π-hole molecule at R.
______________________________________________________________________________
π-Hole VS,maxa V(R) ΔEa ε(R)b
molecule (kcal/mol) (kcal/mol) (kcal/mol) (au)

Accepted Manuscript
Cl2C=O 22.8 5.5 -4.64 0.005332
FNO2 32.8 8.5 -5.52 0.007301
SO2 32.9 12.3 -6.00 0.01004
F2C=O 40.9 10.0 -6.14 0.008952
SeO2 35.4 14.0 -7.62 0.01123
H3CPO2 47.6 32.9 -18.41 0.04145
H2Si=O 43.4 38.2 -26.69 0.04925
Cl3B 24.0 41.9 -29.67 0.07069
FPO2 58.4 51.5 -32.35 0.06246
F2Si=O 66.7 58.2 -42.38 0.07063
_____________________________________________________________________________
a
Ref. 32.
b
Ref. 87.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

22

Figure Captions

Figure 1. Computed electrostatic potential on the 0.001 au molecular surface of F2C(H)Br, 1.

The bromine is in the foreground, to the right; the hydrogen is in the rear at the top, and a
fluorine is in the rear at the bottom. Color ranges, in kcal/mol: Red, more positive than 20;
yellow, between 20 and 10; green, between 10 and zero; blue, negative. Black hemispheres
indicate the most positive potentials (VS,max) corresponding to the σ-holes of the bromine on the
extension of the C-Br bond and of the hydrogen on the extension of the C-H bond.

Accepted Manuscript
Figure 2. Computed electrostatic potential on the 0.001 au molecular surface of Se(Cl)CN, 2.
The selenium is in the foreground, the chlorine in the rear at the left, the cyanide group in the
rear at the right. Color ranges, in kcal/mol: Red, more positive than 30; yellow, between 30 and
15; green, between 15 and zero; blue, negative. Black hemispheres indicate the most positive
potentials (VS,max) corresponding to the σ-holes of the selenium on the extensions of the Cl-Se
and NC-Se bonds.

Figure 3. Computed electrostatic potential on the 0.001 au molecular surface of Cl2C=O, 3. The
two chlorines are in the lower foreground, the oxygen is in the rear at the top. Color ranges, in
kcal/mol: Red, more positive than 14; yellow, between 14 and 7; green, between 7 and zero;
blue, negative. Black hemispheres indicate the most positive potentials (VS,max) corresponding to
the π-holes above and below the carbon and the σ-holes of the chlorines on the extensions of the
C-Cl bonds.

Figure 4. Computed electrostatic potential on the 0.001 au molecular surface of the π-hole
complex between Cl2C=O and NH3. The oxygen is in the foreground with the two chlorines in
the rear; the ammonia is to the right. Color ranges, in kcal/mol: Red, more positive than 11;
yellow, between 11 and zero; green, between zero and -11; blue, negative than -11. Black
hemispheres indicate the most positive potentials (VS,max) corresponding to the σ-holes of two
hydrogens on the extensions of their N-H bonds.

Figure 5. ΔE predicted with eq. (5) plotted against computed ΔE, both in kcal/mol, for σ-hole
interactions in Table 1. R2 = 0.950.

Figure 6. ΔE predicted with eq. (5) plotted against computed ΔE, both in kcal/mol, for π-hole
interactions in Tables 2 and 3. R2 = 0.951.

Figure 7. ΔE predicted with eq. (5) plotted against computed ΔE, both in kcal/mol, for σ-hole
interactions in Table 1 and π-hole interactions in Tables 2 and 3. R2 = 0.904.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

23

Accepted Manuscript
Figure 1. Computed electrostatic potential on the 0.001 au molecular surface of F2C(H)Br, 1.
The bromine is in the foreground, to the right; the hydrogen is in the rear at the top, and a
fluorine is in the rear at the bottom. Color ranges, in kcal/mol: Red, more positive than 20;
yellow, between 20 and 10; green, between 10 and zero; blue, negative. Black hemispheres
indicate the most positive potentials (VS,max) corresponding to the σ-holes of the bromine on the
extension of the C-Br bond and of the hydrogen on the extension of the C-H bond.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

24

Accepted Manuscript
Figure 2. Computed electrostatic potential on the 0.001 au molecular surface of Se(Cl)CN, 2.
The selenium is in the foreground, the chlorine in the rear at the left, the cyanide group in the
rear at the right. Color ranges, in kcal/mol: Red, more positive than 30; yellow, between 30 and
15; green, between 15 and zero; blue, negative. Black hemispheres indicate the most positive
potentials (VS,max) corresponding to the σ-holes of the selenium on the extensions of the Cl-Se
and NC-Se bonds.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

25

Accepted Manuscript
Figure 3. Computed electrostatic potential on the 0.001 au molecular surface of Cl2C=O, 3. The
two chlorines are in the lower foreground, the oxygen is in the rear at the top. Color ranges, in
kcal/mol: Red, more positive than 14; yellow, between 14 and 7; green, between 7 and zero;
blue, negative. Black hemispheres indicate the most positive potentials (VS,max) corresponding to
the π-holes above and below the carbon and the σ-holes of the chlorines on the extensions of the
C-Cl bonds.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

26

Accepted Manuscript
Figure 4. Computed electrostatic potential on the 0.001 au molecular surface of the π-hole
complex between Cl2C=O and NH3. The oxygen is in the foreground with the two chlorines in
the rear; the ammonia is to the right. Color ranges, in kcal/mol: Red, more positive than 11;
yellow, between 11 and zero; green, between zero and -11; blue, negative than -11. Black
hemispheres indicate the most positive potentials (VS,max) corresponding to the σ-holes of two
hydrogens on the extensions of their N-H bonds.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

27

-5

-10

E
(predicted)

Accepted Manuscript
-15

-20

-25
-25 -20 -15 -10 -5 0

 E (computed)

Figure 5. ΔE predicted with eq. (5) plotted against computed ΔE, both in kcal/mol, for σ-hole
interactions in Table 1. R2 = 0.950.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

28

-10

Accepted Manuscript
-20
E
(predicted)

-30

-40

-40 -30 -20 -10 0

 E (computed)

Figure 6. ΔE predicted with eq. (5) plotted against computed ΔE, both in kcal/mol, for π-hole
interactions in Tables 2 and 3. R2 = 0.951.

This article is protected by copyright. All rights reserved.

ChemPhysChem 10.1002/cphc.201900968

29

-10

Accepted Manuscript
-20
E
(predicted)

-30

-40

-40 -30 -20 -10 0

 E (computed)

Figure 7. ΔE predicted with eq. (5) plotted against computed ΔE, both in kcal/mol, for σ-hole
interactions in Table 1 and π-hole interactions in Tables 2 and 3. R2 = 0.904.

This article is protected by copyright. All rights reserved.