DOI: 10.1002/cphc.
201200068
Electrostatics at the Origin of the Stability of Phosphate-Phosphate
Complexes Locked by Hydrogen Bonds
Ignasi Mata,[a] Ibon Alkorta,[b] Elies Molins,[a] and Enrique Espinosa*[c]
In the hierarchy of intermolecular interactions, ion–ion forces
are at the topmost position, followed by ion–dipole and
dipole–dipole forces. The hydrogen bond (HB) is regarded as
the strongest dipole–dipole interaction,[1] being the strongest
intermolecular force between neutral systems and also playing
an important role in charged systems. Although there has
been some discussion in the past about the nature of intera-
nionic hydrogen bonds (IAHBs),[2] experimental evidence sup-
ports its classification as conventional HBs.[3] Moreover, the ten-
dency of some ions to form hydrogen-bonded chains or sheets
in solid state is exploited in crystal engineering for controlling
crystal packing and properties.[4] Hydrogen-bonded anionic as-
semblies found in the solid state have been detected in solu-
tion,[5] indicating that, with the adequate environment (cations
or polar solvent) HBs can compensate ion–ion repulsion. Inter-
anion and intercation HBs in the solid state often involve mole-
cules of biological and pharmaceutical interest,[6] suggesting
that these interactions play a significant role in biochemical
processes.
Although stable hydrogen-bonded anion–anion or cation–
cation complexes in gas phase are, in general, dismissed, they
have been postulated from theoretical calculations[7] and de-
tected by spectroscopy.[8] These clusters are energetically un-
favorable (their interaction energy is positive, Ei > 0), but an en-
ergetic barrier must be overcome before dissociation, which
ensures their stability. These results suggest that, once formed
under the influence of a suitable environment, anion–anion
and cation–cation interactions can present an intrinsic stability
that would allow the complex to remain stable.
In aqueous solutions at physiological pH, phosphoric acid is
partly deprotonated, appearing as dihydrogen (H2 PO4 ) and hy-
drogen (HPO2 4 ) phosphate. Dihydrogen phosphate is well
known for its tendency to form strong IAHBs, to the point that
hydrogen-bonded phosphate chains and sheets are used in
crystal engineering for strengthening cohesive forces in the
crystal.[9] Spectroscopy results demonstrate that phosphate ag-
[a] Dr. I. Mata, Prof. E. Molins
Institut de Cincia de Materials de Barcelona (CSIC)
Campus UAB, 08193 Bellaterra (Spain)
[b] Prof. I. Alkorta
Instituto de Qumica Mdica (IQM-CSIC)
Juan de la Cierva 3, 28006 Madrid (Spain)
[c] Prof. E. Espinosa
Laboratoire de Cristallographie, Rsonance Magntique et Modlisation
(UMR 7036), Universit de Lorraine, Facult des Sciences et Technologies, BP
70239
Boulevard des Aiguillettes, 54506 Vandoeuvre-ls-Nancy (France)
E-mail: enrique.espinosa@crm2.uhp-nancy.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cphc.201200068.
ChemPhysChem 2012, 13, 1421 – 1424  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
gregation takes place in oversaturated solutions prior to the
formation of the crystal nucleus.[10] Phosphate is also an impor-
tant anion in biochemistry, being involved in processes of
energy storage and transfer that requires overcoming electro-
static repulsion with the help of suitable cations.[11]
The strength of IAHBs involving H2PO4 moieties is revealed
by the short H···O distances observed by neutron diffraction.
Thus, in the crystal structures of l-histidinium phosphate phos-
phoric acid (LHP)[12] and l-argininium phosphate monohydrat-
ed (LAP),[13] the shortest O···H intermolecular distance corre-
sponds to an IAHB [1.420(1)  in LHP, 1.569(3)  in LAP], while
the shortest distance in a non-IAHB is significantly larger
[1.522(1)  in LHP, 1.592(4)  in LAP]. This result suggests that
phosphate is well suited for the formation of anionic com-
plexes, similar to those already observed in larger anions.[8] In
order to establish the feasibility of these complexes, and to ex-
plain how the interplay of HB and ionic forces allows their for-
mation, we have undertaken a theoretical study of the
(H2 PO4 )2 system in the gas phase.
The potential energy surface (PES) of this system was ex-
plored by performing geometrical optimizations of (H2 PO4 )2
with different orientations and symmetries (C2 or Cs) of the
monomers. All the calculations converged to one of the seven
hydrogen-bonded complexes (1–7) represented in Figure 1, ex-
hibiting local PES minima with Ei > 0. In Figure 1, complexes
are sorted by increasing Ei, showing that, as the number of
IAHBs is larger and their H···O distances (dH···O) shorter, Ei is
lower. This feature outlines the role of hydrogen bonding in
compensating the ionic repulsion.
In its simplest representation, an HB can be understood as
a Coulombic electrostatic interaction between the donor and
acceptor charge distributions, each of them unaffected by the
other. This is an oversimplified model of the HB, as it ignores
important effects such as mutual polarization of the closed
shells, and it is inadequate for an accurate description when
these closed shells present a significant overlap. Nevertheless,
this interpretation is on the basis of the analysis of the molecu-
lar electrostatic potential [f(r)],[14] which is routinely applied in
the study of intermolecular interactions.
According to the topological analysis of f(r),[15] an anion is
enclosed by a zero-flux surface of f(r), that is, a surface not
crossed by any electric field line. This surface, henceforth the f
surface, has been proposed as a definition for the anion shape
and size.[16] Applying the Gauss theorem to the volume en-
closed by the f surface, this region must present a zero net
charge, and therefore the 1(r) falling outside the f surface in-
tegrates to the net charge of the anion. As 1(r) within that
volume completely screens the positive charge of the nuclei,
another anion outside the f surface would be repelled by the
1421
 Figure 2. Electric field lines in the plane defined by both OH groups in an
isolated H2 PO4 anion with Cs symmetry. Orange, red and black are for lines
starting at P, O and H nuclei, respectively. The P atom is out of the plane by
1.06 . The envelope of the volume filled by the field lines is the f surface.
Influence zones of H atoms are defined by the field lines converging at the
H nuclei. The shaded circle is the intersection with a sphere sharing the van
der Waals radius of oxygen (1.52 ), the center being 1.09  out of the
plane. This sphere approximately corresponds to the volume occupied by
the 1(r) of an O atom and is situated at the P···O and O···O distances ob-
served in 1 (3.15 and 2.81  respectively). The O atom 1(r) inside the shaded
area and enclosed by the f surface is attracted towards the phosphate.

Figure 1. Conformation of the seven stable (H2 PO4 )2 complexes, indicating

their HBs and dH···O distances. 1–7 are sorted by increasing Ei.

overall negative charge of the former. However, if part of the

1(r) corresponding to the approaching anion falls inside the
volume enclosed by the f surface, the concerned 1(r) would
experience an attractive force toward the nuclei enclosed
within the volume. The influence zone of an H atom belonging
to a hydrogen bonding donor is the fragment of the volume
filled by the electric field lines starting at the H nucleus.[17] The
1(r) inside the influence zone (whether belonging to the hy-
drogen or the acceptor) is attracted to the H nucleus.
In Figure 2, the f surface (the envelope of electric field lines)
and the influence zones of two hydrogens in an isolated
H2 PO4 with Cs symmetry can be visualized from the plot of the
electric field lines. A sphere representing the van der Waals
volume of the acceptor O atom at the geometry of the com-
plex 1 has been added (gray circle). The oxygen electrons,
which are expected to fill this sphere, fall partially inside the in-
fluence zones of the H atoms. Hence, in spite the overall nega-
tive charges of both anions, part of the acceptor 1(r) in the HB
region should be attracted toward the H nucleus.
The penetration of the acceptor 1(r) inside the influence
Figure 3. Electric field lines in complexes 1 (top panel, plane defined by one
zones of the donor can be also observed once the complex is
O atom and two H atoms in a bifurcated HB) and 2 (bottom panel, plane de-
formed. Indeed, superposing the atomic volumes calculated fined by the short HB). Color lines are defined in the caption of Figure 2.
from the topological analysis of 1(r)[18] with the influence Shaded region is the atomic volume of the acceptor oxygen. A is the part of
zones defined by the electric field lines (Figure 3), it is ob- the O atom volume inside the zone of influence of the H atoms of the
donor, where 1(r) is attracted toward the H nuclei. B is the part of the O
served that the atomic volume of the acceptor O atom pene-
atom outside the f surfaces of both donor and acceptor, where 1(r) is not
trates the H atoms influence zones in the donor. 1(r) in the in- attracted toward any nucleus. C is the part inside the volume enclosed by
tersection of the atomic volume and the influence zone is its own f surface, where interaction with its own nucleus prevails.

1422 www.chemphyschem.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemPhysChem 2012, 13, 1421 – 1424
screened from the O nucleus by the remaining 1(r) of the O
atom and is attracted toward the H nucleus in the HB donor,
which behaves as the electrophilic site of the interaction.
At equilibrium, the forces at the nuclei, arising from their in-
teraction with the surrounding charge distribution, must be
zero. In a stable configuration, a restoring force acts on the
nuclei when they move slightly from the equilibrium position.
Stability in complexes 1–7 takes place when enough 1(r) is
locked in the HB region to induce attractive forces when dH···O
increases. Thus, the stability of 1–7 can be explained by elec-
trostatic forces that arise when 1(r) of one phosphate interacts
with the electrophilic influence zone, limited by the f surface,
of the other. At larger distances there is not enough 1(r) inside
the electrophilic zone, and repulsive ionic forces prevail. As
a consequence of the fundamental interplay between the sta-
bility of the complexes and their associated electrostatics, the
electrostatic interaction energy of the HBs, calculated[19] from
the integration of the electrostatic moments on the basins[20]
of the interacting H···O atoms and summed over the HBs in
each complex, presents a clear correlation with Ei (see the Sup-
porting Information).
Additional stabilization is expected from the significant over-
lap of donor and acceptor closed shells, as the concomitant re-
organization of 1(r) results in a significant electron localization
in the HB region that confers to the interaction its partial cova-
lent (or, according to QTAIM terminology, shared) character.[21]
This electron localization is related to the early steps in the
transformation of the closed shell into a shared interaction[22]
and can be detected from the topological analysis of 1(r).
According to QTAIM, a bonding interaction is characterized
by a saddle conformation of 1(r) in the bonding region, ap-
pearing a concomitant saddle point called the bond critical
point (BCP). The ratio Cb = j Vb j /Gb (Vb and Gb being respective-
ly the electron potential and kinetic energy densities at BCP) is
a measure of the closed-shell or shared character of the HB,[22]
and therefore can be used as a measure of the partial covalent
character of the HB. While interactions with Cb < 1 and Cb > 2
are of pure closed-shell and shared types, respectively, 1 < Cb <
2 represents an interaction with an incipient shared character
that is more important as Cb approaches 2. IAHBs in 1–7 at
equilibrium geometries present 0.99 < Cb < 1.10, while values
expected from average Vb(dH···O) and Gb(dH···O) dependencies cal-
culated from a large set of H···O interactions[23] are bound to
0.88 < Cb < 1.01 for the same range of dH···O distances. As
a result, Cb is systematically larger in 1–7 than the values ex-
pected from the average dependencies (only one IAHB exhibits
Cb < 1), indicating that IAHBs in 1–7 share more charge than
the average of H···O interactions at the same geometries. This
excess of shared character agrees with the observation that
the transition to a shared interaction is favored when the ac-
ceptor presents very polar or ionic bonds,[24] which is the case
of PO bonds.[25] Thus, the stability of the complexes is rein-
forced by the electron localization in the HB, which is favored
by the electron polarization of the PO bond. A similar in-
crease in Cb is observed in two neutral (H3PO4)2 complexes
with interaction distances (dH···O = 1.610 and 2.017 ) close to
those observed in 2 and 5 and geometries similar to those of
ChemPhysChem 2012, 13, 1421 – 1424  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1 and 6 (see the Supporting Information). Moreover, in the cal-
culated IAHBs, the delocalization index,[26] which is another in-
dicator of electron sharing derived from integration of the
atomic volumes, follows the same dependency with dH···O than
in HBs of neutral complexes (see the Supporting Information),
indicating that the negative charge of the anions has no signif-
icant effect on this property of the H···O hydrogen bond.
The dissociation curves of 1–7 (Figure 4) have been calculat-
ed by increasing the P···P distance (dP···P) in small steps, mini-
mizing the rest of the geometry at each step. Starting at the
equilibrium configuration, Ei rises as dP···P increases because at-
tractive forces coming from the penetration of the acceptor
1(r) within the donor influence zone diminish in magnitude. At
the highest point of the energetic barrier there is a transition
state where the attractive force is lost because of the low 1(r)
contribution of the acceptor, avoiding enough charge to be
locked in the bonding region. The discontinuities observed in
some curves are a consequence of the electrostatic interaction,
inducing reorientations of the monomers that minimize ionic
repulsion. Hence, when the IAHB is weak enough, this reorien-
tation takes place, breaking the IAHB and decreasing Ei.
Figure 4. Interaction energy of 1–7 as a function of dP···P. Solid/dashed lines
are calculated by increasing/decreasing dP···P in small steps, starting at the
equilibrium conformation. Discontinuities on the curves correspond to
breaking or formation of HBs, implying reorientations of the complexes.
On the other hand, when decreasing dP···P in small steps
while minimizing the geometry of the rest of the complex,
most of the complexes collapse into the curve associated to 1,
which presents the lowest Ei value (Figure 4). The steps in
these curves can be explained in similar terms as those de-
scribed for the dissociation curves, although in this case dis-
continuities are due to HB formation instead of HB breaking.
The picture arising from Figure 4 suggests a PES dominated
by ionic repulsion at long dP···P and by Pauli repulsion, arising
from the large overlap of the closed shells, at very short dP···P.
In the range 3 9 dP···P 9 7 , attractive forces arising from hy-
drogen bonding induce a complex landscape of local minima
connected by transition states that gives an intrinsic stability
to (H2 PO4 )2. Accordingly, it can be assumed that, if ionic repul-
sion is overcome and a hydrogen-bonded complex is formed,
the dimer can remain stable in spite of being energetically un-
favorable.
www.chemphyschem.org 1423
 Given the complexity of multidimensional PESs, it is difficult
to give precise values of energetic barriers. From Figure 4, the
lowest energetic barrier to be overcome in order to dissociate
one of such complexes is ~ 12.2 kJ mol1 for 7, while the most
stable complex 1 would present an energetic barrier of
~ 68.7 kJ mol1 that would reduce to ~ 60.7 kJ mol1 if the com-
plex is transformed into 2 first. These values can be taken as
good indicators of the stability of the (H2 PO4 )2 hydrogen-
bonded complexes in the gas phase, although we cannot ex-
clude other stable complexes and/or transition states in the
multidimensional PES. On the other hand, the effect of the en-
vironment in the (H2 PO4 )2 PES, such as that of the solvent or
of the crystal phase, can be significant, lowering the energetic
barrier or even turning the complex into energetically favora-
ble.
In summary, the phosphate–phosphate interaction presents
an intrinsic stability thanks to the formation of HBs involving
a significant sharing of charge. The electrostatics associated to
the formed HBs are at the origin of the stability and therefore
of the locking of the complex. The large energetic barrier ob-
served in the (H2 PO4 )2 PES suggests an important role of
IAHBs in processes involving interphosphate aggregation.
Thus, once created, the complexes can be stable, prone to sur-
vive changes induced by the environment, either in solution or
in solid phase. Overall, the stability of phosphate complexes,
reached by the electrostatics in their locked HB interactions,
can be invoked as the essential reason for the formation of
phosphate chains or phosphate layers in crystal structures, or
the ubiquity of phosphate assemblies in many biological pro-
cesses involving IAHBs.
Acknowledgements
This work was supported by the Spanish Ministries of Education
(Grant CTQ2009-12520-C03-3 and CONSOLIDER CSD2007-00041)
and Science and Innovation (Grant CTQ2009-13129-C02-2), the
Catalan Government (Grant PRC 2009SGR-203), and the Autono-
mous Community of Madrid (Grant MADRISOLAR2, S2009/PPQ-
1533), I.M. thanks the Spanish Research Council (CSIC) for a JAE-
Doc fellowship financed by the European Social Fund. M. J. L.
Mills and P. L. A. Popelier are acknowledged for allowing us to
use the NYX program for computing the electrostatic interaction
energies.
1424 www.chemphyschem.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Keywords: ab initio calculations · anions · hydrogen bonds ·
noncovalent interactions · phosphate complexes
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Received: January 27, 2012
Published online on March 7, 2012
ChemPhysChem 2012, 13, 1421 – 1424