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On the effects of the basis set superposition error


on the change of QTAIM charges in adduct
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Cite this: RSC Adv., 2016, 6, 110642


formation. Application to complexes between
morphine and cocaine and their main metabolites†
David A. Rincón,*a M. Natália D. S. Cordeirob and Ricardo A. Mosqueraa

Eleven different complexes were found between heroin (or its main metabolite, morphine) and cocaine (or
its main metabolite, ecgonine methyl ester) in a B3LYP computational study. Ten of these complexes display
intermolecular hydrogen bonds, while only one is a stacked structure. All of them display positive
complexation energies in the gas phase that turn into negative values in aqueous solution according to
PCM calculations. Complexation energies become even more negative when explicit solvation water
molecules are taken into account. Thus, complexes between these compounds could be present in
biological media. The electron density of the 11 complexes was analysed within the QTAIM framework
distinguishing three terms for every atomic property: (i) geometry distortion; (ii) BSSE estimated by
extending the counterpoise (CP) method; and (iii) binding. We notice that: (i) geometry distortion effects
Received 12th September 2016
Accepted 14th November 2016
are basically localised in the atoms involved in intermolecular bonds (interaction sites); (ii) counterpoise
corrections for atomic properties are very small; and (iii) binding CP-corrected effects spread throughout
DOI: 10.1039/c6ra22736h
the whole complex. The later are the most significant and indicate the important role played by
www.rsc.org/advances hydrogens outside the interaction sites as electron density sources and sinks in complex formation.

(as in the mixture known as speedball) shows a synergic


1. Introduction interaction which increases dramatically the dopamine release
Cocaine and morphine were consumed millennia ago. In the in the synaptic cle,8 but not much more is known about the
late Bronze Age, leaves of Erythroxylum coca were consumed by higher addiction observed for such kind of combinations.4,6,9
the aboriginal people of South America. This tradition was Therefore, there are new different lines of research that are
based on its nutritional richness.1 In Byzantium times, the bringing more information to get insight on this matter.10 It is
medical tradition for the treatment of pain was through not possible to discard that complexes with high biochemical
providing powder or drops of Papaver somniferum latex.2 In activity can be formed between both drugs or between crossed
modern times, the traditional chewing of coca leaves can be metabolites.
still found within the Andes Mountains area. In contrast, the The rst aim of this paper was to study the stability of the
consumption of the main phytochemical components of these complexes formed between heroin (or morphine) with
plants is a worldwide affecting health problem. The cocaine (or ecgonine methyl ester). To this end, we have
consumption of cocaine, morphine and their derivatives performed a conformational analysis for all the complexes
develops drug dependence3,4 through a mechanism which is that can be formed between the four different pairs of
not fully understood yet. It is known the cocaine side effects molecules and evaluated their binding energy using the
occur through the modication of the biochemical activity of a posteriori counterpoise (CP) correction of the Basis Set
the dopaminergic, serotonergic and noradrenergic pathways in Superposition Error (BSSE), proposed by Boys and Bernardi.11
the brain,5,6 while those of morphine occur through the The electron density computed for the conformers was ana-
dopaminergic pathway, modulated by the m-opiate and GABA lysed by means of the Quantum Theory of Atoms in Molecules
receptors.7 The combined consumption of cocaine and heroin, (QTAIM).12 This work also explores how the computed elec-
tron density reorganization experienced by monomers upon
a
Departamento de Quı́mica Fı́sica, Universidade de Vigo, Lagoas-Marcosende, 36310
complexation is inuenced by BSSE. This analysis has been
Vigo, Spain done introducing atomic contributions for the CP correction.
b
REQUIMTE, Departamento de Quı́mica e Bioquı́mica, Universidade do Porto, Rua do Thus, atomic electron density reorganizations were split into
Campo Alegre 687, 4169-007 Porto, Portugal terms due to binding CP-corrected interactions, geometry
† Electronic supplementary information (ESI) available. See DOI: deformation, and BSSE.
10.1039/c6ra22736h

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2. Computational details the intermolecular hydrogen bond. To this end, solvent effects
were considered by using the integral equation formalism
Heroin, H, and morphine, M, share (5a,6a)-7,8-didehydro-4,5- polarizable continuum model (IEF-PCM).16 It treats solvation as
epoxy-17-methylmorphinan structure (Fig. 1) and only differ a perturbation, dened in terms of the surface apparent
in the functional groups at positions 3 and 6. In both positions, charges, which, in turn, depend on the solute charge distribu-
heroin has two acetyl groups while those of morphine are tion estimated from the solute wave function.
hydroxyls. Cocaine, C, and ecgonine methyl ester, E, share Furthermore, the van der Waals interactions were also
methyl-(1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxy- modeled. To this end, the 6-31++G** 6d basis set and the
late structure (Fig. 1) and only differ in the functional group methods of the density functional theory B3LYP and M06 were
attached at position 3. It is a benzoyloxy group in cocaine and used to perform the following calculations of the most stable
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a hydroxyl group in ecgonine methyl ester. Formation energies complex formed between heroin and ecgonine methyl ester.
for diverse complexes between heroin (or morphine) with Four different optimization procedures were done: (i) conven-
cocaine (or ecgonine methyl ester) were calculated. The electron tional optimization, (ii) optimization including the van der
density reorganization involved in the complexation processes Waals interactions through the potential of Grimme,17 (iii)
was analyzed using QTAIM and considering the effect of BSSE introducing the correction to the basis set superposition error
through the method proposed herein: a QTAIM partitioning by the counterpoise method and (iv) the sum of the inclusion of
method for CP correction. Grimme potential with counterpoise method.

2.1. DFT calculations 2.2. QTAIM calculations


All the calculations for the complexes studied here and their The QTAIM analysis of the electron density, r(r), for all of these
corresponding monomers were carried out using the GAUSSIAN systems was carried out with the AIMALL soware.18 This anal-
09 soware revision D.01.13 The structures of these complexes ysis allows obtaining the atomic basins and their corresponding
were fully optimized with the CP correction using the density properties, such as the electron population, N(U), and energy,
functional theory (DFT). The correlation functional used in E(U). Integration errors were estimated through the differences
these calculations was that proposed by Lee, Yang and Parr14 between molecular properties and those obtained by summation
together with the Becke's three parameter exchange functional P P
of the atomic ones, N  N(U) and E  E(U). Their absolute
(B3LYP15) using the 6-31++G(d,p) 6d basis set. The vibrational values were always smaller than 2.5  103 au and 3.4 kJ mol1,
frequencies and zero-point energy (ZPE) corrections were respectively (ESI material, Table S1†). The absolute values ob-
computed at the same DFT level, in order to ensure that the tained for L(U) were always smaller than 1.5  103 au.
optimized structures were true minima.
In order to evaluate the stability of complexes formed
between cocaine and heroin and/or their metabolites. The most 2.3. A QTAIM partitioning method for the BSSE
stable complex, HE1, (Fig. 2) was modeled with PCM and with Basis set superposition error (BSSE) has been long time recog-
the insertion of three water molecules in the surroundings of nised as a limitation affecting the calculation of interaction

Fig. 1 Molecular structure and atom numbering for the 8-azabicyclo[3.2.1]octane-2-methyl-ester structure, which is shared by cocaine and
ecgonine methyl ester (left), and for the (5a,6a)-7,8-didehydro-4,5-epoxy-17-methylmorphinan structure (right), shared by heroin and
morphine. In heroin, O10 and C10 correspond to the atoms in the substituent attached to O3, while O100 and C100 refer to atoms in the group
attached to O6.

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Fig. 2 QTAIM molecular graphs of all the complexes study herein, organized by increasing CP-corrected complexation energies. The complex
structures were calculated at B3LYP/6-31++G(d,p) 6d in gas phase.

energies using a nite basis set. In these calculations, the energy geometry adopted by one (or both) of the monomers in the AB
of the complex is lowered because each of the interacting frag- complex is closer to a conformer which is not the lowest
ments is described with more basis functions in the complex energy one. Then DdefE dened by (2) can be split into four
than when it is isolated. In order to correct this error, Boys and terms (eqn (4)), two are provided by the relative energies of
Bernardi proposed the CP correction method.11 If this (or other) the conformers in the isolated monomers, usually called
BSSE correction is not employed (as could be done in the innite conformational terms, DconfE. The others are due to the
basis set limit), the calculated complexation energy, DcE, for two geometry distortions experienced by those conformers in the
interacting systems, A and B, would be given by eqn (1), where complex, DgdE.
each EZY(X) symbol denotes the energy of the X fragment in the Y
geometry when computed with the Z basis set. The corre- DdefE(AB) ¼ DconfE(A) + DgdE(A) + DconfE(B) + DgdE(B) (4)
sponding deformation, DdefE, and binding, DbE, energies due,
respectively, to: (i) geometrical distortion of the molecules, A and Once the complex AB has been calculated using a nite basis
B, in order to become bonded in the formed complex; and (ii) set, the BSSE comes up and, according to CP correction, the
intermolecular interaction once both fragments are in the complexation and binding energies are overestimated to an
geometry of the complex, are given by (2) and (3). extent given by eqn (5). The CP-corrected energy for the AB
complex formation between fragment A and B is obtained by (6),
DcE(AB) ¼ EAB
AB(AB)  EA(A)  EB(B)
A B
(1) and the corresponding CP-corrected binding energy by (7).

DdefE(A,B) ¼ [EA
AB(A)  EA(A)] + [EAB(B)  EB(B)]
A B B
(2) DBSSEE(AB) ¼ [EA
AB(A)  EAB(A)] + [EAB(B)  EAB(B)]
AB B AB
(5)

DbE(A,B) ¼ EAB
AB(AB)  EAB(A)  EAB(B)
A B
(3) DCP
c E(AB) ¼ [EAB(AB)  EA(A)  EB(B)] + DBSSEE(AB) (6)
AB A B

In some cases, two components can be considered for b E(AB) ¼ [EAB(AB)  EAB(A)  EAB(B)] + DBSSEE(AB) (7)
DCP AB A B

each monomer within DdefE. This happens when the

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QTAIM allows a disjoint partitioning of any molecular electron population of atoms involved (or not) in intermolecular
property, P, of a certain molecular system, S, into their atomic bonds is affected by BSSE. Thus, the usual variations of atomic
counterparts, P(U), (eqn (8)) where U denotes an atom in the electron population computed for a complexation process,
system. DcN(U), can be corrected by estimating the effects of BSSE on it
X by considering DBSSEN(UX), giving rise to the CP-corrected term,
PðSÞ ¼ PðUÞ (8)
U3S
DcCPN(U). Moreover, DcCPN(U) can be subsequently split into
deformation, DdefN(U), and CP-corrected binding terms, as
shown in eqn (16). These terms are given by eqn (17)–(19). While
Thus, molecular energy, E, can be split into atomic ones, the two formers are physically meaningful, the latter only esti-
E(U). In the same vein, atomic contributions to CP-uncorrected mates the effect of a computational shortcoming connected to
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or corrected complexation or binding energies, as well as the basis set size.


deformation energies can be obtained through eqn (9)–(13). In
these equations, either EAA(U) ¼ 0 or EBB(U) ¼ 0, depending on Dc NðUÞ ¼ NXX ðUX Þ  NM
M
ðUM Þ
¼ DCP NðUÞ  D BSSE NðUÞ (16)
which molecule contains the U atom. Thus, any of these c
b NðUÞ þ Ddef NðUÞ  DBSSE NðUX Þ
¼ DCP
expressions can be reduced to the difference between the
atomic energy within the complex, X, or in the isolated
molecule, M, enclosing the atom U under study. Moreover, it is DdefN(U) ¼ NM X (UX)  NM(UM)
M
(17)
possible to dene an atomic contribution to the CP correction,  
b NðUÞ ¼ NX ðUX Þ  NX ðUM Þ þ NX ðUM Þ  NX ðUM Þ
DCP X M M X
DBSSEE(UX) as the difference between those atomic energies (18)
¼ NXX ðUX Þ  NXX ðUM Þ
obtained for U in the isolated molecule with the basis set
employed for the monomer, EM X (UM), and that used for the
DBSSEN(UX) ¼ NM
X (UM)  NX(UM)
X
(19)
whole system, EMX (U M), both of them computed in the geometry
of the complex (eqn (14)).
Moreover, when the geometry of a fragment in a certain
 AB 
Dc EðUÞ ¼ EAB ðUAB Þ  EAA ðUA Þ  EBB ðUB Þ complex corresponds to a distortion of a non most stable
(9)
¼ EXX ðUX Þ  EMM
ðUM Þ conformer, the deformation energy involves a conformational
 AB  term, DconfE, given by the relative energy of that conformer.
Db EðUÞ ¼ EAB ðUAB Þ  EAB
A
ðUA Þ  EAB
B
ðUB Þ
(10)
¼ EX ðUX Þ  EX ðUM Þ
X M

 AB  3. Results and discussion


c EðUÞ ¼ EAB ðUAB Þ  EA ðUA Þ  EB ðUB Þ þ DBSSE EðUAB Þ
DCP A B

¼ EXX ðUX Þ  EM
M
ðUM Þ þ DBSSE EðUX Þ 3.1. On the stability of complexes formed between cocaine
(11) and heroin and/or their metabolites

 AB  In order to understand complexation energy from its atomic


b EðUÞ ¼ EAB ðUAB Þ  EAB ðUA Þ  EAB ðUB Þ þ DBSSE EðUAB Þ
DCP A B
contribution into the QTAIM framework, the conformational
¼ EXX ðUX Þ  EXM ðUM Þ þ DBSSE EðUX Þ analysis was carried out to obtain the most stable complexes
(12) between heroin (or morphine) with cocaine (or ecgonine methyl
 A   B  ester) but its complete conformational distribution. Therefore,
Ddef EðUÞ ¼ EAB ðUA Þ  EAA ðUA Þ þ EAB ðUB Þ  EBB ðUB Þ the conformational analysis was done by a manual procedure.
(13)
¼ EXM ðUM Þ  EM
M
ðUM Þ The criterion to nd complexes was dened on the basis that
intermolecular hydrogen bonds and stacking interactions
DBSSEE(UX) ¼ EM
X (UM)  EX(UM)
X
(14) stabilize these monomers due to the presence of these func-
tional groups: hydroxyl in M and E; ammonium in M, H, C and
BSSE may affect not only to atomic energies, but to any other E; acetyl in H, E and C; aromatic rings in M, H and C; and vinylic
atomic property, P, and the corresponding atomic CP correc- hydrogens in M and H (Fig. 1). The former interaction was
tion, DBSSEP(UX), can be obtained through the generalization of searched between hydrogen donor atoms, such as O–H, N–H
eqn (14), yielding eqn (15). and ]C–H, with acceptor atoms, such as ]O and the oxygen in
–O–H. The latter interaction was searched between aromatic
DBSSEP(UX) ¼ PM
X (UM)  PX(UM)
X
(15) groups and all the previously functional groups described.
Thus, we have found eleven different complexes between heroin
Hereaer, specic values of QTAIM atomic properties will be and morphine with cocaine and ecgonine methyl ester (Fig. 2).
denoted as Pba(Uc), noticing that the density property P was These complexes are named making reference to their consti-
integrated within the atomic basin U in the c molecular system tuting monomers. Whereas no energy minimum was obtained
displaying a geometry when using the b basis set. We will pay for the adduct containing heroin and cocaine, two different
particular attention to atomic electron populations, making minima (HE1 and HE2) are found for the complex between
extensive use of: NXX(UX), NM X M
M(UM), NX(UM), and NX (UM) values. heroin and ecgonine methyl ester, morphine and cocaine were
This allows estimating (to our knowledge for the rst time) to found attached in four different arrangements (MC1–MC4), and
which extent the depletion or enlargement experienced by the ve complexes are formed by morphine and ecgonine methyl

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ester (ME1–ME5). These 11 structures display intramolecular Table 1 Distances, R (in Å), and corresponding BCP parameters
(only within cocaine and ecgonine methyl ester monomers) and (multiplied by 103 and in au) electron density, rBCP, its Laplacian,
V2rBCP, and total energy density, HBCP for hydrogen bonds and
intermolecular hydrogen bond, IHB, but in one case, MC3,
stacking interactions displayed by the complexes founda,b
where the monomers display stacking interactions with no IHB.
The diverse structures found for each of the three different Complex Interaction R rBCP VrBCP HBCP
pairs of molecules (HE, MC and ME) differ in the atoms
involved in the main intermolecular bond, as shown in Table 1. Intramolecular hydrogen bond
HE1 (O10 /H–N8)E 1.791 40.17 113.68 1.35
All the structures obtained for these adducts display signif- HE2 (O10 /H–N8)E 1.771 42.04 119.10 1.47
icant positive values for complexation energies (even uncor- MC1 (O10 /H–N8)C 1.781 41.05 117.09 1.36
rected ones). They become slightly larger when zero point MC2 (O10 /H–N8)C 2.058 22.95 67.97 0.50
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vibrational corrections, ZPE, are considered (Table 2). The least MC3 (O10 /H–N8)C 1.782 40.91 116.68 1.35
positive values of complexation energies correspond to the two MC4 (O10 /H–N8)C 1.931 29.78 85.64 0.96
ME1 (O10 /H–N8)E 1.778 41.29 117.38 1.40
complexes established between heroin and ecgonine methyl ME2 (O10 /H–N8)E 1.783 40.86 116.03 1.37
ester, whose DcCPE values are, at least, 10 kJ mol1 less positive ME3 (O10 /H–N8)E 1.937 29.37 84.17 0.97
than any ME complex. ME4 (O10 /H–N8)E 1.893 32.30 91.52 1.12
3.1.1. The solvent effects on stability of the most stable ME5 (O10 /H–N8)E 1.934 29.61 84.94 0.99
complex, HE1. In contrast, both DcE and DcCPE values become
Intermolecular hydrogen bond (IHB)
negative when the calculations are carried out in aqueous
HE1 C100 ]O100 /H–O3 1.960 24.34 67.71 0.55
solution modelled with PCM. Thus, DcCPE is 19.2 kJ mol1 for C200 –H/O30 2.487 7.94 30.75 1.09
HE1. As PCM does not consider IHB with solvent molecules, we HE2 C10 ]O10 /H–O3 1.887 28.29 81.26 0.18
thought that it was more reliable to perform PCM calculations C20 –H/O30 2.610 6.33 25.07 1.06
for complex formation including explicitly some water mole- MC1 O6–H/O100 ]C100 1.883 25.96 85.33 0.87
O6/H6a–C6 2.563 7.42 25.80 0.81
cules. This task was only carried out for the complex formed O6/H4e–C4 3.081 2.68 11.00 0.65
with HE1 with 3 explicit water molecules, HE1$3W. The water MC2 O3/H–N8 2.218 14.10 46.23 0.29
molecules were inserted in the surroundings of the IHB region, O3–H3/O10 ]C10 2.210 13.81 58.85 1.55
two around the donor and one on the acceptor atom (Fig. 3). O/H8a–C8 2.501 8.15 28.76 0.83
These positions of the added water molecules to the atoms O/H–C5 3.113 2.66 10.54 0.67
O6/H–C5 3.035 2.61 10.66 0.70
involved in IHB were chosen to stabilize the IHB through charge
MC4 O3–H3/O10 ]C10 2.179 13.79 56.85 1.28
transferred from water molecules.19 The complex was optimized O3/H–N8 2.426 8.31 32.56 0.94
in gas phase and then was subsequently subjected to a PCM ME1 O3/H–O3 2.039 19.20 56.12 0.29
single point calculation. The same computational procedure O6/H6a–C6 4.573 0.11 0.41 0.04
was considered for the complexes formed by one heroin mole- ME2 O6/H–O3 1.976 22.31 64.51 0.29
ME3 O3–H3/O10 ]C10 2.163 14.43 59.60 1.31
cule attached to two water molecules, H$2W, and that formed by O3/H8–N8 2.353 9.80 37.30 0.87
ecgonine methyl ester with three water molecules, E$3W O/Ha–C8 2.700 5.15 19.86 0.91
(Fig. 3). Heroin and ecgonine methyl ester were arranged in the ME4 O3–H3/O10 ]C10 2.108 15.04 54.97 0.76
corresponding initial geometry of H$2W and E$3W complexes O/Hg–C20 3.472 1.16 4.98 0.37
in the same conformation displayed by those monomers in the O6/Hg+–C20 3.608 0.98 3.84 0.29
ME5 O6–H6/O10 ]C10 2.098 16.41 63.68 1.05
HE1$3W optimized structure. Thus, the BSSE-uncorrected O6/H–N8 2.392 8.82 34.30 0.92
energy variation for the process indicated by eqn (20) was
obtained. Stacking interactions
MC3 O3/C2r 3.397 4.59 14.79 0.60
H$2W + E$3W / HE1$3W + 2W (20) O3/O10 3.597 2.46 11.20 0.63
H5/H3r 2.810 1.99 6.56 0.44
O/C3r 4.053 1.39 5.25 0.34
O6/H3r–C3r 3.319 1.87 7.04 0.50
BSSE corrections for this energy were obtained considering H2/O10 ]C10 3.338 1.64 6.67 0.45
the three-step process, detailed in Scheme 1. The two fragments
a
for CP corrections can be clearly identied in the products Most signicant IHBs are in boldface. b Atomic numbering for IHBs
and stacking interactions refer to the rst monomer in the acronym
(steps I and II) or in the reagents (step III) for every step. before the interaction sign (/) and to the second one aer it. These
Table 3 details DCPE obtained for each step in gas phase and values were calculated at B3LYP/6-31++G(d,p) 6d in gas phase.
PCM modeled aqueous solution. The global complexation
process (19) displays a positive value for DcCPE in gas phase
(9.68 kJ mol1), but turns into a negative one (73.30 kJ mol1) clusters,19 this is a consequence of interacting the lone pair on
in aqueous solution. the accepting oxygen with an empty hydride antibond of the
The analysis of charge transfer involved in the formation of donating O–H atoms, nO /s*OH . Occupancy of the antibonding
hydrogen bonds in water clusters have been studied by several orbital raises the energy of the O–H species while stabilizing the
research groups.19 Albrecht et al. properly described the charge oxygen. The stabilization increases as the cluster size increases
transfer during the hydrogen bond formation in water because of hydrogen bond cooperativity. This can be described

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Table 2 Uncorrected, DcE, and CP-corrected, DcCPE, complexation


energies, basis set superposition error, BSSE, and CP-corrected
binding energies for the complexes here studied. Geometry distortion,
DgdE, and conformational terms, DconfE, for their constituting mono-
mers. Contributions to DcE to due zero point energy corrections,
DZPE, are also shown. All values are in kJ mol1a,b

DgdEb DconfE Scheme 1

Complex DZPE DcEa DBSSEE DcCPE H/M C/E H/M C/E

HE1 4.50 74.94 2.33 77.28 3.94 0.87 0.00 1.84 Thus, the calculations here reported indicate that the formation
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HE2 3.39 81.36 2.42 83.77 12.79 1.00 0.00 1.84 of this kind of complexes in human uids cannot be discarded.
MC1 3.42 80.95 4.30 85.24 0.45 2.32 5.38 0.00 Moreover, it could be explored as a reason behind the stronger
MC2 3.33 88.21 4.57 92.78 2.47 6.67 13.12 0.00 addiction observed for combined abuse of heroin and cocaine.
MC3 0.46 103.38 3.30 106.68 0.53 0.60 0.00 0.00
3.1.2. The intramolecular van der Waals interactions on
MC4 1.01 104.86 3.15 108.01 1.18 2.48 0.00 0.00
ME1 3.09 91.47 2.67 94.15 2.29 0.62 12.05 0.00 the most stable complex, HE1. The general characteristics of
ME2 3.24 93.91 2.60 96.51 1.31 1.38 0.00 1.84 the structures of heroin and ecgonine methyl ester, which are
ME3 2.80 93.69 3.63 97.32 3.14 2.60 12.05 0.00 part of the complex HE1, are described by polar and nonpolar
ME4 2.90 98.86 3.01 101.87 1.09 1.13 5.38 0.00 groups. In the rst case, heroin has two carboxylate groups and
ME5 2.78 102.97 3.09 106.06 0.87 2.34 5.38 0.00
an ammonium group, and ecgonine methyl ester has a hydroxyl
a
DZPE corrections not included. b Total deformation energy, as dened group, a carboxylate group and an ammonium group. On the
by eqn (2), is obtained by adding the corresponding DconfE and DgdE
other hand, the remaining structures that comprise these
terms. These values were calculated at B3LYP/6-31++G(d,p) 6d in gas
phase. molecules are aliphatic, in both systems, and an aromatic, in
heroin. These molecules bind by means of polar groups.
However, the interactions with non-polar groups are not
through changing cluster geometry: decreasing O/O distances considered in a conventional optimization. Therefore, the study
coupled with increasing O–H covalent bond lengths indicate of interactions van der Waals is relevant.
a weakening of the covalent OH bond and strengthening of the For this purpose, the results of calculating the interaction
H/O hydrogen bond interaction. Furthermore, there is an energy for HE1 complex will be analyzed in this order: (i)
increasingly linear O–H/O angle as the size of the ring conventional optimization with DFT methods: B3LYP and M06,
increases. We notice that the explicit inclusion of water mole- (ii) with the inclusion of potential Grimme, (iii) with the
cules stabilizes the complex formed between heroin and one of inclusion of the correction to the basis set superposition error
cocaine metabolites, ecgonine methyl ester. This stabilization is by the counterpoise method and (iv) with the inclusion of
well supported by the geometrical variations observed on the Grimme potential with the counterpoise method (Table 4).
bond distances and angles of the atoms involved in the inter- The value of the interaction energy obtained with B3LYP is
molecular hydrogen bond between heroin and ecgonine methyl 2.14 kJ mol1 greater than M06. This is because M06 includes in
ester. The obtained bond distances in gas phase are shown and its denition 27% of potential Hartree–Fock exchange. Instead,
in aqueous phase are in parenthesis. O/O is 2.88737 Å (2.85010 B3LYP includes 20% of the difference between the potential of
Å), O–H 0.97687 Å (0.97837 Å), H/O hydrogen bond interaction Hartree–Fock exchange regarding the potential of the local
1.95990 Å (1.90066 Å), and O–H/O angle 157.647 (162.831 ). density. This difference in the weight of Hartree–Fock exchange
potential shows that the interaction, through the polar groups,
is stabilized by the electronic exchange.
When the dispersion terms of the nonpolar groups in HE1
complex are taken into account, those stabilize the interaction

Table 3 CP-Corrected complexation energies, DCPE, for the different


steps in Scheme 1 are shown. These energy values were obtained from
calculations at B3LYP/6-31++G(d,p) 6d in gas phase and in aqueous
solution. In both cases, the inclusion of explicit water molecules at the
atoms involved in the intermolecular hydrogen bond were taken into
account as is shown in Fig. 3

DCPE

Step GAS PCM


Fig. 3 B3LYP/6-31++G(d,p) 6d optimized structure for the HE1$3W
complex (H monomer on the left). Dotted lines indicate hydrogen H$2W / H$W + W 17.45 14.10
bonds. The complex structures with the inclusion of water molecules E$3W / E$2W + W 16.49 21.46
was calculated at B3LYP/6-31++G(d,p) 6d in aqueous solution through H$W + E$2W / 9.68 73.30
PCM. HE1$3W

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Table 4 The interaction energy values obtained in gas phase for HE1 complex were calculated at 6-31++G** 6d with different methods. The
energy value for complex with the basis set of complex in geometry of complex, EXX(X), monomers with the basis set of the complex in geometry
of complex, EXX(M), monomers with the basis set of isolated monomer in geometry of isolated monomer, EM M(M) as well as the uncorrected, DcE,
and CP-corrected, DcCPE, complexation energies and DBSSEE are shown. The terms EXX(X), EM M(M) and DcE correspond to eqn (1) and DBSSEE,
EXX(M) and DcCPE correspond to eqn (5)–(7), respectively. The energy values of the systems are in au and energy derived values are in kJ mol1

Method Complex Monomers EXX(X) EXX(M) EM


M(M) DcE DCP
c E DBSSEE

B3LYP HE1 H 1917.48289 — 1245.34854 72.46 — —


E — 672.16195
M06 HE1 H 1916.25656 — 1244.55290 71.76 — —
E — 671.73099
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B3LYP-D3 HE1 H 1917.58611 — 1245.41173 63.45 — —


E — 672.19855
M06-D3 HE1 H 1916.27612 — 1244.56514 67.27 — —
E — 671.73660
B3LYP + CP HE1 H 1917.48289 1245.34837 1245.34797 69.01 70.99 1.98
E 672.16184 672.16149
M06 + CP HE1 H 1916.25634 1244.55177 1244.55135 67.93 69.94 2.01
E 671.73121 671.73086
B3LYP-D3 + CP HE1 H 1917.58619 1245.41079 1245.41035 59.01 61.24 2.23
E 672.19873 672.19831
M06-D3 + CP HE1 H 1916.27587 1244.56401 1244.56358 63.48 65.60 2.12
E 671.73685 671.73647

energy. In the case of the energy of interaction calculated with indicated in Section 2.3 (Table 2) are successfully reproduced
B3LYP with the inclusion of the potential Grimme, it was ob- (within 2.0 kJ mol1) with atomic QTAIM energies, E(U).
tained that the latter is 10.45 kJ mol1 more stable than the one The values shown in Table 2 and formula introduced in
obtained with only B3LYP. In the case of M06, a similar trend Section 2.3 allow obtaining CP-corrected binding, DbCPE, and
was observed, which is that the interaction energy calculated deformation energies, DdefE, for the eleven complexes found.
with M06 and the van der Waals interactions is 4.48 kJ mol1 We highlight that all binding energies are positive, precluding
more stable than that obtained only with M06. From these negative DcCPE values. Clearly, DbCPE values are positive because
results, the importance of including the terms of dispersion in the repulsion between the global positive charges exhibited by
the calculation of the interaction energy is observed. Although both monomers exceeds the stabilization due to IHBs formation
the potential of Grimme not describe the real origin of the or that obtained from stacking interactions in MC3. The least
dipole–dipole interaction between the molecules forming the unfavourable binding corresponds to HE complexes (68.1 and
complex, but rather its effect on the effective potential of 70.6 kJ mol1 for, respectively, HE2 and HE1). In contrast, the
mideld of the respective density functional. most unfavourable binding corresponds to the stacked complex
Furthermore, by correcting the interaction energy overlaying MC3 (105.6 kJ mol1).
the BSSE by the method of counterpoise, it was found that the We also notice that the largest DgdE values correspond to
optimized geometry with B3LYP with the counterpoise method heroin and cocaine in HE2 and MC2, respectively. Both mole-
is 2.91 kJ mol1 more stable than that obtained with only cules display just one low energy conformer, while morphine
B3LYP. Analogously to the interaction energy values obtained displays four and the ecgonine methyl ester two.20,21 Conse-
with M06, the difference is 1.82 kJ mol1. quently, conformational terms, DconfE are important only for
Finally, at the optimization of the complex geometry with some of the complexes containing E or M monomers. In fact,
either B3LYP or M06 with the potential of Grimme and the the largest deformation energies, DdefE, correspond to MC2
counterpoise method was obtained that the interaction energy (22.3 kJ mol1) and ME3 (17.8 kJ mol1) because of the
obtained with B3LYP is 14.89 kJ mol1 more stable than that conformational change experienced by the morphine
obtained with only B3LYP. Similarly, to M06, the difference is monomer.
8.28 kJ mol1. We believe it is worth to include here a short comment on
how aqueous solution stabilizes these complexes, yielding
negative DcCPE values in PCM calculations. The global charge of
3.2. Complexation energy terms in gas phase complexes
complexes doubles that of monomer and results in a more
Retaking our methodology objective, assessing BSSE effects on effective solvent polarisation for the former which compensates
electron density rearrangements involved in complex forma- the still positive DbCPE values observed with PCM. Moreover, the
tion, and for the sake of simplicity, we have considered gas inclusion of explicit water molecules gives rise to larger
phase complexes established without including water distances among the most positive atoms in the complex. We
molecules. highlight these are not the nitrogen atoms, as incorrectly indi-
Complexation energies, not including DZPE values, as well cated by the usual Lewis structures employed to represent them.
as all their components mentioned and CP corrections

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As shown in previous electron density analysis,20,21 the positive where IHB are established. Thus, the heroin monomer is mainly
charge of any of the four monomers is basically shared among distorted around O6 in HE1, while its largest distortions
the ammonium hydrogen and those hydrogens of the methyl- concentrate around O3 in HE2, as the IHBs formed are,
ammonium group, with a contribution from the bridgehead respectively, O6–C100 –O100 /H3–O3 and O3–C10 –O10 /H3–O3.
carbons in H and M and of bicycle hydrogens in C and E. They are reinforced in both cases by an additional (and weak) C–
H/O3 IHB (Fig. 4). In the same vein, the E monomer is mainly
distorted, in HE1 and HE2, around the hydroxyl group (O3). The
3.3. Variation of atomic properties involved in complex map of distortions is completed by those of the intramolecular
formation HB in C and E monomers, which is present in all the complexes
The method introduced in Section 2.3 allows distinguishing here obtained. We also notice that the bonds including the
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between binding and deformation (even splitting it into furan oxygen of H and M monomers (C4–O and C5–O) display
conformational and geometry distortion) effects on the electron moderate distortions in most of the 11 complexes.
density reorganization accompanying complexation. Moreover, The principal variations experienced by the main atomic
we can make a CP correction for binding effects on electron properties due to the geometry deformation involved in the
density. In this section we report and discuss separately the complexation process, DdefN(U), DdefE(U), DdefM(U), and Ddef-
effects of conformational and geometry distortion, BSSE, and v(U), are shown for HE1, as an example, in Fig. 4, while the
CP corrected binding. We detail the amount of CP-corrections corresponding values for all the systems studied herein are re-
and where they become signicant. Once more, for the sake ported as ESI material.† All these conformational variations are
of clarity, we restrict our discussion to gas phase complexes with analyzed below for each monomer.
no water molecules. Heroin (only present in two complexes) distorts to interact
3.3.1. Effects due to deformations of monomers. In order through its acetyl groups (at position 6 in HE1 and the one at
to analyze deformations (including conformational reorgani- position 3 in HE2) as H-acceptor. As indicated above, the largest
zations and geometry distortions) and their effects, we look at DdefRij values are shown by two bonds in the acetyl group: C]O
variations of bond lengths, Rij, and some QTAIM atomic prop- (lengthens) and C–O (shrinks). In accordance, DdefN(U) values
erties: electron population, N(U), energy, E(U), the module of for HE1 (Fig. 4) and HE2 (ESI material†) indicate that electron
the rst moment of the electron density, M(U), and atomic density is transferred from the C]O group to reinforce the CO
volume, v(U). bond at position 3 or 6 of the heroin backbone. In fact, the
Table 5 summarizes the bonds whose length is distorted by methyl group in the acetyl unit only increases scarcely its elec-
more than 5  103 Å. They are concentrated in those regions tron population aer this deformation (4  103 au in HE1 and

Table 5 Most significant variations of bond lengths experienced by the monomers (indicated by the letter preceding complex acronym) of the
complexes here studied, DdefRij, (in Å multiplied by 103). Variations whose absolute values are below 5  103 Å and those affecting C–H bonds
are not shown. These values were calculated at B3LYP/6-31++G(d,p) 6d in gas phase

Bond in
H/M H, HE1 H, HE2 M, MC1 M, MC2 M, MC3 M, MC4 M, ME1 M, ME2 M, ME3 M, ME4 M, ME5

C3–O3 — 8 — 10 — 12 17 1 10 8 1
C3–C4 — — — 5 — — — — — — —
C4–O 5 — — 7 — 5 0 7 — — 7
C5–O 6 — — 7 — 6 5 7 8 — 4
C6–O6 11 — — 5 — — — 18 5 — 13
C6–C7 — — — — — — — — 5 — 3
O6–H — — 8 — — — — — — — —
O3–C10 — 31 — — — — — — — — —
C10 ]O10 — 14 — — — — — — — — —
O6–C100 25 1 — — — — — — — — —
C100 ]O100 13 0 — — — — — — — — —

Bond in
E/C E, HE1 E, HE2 C, MC1 C, MC2 C, MC3 C, MC4 E, ME1 E, ME2 E, ME3 E, ME4 E, ME5

C2–C3 — — — — — — — 5 — — —
C3–O3 4 6 7 — — — — — — — —
O3–H 10 12 — — — — 5 6 — — —
N8–H — — — 10 — 8 — — 10 7 9
O10 / 27 7 — 278 — 151 — 18 165 102 154
H(N8)
O3–C100 — — 17 — — — — — — — —
C100 ]O100 — — 10 — — — — — — — —

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7  103 au in HE2). This distortion of the geometry also deformed M monomers are those bonded through their both
reduces the polarisation of both atoms of the carbonyl group hydroxyl groups (MC2, MC3, and ME1). In these, cases Ddef-
and increases that of the attached sp3 oxygen. Overall, the C–O– N(C3) and DdefN(C6) are both positive.
C]O unit involved in IHB destabilizes more than that the Cocaine is in four complexes. Its distortions are oriented
whole H monomer (28 vs. 3.6 kJ mol1 in HE1, and 41 vs. 13.7 kJ toward forming two types of intermolecular interactions:
mol1 in HE2). The difference between both quantities is due to stacking or IHB. Moreover, C can work as H donor or H acceptor
stabilizations spread among the remaining atoms of the or both things depending on the complex considered. The
monomer. stacked complex MC3 displays the lowest DdefE(C) value, 0.60 kJ
Morphine is included by nine of the eleven complexes herein mol1, with no signicant bond distortion (all are smaller than
studied. When this molecule is isolated, it shows six stable 3  103 Å), either in C or in M (Table 5). The largest |DdefRij|
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conformers.20 They arise from the two possible orientations of values are placed within the benzoyloxy group attached to C3 in
the 3-OH group with regard to the attached aromatic ring MC1, where this monomer is H acceptor exclusively. When
(synperiplanar, s, or antiperiplanar, a) and from the three cocaine also acts as H donor (MC2 and MC4) N8–H8 shrinks
different dispositions of the 6-OH group with regard to its signicantly and the N8–H8/O10 ]C10 intramolecular
attached aliphatic ring (named g, t, and g0 for approximate hydrogen bond lengthens. DdefN(U) and DdefE(U) values within
values of 60 , 180 or 60 in the C5–C6–O–H dihedral angle). the benzoyloxy group follow the same trends detailed above for
Four of them are observed within the nine complexes. The most the acetyl groups of heroin. The electron density lost by the
stable (ag0 ) corresponds basically to the M monomer in MC3, C100 ]O100 unit is mainly transferred to O3, and not to the phenyl
MC4, and ME2 complexes, while sg0 closely reminds the group. In contrast, the electron density lost by N8 (and attached
geometry displayed in MC1, ME4 and ME5, and those of higher methyl) in MC2 and MC4 is mainly transferred to the ammo-
energy are included in ME1 and ME3 (sg) and MC2 (st). In all the nium hydrogen atom.
complexes, the M monomer displays small distortions from the Ecgonine methyl ester is in seven complexes. It distorts from
corresponding conformer, as can be anticipated from DgdE two of its most populated conformers.21 One observed in ME1,
values (Table 2). MC1 and MC3 display the least deformed M ME3, ME4, and ME5, while the other is in HE1, HE2, and ME2.
monomers (Table 5). In the rest of the complexes, the largest Its complexes can be also classied considering the role E plays
|DdefRij| values correspond to the C–O bond with the hydroxyl in IHBs: H donor in HE1, HE2, ME1 and ME2; H acceptor in
group at positions 3 or 6, depending on which is the interaction ME4; and both roles in ME3 and ME5. When E acts exclusively
site for M in the complex. The electron density of the corre- as H-donor its interaction site is the 3-OH group, but when it
sponding oxygen (O3 or O6) depletes, and it is mostly trans- also acts as H-acceptor the H-donor site is the N8–H8 bond.
ferred to its attached carbon, whose DdefN(U) values span from ME1 shows the lowest deformation energy for E (Table 2) with
5  103 to 31  103, and rarely to the hydroxyl hydrogen, no bond distorted by more than 5  103 Å (Table 5). Slightly
whose DdefN(U) values are below 6  103 au. The most larger DdefE(E) values are displayed in the other complexes

Fig. 4 Significant DdefN(U) (in boldface and in au multiplied by 103), DdefE(U) (in italics and expressed in kJ mol1), DdefM(U) (in au multiplied by
103), and Ddefv(U) (in parenthesis and in au) values in HE1. See ESI material† for these values in the remaining complexes studied in this work.
DdefN(U), DdefE(U), DdefM(U) and Ddefv(U) are not shown when their absolute values are below 103 au, 1 kJ mol1, 103 au, and 1 au respectively.
All the values were calculated at B3LYP/6-31++G(d,p) 6d in gas phase.

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where the E monomer is exclusively H-donor, and the most atoms of the acetyl group at C3 represent 41% of S|DdefN(U)|,
distorted bonds are concentrated around the 3-OH group, with 60% of S|DdefE(U)|, 38% of S|DdefM(U)| and 25% of S|Ddefv(U)|
the intramolecular hydrogen bond scarcely affected. In in HE2. The smaller localization of the distortions observed for
contrast, when E is H-acceptor, the largest distortions are H monomer in HE2 can be explained considering that the
experienced by the N8–H bond and the N8–H8/O10 ]C10 interaction site is attached to an aromatic ring. In cocaine, we
intramolecular hydrogen bond lengthens by more than 0.1 Å. distinguish three cases: (i) in MC1 the interaction site is part of
DdefN(N8) is positive in the seven E complexes, but there is the benzoyloxy group and C3, O3, C100 , and O100 give rise to 50%
a quantitative difference between the cases where the E inter- and 63% of S|DdefN(U)| and S|DdefE(U)|, respectively; (ii) in
action site is 3-OH (1  103 au < DdefN(N8) < 3  103 au) and MC2 and MC4, cocaine mainly interacts through N8 and H8 and
those where N8–H is involved in IHBs (DdefN(N8) > 8  103 au). their respective contributions are 29%, 22% and 24%, 35%; and
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When the distortions of the four monomers are compared (iii) the atoms of the two C–OH bonds of MC3 display the largest
we notice two general trends: (i) heroin acetyl groups produce DdefN(U) and DdefE(U) values. In fact, they account for almost
larger geometry distortion of the aliphatic part of their common one half (51%) of S|DdefN(U)| and S|DdefE(U)|. Nevertheless,
backbone than the hydroxyl groups of morphine, as shown by this percentage diminish up to 32% in DdefM(U) and even to
larger DdefE values; (ii) cocaine and ecgonine methyl ester 12% in Ddefv(U), indicating the less localized character of
monomers that interact affecting their intramolecular hydrogen stacking interactions.22 Two different behaviours have been
bond display larger deformation energies than those that distinguished above for ecgonine methyl ester: interaction as
interact through 3-OH hydroxyl. O–H hydrogen donor (HE1, HE2, ME1, and ME2), where C3 and
We highlight that, in all cases, if we exclude the stacked O3 atoms display the largest DdefP(U) values and simultaneous
complex MC3, distortions are clearly localized in specic areas interaction as H-acceptor and N–H hydrogen donor (ME3, ME4,
of each monomer, which coincide with the interaction sites for and ME5), where the most signicant DdefP(U) values corre-
complex formation. Thus, in morphine, the hydroxyl group and spond to N8, H8, O10 , and C10 . Once again the participation of
the attached C atom at positions 3 or 6 amount for 35  12% of |DdefP(U)| for these atoms accounts for signicant percentages
S|DdefN(U)|, with almost all monomers within the 1s interval of the corresponding S|DdefP(U)| quantity.
and only those of MC2 (17%), ME2 (52%) and ME3 (21%) out of 3.3.2. BSSE effect on atomic properties. As previously
it. The corresponding contribution for DdefE(U) is of 44  10%, detailed, it can be expected that BSSE affects to any atomic
and only MC2, ME2 and ME3 are more than 1s from the property. In this section, we analyze, making use of DBSSEP(U)
average. When the same study is carried out along H mono- quantities dened in eqn (15), the effect of BSSE on DcN(U),
mers, just four atoms, the acetyl group at C6 represent 50% of DcE(U), DcM(U) and Dcv(U) for the complexes here studied.
S|DdefN(U)|, 66% of S|DdefE(U)|, 57% of S|DdefM(U)|, and 41% Overall, we notice that the DBSSEP(U) in all these complexes were
of S|Ddefv(U)| in HE1. In the same vein, the corresponding four always small. Their highest absolute values for each monomer

Fig. 5 Significant DBSSEN(U) (in boldface and in au multiplied by 103), DBSSEE(U) (in italics and expressed in kJ mol1) DBSSEM(U) (in au multiplied by
103), and DBSSEv(U) (in parenthesis and in au) values in HE1. Reddish colour atoms indicate atoms where DcCPE(U) > DcE(U), while greenish ones
are the atoms extra-stabilized according to CP-uncorrected atomic energies, that is: DcCPE(U) < DcE(U). See ESI material† for these values in the
remaining complexes studied in this work. DBSSEN(U), DBSSEE(U), DBSSEM(U) and DBSSEv(U) are not shown when their absolute values are below 5
 104 au, 1 kJ mol1, 5  104 au, and 0.1 au, respectively. All the values were calculated at B3LYP/6-31++G(d,p) 6d in gas phase.

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are conned between 0.5  103 and 2.2  103 au for DBSSE- 3.3.3. CP corrected atomic properties related to intermo-
N(U), 1.8 and 14.4 kJ mol1 for DBSSEE(U), 1.0  103 and 13.5  lecular interactions. CP corrections to BSSE for atomic proper-
103 au for DBSSEM(U), and 0.1 to 0.4 au for DBSSEv(U). Thus, ties detailed above were employed, as indicated in eqn (18) to
even for the most affected properties in relative values, DcE(U) obtain CP-corrected atomic binding energies, DbCPE(U), and
and DcM(U), the inuence of BSSE partitioned into its atomic the variations due to binding for atomic electron population,
contribution for complex formation by IHB does not seem to be DbCPN(U), atomic module of the rst moment of the electron
of high signicance. density, DbCPM(U), and atomic volume, DbCPv(U). The results
Even though, as depicted by Fig. 5 for HE1, there are scarce obtained are shown in Fig. 6 for HE1, as an example, and pre-
atoms displaying differences between DcP(U) and DcCPP(U) (or sented in ESI material† for the remaining complexes. As com-
between DbP(U) and DbCPP(U)) within the signicant gures. As mented above, adding geometry distortion and binding
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could be expected, part of the largest |DBSSEP(U)| values corre- contributions provides complexation ones.
spond to atoms placed in the region where the number of basis Although the gure details the variations of atomic proper-
functions centred close enough enlarges in the complex. That ties experienced by those atoms involved in intermolecular
is, atoms placed where the two monomers approach each other, interactions, we notice that, in contrast with variations due to
no matter if these atoms are involved or not in intermolecular geometry distortion, which are localized, binding introduces
bonds. Thus, we notice that the most positive DBSSEN(U) values signicant modications in the atomic properties of the whole
in HE1 correspond to H(O3) in E (the H involved in IHB) and to complex with regard to those in isolated monomers. This is
H(C2r) in H, which is not involved in any intermolecular bond, shown in Fig. 6 by comparing the summations of DbCPN(U) and
but placed in the contact region between the monomers of this DbCPE(U) for each monomer and the corresponding sum
complex. Nevertheless, other DBSSEN(U) values do not have a so extended only to those atoms not involved in intermolecular
simple explanation. Thus, we notice that DBSSEN(C2) in H is bonds. As previously shown for much more simple complexes,25
negative in spite it is close to the contact region between the electron density transferred between monomers in HE1
monomers and does not participate in any intermolecular (0.028 au) (or in any other complex here studied) is exceeded by
bond. It is the unique atom bonded to H(C2r), but we think that the loss of electron density shown by the atoms not involved in
DBSSEN(U) cannot be considered the result of electron density IHBs in the electron density donor (heroin, in this case) (0.037
displacement through chemical bonds, as other N(U) variations au). We highlight the relevant role played by the hydrogens of
accompanying protonation,24 or other chemical processes like this part of the molecule, which all together lose 0.040 au.
complexation itself. In fact, BSSE effects are consequences of Looking at the acceptor monomer, ecgonine methyl ester in this
the spatial reinforcement or depletion of the number of basis case, we observe that most of the electron density transferred
functions whose numerical values are high enough. results in increasing the electron density of that part of the

Fig. 6 Most significant DbCPN(U) (in boldface and in au and multiplied by 103), DbCPE(U) values (in italics and expressed in kJ mol1), DbCPM(U) (in
au multiplied by 103), and DbCPv(U) (in parenthesis and in au) in HE1. See ESI material† for corresponding values for the remaining complexes
studied here in. Summation of these atomic variations (excluding DbCPM(U)) are shown for whole monomers (M), atoms and groups whose
variation is not detailed (M0 ), and hydrogens not detailed or included in the methyl group attached to C300 (H(M0 )). The arrow indicates the total
electron density transference between both monomers (in au multiplied by 103). All the values were calculated at B3LYP/6-31++G(d,p) 6d in gas
phase.

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molecule which is again not involved in IHBs (0.020 au). interactions and also that of heavy atoms in the rest of each
Moreover, the hydrogens of this part of E are the atoms that, in monomer.
total, increase their electron density the most (0.016 au in HE1). As shown in the three cases analyzed in detail, the electron
That is, the hydrogens on the periphery of the monomers play density can be transferred from the H/M monomer to the E/C
a very important role for understanding electron density reor- one (HE1, HE2, MC2, ME1, and ME2), or it can follow the
ganization in complex formation. This role reminds that of sink opposite way (MC1, MC3, MC4, ME4, and ME5). Moreover, this
or source of electron density, shown initially by Stutchbury and electron density transference can be negligible (ME3).
Cooper three decades ago,26 for the hydrogens of methyl groups
in protonations and deprotonations, and conrmed by our 4. Conclusions
group for the protonation of a wide series of compounds.24,27
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Among the complexes here obtained, ME2 is the simplest B3LYP optimizations carried out for complexes formed between
case for analyzing how electron density reorganizes because of heroin or morphine with cocaine or ecgonine methyl ester lead
intermolecular binding. In fact, this is the only complex where to obtain eleven different minima described in this work. While
we only nd one intermolecular bond path (the IHB connecting all the structures obtained display positive values for complex-
O6 in M to H3 in E) in QTAIM analysis (Table 1). For this ation energy in gas phase, these values become negative in
analysis we consider the following four disjoint fragments in aqueous solution simulated with PCM. Explicit inclusion of
ME2: (i) the atomic basins of the H-acceptor C–O–H unit of water molecules stabilizes the complexes more. Thus, the
morphine (C6, O6 and H6) in the IHB; (ii) the remaining atoms calculations here reported indicate that the formation of this
of morphine; (iii) the atomic basins of the H-donor unit H–O3– kind of complexes in human uids cannot be discarded, and
C3 of ecgonine methyl ester; and (iv) the remaining atomic could be explored as a reason behind the stronger addiction
basins of ecgonine methyl ester. They are denoted as fragments observed for combined abuse of heroin and cocaine.
I, II, III, and IV in what follows. For each of these fragments we Moreover, the calculated interaction energy for the most
have performed atomic integrations of the proper density stable complex, HE1, with M06/6-31++G** 6d is more stable
function for the zero-ux atomic basins of these fragments, than B3LYP/6-31++G** 6d due to the denition of the former
dened from electron densities computed for the complex and density functional, which gives more weight to the Hartree–
the monomer with the geometry and basis functions of the Fock exchange potential. Furthermore, the modeling of the
complex (respectively [rXX(r)]X and [rXX(r)]M), as indicated by eqn dipole–dipole interactions between the molecules of the
(18). The results indicate that binding is the responsible of complex allows a better description of the interaction, which is
transferring 0.023 au from M to E. The electron density of both reected in a more stable interaction energy of the complex. On
fragments involved in the IHB (I and III) is reinforced in, 0.050 the other hand, when the interaction energy is calculated with
and 0.009 au, respectively. The electron density of fragment IV is the inclusion of the dispersion terms with the BSSE correction
also reinforced by binding (0.013 au), while the atoms not by counterpoise method is observed that the difference between
involved in IHB in M monomer (fragment II) are the ones losing the latter value and that obtained only with the density func-
electron density (0.072 au). Once again, hydrogens play tional is equal to the sum of its parts, this is to say that the
a leading role in the electron density reorganization as they difference of the interaction energy value obtained with the
provide most of the electron density (0.066 au) lost by fragment Grimme potential from the obtained only with the respective
II and receive almost one half of that received by fragment IV density functional plus the difference of the interaction energy
(0.012 au). These results also lead us to conclude that repre- value obtained with the counterpoise method from the obtained
senting the IHB formation as a certain kind of nucleophilic only with the respective density functional. Whose errors rela-
attack from the H-acceptor to the H of the donor unit is tive to the values obtained with B3LYP and M06 are of 7.22%
unreliable. and 0.36%, respectively.
It is also worth to discuss the electron density reorganization The reorganization of electron density in the formation of
accompanying MC3 formation, as it is the unique complex these eleven complexes in gas phase was subjected to a QTAIM
formed by stacking interactions. In this case, the electron analysis distinguishing between deformation and binding
density ows from C to M. The transference is certainly small terms for atomic properties. While deformation terms are
(0.004 au), as previously found in stacking complexes,23,28 but computed for structures obtained with the same basis set,
exceeds that obtained for other IHB complexes in this study. In binding terms are affected by basis set superposition error. In
contrast with IHB complexes, both molecular fragments this work, we have extended the counterpoise method to obtain
dened by collecting the atoms not involved in stacking bond CP corrections for binding atomic properties, as the difference
paths, display negative values SDbCPN(U) values (0.028 au in C between a certain atomic property computed with the electron
and 0.027 au in M). Again, both fragments formed by the density of the optimized structure of the complex and with that
atoms connected by bond paths reinforce signicantly their computed for isolated monomer with the geometry and basis
electron population (0.022 au in C and 0.031 au in M). In this set of the complex. These corrections were found to be very
case, the set of hydrogens not included in intermolecular bond small in the eleven complexes here reported.
paths plays the role of electron density donors (0.021 au in C The values of the four atomic properties here considered
and 0.035 au in M). The electron density taken from these (electron population, total energy, module of the rst moment
hydrogens reinforces that of the atoms involved in stacking of the electron density and volume) indicate that: (i) geometry

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