This journal is c the Owner Societies 2011 Phys. Chem. Chem. Phys., 2011, 13, 5105–5113 5105
Cite this: Phys. Chem. Chem. Phys., 2011, 13, 5105–5113
Halogen bonded complexes between volatile anaesthetics (chloroform,
halothane, enflurane, isoflurane) and formaldehyde: a theoretical study
Wiktor Zierkiewicz,*aRobert Wieczorek,
bPavel Hobza
cdand Danuta Michalska
a
Received 8th October 2010, Accepted 12th January 2011
DOI: 10.1039/c0cp02085k
The structures and intermolecular interactions in the halogen bonded complexes of anaesthetics
(chloroform, halothane, enflurane and isoflurane) with formaldehyde were studied by ab initio
MP2 and CCSD(T) methods. The CCSD(T)/CBS calculated binding energies of these complexes
are between �2.83 and �4.21 kcal mol�1. The largest stabilization energy has been found
for the C–Br� � �O bonded halothane� � �OCH2 complex. In all complexes the C–X bond length
(where X = Cl, Br) is slightly shortened, in comparison to a free compound, and an increase
of the C–X stretching frequency is observed. The electrostatic interaction was excluded as being
responsible for the C–X bond contraction. It is suggested that contraction of the C–X bond
length can be explained in terms of the Pauli repulsion (the exchange overlap) between the
electron pairs of oxygen and halogen atoms in the investigated complexes. This is supported by
the DFT-SAPT results, which indicate that the repulsive exchange energy overcompensates the
electrostatic one. Moreover, the dispersion and electrostatic contributions cover about 95% of
the total attraction forces, in these complexes.
1. Introduction
Anaesthesia is a reversible phenomenon and general
anaesthetics act by perturbing weak intermolecular inter-
actions without breaking or forming covalent bonds. Despite
the fact that volatile anaesthetics, such as chloroform,
halothane, enflurane and isoflurane, have been used clinically,
the mechanism of their action is still not fully understood.
They may act by a direct bonding to neuroreceptors.1–6
Sandorfy1 reported that they can form weak van der Waals
complexes or intermolecular hydrogen bonds, and the strength
of these interactions is in the range between 1.0 and
2.2 kcal mol�1. Investigation of the halogen bonds and
hydrogen bonds may help to explain anaesthetic properties
of polyhalogenated alkanes and ethers.7–9 A number of
experimental and theoretical evidences confirm that the halogen
bond plays an important role in a wide variety of biological
phenomena such as protein–ligand complexation.10–15
Eckenhoff and coworkers16 reported the crystal structure of
the halothane/apoferritin and isoflurane/apoferritin complexes.
For the halothane complex it has been shown that in the binding
pocket the distance between the bromine atom of halothane and
the carbonyl oxygen atom of leucine (3.11 A) is smaller than the
sum of the corresponding van der Waals radii (3.37 A).
Studies of the electrostatic potentials of the halogen bonded
systems show that the lone electron pairs of the halogen atom
bonded to the carbon atom form a belt of negative
electrostatic potential around its central part leaving the outer-
most region positive, the so-called s-hole.17,18 The halogen
bonding was explained as a noncovalent interaction between a
covalently bound halogen on one molecule and a negative site
of another.7,19–21 Recently, it has been shown that the
interaction energy in these complexes is dominated by the
dispersion and electrostatic contributions.22–24 Halogen bonds
are similar to hydrogen bonds in many respects. Therefore,
they may collaborate or compete with each other.25–30
The aim of this work is to elucidate the nature of inter-
actions in the chloroform, halothane, enflurane and isoflurane
complexes with formaldehyde using ab initio MP2 and
CCSD(T) methods. The studies on the halogen bond inter-
actions between anaesthetics and amino acids are important
for understanding their mechanism of action, in biological
systems. Therefore, the complexes investigated in this work
can serve as the models for such studies.
The structures, binding energies and harmonic frequencies
of these complexes are discussed. The C–X (XQCl, Br) bond
in anaesthetics becomes shorter and stronger upon formation
of a complex with formaldehyde. The possible explanation of
this phenomenon is presented.
a Faculty of Chemistry, Wroc!aw University of Technology,Wybrzeze Wyspianskiego 27, 50-370 Wroc!aw, Poland.E-mail: [email protected]; Fax: +48 71-320-4360;Tel: +48 71-320-3455
b Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14,50-383 Wroclaw, Poland
c Institute of Organic Chemistry and Biochemistry, Academy ofSciences of the Czech Republic and Center for Biomolecules andComplex Molecular Systems, 166 10 Praha 6, Czech Republic
dDepartment of Physical Chemistry, Palacky University,771 46 Olomouc, Czech Republic
PCCP Dynamic Article Links
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2. Theoretical methods
Full geometry optimizations of the isolated anaesthetic
molecules (chloroform, halothane, enflurane, isoflurane) and
their halogen bonded complexes with formaldehyde were
performed by the ab initio second order Møller–Plesset
perturbation (MP2) method31 using the 6-311++G(d,p) basis
set.32,33 The counterpoise CP-corrected gradient optimization
has been used.34 Subsequently, vibrational harmonic
frequencies and infrared intensities have been calculated for
all species considered in this work.
To elucidate the relativistic effects for the halothane� � �formaldehyde complex with the C–Br� � �O halogen bond, we
have performed additional calculations using the LanL2DZdp
pseudopotential basis set35 for the bromine atom and the
6-311++G(d,p) basis set for the other atoms. Moreover, the
geometry of the halothane� � �formaldehyde complex has been
optimized at the MP2/cc-pVTZ level. Further, the interaction
energy has been calculated using both the aug-cc-pVTZ basis
set36,37 on all atoms and mixed aug-cc-pVTZ-PP basis set38 on
the bromine atom and aug-cc-pVTZ on other atoms.
The CCSD(T) complete basis set (CBS) limit interaction
energies have been obtained as a sum of the MP2/CBS
interaction energies and the CCSD(T) correction term, which
is defined as a difference between the MP2 and CCSD(T)
interaction energies determined in a smaller basis set (6-31G*).39,40
The CBS limit energies were evaluated by an extrapolation
of the Hartree–Fock energy and the MP2 correlation energy
from the cc-pVTZ and cc-pVQZ basis sets.36,37 The two-point
extrapolation methods of Helgaker et al. were used.41,42
To get a detailed insight into the nature of bonding in
these complexes, the symmetry adapted perturbation theory
DFT-SAPT43 calculations were carried out at the PBE0/aug-cc-
pVTZ level.44 The SAPT method determines the total inter-
action energy as the sum of the first- and second-order
perturbation terms. The favorable performance of the method
is due to a combination of the DFT treatment for monomers
and SAPT treatment for interaction between monomers.
A natural bond orbital (NBO) analysis45 was performed at
the MP2/6-311++G(d,p) level of theory. To calculate the
positive sigma hole potentials, the electrostatic potential
surface maxima on halogen atoms of isolated s-hole donors
have been computed at the B3PW91/6-31G(d,p) level using the
WFA (Wavefunction Analysis Program).46
All calculations were carried out with the GAUSSIAN 0947
or MOLPRO 200648 programs.
3. Results and discussion
3.1 Structures
Fig. 1 shows the structures of the chloroform� � �OCH2 and
halothane� � �OCH2 complexes optimized at the MP2/
6-311++G(d,p) level. It should be mentioned that the most
stable conformer of halothane has been selected for investiga-
tions.49–52 As is seen from this figure, two structural isomers of
the halothane� � �formaldehyde complex have been found. The
(A) complex with the C–Br� � �O halogen bond is more
stable, by 0.44 kcal mol�1, than the (B) complex with the
C–Cl� � �O bond.
Fig. 2 illustrates the structures of the formaldehyde
complexes with the most stable conformers of enflurane53–56
and isoflurane. In the case of the isoflurane� � �OCH2 complex,
the MP2 calculations have revealed the presence of two
structural isomers, (A) and (B), where (A) is more stable by
0.16 kcal mol�1. The formation of these two isomers can be
explained as a consequence of the weak secondary interaction
between the hydrogen atom of formaldehyde and the fluorine
atom of isoflurane.
Tables 1 and 2 list the selected geometrical and vibrational
parameters for the investigated complexes. As follows from
Table 1, the C1–X2 bond (where X = Cl, Br) is contracted
upon complexation. In the chloroform and isoflurane
complexes the C1–Cl2 bond length is contracted by �0.003 A,
while the smallest change (�0.001 A) is observed in the
halothane� � �OCH2 (A) complex. As follows from Table 2, a
Fig. 1 Optimized structures of chloroform� � �formaldehyde and two
halothane� � �formaldehyde (A and B) complexes with selected atom
numbering. Calculations were performed at the MP2/6-311++G(d,p)
level.
Fig. 2 Optimized structures of enflurane� � �formaldehyde and two
isoflurane� � �formaldehyde (A and B) complexes with selected atom
numbering. Calculations were performed at the MP2/6-311++G(d,p)
level.
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contraction of the C1–X2 bond is concomitant with a small
(up to 4 cm�1) increase of the C–X stretching frequency
(blue-shift). For the enflurane� � �OCH2 complex, the infrared
intensity of the corresponding mode decreases by�15 kmmol�1.
In other complexes the decrease of the IR intensity is smaller
(from 0 to �5 km mol�1).
Recently, van der Veken and coworkers57 have confirmed
experimentally the small (+1.7 cm�1) blue-shift of the n(C–Cl)stretching frequency in the trifluorochloromethyl dimethyl
ether complex containing the C–Cl� � �O halogen bond. The
MP2/6-311++G(d,p) calculated contraction of the C–Cl bond
was �0.006 A.
As shown in Table 1, upon complexation, the C3–O4 bond is
elongated by 0.001 A, in all complexes. This is accompanied by
a small (up to 2 cm�1) red-shift of the n(C3–O4) stretching
frequency and the decrease of the infrared intensity of this
mode, by about �11 km mol�1 in all complexes, except for
the halothane� � �formaldehyde (A) complex, where the IR
intensity decreases only by �1 km mol�1 (Table 2).
The sum of the van der Waals radii of the chlorine–oxygen
and the bromine–oxygen atoms is 3.27 and 3.37 A,
respectively.58 As follows from Table 1, in the chloroform
and halothane (A) and (B) complexes, the intermolecular
X2� � �O4 distances are smaller than the corresponding sum of
the vdW radii.
In the enflurane� � �OCH2 and isoflurane� � �OCH2 complexes
the Cl2� � �O4 distance is equal to (or is slightly larger than) the
sum of the vdW radii. Despite this fact, the theoretical
methods have predicted that these complexes are stable.
Auffinger et al.10 on the basis of the Protein Data Basis
(PDB) survey have reported that the average Br� � �O distance
(3.15 A) is longer, by 0.09 A, than the average Cl� � �O distance.
However, in the halothane–formaldehyde (A) complex the
MP2 calculated Br� � �O distance (3.14 A) is shorter (by 0.06 A)
than the Cl� � �O distance in the (B) complex, as shown in Table 1.
A similar effect was reported for the complexes of hypohalous
acids with formaldehyde59 and for the F3CBr� � �OCH2 and
F3CCl� � �OCH2 complexes.60 On the other hand, calculations
performed at the MP2/6-311++G(d,p) level for the F3CBr and
F3CCl complexes with dimethyl ether predicted the same Br� � �Oand Cl� � �O atom distances (2.89 A),57 whereas MP2 calculations
of the halothane� � �dimethyl ether predicted a longer Br� � �Odistance than Cl� � �O, by about 0.05 A.61 This comparison shows
that the intermolecular Br� � �O and Cl� � �O distances are different,
in various systems.
The sum of the van der Waals radii of the chlorine–
hydrogen and bromine–hydrogen atoms is 2.95 and 3.05 A,
respectively.58 In the CHCl3� � �OCH2, CHClBrCF3� � �OCH2 (A),
CHClBrCF3� � �OCH2 (B), enflurane� � �OCH2, isoflurane� � �OCH2 (A) and isoflurane� � �OCH2 (B) complexes, the shorter
distance between the H atom of OCH2 and the halogen atom is
equal: 3.29, 3.53, 3.29, 2.99, 3.91 and 3.39 A, respectively. All
these distances are larger than the corresponding sum of the
vdW radii. Nevertheless, some weak secondary interactions
may also occur in these complexes. Especially, in the
enflurane� � �OCH2 complex, where the closest H� � �F distance
is only slightly larger (0.04 A) than the sum of the vdW
radii.
In biological molecules with the halogen bond, the average
C–X� � �O and X� � �O–C angles are 1601–1801 and about 901,
respectively.10 The results collected in Table 1 show that the
C1–X2� � �O4 angles in the C–Cl� � �O bonded complexes are
smaller than the C–Br� � �O angle in the halothane (A) complex.
Table 1 Selected structural parameters of the anaesthetic� � �formaldehyde complexes (distances r, d, in A, angle y in 1). Results from the MP/6-311++G(d,p) and the MP/6-311++G(d,p)/LanL2DZdp calculations
r(C1–X2) r(C3–O4) d(X2� � �O4) y(C1–X2� � �O4) y(X2� � �O4–C3)
Chloroform� � �OCH2 1.762 1.214 3.23 166.9 101.2(�0.003)a (+0.001)
Halothane� � �OCH2 (A) 1.930 1.214 3.14 171.1 110.8(�0.001) (+0.001)
Halothane� � �OCH2 (A)b 1.934 1.214 3.13 171.1 110.6(�0.001) (+0.001)
Halothane� � �OCH2 (B) 1.758 1.214 3.20 164.5 101.8(�0.002) (+0.001)
Enflurane� � �OCH2 1.750 1.214 3.30 154.1 97.3(�0.002) (+0.001)
Isoflurane� � �OCH2 (A) 1.764 1.214 3.27 160.5 98.3(�0.003) (+0.001)
Isoflurane� � �OCH2 (B) 1.764 1.214 3.28 158.6 97.8(�0.003) (+0.001)
a In parentheses are shown differences between the values in the complex and in the isolated molecule. b Results from the MP2 calculations with
the LanL2DZdp basis set for the bromine atom and the 6-311++G(d,p) basis set for the other atoms.
Table 2 Selected vibrational parameters of the anaesthetic� � �formaldehyde complexes (vibrational frequency n, in cm�1, infraredintensity I, in km mol�1). Results from the MP/6-311++G(d,p)calculations
n(C1–X2) I(C1–X2) n(C3–O4) I(C3–O4)
Chloroform� � �OCH2 388 (+4)a 1 (0) 1760 (�1) 64 (�10)Halothane� � �OCH2 (A) 739 (+1) 14 (�5) 1759 (�2) 73 (�1)Halothane� � �OCH2 (A)b 741 (+2) 13 (�5) 1758 (�3) 72 (�2)Halothane� � �OCH2 (B) 849 (0) 70 (�5) 1760 (�1) 64 (�10)Enflurane� � �OCH2 862 (+2) 45 (�15) 1759 (�2) 63 (�11)Isoflurane� � �OCH2 (A) 764 (0) 28 (�1) 1760 (�1) 63 (�11)Isoflurane� � �OCH2 (B) 764 (+1) 26 (�3) 1760 (�1) 63 (�11)a In parentheses are shown differences between the values in the
complex and in the isolated molecule. b Results from the MP2 calcula-
tions with the LanL2DZdp basis set for the bromine atom and the
6-311++G(d,p) basis set for the other atoms.
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The deviation of the C1–X2� � �O4 angles from 1801 can be
attributed to the secondary weak interaction between the
hydrogen atom of formaldehyde and halogen atom or atoms
of the halogen donor. The biggest deviation (25.91) of this
angle has been found in the enflurane� � �OCH2 complex. It
should be mentioned that the H� � �O distance (2.97 A) between
the H atom of formaldehyde and O atom of enflurane is larger,
by 0.25 A, than the sum of the corresponding vdW radii.
The Cl� � �O4–C3 angles are in the range 97.31–101.81, and all
are smaller than the Br� � �O4–C3 angle (110.81) in the
halothane (A) complex. A similar effect was reported earlier
for the halomethane� � �formaldehyde complexes, and it was
attributed to larger contribution of a dispersion energy in the
Cl� � �O interaction.23
To answer the question whether the relativistic effects are
important in the halothane� � �formaldehyde complex (A) with
the C–Br� � �O halogen bond, the additional MP2 calculations
have been performed using the LanL2DZdp pseudopotential
basis set for the bromine atom and the 6-311++G(d,p) basis
set for the other atoms. A similar method was used by
Michielsen et al.61 The results are presented in Tables 1 and 2.
As follows from Table 1 the use of the LanL2DZdp basis set
for Br leads to an elongation of the C1–Br bond by 0.004 A,
and a shortening of the Br� � �O4 distance by 0.01 A. The
stabilization energies of this complex calculated at the
MP2/6-311++G(d,p) and MP2/6-311++G(d,p)/LanL2DZdp
levels are �2.00 and �2.03 kcal mol�1, respectively. Thus,
the difference between the binding energies is only 1.5%,
which indicates that the relativistic effects are negligible for
the halothane� � �formaldehyde complex with the C–Br� � �Obond. However, it should be mentioned that, in the case of
the H3CBr� � �OCH2 complex, the relativistic effects evaluated
at different levels of theory were slightly higher, the MP2
interaction energy of this complex calculated with the aug-cc-
pVTZ-PP basis set on the bromine atom and aug-cc-pVTZ on
all other atoms was larger by 4.2% than that calculated using
the aug-cc-pVTZ on all atoms.23 We have performed calcula-
tions on the same level of theory for the halothane� � �formaldehyde complex (A) and the results are very similar,
the difference between the two interaction energies is 4.5%.
Thus, the relativistic effects in the investigated system are
rather small.
In order to make the comparison between formaldehyde
and formamide as the s-hole acceptors, the chloroform� � �formamide complex has also been studied (Fig. 3).
In the latter, the shortening of the C1–Cl2 bond caused by
complexation (�0.005 A) is larger than that in the chloro-
form� � �formaldehyde complex (�0.003 A). Contraction of the
C1–Cl2 bond is concomitant with an increase of the C–Cl
stretching frequency (+4 cm�1). The infrared intensity of the
corresponding mode increases by +7 km mol�1. The Cl2� � �O3
distance in the chloroform� � �OCHNH2 complex is shorter (by
0.08 A) than that in the chloroform� � �formaldehyde complex.
The C1–Cl2� � �O4 angle (170.21) is larger by 3.31 despite the fact
that the shorter distance between the H atom of OCHNH2 and
the halogen atom (3.29 A) is the same as that in the formalde-
hyde complex.
3.2 NBO analysis
The selected NBO data are listed in Table 3. As follows from
this table, the halogen atom shows the largest change of the
atomic charge, upon complexation. The charge on X2
increases in the range between 0.012 and 0.018 e
(halothane� � �OCH2 (A) complex).
Examination of occupancies of the bonding s(C1–X2) and
antibonding s*(C1–X2) orbitals indicates that the change
in the electron density on these orbitals is negligible (smaller
than �0.002 e), upon complexation.
Fig. 3 Optimized structure of the chloroform� � �formamide complex
with selected atom numbering. Distances in A, angles in 1. Results
from the MP2/6-311++G(d,p) calculations.
Table 3 Charges (q in e) on selected atoms, charge transfer (CT in e) in anaesthetic� � �formaldehyde complexes calculated at the MP2/6-311++G(d,p) level
C1 X2a O4 C3 CTb
Chloroform� � �OCH2 �0.310 0.052 �0.469 0.287 0.002(�0.002)c (+0.013) (�0.005) (+0.001)
Halothane� � �OCH2 (A) �0.402 0.131 �0.473 0.290 0.007(�0.008) (+0.018) (�0.009) (+0.004)
Halothane� � �OCH2 (B) �0.397 0.065 �0.470 0.287 0.003(�0.003) (+0.012) (�0.006) (+0.001)
Enflurane� � �OCH2 0.160 0.036 �0.472 0.286 0.002(�0.007) (+0.013) (�0.008) (0.000)
Isoflurane� � �OCH2 (A) 0.018 0.034 �0.469 0.286 0.002(�0.006) (+0.012) (�0.005) (0.000)
Isoflurane� � �OCH2 (B) 0.018 0.034 �0.468 0.286 0.002(�0.006) (+0.012) (�0.004) (0.000)
a X2 means the bromine atom in the halothane� � �OCH2 (A) complex and chlorine atoms in all other complexes. b Charge transfer from
formaldehyde to a s-hole donor. c In parentheses are shown the changes of the charges caused by complexation, calculated as differences between
the values in the complex and in the isolated molecule.
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As follows from the last column of Table 3, the charge
transfer (CT) from formaldehyde to halothane (A complex) is
equal to 0.007 e, while in the remaining complexes it is about
twice smaller. It is worth to mention that the values of CT
are similar to those found for weak hydrogen bonds.62
The NBO analysis has been performed also for the
chloroform� � �formamide complex. These results have revealed
that the change of the charge on the chlorine atom caused by
complexation equals +0.023 e, which is much larger than that
in the chloroform� � �formaldehyde complex (+0.013 e). This
fact can be explained as a consequence of different charges on
the O4 atoms in the s-hole acceptors. The charges on the
oxygen atoms in formaldehyde and formamide are �0.464 and�0.564 e, respectively. The larger the electron density (ED) on
the oxygen atom, the larger the decrease of ED on the
chlorine atom.
3.3 Contraction of the C–X2 bond
Recently, it has been suggested that in the halogen bonded
complexes with weak hyperconjugative interaction, the
electrostatic interaction is responsible for contraction of the
Y–X bond (where Y = C, N, Si and X = Cl, Br).63 Thus, we
have also investigated the role of electrostatic and polarization
effects in chloroform and its complex with formaldehyde. The
Merz–Kollman charges of formaldehyde atoms (obtained
from the complex) were placed at the positions of the
respective atoms. In this treatment, the geometry changes were
caused by both electrostatic and polarization interactions
between chloroform and the inhomogenous electric field.
According to these calculations, the C1–Cl2 bond of chloro-
form was only slightly elongated (by 0.0002 A) upon the
electric field of the proton acceptor. In addition, geometry
optimization of the isolated halogen donors was performed in
the uniform electric field parallel to the C1–Cl2 bond. These
results have shown that in the homogenous electric field (in the
range from 0.004 to 0.024 au) the C1–Cl2 bond length is
elongated. This excludes the electrostatic interaction as being
responsible for the contraction of the C1–Cl2 bond length.
To examine the Hermansson64 and the Qian/Krimm65
models for predicting contraction or elongation of the
C1–X2 bond (blue-shifting or red-shifting complexes,
respectively) we calculated the derivatives of the permanent
dipole moments (qm0/qRC1–X2) and their directions for each
anaesthetic, see Table 4. According to these models the change
in the frequency of the C1–X2 bond should be related to the
magnitudes and directions of the derivatives qm0/qRC1–X2and
qmind/qRC1–X2, where mind is the dipole moment induced by the
electric field of the s-hole acceptor. Since qmind/qRC1–X2is in
the direction of the electric field, it always supports an
elongation of the C1–X2 bond.66
As is seen from Table 4 only in the case of halothane
(X2 = Br) the qm0/qRC–Br has a negative value. This indicates
that the negative dipole gradient for the C1–X2 bond is not the
necessary condition for the blue-shift of the C1–X2 stretching
vibration.
In the last column of Table 4 the values of angle between the
dipole moment and the bond from C1 to X2 are collected. An
angle of 1801 correlates with a contraction of this bond
(blue-shifting complexes), while an angle of 01 indicates possi-
bility of an elongation of the bond (red-shifting complexes).66
As follows from this table only in the case of enflurane the
value of this angle (1501) is nearest to 1801. In the other
molecules the dipole derivatives are more or less perpendicular
to the uniform electric field. Thus, it is impossible to derive the
definite conclusions regarding the nature of contraction of the
C1–X2 bond on the basis of these results.
In the case of the blue-shifted hydrogen bonded complexes
Schlegel et al.67 suggested that the Pauli repulsion between two
fragments is responsible for the contraction of the X–H bond.
Now, the question arises: can the analogous Pauli repulsion
(the exchange overlap) effect explain the changes of the C–X
bond length in the investigated complexes?
The halogen atom has three electron pairs which form a belt
of negative electrostatic potential around the central part of
this atom, leaving the outermost region positive (s-hole).17,18
The oxygen atom of formaldehyde has two lone pair orbitals
LP(1)O4 and LP(2)O4. The LP(2)O4 orbital is involved in the
formation of the halogen bond, and it overlaps with the
s*(C1X2) orbital of the investigated anaesthetic. This
orbital interacts with the halogen atom through the s-hole.Simultaneously, electrons of the LP(1)O4 orbital can
repulse the electron pairs on the halogen atom. In our opinion,
this repulsion is responsible for pushing the halogen atom
towards the carbon atom, which makes the C1–X2 bond
shorter.
Fig. 4 illustrates the contours of the selected orbital ampli-
tudes in the plane passing through the C1, Cl2 and O4 atoms, in
the CHCl3� � �OCH2 complex. The overlap of LP(2)O4 with the
s*(C1Cl2) orbitals is shown in Fig. 4A, while the overlap of
LP(1)O4 with LP(1)Cl2 and overlap of LP(1)O4 with LP(2)Cl2are depicted in Fig. 4B and C, respectively. It should be
mentioned that the contour of the third electron pair orbital
of the Cl atom (LP(3)Cl2) is not seen in the selected plane.
If the suggested idea of repulsion is responsible for this
effect, then in the case of a halogen acceptor with only one
electron pair (for instance the N atom), the contraction of the
C–X bond should be smaller (in comparison to the O atom
acting as the halogen acceptor) or elongation of this bond
should be observed.
In the C–X� � �O halogen bonded complexes of F3C–X with
dimethyl ether, the C–X bonds (X=Cl, Br, I) were contracted
by �0.005, �0.006 and �0.004 A, respectively. On the other
hand, in the C–X� � �N halogen bonded complexes of F3C–X
with trimethylamine, the C–X bonds (X = Br, I) were
elongated by 0.005 and 0.015 A, respectively, or negligibly
contracted (by �0.001 A for X = Cl).60,68 Analogous results
Table 4 Derivatives of the permanent dipole moments of anaesthetics(qm0/qRC–X2
in D A�1) and the angle between the dipole moment andthe bond from C1 to X
2(angles in 1). Calculations performed at the
MP2/6-311++G(d,p) level
qm0/qRC–X2Angle
Chloroform (X2= Cl) 0.30 108Halothane (X2= Br) �0.35 84Halothane (X2= Cl) 0.02 93Enflurane (X2= Cl) 2.12 150Isoflurane (X2= Cl) 1.13 106
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were obtained for the F3Y–X (Y = C, N, Si; X = Cl, Br)
complexes with H2O and NH3.63
These results seem to support our explanation of the origin
of the contraction of the C–X bond in the studied anaesthetics,
upon complexation.
3.4 Binding energies
The binding energies calculated by the CCSD(T)/CBS,
MP2/CBS and HF/CBS methods are compared in Table 5.
As is seen in this table, the interaction energies obtained at the
CCSD(T)/CBS level (DECCSD(T)/CBS) are in the range between
�2.83 and �4.21 kcal mol�1. All the theoretical methods
consistently indicate that the C–Br� � �O halogen bonded
complex of halothane� � �OCH2 (A) has the largest binding
energy. It is known that the magnitude of the binding energy
increases with the increasing halogen size.23 Indeed, in the
halothane� � �OCH2 (A) complex (C–Br� � �O bond) binding
energy is larger, by about 31%, than that in the halothane� � �OCH2 (B) complex (C–Cl� � �O bond), as revealed by the
CCSD(T)/CBS calculations. A similar effect was reported for
the H3CBr� � �OCH2 and H3CCl� � �OCH2 complexes, calcu-
lated at the same level of theory (CCSD(T)/CBS), the former
complex had a stronger binding energy (by about 32%) than
the latter.23 Moreover, for two halothane� � �dimethyl ether
complexes, that with the C–Br� � �O bond had a larger inter-
action energy (�3.82 kcal mol�1) than the other, with the
C–Cl� � �O bond (�2.58 kcal mol�1).61
The CCSD(T) correction terms (calculated as differences
between DECCSD(T)/CBS and DEHF/CBS) are about 60–70% of
the total interaction energies. This indicates that dispersion is
very important in the formation of these complexes.
For the chloroform� � �formamide complex the calculated
CCSD(T)/CBS, MP2/CBS and HF/CBS binding energies are
�3.42, �3.48 and �1.13 kcal mol�1, respectively. Thus,
the chloroform� � �OCHNH2 complex is more stable than
chloroform� � �OCH2 by �0.53 kcal mol�1.
It was shown that the positive surface potential maxima
Vs,max correlate with the interaction energies, in the bromo-
benzene and bromopyridine complexes with acetone.24 To
check this idea, the positive sigma hole potentials for isolated
anaesthetics have been calculated. The most positive values of
Vs,max on the chlorine and bromine atoms in anaesthetics
investigated are listed in Table 6.
For the chlorine atoms, the values of Vs,max range from
8.8 kcal mol�1 (isoflurane) to 14.3 kcal mol�1 (halothane)
while for the bromine atom in halothane Vs,max is
20.8 kcal mol�1. Trogdon et al.9 calculated the Vs,max values
on the chlorine and bromine atoms in the same anaesthetics at
the HF/6-31* level of theory. They obtained slightly larger
values: 14.5, 22.3, 15.3, 13.0, 14.1 kcal mol�1 for chloroform,
halothane (Br), halothane (Cl), enflurane and isoflurane,
respectively.
In the series of anaesthetics investigated in this work we
have found the linear relationship between the interaction
energies DECCSD(T)/CBS and the Vs,max with a correlation
coefficient of 0.77. A rather poor correlation clearly indicates
that the electrostatic term is not the dominant one and the
dispersion and polarization energy terms contribute to a
stabilization of the halogen bond as well.
3.5 Decomposition of interaction energies
The DFT symmetry adapted perturbation theory (DFT-SAPT)
analysis has been performed at the PBE0/aug-cc-pVTZ level of
theory. The results are collected in Table 7. The DFT-SAPT
interaction energies vary between �2.58 and �3.92 kcal mol�1.
In all Cl� � �O halogen bonded complexes considered in this
Fig. 4 Contours of the selected orbitals amplitude in plane passing
through C1, Cl2 and O4 atoms, in the CHCl3� � �OCH2 complex.
Overlap of the LP(2)O4 and s*(C1Cl2) orbitals (A), LP(1)O4 and
LP(1)Cl2 orbitals (B), LP(1)O4 and LP(2)Cl2 orbitals (C).
Table 5 Binding energies calculated by the CCSD(T)/CBS(DECCSD(T)/CBS), MP2/CBS (DEMP2/CBS), HF/CBS (DEHF/CBS) andcorrelation energies. All values are in kcal mol�1
DEHF/CBS DEMP2/CBS DECCSD(T)/CBS DEcorr a
Chloroform� � �OCH2 �0.95 �2.99 �2.89 �1.94Halothane� � �OCH2 (A) �1.61 �4.36 �4.21 �2.60Halothane� � �OCH2 (B) �1.13 �3.29 �3.21 �2.08Enflurane� � �OCH2 �1.39 �3.72 �3.67 �2.28Isoflurane� � �OCH2 (A) �0.91 �2.99 �2.93 �2.03Isoflurane� � �OCH2 (B) �0.75 �2.88 �2.83 �2.08a Difference between DECCSD(T)/CBS and DEHF/CBS.
Table 6 Vs,max (in kcal mol�1) on X2 (X2 = Cl or Br) atoms forisolated anaesthetics calculated at the B3PW91/6-31G(d,p) level
Vs,max on X2
Chloroform (X2 = Cl) 13.8Halothane (X2 = Br) 20.8Halothane (X2 = Cl) 14.3Enflurane (X2 = Cl) 11.1Isoflurane (X2 = Cl) 8.8
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work, the dispersion ED(2) energy is the dominant attraction
component representing about 50% of the total attraction
forces, while the electrostatic Eel(1) forces account for about
40–45% of the total energy. In the Br� � �O halogen bonded
complex of halothane (A), Eel(1) contributes 51%, while ED
(2)
contributes 38% to the total energy. Similar results were
obtained for the halomethane� � �formaldehyde complexes.23
In the chloroform� � �formamide complex, electrostatic and
dispersion energies contribute about 45% each to the total
energy. For all complexes investigated, the repulsive exchange
energy Eex(1) overcompensates Eel
(1), thus the first-order
energies E(1) are repulsive by less than 0.70 kcal mol�1. The
magnitude of the repulsive exchange energy supports the
conclusion that the Pauli repulsion (the exchange overlap)
effect is responsible for the contraction of the C–X bond in the
anaesthetics upon complexation.
The contribution of the induction Ei(2) energy to the total
attraction energy is about 5%. These results show that the
dispersion and electrostatic contributions cover about 95% of
the total attraction forces, in these complexes.
3.6 Comparison of the halogen bond and hydrogen bond
Both types of the intermolecular interactions share several
characteristics such as strength or the hyperconjugation
between antibonding orbital of the C–X bond (X = Cl, Br)
and the electron pair of the oxygen atom. In this work we
would like to point out the different mechanisms responsible
for the contraction of the C–H bond (in the blue-shifted
hydrogen bonded complexes) and the C–X bond (in the
complexes considered in this work). In both cases the oxygen
atom is the acceptor for the H or X atoms. In the former
complexes the electrostatic interaction plays the crucial role,
while in the latter complexes the repulsion between the
electron pairs of the oxygen and halogen atoms is the driving
force. In both cases the contraction of the C–H or C–X bonds
is accompanied by an increase of the C–H or C–X stretching
frequencies (blue-shift).
4. Conclusions
In this work the structures and binding energies of the halogen
bonded complexes of anaesthetics (chloroform, halothane,
enflurane and isoflurane) with formaldehyde were studied
using ab initio MP2 and CCSD(T) methods. The understand-
ing of the halogen bond interaction between anaesthetics and
amino acids is important for elucidation of their mechanism of
action, in biological systems. Thus, the complexes investigated
in this work can serve as the models for such studies. The most
important conclusions are the following:
(1) All anaesthetics studied in this work make stable
complexes with formaldehyde through the Cl� � �O halogen
bonding. In addition, halothane also forms the Br� � �O halogen
bonded complex (B). According to the MP2 method, the
halothane� � �OCH2 complex with the C–Br� � �O halogen bond
is more stable, by 0.44 kcal mol�1, than that the other one. In
the case of the isoflurane� � �OCH2 complex, the MP2 calcula-
tions have revealed the presence of two structural isomers,
which differ in energy by 0.16 kcal mol�1.
(2) Binding energies calculated by the CCSD(T) complete
basis set (CBS) limit method for six halogen bonded
anaesthetic� � �formaldehyde complexes vary between �2.83and �4.21 kcal mol�1. The largest DECCSD(T)/CBS has been
found for the C–Br� � �O halogen bonded halothane� � �OCH2
(A) complex, while the smallest binding energy has been
obtained for the isoflurane� � �OCH2 (B) complex.
(3) The C–X bond lengths (where X = Cl, Br) are
contracted upon complexation. It is suggested that the main
reason for contraction of the C–X bond is a repulsion between
the lone electron pair orbitals (the exchange overlap) of the
oxygen and halogen atoms.
(4) In the chloroform and two halothane complexes with
formaldehyde, the intermolecular (X� � �O) distance is smaller
than the sum of the corresponding van der Waals radii. In
the enflurane� � �OCH2 and isoflurane� � �OCH2 complexes the
intermolecular distance is equal to or slightly longer than the
sum of the corresponding vdW radii. However, all the calcula-
tions performed in this work predict these complexes to be
stable.
(5) The DFT-SAPT results show that the dispersion and
electrostatic contributions cover about 95% of the total
attraction forces, in these complexes. In the Cl� � �O halogen
bonded complexes, the dispersion is the dominant
attraction component representing about 50% of the total
attraction forces, while the electrostatic forces account for
about 40–45% of the total energy. In the Br� � �O halogen
bonded complex of halothane, the electrostatic and dispersion
terms contribute 51% and 38%, respectively, to the total
attraction forces.
(6) According to the DFT-SAPT results for all complexes
investigated, the repulsive exchange energy overcompensates
the electrostatic one. This supports our conclusion that the
Pauli repulsion (the exchange overlap) effect is responsible for
Table 7 First- and second-order perturbative DFT-SAPT (PBE0/aug-cc-pVTZ) energies (kcal mol�1) for the investigated anaesthetic� � �OCH2
complexes
Eel(1) Eex
(1) E(1) Ei(2) ED
(2) E(2) d(HF) DEDFT�SAPT
Chloroform� � �OCH2 �2.47 2.88 0.41 �0.31 �2.68 �2.99 �0.15 �2.73Halothane� � �OCH2 (A) �4.70 5.24 0.54 �0.65 �3.49 �4.14 �0.32 �3.92Halothane� � �OCH2 (B) �2.85 3.21 0.36 �0.35 �2.90 �3.25 �0.17 �3.06Enflurane� � �OCH2 �2.84 3.10 0.26 �0.34 �3.37 �3.71 �0.15 �3.60Isoflurane� � �OCH2 (A) �2.33 2.81 0.48 �0.29 �2.81 �3.10 �0.14 �2.76Isoflurane� � �OCH2 (B) �2.05 2.74 0.69 �0.29 �2.84 �3.13 �0.14 �2.58Eel
(1) electrostatic energy; Eex(1) exchange–repulsion energy; E(1) sum of Eel
(1) and Eex(1); Ei
(2) induction energy; ED(2) dispersion energy; E(2) sum of
Ei(2) and ED
(2); d(HF) sum of higher order HF contributions; DEDFT–SAPT sum of E(1), E(2) and d(HF) energies.
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the contraction of the C–X bond in the anaesthetics upon
complexation.
(7) Calculations performed for the chloroform� � �formamide
and chloroform� � �formaldehyde complexes at the CCSD(T)/
CBS level of theory have revealed that the former is more
stable by �0.53 kcal mol�1.
Acknowledgements
The authors are indebted to Wroclaw University of Techno-
logy for financial support, Grant No. 344113. The generous
computer time from the Poznan Supercomputer and
Networking Center as well as Wroclaw Supercomputer and
Networking Center is acknowledged. This work was a part of
the research project No. Z40550506 of the Institute of Organic
Chemistry and Biochemistry, Academy of Sciences of the
Czech Republic and it was also supported by Grants No.
LC512 and MSM6198959216 from the Ministry of Education,
Youth and Sports of the Czech Republic. The support of
Praemium Academiae, Academy of Sciences of the Czech
Republic, awarded to PH in 2007 is also acknowledged.
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