Open Journal of Physical Chemistry, 2013, 3, 127-137
Published Online November 2013 (http://www.scirp.org/journal/ojpc)
http://dx.doi.org/10.4236/ojpc.2013.34016
Open Access OJPC
Computational Study of the Alkylation Reaction of the
Nitrogen Mustard Mechlorethamine Using NBO Model
and the QTAIM Theory
Michell O. Almeida1,2, Sérgio Henrique D. M. Faria1,3*
1Universidade Paulista, Limeira, Brazil
2CCNH—Universidade Federal do ABC, Santo André, Brazil
3Instituto de Química, Universidade Estadual de Campinas, Campinas, Brazil
Received July 26, 2013; revised August 24, 2013; accepted September 1, 2013
Copyright © 2013 Michell O. Almeida, Sérgio Henrique D. M. Faria. This is an open access article distributed under the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original
work is properly cited.
ABSTRACT
Substances known as nitrogen mustards turn into aziridinium ion through the intramolecular cyclization SN1. This ion
reacts with the DNA preferably at the N7 position of the guanine, and because of this, it is an important antineoplastic
agent. Based on this, the objective of this study is to quantify the interaction between the nitrogen mustard mechlore-
thamine and the guanine, using the NBO analysis and the QTAIM theory. The results of the NBO analysis showed that
when the triangular cycle C4-N1-C5 is formed, there is some resonance among these atoms. This analysis also showed
that the electronic transition at the sigma antibondingorbital σ* N1-C4 presents higher perturbation energy of second
order, indicating that this bond is broken at the nucleophilic attack of the N7 nitrogen of guanine. The analysis that re-
fers to the electron density obtained by the QTAIM theory indicates that the guanine proximity enables an electron den-
sity polarization of the BCPs aziridinium ion of mechlorethamine making that the frontal part of the ion becomes elec-
tron deficient. Finally, the relative results to the Laplacian of the electron density obtained by the QTAIM theory
showed that the guanine approximation increases the “hole” factor at the C4, proving that the nucleophilic attack based
on the “lump-hole” concept causes the region of that atom is the site of alkylation reaction.
Keywords: NBO; QTAIM; Aziridinium; Ion; Nucleophilic Attack; Electron Density; Laplacian of the Electron Density
1. Introduction
Antitumor alkylating agents are classified as Celular-
Cycle non specific [1] and form crosslinked bonds with
DNA. These crosslinked bonds cause DNA lesions re-
quiring complex repair mechanisms, including replica-
tion inhibition. Because of it, in 1942, mechlorethamine
was successfully used to induce transient tumor remis-
sion in a patient with lymphoma, this event marked the
beginning of the modern era cancer chemotherapy [1].
Among the alkylating agents, the mechlorethamine was
the first anti-cancer drug effectively used for clinic pur-
pose, and today it is the most common one used against
tumor cells [2].
The alkylating agents efficiency, like the mechlore-
thamine, was studied previously using molecular model
[3,4] and also by rational planning [5,6] that highlighted
the correlation between the intramolecular distance of the
electrophilic centers of these agents and the nucleophilic
nitrogen of nucleotide [1]. As the traditional QSAR tech-
niques are laborious and require a long investigation time
and high cost [7], the computational analysis of the alky-
lating agents is becoming more attractive.
The mustard nitrogen compounds are among the most
popular agents studied [2,8-11] by the theoretical com-
putational chemistry. These compounds form the azirid-
inium ion, being this ion highly reactive through the in-
tramolecular cyclization SN1. The ion reacts with the
DNA, preferably at the guanine N7 position [1], however
experiments have been noticing alkylation at the posi-
tions N1, N3, N6 e O6. [1,2]. The physical fundamental
understanding of this alkyalting family reaction can be
interesting for the development on new drugs.
*Corresponding author.

M. O. ALMEIDA, S. H. D. M. FARIA
128
With this objective, one of the ways to theoretically
quantify the interaction intensity between the nitrogen
mustards and the guanine, besides the analysis of the
highest occupied molecular orbital (HOMO) [12], lowest
unoccupied molecular orbital (LUMO) [13] and its dif-
ference [14-16], it is through the NBO model [17]. A
distinguishing feature of localized NBO functions is the
simultaneous requirement of orthonormality and maxi-
mum occupancy, leading to compact expressions for
atomic and bond properties [18]. This way, ab initio
wavefunctions transformed to NBO form are found to be
in good agreement with the Lewis concept and with the
classic bond form with hybridization and polarization
from Pauling-Slater-Coulson [18-21].
Another way to quantify the nitrogen mustards inter-
action with the guanines is using the QTAIM theory
(Quantum Theory: Atoms in Molecules) [22] from Bader.
At this theory, the Laplacian of the electron density
2

 is shown at the local form of the virial theorem
giving the mechanics of an atom inside of a molecule
[23]. This way, the Laplacian can identify the reactivity
sites of the molecule [23,24].
So, the objective of the present study is to quantify the
interactions of the mechlorethamine molecule with the
guanine using the Natural Bond Orbital (NBO) Analysis
from Donor-Acceptor Viewpoint, the electron density,
and the Laplacian of the electron density obtained by the
QTAIM theory.
2. Computationaldetails
The tridimensional molecule structures were built using
the software GaussView 3.0 [25]. The structures of the
mechlorethamine molecule were drawn in several steps
of thealkylation reaction with the guanine. These struc-
tures were built in four states: isolated mechlorethamine,
isolated aziridinium ion of mechlorethamine, aziridinium
ion in the presence of guanine and the transition state of
the aziridinium ion. All these structures were optimized
to the lower energy state with the program Gaussian03
[26] at the level B3LYP with the basis set 6-31G (d, p).
All the post calculations were made with the same
wavefunction, B3LYP/6-31G (d, p). The transition state
of the aziridinium ion was obtained with the QST3 algo-
rithm. With the optimized geometry, using the same
software [26], the Natural Bond Orbitals (NBO) were
obtained and also the electronic transitions determined by
this theory. The electronic transitions chosen for the dis-
cussion were the ones with the second order perturbation
energy E2 ≥ 5 kcal·mol−1. All these calculations were
made in a machine SGI Altix 1350/Altix 450 with 174
CPU’s Intel Itanium2, 866GB of RAM memory, tech-
nology NUMAFlexGeração 4, interconnection Infiniband
and storage system SGI TP9300 with 43 TB. This system
is installed at CENAPAD-SP [27].
Using personal computers, continuing from the opti-
mized geometries obtained, the critical points position
(3,−1) and (3,−3) of the gradient of the electron density,
were determined. Later, the electron density of these
critical points were calculated and also the Laplacian of
these densities, using the QTAIM theory. These quanti-
ties were calculated using the software AI M2000 [28].
This software was also used to generate the relief maps
of Laplacian of the electron density.
3. Results and Discussion
3.1. Construction of the Mechlorethamine
Molecule in Different States of the
Alkylation Reaction
The different steps of the mechlorethamine molecule
alkylation with the guanine have been widely discussed
at the previous art [1,2,8-11,29,30]. It is know that this
molecule reacts with aintramolecular cyclization SN1
releasing a chloride ion, forming the aziridinium ion.
Right after the aziridinium ion gets close to the guanine,
it goes to a transition state and lately suffers a nucleo-
philic attack from the N7 of these nitrogenous base.
This way, the molecules used in this study, according
to the reaction steps, were built using the software
Gaussview03 and they were optimized to the lowest en-
ergy state using the program Gaussian03. The molecules
were built in the following order:
State (1)—isolated mechlorethamine molecule
State (2)—isolated aziridinium ion of mechlore-
thamine molecule
State (3)—molecular cluster formed by the aziridinium
ion of mechlorethamine + guanine
State (4)—mechlorethamine molecule at the transition
state + guanine (obtained with the algorithm QST3 from
Gaussian03)
These geometries obtained for the four states of the
reaction, shown at Figure 1, were used at the NBO analy-
sis and also to obtain the electron density of the QTAIM
theory.
3.2. NBO Analysis of the Intermolecular
Interaction between Donor and Acceptor at
the Four Reactions States
Thedata obtained with the NBO analysis represent the
electronic transition within only one reaction state. The
NBO analysis of the mechlorethamine molecule (state 1)
did not show any electronic transition that satisfies the
minimum stabilization energy condition E2 ≥ 5
kcal·mol−1. However, Table 1 shows that when the
mechlorethamine becomes the aziridinium ion, forming
the triangle C4-N1-C5 (state 2), there is a kind of reso-
nance between the electrons of the sigma bond N1-C4 and
N1-C5. However, a slight asymmetry can be noticed at
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M. O. ALMEIDA, S. H. D. M. FARIA
Open Access OJPC
129
(State 1) (State 2)
(State 4)(State 3)
Figure 1. Alkylation reaction mechanism of the mechlorethamine with the DNA guanine, separated in 4 states.
Table 1. Electronic transitions obtained by NBO Analysis of states (2) and (3) with the wavefunction B3LYP/6-31G (d, p).
DonorNBOAcceptor NBO E2 (kcal/mol)Donor NBO Acceptor NBO E2 (kcal/mol)
Intramolecular Interactions State (2) IntramolecularInteration State (3)
BD (  ) N1-C4 BD*(  *)N1-C5 6.81 BD (  ) N1-C4 BD*(  *)N1-C5 8.10
BD (  ) N1-C5 BD*(  *)N1-C4 6.89 BD (  ) N1-C5 BD*(  *)N1-C4 8.39
BD (  ) N1-C4 BD*(  *)N1-C3 5.28
BD (
 ) N1-C4 BD*(  *)C4-C5 5.63
Intramolecular Interactions of Guanine (Cluster)
BD (  ) N19-C20 BD*(  *)C21-C24 5.42 LP N22 BD*(*)C21-C25 39.47
BD () N19-C20 BD*(*)C21-C25 13.17 LP N22 BD*(  *)N22-H34 9.83
BD (  ) C20-N22 BD*(  *)C25-N28 6.07 LP O26 24
*
C
RY 14.09
BD () C21-C25 BD*(*)N19-C20 17.18 LP O26 BD*(  *)C21-C24 17.91
BD () C21-C25 BD*(*)C24-O26 31.18 LP O26 BD*(  *)C24-N27 28.82
BD () C21-C25 BD*(*)N28-C30 7.11 LP N27 BD*(*)C24-O26 50.76
BD () C24-O26 BD*(*)C21-C25 5.08 LP N27 BD*(*)N28-C30 60.57
BD (  ) C25-N28 BD*(  *)C30-N31 5.88 LP N28 BD*(  *)C21-C25 10.30
BD (  ) N28-C30 BD*(  *)N22-C25 6.07 LP N28 BD*(  *)N27-C30 14.22
BD () N28-C30 BD*(*)C21-C25 28.46 LP N31 BD*(*)N28-C30 64.29
BD (  ) N31-H33 BD*(  *)N27-C30 6.28 BD* () N19-C20 BD*(*)C21-C25 29.24
CR O26 RY* C24 5.11 BD* () N28-C30 BD*(*)C21-C25 72.65
LP N22 BD*(*)N19-C20 48.98
Intermolecular Interactions
LP N19 BD*(
 *)N1-C4 35.26

M. O. ALMEIDA, S. H. D. M. FARIA
130
the stabilization energy of the electronic transition at the
acceptor antibonding orbitals σ* of the carbons of the
triangular cycle C4-N1-C5. The data indicate that the
electronic transition at the antibonding orbital σ* N1-C4
stabilizes the system more, making that this carbon (C4)
be more susceptible to a nucleophilic attack.
Looking at the data regarding state 3, at Table 1, an
increase of around 20% can be noticed at the stabilization
energy E2 of the acceptor antibonding σ* of the train-
gular cycle carbons C4-N1-C5. It is also observed the ap-
pearance of two new intramolecular transitions of the
aziridinium ion in which the electronic donor is the bond
orbital σ N
1-C4, another indication that this bond is the
most probable to be cleaved with the guanine nucleo-
philic attack. The electronic transitions obtained for the
guanine are the typical resonance transitions of the aro-
matic rings and of the carbonyl formed by the atoms C24
and O26. The most important transitions that occur at the
guanine were with 72.65 kcal·mol−1
and with 64.29 kcal·mol−1.
*
N28-C30 C21-C25
ππ
*
π
N31N28-C30
Another relevant electronic transition is the intermo-
lecular transition of E2 = 35.26
kcal·mol−1 indicating that a nucleophilic attack of the N19
(the guanine N7 mentioned at the references [1,2,9]) pos-
sibly contributes to the
 N1-C4 bond break.
LP 
*
N19 N1-C4
LP  
The algorithm QST3 that determined the geometry of
theaziridinium ion of mechlorethamine transition state
(state 4) shows that before the alkylation, there is a break
at the triangular cycle C4-N1-C5. This new geometry is
obtained with the bond break of σ N
1-C4, what was al-
ready predicted by the NBO analysis of Table 1 and by
the new intramolecular transition with
10.75 kcal·mol−1 from Table 2. Among the guanine intra-
molecular transitions at this reaction state, two Lone Pair
transitions of the C21, e
can be highlighted, with stabilization
energies of 244.46 and 97.92 kcal·mol−1 respectively.
*
N1-C4 N1-C5
 
*
C21 N22-C25
LP π
*
*
C21 C24-O26
LP π
LP
It is interesting to notice that at this reaction step,
where there is the transition state, the intermolecular
transition N19N1-C4 presents a second order en-
ergy of E2 = 63.59 kcal·mol−1. This value corresponds
to an increase of 80.35% in the E2 energy of this transi-
tion when compared to the value obtained at the previous
state (3). This result demonstrates that there is a transi-
tion state (4) of the aziridinium ion of mechlorethamine
that favors the nucleophilic attack of the guanine N7 at
the ion C4.
 
It is thought that this fact happens due to the proximity
of the C4 to N7 at the transition state (4), because the
distance between these two atoms at the state (4) is 2.11
Å, while at state (3) this same distance is 3.34 Å (Fig-
ure 2).
3.3. Application of the QTAIM Theory to Obtain
the Electron Density and the Laplacian of
the Electron Density of Molecules at the
Four Reaction Sites
The QTAIM theory (Quantum Theory: Atoms in Mole-
cules) was used to calculate the electron density and the
Laplacian of the electron density for the critical points
(3,−1) and (3,−3) and for all the structures at each alkyla-
tion reaction state of the mechlorethamine with the gua-
nine (Figure 3).
It can be noticed by Table 3, that in all changes of
state, the critical points of electron density variation
(State 3)
3.34 Å
(State 4)
2.11 Å
Figure 2. Distance between the N19 (guanine N7) and themechlorethamine C4 at the state (3) and (4) of the alkylation reaction.
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M. O. ALMEIDA, S. H. D. M. FARIA 131
Table 2. Electronic Transitions obtained by NBO Analysis of state (4) with the wavefunction B3LYP/6-31G (d, p).
Donor NBO Acceptor NBO E2 (kcal/mol) Donor NBO Acceptor NBO E2 (kcal/mol)
Intramolecular Interactions of Aziridinium Ion (TS)
BD (  ) N1-C4 BD*(  *)N1-C5 10.75
Intramolecular Interactions of Guanine (Cluster)
BD (  ) N19-C20 LP C21 26.91 LP N19 BD*(  *)C20-N22 6.81
BD (  ) C20-N22 BD*(  *)C25-N28 5.40 LP C21 BD*(*)N19-C20 60.94
BD (  ) N19-C21 BD*(  *) C21-C24 5.28 LP C21 BD*(*)N22-C25 244.46
BD () N22-C25 LP C21 12.34 LP C21 BD*(*)C24-O26 97.92
BD () N22-C25 BD*(*) N19-C20 29.35 LP O26 RY* C24 14.07
BD () C24-O26 LP C21 6.89 LP O26 BD*(  *)C21-C24 16.87
BD (  ) C25-N28 BD*(  *)C30-N31 5.33 LP O26 BD*(  *)C24-N27 29.32
BD (  ) N28-C30 BD*(  *)N22-C25 6.84 LP N27 BD*(*)C24-O26 49.44
BD () N28-C30 BD*(*)N22-C25 40.59 LP N27 BD*(*)N28-C30 58.95
BD (  ) N31-H33 BD*(  *)N27-C30 6.19 LP N28 BD*(  *)C21-C25 10.84
CR O26 24
*
C
RY 5.40 LP N28 BD*(
 *)N27-C30 14.64
Intermolecular Interactions
LP N19 BD*(  *)N1-C4 35.26
(State 1)
(State 3)
(State 2) (State 4)
Figure 3. Structures of the 4 reaction states with the critical points obtained by the QTAIM theory. The red critical points are
the Bond Critical Points (BCP), and the yellow critical points are the Ring Critical Points (RCP).
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M. O. ALMEIDA, S. H. D. M. FARIA
132
Table 3. Electron density of states 1, 2, 3 and 4 of the critical points NACP (Nuclear Atractor Critical Point) (3,−3) and of the
critical points BCP (Bond Critical Points) (3,−1) obtained by QTAIM with wavefunction B3LYP/6-31G (d, p).
NACP
(3,−3)
ρ (u.a.)
State 1
ρ (u.a.)
State 2
ρ (u.a.)
State 3
ρ (u.a.)
State 4
Δρ (u.a.)
State (2-1)
Δρ (u.a.)
State (3-2)
Δρ (u.a.)
State (4-3)
N1 2.1728 2.1726 2.1727 2.1730 −0.0002 0.0001 0.0003
C2 1.9459 1.9466 1.9466 1.9462 0.0007 0.0000 −0.0004
C3 1.9452 1.9455 1.9458 1.9454 0.0003 0.0003 −0.0004
C4 1.9452 1.9464 1.9465 1.9422 0.0012 0.0001 −0.0043
C5 1.9444 1.9464 1.9465 1.9468 0.0020 0.0001 0.0003
C6 1.9444 1.9447 1.9448 1.9446 0.0003 0.0001 −0.0002
Cl7 7.9550 7.9549 7.9549 7.9550 −0.0001 0.0000 0.0001
H8 0.1273 0.1258 0.1262 0.1256 −0.0015 0.0004 −0.0006
H9 0.1279 0.1256 0.1260 0.1270 −0.0023 0.0004 0.0010
H10 0.1279 0.1251 0.1256 0.1257 −0.0028 0.0005 0.0001
H11 0.1272 0.1249 0.1259 0.1268 −0.0023 0.0010 0.0009
H12 0.1284 0.1248 0.1221 0.1259 −0.0036 −0.0027 0.0038
H13 0.1278 0.1248 0.1259 0.1268 −0.0030 0.0011 0.0009
H14 0.1273 0.1249 0.1207 0.1257 −0.0024 −0.0042 0.0050
H15 0.1284 0.1267 0.1250 0.1277 −0.0017 −0.0016 0.0027
H16 0.1278 0.1263 0.1250 0.1269 −0.0015 −0.0013 0.0019
H17 0.1272 0.1266 0.1273 0.1271 −0.0006 0.0007 −0.0002
H18 0.1284 0.1258 0.1267 0.1262 −0.0026 0.0009 −0.0005
BCP
(3,−1)
ρ (u.a.)
State 1
ρ (u.a.)
State 2
ρ (u.a.)
State 3
ρ (u.a.)
State 4
Δρ (u.a.)
State (2-1)
Δρ (u.a.)
State (3-2)
Δρ(u.a.)
State (4-3)
N1-C2 1.3472 1.2342 1.2446 1.2483 −0.1130 0.0104 0.0037
N1-C3 1.3497 1.2418 1.2083 1.2794 −0.1079 −0.0335 0.0711
N1-C4 − 1.0124 1.0036 − 1.0124 −0.0088 −1.0036
N1-C5 1.3487 1.0170 0.9985 1.5739 −0.3317 −0.0185 0.5754
C4-C5 1.2499 0.9859 0.9922 1.5367 −0.2640 0.0063 0.5445
C3-C6 1.2167 1.2561 1.2479 1.2525 0.0394 −0.0082 0.0046
Cl7-C6 0.9888 1.0330 1.0215 1.0175 0.0442 −0.0115 −0.0040
C2-H8 0.9687 0.9715 0.9777 0.9692 0.0028 0.0062 −0.0085
C2-H9 0.9997 0.9784 0.9788 0.9900 −0.0213 0.0004 0.0112
C2-H10 0.9998 0.9495 0.9556 0.9529 −0.0503 0.0061 −0.0027
C3-H15 1.0128 0.9977 0.9688 1.0067 −0.0151 −0.0289 0.0379
C3-H18 0.9856 0.9658 0.9813 0.9681 −0.0198 0.0155 −0.0132
C4-H11 0.9855 0.9487 0.9605 0.9747 −0.0368 0.0118 0.0142
C4-H12 1.0128 0.9502 0.9299 0.9814 −0.0626 −0.0203 0.0515
C5-H13 1.0004 0.9463 0.9602 0.9699 −0.0541 0.0139 0.0097
C5-H14 0.9676 0.9530 0.9147 0.9577 −0.0146 −0.0383 0.0430
C6-H16 0.9677 0.9691 0.9679 0.9703 0.0014 −0.0012 0.0024
C6-H17 1.0001 0.9884 0.9926 0.9940 −0.0117 0.0042 0.0014
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M. O. ALMEIDA, S. H. D. M. FARIA
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(3,−3), which means the atomic nuclei, this variation is
very low. The exception is the critical points that corre-
spond to the carbon atoms 4 and 5, when the system
passes from state 1 to state 2. The positive signal of Δρ
indicates that these atoms had an electron density in-
crease when the triangular cycle C4-N1-C5 was formed,
probably because of the N1 higher electronic sharing with
these atoms. The variation of electron density of the
Hatoms usually have an order of magnitude around de
~10−3 u.a. because of its high polarization capacity, not
being important to the analysis of the alkylation reaction
mechanism.
hydrogen with the carbonyl oxygen (H16-O 26, H15-O26,
H14-O26) and two bonds of hydrogen with the guanine N7
(H12-N19 e H15-N19). Even more noticeable are the Δρ
data that corresponds to the change from state 2 to state 3.
All the negative values of Δρ that correspond to the
BCPs of the aziridinium ion are related to the critical
points that are placed in a frontal position to the guanine
molecule approach. The positive values of the ion BCPs
correspond to the critical points that are in the opposite
direction to the nitrogenous base.
According to these results, it is believed that the gua-
nine approach causes an electron density polarization of
the aziridinium BCPs, making the frontal part of the
more susceptible to the nucleophilic attack, while the
critical points at the opposite direction present a gain in
electron density. When the Δρ from states (3) and (4) are
compared, the triangular bond σ N1-C4 is broken, proba-
bly shifting the electron density of the region between
these two atoms to the critical points N1-C5 and C4-C5,
since these two BCPs had an expressive gain in the elec-
tron density of 0.5754 and 0.5445 u.a. respectively. The
sum of these two Δρ values being 1.1200 u.a. is very
close to the N1-C4 BCP Δρ value of −1.0036 u.a., a good
indication that this electron density is distributed between
the triangular cycle atom at the transition state.
It is interesting to note that the Δρ values between
states 1 and 2 of the BCPs (Bond Critical Point) are
much higher than the values at of the critical points
(3,−3). It also can be noticed that the sum of the Δρ val-
ues for the critical points (3,−1) with the negative signal
results in −1.0772 u.a., a close value to the determined
value of ρ for the bond critical point N1-C4 of 1.0124 u.a.
This result maybe can suggest that there is an electron
delocalization of these BCPs at the formation process of
the bond σ N1-C4 when the triangular cycle C4-N1-C5 is
formed.
Figure 4 shows that when the aziridinium ion of
mechlorethamine is close to the guanine molecule, there
is the formation of hydrogen bonds (3,−1): three bonds of
Figure 4. Structure at state (3) showing the mechlorethamine approach to the guanine. The picture shows that the BCPs
16-O26, H15-O26, H14-O26, H12-N 19 and H15-N19 are hydrogen bonds. H

M. O. ALMEIDA, S. H. D. M. FARIA
134
In the Table 4 that refers to the Laplacian of the elec-
tron density, it is noticed that at the aziridinium ion of
mechlorethamine (state 2), there is a low asymmetry be-
tween the Δ2ρ values of the carbon 4 and 5 (3.3838 and
Table 4. Laplacian of the Electron density of states 1, 2, 3 and 4 of the critical points NACP (Nuclear Attractor Critical Point)
(3,−3) and the critical points BCP (Bond Critical Points) (3,−1) obtained by QTAIM with wave function B3LYP/6-31G (d, p).
NACP
(3,−3)
Δ2ρ (u.a.)
State 1
Δ2ρ (u.a.)
State 2
Δ2ρ (u.a.)
State 3
Δ2ρ (u.a.)
State 4


2

 (u.a.)
State (2-1)


2

 ) (u.a.)
State (3-2)

2


 (u.a.)
State (4-3)
N1 2.4213 2.4235 2.4248 2.4250 0.0022 0.0013 0.0002
C2 3.3851 3.3858 3.3833 3.3857 0.0007 −0.0025 0.0024
C3 3.3832 3.3832 3.3853 3.3859 0.0000 0.0021 0.0006
C4 3.3839 3.3838 3.3830 3.3627 −0.0001 −0.0008 −0.0203
C5 3.3824 3.3836 3.3829 3.3864 0.0012 −0.0007 0.0035
C6 3.3828 3.3878 3.3882 3.3854 0.0050 0.0004 −0.0028
Cl7 25.1423 25.1530 25.1589 25.1635 0.0107 0.0059 0.0046
H8 0.2475 0.2448 0.2458 0.2442 −0.0027 0.0010 −0.0016
H9 0.2499 0.2440 0.2450 0.2475 −0.0059 0.0010 0.0025
H10 0.2498 0.2429 0.2443 0.2452 −0.0069 0.0014 0.0009
H11 0.2489 0.2421 0.2447 0.2462 −0.0068 0.0026 0.0015
H12 0.2511 0.2420 0.2344 0.2429 −0.0091 −0.0076 0.0085
H13 0.2489 0.2420 0.2447 0.2472 −0.0069 0.0027 0.0025
H14 0.2475 0.2421 0.2306 0.2440 −0.0054 −0.0115 0.0134
H15 0.2510 0.2466 0.2417 0.2493 −0.0044 −0.0049 0.0076
H16 0.2489 0.2457 0.2428 0.2469 −0.0032 −0.0029 0.0041
H17 0.2489 0.2464 0.2480 0.2474 −0.0025 0.0016 −0.0006
H18 0.2510 0.2446 0.2468 0.2461 −0.0064 0.0022 −0.0007
BCP
(3,−1)
Δ2ρ (u.a.)
State 1
Δ2ρ (u.a.)
State 2
Δ2ρ (u.a.)
State 3
Δ2ρ (u.a.)
State 4


2

 (u.a.)
State (2-1)


2

 (u.a.)
State (3-2)

2


 (u.a.)
State (4-3)
N1-C2 −0.7180 −0.7079 −0.7014 −0.6660 0.0101 0.0065 0.0354
N1-C3 −0.7388 −0.7514 −0.7232 −0.7027 −0.0126 0.0282 0.0205
N1-C4 - −0.5191 −0.5182 - −0.5191 0.0009 0.5182
N1-C5 −0.7373 −0.5172 −0.5129 −0.9286 0.2201 0.0043 −0.4157
C4-C5 −0.5391 −0.2799 −0.2855 −0.6744 0.2592 −0.0056 −0.3889
C3-C6 −0.5080 −0.5379 −0.5305 −0.5367 −0.0299 0.0074 −0.0062
Cl7-C6 −0.5648 −0.5726 −0.5808 −0.5702 −0.0078 −0.0082 0.0106
C2-H8 −0.1888 −0.1724 −0.1778 −0.1714 0.0164 −0.0054 0.0064
C2-H9 −0.2020 −0.1749 −0.1758 −0.1876 0.0271 −0.0009 −0.0118
C2-H10 −0.2020 −0.1499 −0.1557 −0.1632 0.0521 −0.0058 −0.0075
C3-H15 −0.2245 −0.2033 −0.1746 −0.2156 0.0212 0.0287 −0.0410
C3-H18 −0.2068 −0.1694 −0.1854 −0.1828 0.0374 −0.0160 0.0026
C4-H11 −0.2069 −0.1389 −0.1464 −0.1509 0.0680 −0.0075 −0.0045
C4-H12 −0.2245 −0.1401 −0.1292 −0.1634 0.0844 0.0109 −0.0342
C5-H13 −0.1970 −0.1360 −0.1462 −0.1674 0.0610 −0.0102 −0.0212
C5-H14 −0.1667 −0.1419 −0.1153 −0.1586 0.0248 0.0266 −0.0433
C6-H16 −0.1668 −0.1701 −0.1682 −0.1715 −0.0033 0.0019 −0.0033
C6-H17 −0.1968 −0.1854 −0.1887 −0.1900 0.0114 −0.0033 −0.0013
Open Access OJPC

M. O. ALMEIDA, S. H. D. M. FARIA 135
3.3836 u.a. respectively), besides there is also an asym-
metry to the BCPs N1-C4 and N1-C5 (−0.5191 and
−0.5172 u.a.).
Can also be observed in the Table 4 that the state (3),
with the presence of the guanine, an increase on the
Laplacian difference is seen between the BCPs N1-C4 and
N1-C5 for states (2) and (3), being now 2

 = 0.0053
u.a.. It is also observed at state (3), a reduction in the
Laplacian of the electron density of C4 with respect to the
state (2), and when states (3) and (4) are compared, this
reduction is even greater (


2u.a.
 0.0203. This
demonstrates that the guanine approach increases the
hole factor at the C4 (Figure 5), and that the nucleophilic
attack, based on the lump-hole concept, makes the region
of this atom to become the reaction site for this alkyla-
tion.
C4
N
1
C5
N
1
C5
C4
Electrophile or hole (hole factor increased by guanine)
Figure 5. Relief maps of the Laplacian of the electron den-
sity of the states 2 (up) and 3 (down). It is noticed a greater
hole at carbon 4 at the structure on right, emphasizing that
the guanine presence increases the electrophilic carater of
4. Conclu
this atom.
sions
NBO analysis clearly showed that
e Atoms in Molecules
(Q
btained for the Laplacian of the electron
de
5. Acknowledgements
CENAPAD-SP. Michell O.
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