Benallou & al. / Mor. J. Chem.

2 N°X (2014) 110-124

Quantitative study by the Electrophilic and Nucleophilic indexes

of chemical reactivity for the intramolecular Diels-Alder reaction
of the Triene-Amide Molecule. DFT investigation

A. Benalloua, H. Garmesb, N. Knouzic, H. El Alaoui El Abdallaouia*

a
Team of chemoinformatics research and spectroscopy and quantum chemistry, physical and chemistry
lab.
b
laboratory of bio-organic chemistry, Department of chemistry, Faculty of Science El Jadida.
University Chouaib Doukkali, B. P. 20, 24000 El Jadida, Maroc.
c
laboratory Biomolecules and organic synthesis, Faculty Ben M’Sik, University Mohammedia –
Casablanca, BP 7955 Casablanca Maroc

*Corresponding author E-mail: elalaoui.habib@yahoo.fr

Received 14 May 2014, Revised 02 June 2014, Accepted 06 June 2014.

Abstract
In this study, we proposed to examine the reactivity of the intramolecular cycloaddition Diels-
Alder (IMDA) reaction of the molecule triene amide by chemical descriptors established
globally in the intermolecular reactions (DA), such as of electrophilic index ω and the
nucleophilic index N. In order to provide the power releasing or withdrawing of electrons of the
diene (D) and dienophile (Dp) fragments in the intramolecular molecule, the polarity of the
reaction can be evaluated by the application of these two factors, applied locally to the diene (D)
and dienophile (Dp) fragments, other parameters have been introduced to enrich these results,
such as transferability index γ and charge transfer (CT) in a transition state. During our study we
used density functional theory (DFT) in the hybrid B3LYP and basis set level 6-31G (d, p), the
geometries are optimized for the reactants, transition states as well for products, the calculation
of the charge transfer is carried out using the natural population analysis (NPA), the results
obtained show that the diene (D) fragment is donor of electrons in the IMDA reaction.

Keyword: regioselectivity, intramolecular, nucleophililic, electrophilic, IMDA, DFT.

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1. Introduction
The Diels Alder (DA) reaction is one of the most useful methods for the construction of six
cycles. And attracted a considerable interest for two experimental [1-8] and [9-14] theoretical
scientists. There are many variants of the Diels–Alder reaction, by varying the nature of the
diene (D) and dienophile (Dp) many different types of six carboxylic structures can be
composed. The intramolecular Diels–Alder (IMDA) reaction is widely used for the construction
of the cycles in a single synthetic process [15]. This reaction has been used in the construction
of many biological and pharmacological systems and as a highway in the total synthesis of
natural products [16]. The reaction occurs between two (carbon-carbon) of D and Dp fragments
in the same reagent to produce new bonds bearing in the same molecule to produce a polycyclic
compound. The distribution of global electronic properties in fragments or functional groups
within a single molecule is a powerful tool to discuss the reactivity in the intramolecular
reactions. However, the division of combinations or structures are usually arbitrary in nature
and they may or may not have a chemical significance, Gazquez and al [17] they showed that
the distribution of local properties, such as Fukui functions or the local softness, by the use of
the functions based on density, provide support for the calculation of the chemical properties of
fragments. This is the case of the partition prepared by Hirshfeld [18], which to lead the reliable
values of the fukui function. This is consistent with the work of Ayers, Morrison and Roy [19],
that shows that these functions can be used to determine the local properties of the fragments.
Jorge Soto-Delgado and al [20] also used condensed Fukui function [21] for a large property to
the instance of global electrophilicity ω which has been used successfully as the fragment or
functional groups in a single molecule (IMDA) to predict the polarity and the electron flow
between the divisions (fragments). A further indication of reactivity introduced by Domingo and
al [22], the global nucleophilicity N applied similarly to the reaction DA to classify the
nucleophilicity of some reagents.
in our present work we will try to study the chemical reactivity of the intramolecular Diels
Alder of triene amide reaction [23] (scheme 1) as and to measurement of intermolecular
fragments the normal electronic demand NED{diene (electro-releasing)- dienophile (electro-
withdrawing)} or inverse electronic demand IED{diene (electro-withdrawing)-dienophile
(electro-releasing) } by applying the elements used usually to the reaction intermolecular DA
and transmute in the intramolecular Diels Alder (IMDA) reaction namely the global
electrophilic index ω and the global nucleophilic index N.

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f ragment D f ragment Dp
R3 Z
6 Z
R3 R2
5 1 H
Toluene
4 2 R1
 160°C
R2 N
H
N
R1 COR 4
O
R4

hexahydroindole,
T:Triene-Amide substitute majority product

Ta: R1=H, R2=CH2CH3, R3=H, R4=CH3, Z=CN;

Tb: R1=H, R2=CH3, R3=H, R4=CH3, Z=CN;
Tc: R1=H, R2=H, R3=H, R4=CH3, Z=CO2CH3;
Td: R1=H, R2=CH3, R3=CH3, R4=ph, Z=CO2CH3;
Te: R1=CH3, R2=H, R3=H, R4=CH3, Z=CO2CH2CH3.

Scheme 1: Intramolecular Diels–Alder reaction of triene amide for the synthesis of the
hexahydroindole product.

2. Equation model and calculation details

There are a lot of parameters, which are used as descriptors of reactivity in chemical reactions.
a) Global Hardness η: one of these parameters is the hardness η, which is defined as:

Where E, N, μ and v (r) represent respectively, energy, number of electrons, chemical potential
index and external potential of the system, Parr and Pearson [24] have proposed to use the
method of finite differences, we obtain:

Such as I and A are respectively the ionization potential and electron affinity, on the other hand
the global hardness can be calculated from the energies of the frontier molecular orbital εHOMO
and εLUMO as follows [25]:
ε ε
Considering that the G molecule can be arbitrarily partitioned into two fragments A and B and
the corresponding chain is the union (CH2)n (scheme 2).
For an IMDA process, and that we need to calculate the group of electrophilicity of the
fragments A and B within the molecule G. for this purpose, we count on previous work. In fact,
Meneses and al [26], they expressed the hardness local k on an atom (k), by the terms of the
indices of Fukui for an electrophilic and nucleophilic attack and by the energies of the

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frontier molecular orbital εHOMO and εLUMO. This work can be used to define the group hardness
associated with the fragment Ω = A, B by:

Such that:

The electronic chemical potential μ can be calculated from the energies of the frontier molecular
orbital εHOMO and εLUMO as follows [27-28]:
μ ε ε (6)
The electronic chemical potential of the fragment Ω (Ω = A or B), it is given by:

I and A are the first vertical ionization potential and electron affinity of the molecule,
respectively.
By making the simplifications using Koopmans theorem, we can write the electronic chemical
potential for fragments A and B by the forms:

(9)

b) Global electrophilic Index ω

The electrophilic index ω is introduced by Parr and al [29] lie to potential chemical μ is defined
by the following relation:
μ
ω

This index expresses the ability of an electrophile to acquire an additional electronic charge. It
was noted that this electrophilic index has been used to classify a set of reagents involved in
Diels-Alder reactions [31]. A good correlation between the difference of electrophiles for
couples (diene/dienophile) and the feasibility of cycloaddition was found [31]. You can
determine the electrophilic index of an atom to the site k of the molecule by applying the
following equation:
ω ω
with
Such as the index of Fukui electrophilic in attack nucleophilic in the atom k.
The electrophilicity of a fragment F is extracted easily from equation (12), can be written in the
form:

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c) Global nucleophilic Index N

We have used the (HOMO) energies obtained by the method of Kohn-Sham. The
nucleophilicity index (N) empirical (relative) is defined as follows [22]:
(13)
It notes that the scale of the nucleophilicity is references compared with the tetracyanoethylene
(TCE) molecule that is taken as a reference because it presents the lowest energy HOMO in a
great series of molecules already studied in the context of the Diels-Alder cycloadditions polar.
You can determine the local nucleophilicity index of an atom to the site k of the molecule
defined as the product of group nucleophilic index N and the nucleophilic index of Fukui

with
And then the nucleophilic index of Fukui in attack electrophilic in the atom k.
The nucleophilicity of a fragment F is easily extracted from the equation (15), can be written in
the form:

However, there is an additional difficulty for the determination of the nucleophilicity and
electrophilicity the reagents with the IMDA reactions, because both reactants lie within a single
molecule.
This problem can be lifted by using a proper technique dividing the molecule into three parts as
described in scheme 2.

Union Chain
(CH 2 )n

Fragment B
Fragment A
G

Scheme 2: fragmentation for the IMDA reaction in the molecule G.

we proposed in our system, that there are two regions A and B can be considered non-
homogeneous electron gas therefore μA # μB, this principle is used in some work the model of
Tachibana and al [32, 33, 34] who considers that the two regions A and B change the heat, work
and the electrons in the molecule, and the work of Jorge Soto-Delgado and al [20], in this we
define three areas corresponding to the diene moiety (Fragment A), the dienophile moiety
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(Fragment B) and the chain (CH2)n that connects the region A and B. Specifically, the principle
of inequality of the chemical potential [32], is defined as "the constancy of the chemical
potential is perturbed when set an object between the pairs regions, when the transfer of
particles is rather inhibited through the interface, to bring around at the finite difference regional
of chemical potentials even after attains it global chemical equilibrium "[20]. In this case,
relatively to the scheme 1, the body-perturbing is the methylene chain who plays bridge is the D
and Dp fragments within the intramolecular molecule. It is worthy to be mentioned that this
partition is similar to that shown in scheme 2, shows that the contribution of the intramolecular
reactivity the methylene chain is negligible [35]. Thus, Tachibana [32] suggested in his model
the chain of the union plays the role of agent perturbing. Noted that the unperturbed system
naturally, becomes an intermolecular interaction between D and Dp fragments. We can assess
evaluate the global electrophilicity and the global nucleophilicity and other chemical properties
namely the potential chemical μ, and the hardness for the series of molecules in scheme 1.
All structures are optimized by the theoretical method B3LYP and basis set level 6-31G (d, p).
The calculations are performed with the Gaussian program 09 [36]. The electronic structures are
analyzed at the stationary point by using the NBO (natural bond orbital) method [37]. To
determine charge transfer ({CT}) corresponding to the transition state of different reactions
IMDA, this method was designated as reliable to interpret the charge transfer and based on
analysis of population using the B3LYP functional [38]. The global and local electrophilicity is
calculated using the equation 11 and 12 and the global and local nucleophilicity is calculated by
the equation 13 and 14, the indices of fukui nucleophilic and electrophilic of an atomic
site k are calculated using the following equations:

Such as qk(N), qk(N+1) and qk(N-1) are respectively the electron population of the atom k in the
molecule cationic, anionic, and neutral.

3. Results and discussion

For different compounds, the energies of the frontier molecular orbitals HOMO and LUMO, the
electronic chemical potential μ and global hardness , the electrophilic index ω and nucleophilic
index N, are represented in table 1.

HOMO LUMO μ η ω N
Reactifs
(a.u.) (a.u.) (a.u.) (a.u.) (eV) (eV)
Ta -0.2140 -0.0440 -0.129 0.170 1.332 3.299
Tb -0.2144 -0.0438 -0.129 0.171 1.324 3.288
Tc -0.2088 -0.0372 -0.123 0.172 1.197 3.438

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Td -0.2053 -0.0457 -0.125 0.160 1.329 3.533

Te -0.2092 -0.0382 -0.124 0.171 1.223 3.428

According to the results of table 1, observed as the reactants Ta and Tb in which the terminal
function (Z = CN) have equal and the higher chemical potential among the other reagents at a
value of μ = - 0.129 u.a., for the greatest value of the nucleophilicity N is registered to the
reagent Td (Z=CO2CH3) with a value of 3.533 eV, This is an account for the phenyl function in
position R4 (scheme 1), however the lowest value of the potential chemical μ is noted to the
reagent Tc with a value of de -0.123 u.a.

3.1. Prediction of the Nucleophilic/Electrophilic character of fragments

To determine the electrophilic and nucleophilic characters to the D and Dp fragments from
different reagents, we initiated a series of calculations to the cationic, anionic, and neutral
molecule using the natural electron population NPA, to object to count the condensed Fukui
function for different atoms of the reagents
Table. 2: represents the Fukui indices , the electrophilicity index ω and the nucleophilicity
index N of the diene D and dienophile Dp fragments of the compounds Ta, Tb, Tc, Td and Te,
calculated by using the natural population analysis (NPA) by the method B3LYP/6-31 G (d, p).

Diene (D) Fragment Dienophile (Dp) Fragment

ωDp NDp
Reactifs ωD (eV) ND (eV)
(eV) (eV)
Ta 0.545 0.725 0.904 2.983 0.455 0.606 0.096 0.316
Tb 0.556 0.736 0.866 2.848 0.444 0.588 0.090 0.297
Tc 0.554 0.662 0.896 3.079 0.446 0.534 0.097 0.332
Td 0.708 0.941 0.823 2.907 0.292 0.388 0.177 0.626
Te 0.530 0.648 0.932 3.195 0.470 0.575 0.077 0.264

The results in table 2 leads to deduce that:

■ the electrophilic index of diene D fragments for different reagents are superior to those
fragments dienophiles Dp, add that the diene fragment of the reagent Td have the largest value
of electrophilicity (ωD = 0.941eV), the electrophilicity for the dienes fragments in reagents Tc
and Te are very near and they have low values compared with other reagents of ωD = 0.662 and
ωD = 0.648 respectively. The low values of electrophile (ω < 1) show that the two fragments
have a marginal electrophilic power (negligible).
■ the nucleophilicity index of the dienes D fragments for different reagents are much higher
than those of the Dp fragments, thus, the reagent Te take a high value in the order of (ND =
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3.195 eV). Nevertheless, the nucleophilicity values of D fragment are much higher relative to
the electrophilicity such as ND/ωD > 1, Therefore, the diene fragment behaves like a good
nucleophile (electron donor) while the dienophile fragment behaves as electrophile (electron
acceptor) in the reaction IMDA. The concentration of characters electrophile and nucleophile to
the diene fragment can be considered a failure of the description of frontier molecular orbital
(FMO) in the IMDA process. This is analogous to the work of Jorge Soto-Delgado and al [20],
these results are confirmed by the represent graphics of frontier molecular orbital HOMO and
LUMO of reagents (Figure 1).
According to graphical representations of the frontier molecular orbital HOMO and LUMO of
different reagents listed in Figure 1, in compounds Ta, Tb and Td the molecular orbitals HOMO
(electron-rich) and LUMO (poor in electrons) are totally concentrated at the diene fragment, this
is agreement with the results found by applying the condensed Fukui function in site k atomic,
by using the natural population analysis (NPA), in which the electrophilic and nucleophilic
indexes to the diene fragments are many elevated compared with the results of electrophilic and
nucleophilic indexes to dienophiles fragments (Table 2).
On the contrary, to the compounds Tc and Te we found the opposing results in the what found
by the application of Fukui function, which the molecular orbitals HOMO (rich in electrons) are
collected on the diene fragment and the molecular orbital LUMO (poor in electrons) are
gathered in dienophiles fragments. On the one hand, the results of electrophile of the diene and
dienophile fragments are comparable (Table 2), such as for compounds Tc and Te the
electrophilic indexes {ωD(Tc)= 0.662 (eV), ωD(Te)= 0.648 (eV)} and {(ωDp(Tc)= 0.534 (eV),
ωDp(Te)= 0.575 (eV)} of diene and dienophile fragments respectively. On the other hand, the
substituents at position R2 (bridge chain) can perturb this distribution according to their
releasing or withdrawing of electron powers such as: {Ta (R2=CH2CH3), Tb (R2= CH3), Td
(R2=CH3)} and {Tc (R2= H), Te (R2= H)}.
According to these results, in the cycloaddition intramolecular Diels-Alder (IMDA) reaction,
the application of condensed Fukui functions , thus of electrophilic index ω and the
nucleophile index N, commonly used in intermolecular (DA) reactions is not sufficient to be
evaluated to classify the nucleophilicity and the electrophilicity of the fragments in the
intramolecular molecule.
To confirm the Nucleophilic/Electrophilic character of the Diene and Dienophile fragments we
use other factor namely electronic flow γ (Table 4) and the charge transfer CT to the transitions
states (Table 3).

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fg: D f g: D fg: Dp
fg: Dp

Ta

Molecular Orbital HOMO Molecular Orbital LUMO Molecular Orbital HOMO-1 Molecular Orbital LUMO+1
E(HOMO) = -10.966 eV E(LUMO) = -3.012 eV E(HOMO-1) = -12.297 eV E(LUMO+1) = -2.292 eV

fg: D fg: Dp f g: D f g: Dp

Tb

Molecular Orbital HOMO Molecular Orbital LUMO Molecular Orbital HOMO-1 Molecular Orbital LUMO+1
E(HOMO) = -19.968 eV E(LUMO) = -3.011 eV E(HOMO-1) = -12.300 eV E(LUMO+1) = -2.295 eV
f g: Dp
fg: D fg: Dp fg: D fg: Dp
f g: D

Tc

Molecular Orbital HOMO Molecular Orbital LUMO Molecular Orbital HOMO-1 Molecular Orbital LUMO+1
E(HOMO) = -11.012 eV E(LUMO) = -3.634 eV E(HOMO-1) = -12.304 eV E(LUMO+1) = -3.000 eV
fg: Dp fg: Dp
fg: D f g: D
fg: D

Td

Molecular Orbital HOMO Molecular Orbital LUMO Molecular Orbital HOMO-1 Molecular Orbital LUMO+1
E(HOMO) = -10.671 eV E(LUMO) = -3.670 eV E(HOMO-1) = -11.929 eV E(LUMO+1) = -3.262 eV
f g: Dp
fg: D

Te

Molecular Orbital HOMO Molecular Orbital LUMO Molecular Orbital HOMO-1 Molecular Orbital LUMO+1
E(HOMO) = -11.008 eV E(LUMO) = -3.609 eV E(HOMO-1) = -12.300 eV E(LUMO+1) = -2.963 eV

Figure 1: Graphical representation of the frontier molecular orbital HOMO, LUMO and
HOMO-1 and LUMO+1 obtained by NPA analysis and visualized by the gauss view 5.0.8.
Isocontour: 0.018.

3.2 Prediction of the polarity of the reaction IMDA

3.2.1. Calculation of transfer of charge CT at the transition states
Using the natural population analysis (NPA), we calculated the charge transfer for IMDA
reaction for different reagents (Ta, Tb, Tc, Td and Te). The calculations show that the charge
transfer to place of the diene D fragment to the dienophile Dp fragment. Therefore the diene
fragment behaves like electro-releasing and the dienophile fragment behaves like electro-

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withdrawing, the intramolecular cycloaddition Diels-Alder reaction the molecule of triene-

amide is controlled by a normal electronic demand, the charge transfer in compounds Ta and Tb
in which the terminal position related to the dienophile fragment is the CN function is higher
compared to other compounds Tc (0.07e), Td (0.06 e) and Te (0.06 e). To the order of 0.11e
and 0.10 e respectively. The CT values corresponding to the transition states (Figure 3) obtained
are given in table 3.
Table 3: Charge transfer (CT) in e, between diene and dienophile fragments of the transition
states in the reactants Ta, Tb, Tc, Te and Td.

TS Diene Fragment Dienophile Fragment

Ta 0.11e -0.11e
Tb 0.10e -0.10e
Tc 0.07e -0.07e
Td 0.06e -0.06e
Te 0.06e -0.06e

3.2.2. Prediction of the direction of electron flow using the indexes duels:
The direction of electron flow (D →Dp or Dp →D) in the IMDA reaction can be determined
using indexes duels γ1 and γ2 [11] defined by:
γ1 = ωDp + ND
γ2 = ωD + NDp
- If γ1 > γ2, the charge transfer will take place from diene fragment to the dienophile fragment.
- If γ1 < γ2, the charge transfer will take place from the dienophile fragment to the diene
fragment.
- If γ1 = γ2, It is a chemical equilibrium between the two diene and dienophile fragments (CT=
0).
The values obtained for the IMDA reaction are reported in table 4:

Reactifs γ1 (eV) γ2 (eV) Δγ12 (eV)

Ta 3.59 1.04 2.55
Tb 3.43 1.03 2.40
Tc 3.61 0.99 2.62
Td 3.29 1.57 1.73
Te 3.77 0.91 2.86

According the results of table 4 we note that:

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- γ1 > γ2, then the charge transfer has instead been from the diene fragment to the dienophile
fragment, which confirms the results found by charge transfer.
- Δγ12 is slightly significant; that shows that the IMDA is a weakly polar reaction.

2.39 2 .4 1
2.36

3 9
2.10 2. 1 2.0

TS -Ta TS -Tc TS -Tb

CT = 0.11e CT = 0.07e CT = 0.10e

2 .3 6
2 .4 4

2
2.1
2 .0 8

TS -Td TS -Te
CT = 0.06e
CT = 0.06e

Scheme 3: Geometry of the transition state of the IMDA reaction of triene-amide of the
Compounds (Ta, Tb, Tc, Td and Td), charge-transfer {CT} is given in e, interatomic distances
are given in Å.

3.2.3. Prediction of the polarity by using the electrophilic index of regional fragments ωΩ :
The difference of electrophilic ΔωΩ fragments ωΩ (Ω = A or B) is used in the intermolecular
reactions to estimate the reactivity and the polarity of the reaction, is subsequently transmitted
to the process IMDA [38]:
ΔωΩ = │ωA - ωB│
The results obtained are summarized in table 5.
Table 5: Electrophilic index of ωA, ωB and the invariance of electrophile of A and B fragments
(ΔωΩ).

A B
Compoud
η (u.a) μ (u.a) ω (eV) η (u.a) μ (u.a) ω (eV) ΔωΩ=│ωA-ωB│
Ta 0.169 -0.109 0.95 0.119 -0.064 0.46 0.49
Tb 0.161 -0.105 0.93 0.113 -0.062 0.47 0.46
Tc 0.167 -0.104 0.88 0.010 -0.021 0.60 0.28

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Td 0.129 -0.101 1.07 0.023 -0.025 0.36 0.71

Te 0.175 -0.107 0.90 0.004 -0.018 1.10 0.20

 We note that the value ΔωΩ of the Td compound (ΔωΩ = 0.71) is located between (0.5 ≤
ΔωΩ ≤ 1.50), thus for Ta and Tb compounds is close to 0.5 then the IMDA process, for these
systems follow a mechanism moderately polar and is characterized by a charge-transfer CT
marginal in transition state [40], at the exception of compound Td, with a low charge-transfer
CT in a transition state, for the other compounds Tc and Te their values of ΔωΩ is quite low of
0.28 and 0.20 (ΔωΩ ≤ 0.5) respectively, which confirms that these reactions are not polar and are
characterized by a negligible charge transfer CT in transition state [40].
In order to know the percentage of transfer of the nucleophilicity and the electrophilicity
between fragments, we calculated the degree of transferability of each fragment, the results are
summarized in tables 6 and 7.

Table 6: Degree of transferability Tω.

Compounds ωD (eV) ωDp (eV) ω (eV) %( %
Ta 0.725 0.606 1.331 56 44
Tb 0.736 0.588 1.324 55 45
Tc 0.662 0.534 1.197 55 45
Td 0.941 0.388 1.330 70 30
Te 0.648 0.575 1.223 53 47

Table 7: Degree of transferability TN.

Compounds ND (eV) NDp (eV) N (eV) % %
Ta 2.983 0.316 3.299 90 10
Tb 2.848 0.297 3.145 91 09
Tc 3.079 0.332 3.438 90 10
Td 2.907 0.626 3.530 82 18
Te 3.195 0.264 3.428 92 8

In taking into account the results of tables 6 and 7, the electrophilic and nucleophilc characters
are concentrated in the diene D fragment to % (54, 56, 55, 70 and 53) of electrophilicity
characters and to % (90, 91, 90, 82 and 92) of the nucleophilicity characters of the
compounds Ta, Tb, Tc, Td and Te respectively. Therefore, the electronic transfer is done from
the diene to the dienophile fragments.

Conclusion
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In this study, during the intramolecular Diels Alder (IMDA) reaction, we applied the theoretical
approaches namely electrophilic index ω and Nucleophilic index N used usually in the
intermolecular process (DA), the analyses by groups electrophiles and nucleophiles from
fragments show that these characters are concentrated in the fragment diene noted that the ratio
ND/ωD is higher, thus the nucleophilicity is predominant. This is confirmed by the electron flow
and the charge transfer to the transition states and subsequently the diene fragment plays the
role of electron-releasing and the dienophile fragment plays the role electron-withdrawing of
electron for all systems Ta, Tb, Tc, Td and Te. Thus, the charge transfer will take place from the
diene to the dienophile NED (Normal Electronic Demand).

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