This article was downloaded by: [North Dakota State University]On: 01 September 2013, At: 10:27Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: MortimerHouse, 37-41 Mortimer Street, London W1T 3JH, UK

Molecular Physics: An International Journal at theInterface Between Chemistry and PhysicsPublication details, including instructions for authors and subscription information:http://www.tandfonline.com/loi/tmph20

Prediction of the Chemo- and Regioselectivity ofDiels-Alder Reactions of o-Benzoquinone derivativeswith Thiophenes by means of DFT-based ReactivityIndicesAmina Ghomri a b & Sidi Mohamed Mekelleche ba Preparatory School of Science and Technology , B. P. 165,Belhorizon, Tlemcen , 13000 ,Algeriab Laboratory of Applied Thermodynamics and Molecular Modeling N° 53 Departmentof Chemistry, Faculty of Science , University A. Belkaïd , B. P. 119, Tlemcen , 13000 ,AlgeriaAccepted author version posted online: 09 Aug 2013.

To cite this article: Molecular Physics (2013): Prediction of the Chemo- and Regioselectivity of Diels-Alder Reactions of o-Benzoquinone derivatives with Thiophenes by means of DFT-based Reactivity Indices, Molecular Physics: An InternationalJournal at the Interface Between Chemistry and Physics, DOI: 10.1080/00268976.2013.831141

To link to this article: http://dx.doi.org/10.1080/00268976.2013.831141

Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a serviceto authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,typesetting, and review of the resulting proof will be undertaken on this manuscript before final publicationof the Version of Record (VoR). During production and pre-press, errors may be discovered which couldaffect the content, and all legal disclaimers that apply to the journal relate to this version also.

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) containedin the publications on our platform. However, Taylor & Francis, our agents, and our licensors make norepresentations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose ofthe Content. Any opinions and views expressed in this publication are the opinions and views of the authors,and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be reliedupon and should be independently verified with primary sources of information. Taylor and Francis shallnot be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and otherliabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to orarising out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Any substantial or systematicreproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in anyform to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions

1

Prediction of the Chemo- and Regioselectivity of Diels-Alder Reactions

of o-Benzoquinone derivatives with Thiophenes by means of DFT-

based Reactivity Indices

Amina Ghomria,b and Sidi Mohamed Mekellecheb*

aPreparatory School of Science and Technology, B. P. 165,Belhorizon, Tlemcen, 13000,

Algeria .bLaboratory of Applied Thermodynamics and Molecular Modeling N° 53

Department of Chemistry, Faculty of Science, University A. Belkaïd, B. P. 119,

Tlemcen, 13000, Algeria

*Corresponding author: Tel. /fax: +213 43 28 63 49

e-mail: sidi_mekelleche@yahoo.fr & sm_mekelleche@mail.univ-tlemcen.dz

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

2

Prediction of the Chemo- and Regioselectivity of Diels-Alder Reactions

of o-Benzoquinone derivatives with Thiophenes by means of DFT-

based Reactivity Indices.

Global and local reactivity indexes derived from density functional theory

were used to elucidate the regio- and chemoselectivity of Diels–Alder

Reactions of masked o-benzoquinones with thiophenes acted as

dienophiles. The polarity of the studied reactions is evaluated in terms of

the difference of electrophilicity powers between the diene and dienophile

partners. Preferential cyclization modes of these cycloadditions are

predicted using Domingo’s polar model [L. R. Domingo, E. Chamorro, P.

Perez, J. Org. Chem, 2008, 73, 4615] based on the local electrophilicity

index, ωk, of the electrophile and the local nucleophilicity index, Nuk, of

the nucleophile. The theoretical calculations, carried out at the B3LYP/6-

311G(d,p) level of theory, are in good agreement with experimental

findings.

Keywords: Diels-Alder reactions; Chemoselectivity; Regioselectivity;

Global Reactivity indices; Local DFT-based indices.

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

3

1. Introduction

There are many requirements for a chemical reaction to be interesting in organic

synthesis, the regio-chemo and stereo- selectivity are crucial factors to understand

reaction mechanisms. Indeed, one of the most exciting challenges for a chemist is to

control the regio- chemo and stereo- selectivity of the chemical species involved at

the different steps of the overall synthesis process. Diels Alder (DA) reaction is one

of the well-known organic reactions [1-3]. Since the discovery of the DA reaction in

1928, a tremendous amount of theoretical and experimental work has been devoted

to the study of the mechanism and the selectivity of this reaction [4].

Recently the popularity and success of density functional theory (DFT) has

encouraged many groups to use the HSAB (Hard and Soft Acids and Bases)

principle, formulated with DFT [5], as a qualitative and quantitative treatment to

predict reactivity based upon ground state properties (density) in a similar fashion to

FMO theory.

The study of polar processes involving the interaction of electrophiles and

nucleophiles may be significantly facilitated if reliable scales of electrophilicity and

nucleophilicity are available. An excellent source that illustrates this concept well is

the review work recently published by Mayr and Kempf [6]. The development of

theoretical scales of nucleophilicity and electrophilicity, on the other hand, is also

desirable as a validated theoretical scale may be further used to project the global

reactivity onto particular regions on the molecule. Recently, Parr, Szentpály and Liu

proposed a formal derivation of the electrophilicity, from a second-order energy

expression developed in terms of the variation in the number of electrons[7].

Unfortunately, a quantitative definition of global nucleophilicity cannot be deduced

within the same framework, and it remains as an open problem. Very recently ,

Domingo et al. [8] introduced the global and local (regional) nucleophilicity indices

and shown that these new descriptors provide useful clues about the director effects

of the substituents on EAS reactions of six-membered aromatic compounds [9].

The use of the five-membered heterocycles in DA reactions is as old as the reaction

itself, and different possibilities were described [10]. The DA reaction of thiophenes

presents a very important subject of study in organic chemistry[11-14]. Indeed,

thiophene, unlike furan and pyrrole has been shown to be a rather inefficient diene

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

4

in Diels–Alder reactions or other cycloaddition reactions[15]. However, thiophenes

can participate in Diels–Alder reactions as dienes but under harsh conditions[16].

On the other hand, the experiment shows that thiophenes substituted with an

electron-donating group act as dienophiles in their reactions with masked o-

benzoquinones (MOBs) substituted with electron-withdrawing group leading to a

regio- and chemoselective cycloadduct (Figure 1)[17].

<Insert Figure 1 here >

Our aim in this work is first to undertake a theoretical study of the, regio- and

chemoselectivity of DA reactions of the three masked o-benzoquinones 1a

(R=COMe), 1b (R= CO2Me) and 1c (R= CN) with thiophene derivatives DP1-DP4

(Figure 1) and second analyze the feasibility of DA reactions for which the

experimental data are not available, between thiophene derivatives substituted by an

electron-withdrawing group (CN) and a masked o-benzoquinone derivative

substituted by an electron-donating group (OMe) (scheme 1) by means of DFT-

based reactivity indexes.

2. Theoretical Background

2.1 Global quantities

Assuming differentiability of the electronic energy, E, with respect to N and v(r), a

series of response functions appear, probably the most important being the

electronegativity (χ)[18] and hardness [19,20] (η) have been provided with rigorous

definitions within the purview of conceptual DFT[21,22]. Electronegativity is the

negative of chemical potential defined [23].

( )

v r

EN

χ μ ∂⎛ ⎞= − = − ⎜ ⎟∂⎝ ⎠

(1)

μ is the Lagrange multiplier associated with the normalization constraint of

DFT[21,24].

Hardness (η) is defined[25] as the corresponding second derivative,

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

5

2

v(r)v(r)

EN N

μη⎛ ⎞∂ ∂⎛ ⎞= =⎜ ⎟ ⎜ ⎟∂ ∂⎝ ⎠⎝ ⎠

(2)

Softness (S) is the reciprocal of hardness; S = 1/η.

Using a finite difference method, working equations for the calculation of μ and η

may be given as [21]:

2

I Aμ += − (3)

I - Aη =

(4)

Where I and A are the ionization potential and electron affinity, respectively. If

εHOMO and εLUMO are the energies of the highest occupied and lowest unoccupied

molecular orbitals, respectively, then the above equations can be rewritten[26],

using Koopmans’ theorem[27], as

HOMO LUMO 2

εμ ε +≈ (5)

HOMO LUMO - η ε ε≈ (6)

The electrophilicity index, as defined by Parr et al.[7], is given by

2

2

μω

η=

(7)

This quantity can be considered as a measure of the electrophilic power of a system.

Recently, Domingo et al.[8] introduced an empirical (relative) nucleophilicity index,

Nu, based on the HOMO energies obtained within the Kohn–Sham scheme [28] and

defined as:

Nu = EHOMO(Nuc) – EHOMO(TCE) (8)

This nucleophilicity scale takes tetracyanoethylene (TCE) as a reference. This

choice allows us to handle a nucleophilicity scale with only positive values[8].

2.2 Local quantities

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

6

As opposed to the global reactivity descriptors described above, the analysis of site

selectivity in a molecule demands the local descriptors like the Fukui function

defined as [29].

( )

( )( )( )v r N

rf rN v r

ρ δμδ

⎡ ⎤∂⎡ ⎤= = ⎢ ⎥⎢ ⎥∂⎣ ⎦ ⎣ ⎦ (9)

Owing to the discontinuity in the ρ(r) versus N plot, three different approximate

versions but well suited for different varieties of chemical reactions have been

proposed as follows [30].

[ ]( 1) ( )k k kf N Nρ ρ+ = + − (10a) for nucleophilic attack

[ ]( ) ( 1)k k kf N Nρ ρ− = − − (10b) for electrophilic attack

Where ( ), ( 1) ( 1)k k kN N and Nρ ρ ρ− + are the gross electronic populations of the

site k in neutral, cationic, and anionic systems, respectively.

The local electrophilicity index[31], ωk, condensed to atom k is easily obtained by

projecting the global quantity onto any atomic center k in the molecule by using the

electrophilic Fukui indice , yielding to:

ωk = ω kf− (11)

Very recently, Perez et al.[9] proposed a new defining of the local nucleophilicity

index, Nuk, as the product of the global nucleophilicity index, Nu, and the

nucleophilic Fukui index, kf− .

.k kNu Nu f −= (12)

3. Computational details

The quantum chemistry calculations reported in this work have been performed at

B3LYP/6-311G(d,p)[32] level of theory using the Gaussian 03 series of

programs[33] . All stationary points found were characterized as true minima by

frequency calculations. We note that the cationic and anionic systems required in the

calculations of local indices were kept at the same geometry of the neutral system.

The electronic populations were computed using the MPA (Mulliken population

analysis), the charges derived from the electrostatic potential and calculated

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

7

according to Breneman and Wiberg algorithm (ChelpG option)[34] and also by NPA

(natural population analysis).

4. Results and discussion

4.1. Prediction of the relative reactivities of reagent and the polarity of the DA

reactions

Recent studies carried out on DA reactions have shown that the reactivity

indices, defined within the conceptual DFT, are powerful tools for analyzing and

establishing the polar (or non polar) character of such reactions [35]. In Table 1a,

are reported the calculated values of global properties, namely, electronic chemical

potential, μ, global hardness, η, global electrophilicity, ω, and global

nucleophilicity, Nu, and global charge transfer ∆Nmax.

<Insert Table 1a here>

In order to highlight the nucleophilic/electrophilic character of the each of two

reactants as well as the polar character of the DA reactions, we calculated the

HOMO/LUMO gaps and the global electrophilicity differences Δω. The results are

given in Table 1b.

<Insert Figure 1b here>

In the case of DA reaction #1, diene 1a (R=COMe) and dienophile DP1 , the

electronic chemical potential of DP1, μ = -0.122 a.u., is larger than that of diene 1a

μ = -0.179 a.u., indicating that the CT (charge transfer) will take place from DP1 to

diene 1a. Likewise, the global electrophilicity index of DP1, ω = 0.95 eV, is lower

than that of diene 1a, ω = 3.02 eV. Consequently, DP1 will act as a nucleophile,

while the diene 1a will act as an electrophile. The calculated nucleophilicity indexes

also show that DP1, Nu=3.09 eV, is more nucleophile than diene 1a Nu=2.5 eV.

Moreover, maximum charge transfer described by the ΔNmax quantity, which

presents the maximum propensity of the system to acquire additional electronic

charge from the environment is maximum for the diene 1a ΔNmax =1.23, and

minimum for DP1 ΔNmax =0.56. The same conclusions could be made for the

reactions of diene 1a with DP2, DP3 and DP4 dienophiles.

In the case of DA reaction #2 between diene 1b (R= CO2Me) and DP1, the

electronic chemical potential of DP1, μ=-0.122 a.u, is greater than that of diene

1b, μ= -0.167 a.u, indicating that the electron flux in this case will go from the DP1

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

8

to 1b. Similarly, the electrophilicity index of diene 1b, ω =2.63eV, which is greater

than that for DP1, ω =0.95 eV, indicates that diene 1b will act as an electrophile

while DP1 will act as a nucleophile. The calculated values of nucleophilicity indices

(Table 1a, column #7) show that DP1 is moste nucleophile than diene 1b.

Furthermore ΔNmax is maximum for diene 1b ΔNmax =1.15 and minimum for the

DP1 ΔNmax =0.56. The same conclusions could be made for the reactions of diene

1b with DP2, DP3 and DP4 dienophiles.

For DA reaction #3 between diene 1c (R= CN) and DP1, the electronic chemical

potential of DP1, μ=-0.122 a.u, is greater than that of diene 1c, μ= -0.183a.u,

indicating that the electron flux in this case will go from the DP1 to 1c. In addition ,

the electrophilicity index of diene 1c, ω =3.13 eV, which is greater than that for

DP1, ω =0.95 eV, indicates that diene 1c will act as an electrophile while DP1 will

act as a nucleophile. Similarly the calculated values of nucleophilicity indices show

that DP1 is moste nucleophile than diene 6c. Moreover ΔNmax is maximum for diene

1c ΔNmax =1.25 and minimum for the DP1 ΔNmax =0.56. The same conclusions could

be made for the reactions of diene 1c with DP2, DP3 and DP4 dienophiles. .

Table 1.b shows also that |E DienophileHOMO - E Diene

LUMO | gaps are lowest in energy than the

|E DieneHOMO - E Dienophile

LUMO | gaps for the 12 studied reactions. In conclusion, in all reactions,

the o-benzoquinones dienes act as electrophiles (electron acceptors); whereas

the substituted thiophene dienophiles act as nucleophiles (electros donors).

The difference in electrophilicity for the diene/dienophile pair, Δω, was found to be

a measure of the high- or low-polar character of the cycloaddition. The high

electrophilicity differences between the two reagents varying from 1.68 eV, for

reaction #2 to 2.36 eV, for the reaction #12 indicate an appreciable polar character

of the studied DA reactions.

In order to identify the frontier molecular orbitals (FMOs) involved in DA

reactions between the diene and dienophile, it is necessary to compare the electron

densities of some FMOs. The HOMO, HOMO-1 and HOMO-2 densities of the DP1

and DP3 dienophiles (nucleophiles) and the LUMO, LUMO+1 and LUMO+2

densities of the 1a and 1c dienes (electrophiles) are represented in figures 2a-b

respectively. Figure 1a shows clearly that the HOMO and HOMO-1 densities are

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

9

more important on the dienophile cycle in comparison with the HOMO-2 density.

We note that HOMO and HOMO-1 FMOs are close in energy. On the other hand,

figure 2b shows that the LUMO density is more important on the diene cycle in

comparison with the LUMO+1 and LUMO+2 densities. For these reasons, the

HOMO of the dienophile and the LUMO of the diene are retained as the best FMOs

involved in diene-dienophile ineraction.

<Insert Figure 2a here>

<Insert Figure 2b here>

4.2. Prediction of the regio and chemo-selectivity on the studied DA reactions

The best descriptors for studying local reactivity and regioselectivity for a

cycloaddition reaction will be the local electrophilicity [31] and the local

nucleophilicity [8]. In a polar cycloaddition reaction between unsymmetrical

reagents, the more favorable two-center interaction will take place between the more

electrophile center, characterized by the highest value of the local electrophilicity

index, ωk. at the electrophile, and the more nucleophile center, characterized by the

highest value of the local nucleophilicity index, Nuk, at the nucleophile.

The thiophene derivatives have two double bonds (C5-C6 and C7-C8) able to be

involved in the DA reaction. Consequently, all the carbon atoms of the cycle of the

dienophiles were taken into account for the calculation of the local nucleophilicity

indices. The local nucleophilicity Nuk indices for the C5, C6, C7 and C8 sites of the

diènophiles DP1-4 and the local electrophilcity indices ωk for the C1 and C4 sites of

the dienes 1a-c are presented in figures 3a-b. It turns out that the most favorable

two-center interaction, leading to the formation of the cycloadduct will take place

between the C1 (having the maximum value of ωk) of the o-benzoquinones and C8

(having the maximum value of Nuk) of the diènophiles. Consequently, the formation

of the first new sigma bond, as predicted by Domingo’s polar model, is in

agreement with experimental findings for all reactions under investigation.

Results also show that the C7-C8 double bond of the diènophiles is the most reactive

one, indicating that all the studied DA reactions are chemoselective and the C7-C8

double bond is more favored compared to C5-C6 double bond as it has been found

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

10

experimentally. We note that MPA analysis fails to predict the chemo- and

regioselectivity of DA reactions of DP3 with 1a-1c. Indeed, according to MPA, the

local nucleophilicity of the C5 atom, Nuk=0.782 eV, is slightly higher than that of

the C8 atom, Nuk=0.764eV. The failure and the drawback of MPA is well-

recognized although this analysis is largely used quantum chemistry softwares[36].

3.3. Prediction of the feasibitliy of DA reactions of o-benzoquinones with other

thiophene derivatives.

It was shown that a DA reaction is more favored kinetically when the difference of

electrophilcity, Δω, between the two reagents is larger [37]. A linear correlation was

obtained between calculated activation energies of DA reactions and the inverse of

the difference of electrophilicity between the diene and dienophile. In this section,

we have studied the feasibility (easy vs. harsh from an experimental point of view)

of some DA reactions for which the experimental data are not available, between

thiophene derivatives substituted by an electron-withdrawing (CN) substitute and a

masked o-benzoquinone derivative substituted by an electron-donating (OMe)

substituted (scheme 1).

<Insert scheme1 here>

The computed values of the global reactivity indices, namely, the electronic

chemical potential, μ, the global hardness, η, the global electrophilicity, ω, the

global nucleophilicity, Nu as well as the charge transfer ΔNmax for the reagents are

presented in Table 2a. The values of HOMO/LUMO energy gaps of the reagents

and the electrophilicity differences, Δω, are given in Table 2b.

<Insert Table 2a here>

<Insert Table 2b here>

Tables 2a-b show that the Δω values for reactions #13-15 are very small,

indicating a very low polar character of these reactions. Results also show that the

Δω values for reactions #13-15 are remarkably lower than those reactions #1-

12. Consequently, reactions #13-15 are predicted to be disfavored kinetically

compared to reactions #1-12 as it has been found experimentally. Indeed,

experiment shows that such DA reactions are more favored when thiophenes are

substituted by electro-donating groups and the o-benzoquinones are substituted by

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

11

electron withdrawing groups [17]. The HOMO/LUMO energy gaps of reactions

#13-15 are remarkably higher than those of reactions #1-12, also indicating

unfeasibility of DA reactions #13-15.

Concluding Remarks

The preferential cyclization modes and the regio- and chemoselectivity of a series

of DA reactions of o-benzoquinones with substituted thiophenes have been studied

using DFT methods at the B3LYP/6-311G(d,p) level of theory. The

electrophilicity/nucleophilicity character and the direction of the electron flux has

been predicted by the calculation of electronic chemical potentials and

electrophilicity indexes and the maximum charge transfer. The polarity of these

cycloadditions has been put in evidence by the calculation of electrophilicity

differences between reagents. Our results show that the local electrophilicity and

nucleophilicity indices constitute an efficient tool for the prediction of the positional

selectivity of DA reactions.

References

[1] (a) E. V Anslyn, D. Dougherty, Modern Physical Organic Chemistry.

(California, University Science Books, 2006) (b) J. March, Advanced Organic

Chemistry, Ed 4, (New York, Wiley& Sons, Inc, 1992).

[2] W. Carruthers, Cycloaddition Reactions in Organic Synthesis (Oxford,

Pergamon Press plc, 1990).

[3] D. L. Boger, S. N. Weinreb, Hetero Diels-Alder Methodology in Organic

Synthesis. (Academic Press: San Diego, 1987).

[4] (a) R. A. Poirier, C. C. Pye, J. D. Xidos, D. J. Burnell, J. Org. Chem. 60, 2328

(1995); (b) G. O. Jones, K. N. Houk, J. Org. Chem. 73, 1333 (2008); (c) S. J. Min,

G. O. Jones, K. N. Houk, S. J. Danishefsky, J. Am. Chem. Soc. 129, 10078 (2007) ;

(d) L. R. Domingo, M. J. Aurell, M. Arno, J. A. Saez, J. Org. Chem. 72, 4220

(2007); (e) L. R. Domingo, M. T. Picher, P. Arroyo, J. A. Saez, J. Org. Chem. 71,

9319 (2006); (f) L. T. Nguyen, F. De Proft, A. K. Chandra, T. Uchimaru, M. T.

Nguyen, P. Geerlings, J. Org. Chem. 66, 6096 (2001); (g) U. Chiacchio, A.

Rescifina, M. G. Saita, D. Iannazzo, G. Romeo, J. A. Mates, T. Tejero, P. Merino, J.

Org. Chem. 70, 8991 (2005); (h) G. Wagner, Chem. Eur. J. 9, 1503 (2003); (i) A.

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

12

Milet, Y. Gimbert, A. E. Greene, J. Comp. Chem. 27, 157 (2005). (j) S. Damoun,

Vandewoude, F. Mendez, P. Geerlings. J. Phys. Chem. A, 101, 886 (1997).

[5] (a) H. Chermette, J. Comp. Chem. 20, 129 (1999) ;(b) P. Geerlings, F. De Proft,

W. Langenaeker, Chem. Rev. 103, 1793 (2003).

[6] H. Mayr, B. Kempf, A. R, Acc. Chem. Res. 36, 66 (2003).

[7] R. G. Parr, L. V. Szentpály, S. Liu, J. Am. Chem. Soc. 121, 1922 (1999).

[8] L. R. Domingo, E. Chamorro, P. Perez, J. Org. Chem, 73, 4615 (2008).

[9] P. Pérez, L. R. Domingo, M. Duque-Noreña, E. Chamorro, J Mol Struct:

Theochem, 86, 895 (2009).

[10] (a) O. Diels, K. Alder, Ber. 62, 557 (1929); (b) O. Diels, K. Alder, Ann. 490 ,

243 (1931); (c) D. B. Clapp, J. Am. Chem. Soc. 61, 2733 (1939); (d) R. B.

Woodward, H. Baer, J. Am. Chem. Soc. 70, 1161(1948); (e) C. F. H. Allen, J. W.

Gates, J. Am. Chem. Soc. 65, 1283 (1943).

[11] (a) J. Nakayama, H. Nagasawa, Y. Sugihara, A. Ishii, Heterocycles, 52, 365

(2000); (b) J. Nakayama, R. Hasemi, K. Yoshimura, Y. Sugihara, S. Yamaoka, N.

Nakamura, J. Org. Che. 63, 4912 (1998); (c) J. Nakayama, H. Nagasawa, Y.

Sugihara, A. Ishii, J. Am. Chem. Soc. 119, 9077 (1997); (d) J. Nakayama, A.

Hirashima, J. Am. Chem. Soc. 112, 7648 (1990).

[12] G. Seitz, T. Kaempchen, Arch. Pharm, 311, 728 (1978).

[13] M. S. Raasch, J. Org. Chem. 45, 856 (1980).

[14] H. W. Heine, D. K. Williams, J. L. Rutherford, J. Ramphal, E. A. Williams,

Heterocycles, 35, 1125 (1993).

[15] (a) S. Rajappa, N. V. Natekar, In Comprehensive Heterocyclic Chemistry II;

Bird, C. W., Ed.; Pergamon: (Oxford, 1996); 2 Vol. pp. 491–606; (b) J. A. Joule, K.

Mills, G. F. Smith, In Heterocyclic Chemistry; Chapman & Hall: (London, 1995);

(c) P. H. Benders, D. N. Reinhoudt, Trompenaars, W. P. In Thiophene and its

Derivatives; Wiley-Interscience: (New York, 1985; pp. 671).

[16] C. Corral, J. Lissavetzky, I. Manzanares, Synthesis, 29–31 (1997).

[17] C. H. Lai, S. Ko, P. D. Rao, C. C. Liao, Tetrahedron Lett, 42, 7851 (2001).

[18] (a) L. Pauling, The Nature of the Chemical Bond, 3rd ed., (Cornell University

Press: Ithaca, New York, 1960); (b) K. D. Sen, C. Jorgenson, Structure and

Bonding: Electronegativity, Vol. 66,(Springer, Berlin, 1987).

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

13

[19] Pearson, R. G.; Chemical Hardness: Applications from Molecules to Solids,

(Wiley-VCH, Weinheim, 1997).

[20] K. D. Sen, D. M. P. Mingos, Structure and Bonding: Chemical Hardness, Vol.

80, (Springer, Berlin, 1993).

[21] R. G. Parr, W. Yang, Density Functional Theory of Atoms and Molecules,

(Oxford University Press, Oxford, U.K., 1989).

[22] (a) P. Geerlings, F. de. Proft, W. Langenaeker, Chem. Rev. 103, 1793 (2003);

(b) H. Chermette, J. Comput. Chem. 20, 129 (1999).

[23] R. G. Parr, R. A. Donnelly, M. Levy, W. E. Palke, J. Chem. Phys. 68, 3801

(1978).

[24] (a) P. Hohenberg, W. Kohn, Phys. Rev. B. 136 (1964) 864; (b) W. Kohn, L.

Sham, J. Phys. Rev. A. 140, 1133(1965).

[25] R. G. Parr, R. G. Pearson, J. Am. Chem. Soc. 105, 7512(1983).

[26] R. G. Pearson, Inorg. Chem. 27, 734 (1988).

[27] T. A. Koopmans, Physica 1, 104(1933) 104.

[28] W. Kohn, L. Sham, Phys. Rev. 140,1133 (1965).

[29] R. G. Parr, W. Yang, J. Am. Chem. Soc. 106, 4049 (1984).

[30] W. Yang, W. Mortier, J. Am. Chem. Soc. 108, 5708 (1986).

[31] L. R. Domingo, M. J. Aurell, P. Perez, R. Contreras, J. Phys Chem, A. 106

6871 (2002).

[32] (a) A.D. Becke, J. Chem. Phys. 98, 5648 (1993); (b) C. Lee, W. Yang, R.G.

Parr, Phys. Rev. B 37, 785(1988).

[33] M. J. Frisch et al. Gaussian 03 (Revision E.01), Gaussian Inc., Pittsburgh PA,

2004.

[34] C. M. Breneman, K. B. Wiberg, J. Comput. Chem. 11, 361 (1990).

[35] (a) L. R. Domingo, M. J. Aurell, P. Perez, R. Contreras, Tetrahedron 58, 4417

(2002); (b) P. Perez, L. R. Domingo, A. Aizman , R. Contreras, R. The

electrophilicity index in organic chemistry, in Theoretical Aspects of Chemical

Reactivity, ed. A. Toro-Labbé, (Elsevier Science: New York, 2007).

[36] I. N. Levine, “Quantum Chemistry”,( Englewood Cliffs, NJ, Prentice Hall,

2000).

[37] H. Chemouri, S. M. Mekelleche, J. Theo. Com. Chem. 5, 197 (2006).

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

14

Table 1a : Calculated global electronic indices, electronic chemical potential, μ, global

hardness η, electrophilicity indices, ω, nucleophilicity indices, Nu, and maximum

charge transfer ΔNmax for dienes 1a-c and dienophiles DP1-4.

Compound HOMO LUMO µ(ua) η(a.u.) ω(eV) Nu(eV) ΔNmax

1a

-0.252

-0.107

-0.179

0.145

3.02

2.50

1.23

1b -0.239 -0.095 -0.167 0.144 2.63 2.83 1.15

1c -0.256 -0.110 -0.183 0.145 3.13 2.39 1.25

DP1 -0.230 -0.015 -0.122 0.215 0.95 3.09 0.56

DP2 -0.235 -0.012 -0.124 0.222 0.94 2.95 0.55

DP3 -0.224 -0.009 -0.117 0.214 0.87 3.24 0.54

DP4 -0.213 -0.003 -0.108 0.209 0.76 3.57 0.51

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

15

Table 1b: Energy difference between the two possible HOMO/LUMO

combinations for the dienes and dienophiles (values in eV) and the electrophilicity

differences Δω.

Reaction # Diene DienophileHOMO LUMOE E− Dienophile Diene

HOMO LUMOE E− Δω(eV)

1 6.45 3.35 2.07

2 6.11 3.68 1.68

3 6.55 3.27 2.17

4 6.51 3.49 2.08

5 6.17 3.82 1.69

6 6.62 3.41 2.18

7 6.59 3.20 2.15

8 6.25 3.52 1.76

9 6.70 3.11 2.26

10 6.76 2.88 2.26

11 6.42 3.20 1.87

12 6.89 2.79 2.36

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

16

Table 2a : Global indices, electronic chemical potentials, μ, global hardness, η,

electrophilicity indices, ω, nucleophilicity indices, Nu, and maximum charge

transfer ΔNmax for diene 1d and dienophiles DP5-7.

Diene/dienophile HOMO LUMO µ(ua) η(ua) ω(eV) Nu(eV) ΔNmax

1d -0.242 -0.091 -0.167 0.151 2.52 2.75 1.10

DP5 -0.264 -0.069 -0.167 0.194 1.95 2.16 0.85

DP6 -0.269 -0.058 -0.163 0.210 1.73 2.03 0.77

DP7 -0.287 -0.096 -0.192 0.190 2.63 1.54 1.00

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

17

Table 2b : Energy difference between the two possible HOMO/LUMO

combinations for the dienes and dienophiles (values in eV) and the electrophilicity

differences Δω in bold.

Réaction # Diene DienophileHOMO LUMOE E− Dienophile Diene

HOMO LUMOE E− Δω(eV)

13 4.70 4.70 0.56

14 5.00 4.82 0.78

15 3.96 5.32 0.11

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

C3

C4

C2C1

O

OMe

OMeR

C5

C6 C7

C8

S

DP1

C5

C6 C7

C8

S

DP2

C5

C6 C7

C8

S

DP3

C5

C6 C7

C8

S

DP4

OMe

O

OMe

OMe

S

R

O

OMe

OMe

S

R

O

OMe

OMe

S

R

O

OMe

OMe

S

R

OMe

1a-c

2a-c

3a-c

4a-c

5a-c

a( R=COMe)b(R=CO2Me)c(R=CN)

Figure 1. Cyloaddition products of Diels- Alder reactions of masked o-benzoquinones and

thiophene derivatives [17]

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

C3

C4

C2C1

O

OMe

OMeMeO

1d

C5

C6 C7

C8

SR1

R2R3

DP5 (R1=CN; R2=H; R3=H)

DP6 (R1=H; R2=CN; R3=H)

DP7 (R1=CN; R2=H; R3=CN)

Scheme 1 : Structures of reagents 1d and DP5-7.

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

Figure 2a: Optimized geometries and HOMO, HOMO-1, HOMO-2 densities of dienophiles DP1-DP4 calculated at the B3LYP/6-311G(d,p) level of theory

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

Figure 2b: Optimized geometries and LUMO, LUMO+1, LUMO+2 densities of dienes 1a-1c calculated at the B3LYP/6-311G(d,p) level of theory.

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

Figure 3a: Illustration of the first _-bond formation in the first step using Domingo’s polar model for reactions #1-#6. Values are reported as follows: Mulliken (Normal), ChelpG (Bold) and natural (Italic).

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13

Figure 3b: Illustration of the first _-bond formation in the first step using Domingo’s polar model or reactions #7-#12. Values are reported as follows: Mulliken (Normal), ChelpG(Bold) and Natural (Italic).

Accep

ted M

anus

cript

Dow

nloa

ded

by [

Nor

th D

akot

a St

ate

Uni

vers

ity]

at 1

0:27

01

Sept

embe

r 20

13