Diels-Alder reactions for the rational design of benzo[b]thiophenes: DFT-based guidelines for synthetic chemists

Article abstract of DOI:10.1016/j.molstruc.2011.11.050

In this work we studied the capability of several diene/dienophile pairs to undergo Diels-Alder (DA) reactions leading to benzo[b]thiophenes. A variety of synthetically and commercially available nitrothiophenes were chosen as dienophiles. Methyl 5-nitro-3-thiophenecarboxylate was selected as a potential strong electrophilic candidate based on some DFT-based properties and the substitution pattern of the expected product. The mechanistic details concerning the participation of this dienophile in polar DA reactions were investigated through a theoretical point of view. The results were compared with the experimental outcomes. This methodology should allow synthetic chemists to analyze DA reactions in detail in a stage prior to the synthetic job.

Full text of DOI:10.1016/j.molstruc.2011.11.050

Journal of Molecular Structure 1010 (2012) 158–168
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Diels–Alder reactions for the rational design of benzo[b]thiophenes: DFT-based
guidelines for synthetic chemists
a
a
c
Romina Brasca a,b, , María N. Kneeteman , Pedro M.E. Mancini , Walter M.F. Fabian
⇑
a Facultad de Ingeniería Química, Universidad Nacional del Litoral, Santiago del Estero 2829, S3000AOM Santa Fe, Argentina
b Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Av. Rivadavia 1917, C1033AAJ Capital Federal, Argentina
c Karl-Franzens-Universität Graz, Heinrichstrasse 28, 8010 Graz, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 August 2011
Received in revised form 25 November 2011
Accepted 25 November 2011
Available online 8 December 2011
In this work we studied the capability of several diene/dienophile pairs to undergo Diels–Alder (DA) reac-
tions leading to benzo[b]thiophenes. A variety of synthetically and commercially available nitrothioph-
enes were chosen as dienophiles. Methyl 5-nitro-3-thiophenecarboxylate was selected as a potential
strong electrophilic candidate based on some DFT-based properties and the substitution pattern of the
expected product. The mechanistic details concerning the participation of this dienophile in polar DA
reactions were investigated through a theoretical point of view. The results were compared with the
experimental outcomes. This methodology should allow synthetic chemists to analyze DA reactions in
detail in a stage prior to the synthetic job.
Keywords:
Nitrothiophenes
Substituted 1,3-butadienes
Benzo[b]thiophenes synthesis
Polar Diels–Alder reactions
DFT-based descriptors
Reaction mechanism
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
correctly functionalized in order to be activated towards this kind
of DA reactions [7].
Benzo[b]thiophenes constitute many natural products as well
as pharmaceuticals, herbicides, dyes, and other products of tech-
nical importance [1]. For example, 4-(N-methylcarbamoyl)
benzo[b]thiophene (mobam), which is bioisosteric with its naph-
thalene analog, is an effective insecticide [2]; [2-(4-hydroxy-
phenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]
phenyl]-methanone hydrochloride (raloxifene hydrochloride) is an
estrogen agonist/antagonist, commonly referred to as a selective
estrogen receptor modulator [3]; benzo[b]-3-thienylacetic acid
promotes the growth of plants and 3-(2-aminoethyl)benzo[b]thio-
phene is known to have a strong action on the central nervous
system, with an activity higher than that of its indole analog [4].
Moreover, many dyestuffs and promising switches are derived
from benzo[b]thiophene [4,5].
Due to the importance of benzo[b]thiophene derivatives and
taking into consideration the utilization of 5-membered heterocy-
cles to build fused heterocyclic systems, we decided to investigate
some DA reactions involving a variety of electron-deficient thio-
phenes and some electron-rich dienes using Density Functional
Theory (DFT) methods.
The main purpose of this work is to elucidate the feasibility of
the proposed reactions, to establish reactivity trends, to suggest
potentially reactive pairs and to validate the theoretical predic-
tions by experimental work. Therefore, we intend to propose sim-
ple guidelines that can be useful for synthetic practitioners in order
to select the most appropriate reactants.
2. Computational and experimental section
The construction of fused heterocycles can be accomplished in a
simple way through the utilization of suitable heterocyclic ring
systems in thermal DA reactions (Fig. 1) [6]. When the aromatic
systems are intended to be used as dienophiles, they should be
2.1. Computational details
The gas-phase equilibrium geometries of all species described
here were obtained by full optimization at the B3LYP/6-31G(d) le-
vel [8] using GAUSSIAN03 program [9]. This level of theory was
chosen because it was shown to be adequate to model DA reactions
concerning medium-sized molecules [10] and also allows that the
calculations performed here were done in a reasonable time.
All stationary points found were characterized as true minima by
frequency calculations. Transition states were further characterized
⇑
Corresponding author. Address: Laboratorio de Desarrollo Analítico
y Qui-
miometría (LADAQ), Cátedra de Química Analítica I, Facultad de Bioquímica y
Ciencias Biológicas, UNL-CONICET, Ciudad Universitaria, CC 242, 3000 Santa Fe,
Argentina. Tel.: +54 342 4575205.
E-mail addresses: rbrasca@fiq.unl.edu.ar (R. Brasca), walter.fabian@uni-graz.at
(W.M.F. Fabian).
0022-2860/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2011.11.050

R. Brasca et al. / Journal of Molecular Structure 1010 (2012) 158–168
159
Fig. 1. Participation of selected heterocycles as dienophiles in thermal DA reactions.
by intrinsic reaction coordinate (IRC) calculations [11] (15 points
along both directions of the normal mode corresponding to the
imaginary frequency). All B3LYP/6-31G(d) calculated energies were
corrected for zero-point vibrational effects (ZPE) and the free energy
changes were derived from the sums of the electronic and thermal
Gibbs free energies. Zero-point energies and thermal corrections
are unscaled.
Another parameter that was used as a reactivity descriptor is
the polarizability, which measures the relative tendency of the
electronic cloud of a chemical species to be distorted from its nor-
mal shape by a weak external electric field [19]. The mean value
was calculated using the following equation:
a
¼ ðaxx
þ
ayy
þ
azzÞ=3
ð5Þ
Solvent effects on the reaction mechanism were considered by
single-point (SP) calculations on the gas-phase optimized struc-
tures using a self-consistent continuum method [12] in its conduc-
tor-like approximation (CPCM) [13]. Only the electrostatic
component of the solvation energy was taken into account. The
solvent used was benzene because it is the common solvent in
which most of this kind of DA reactions is carried out.
where axx
ability tensor.
,
ayy and azz are the diagonal components of the polariz-
Local reactivity descriptors, which reflect the sites in a molecule
where the reactivity pattern stated by the global quantities should
take place, were also computed. For example, regional Fukui func-
tions [20] were obtained from SP calculations on the optimized
structures of the reactants, using different levels of theory and ba-
sis sets. The condensed Fukui function (Eq. (6)) [21,22] for electro-
philic (nucleophilic) attack involves the HOMO (LUMO) FMO
coefficients (c) and the atomic overlap matrix elements (S). This
scheme has been corroborated for several reactions that are well
documented [23]:
Calculated gas-phase free energies (i.e.
state gas-phase pressure of 1 atm and solution-phase free energies
(i.e.
G⁄) use a standard-state solution-phase concentration of
DG°) use a standard-
D
1 mol/L. Therefore, for the standard state conversion from gas-
phase to solution a value of 1.9 kcal molꢀ1 (2.8 kcal molꢀ1) was
subtracted from the SP/CPCM
[14].
D D
Gꢁact and Grꢁeac at 298 K (433 K)
X
X
2
fka
¼
jc aj þ
c
acmaS
l lm
ð6Þ
l
m
–
l
l
2k
Different DFT-based indexes [15] were calculated in order to
model the chemical reactivity in these polar DA reactions [15b].
For instance, the chemical hardness (g) was approximated in terms
of the energies of the HOMO and LUMO frontier molecular orbitals
(FMO) according to Eq. (1) and the electronic chemical potential
A program that reads the FMO coefficients and the overlap ma-
trix from the Gaussian output files and performs the required cal-
culation was used [24].
Subsequently, other local reactivity parameters were intro-
duced (e.g. electrophilicity [25] and nucleophilicity [26]). There-
fore, in order to analyze at which atomic site of the dienophile
molecule the maximum electrophilicity power will be developed,
Eq. (7) was used [25]:
(l) was calculated using Eq. (2) [16]:
g
¼ ðeLUMO
ꢀ
eHOMO
Þ
ð1Þ
l
¼ ðeLUMO
þ
eHOMOÞ=2
ð2Þ
xk
¼
x
fkþ
ð7Þ
The global electrophilicity index (
x
), which is a useful descrip-
On the other hand, with the purpose of identifying the most
tor of reactivity that allows a quantitative classification of the glo-
bal electrophilic character of a molecule within a unique relative
scale, was calculated using Eq. (3) [17]:
nucleophilic site of the diene molecules, the nucleophilicity index
was calculated using Eq. (8). In this way, the activation caused by
different substituents on 1,3-butadiene derivatives was assessed:
x
¼
l2=2
In order to characterize the electron-rich species, the global
g
ð3Þ
Nk ¼ Nfꢀ
ð8Þ
k
where N is the global nucleophilicity index [18] and Nk is its local
counterpart [26].
nucleophilicity index (N) was calculated using Eq. (4) [18]:
B3LYP calculations indicate that the s-trans conformations of
the dienes are more stable than the s-cis counterparts (Table 1).
The s-cis structures, which show slight deviation from planarity
due to steric effects, are needed to carry out the DA reactions.
N ¼ ðeHOMO;Nu
ꢀ
eHOMO;TCE
Þ
ð4Þ
where eHOMO,TCE is the HOMO energy of tetracyanoethylene (TCE)
(taken as a reference molecule).

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R. Brasca et al. / Journal of Molecular Structure 1010 (2012) 158–168
Table 1
A mixture of acetic anhydride (15.7 mL, 166 mmol) and fuming
nitric acid (1.8 mL, 44 mmol) was cooled to ꢀ14 °C and a cold solu-
tion of methyl 3-thiophenecarboxylate (4.8 g, 34 mmol) in acetic
anhydride (15.7 mL, 166 mmol) was slowly added to the reaction
mixture keeping the temperature at ꢀ12 °C. The reaction mixture
was stirred for 4 h and was allowed to stand overnight at room
temperature. The mixture was poured into ice-water (final vol-
ume: 150 mL), neutralized with a saturated solution of sodium
bicarbonate (150 mL) and extracted with diethyl ether
(10 ꢂ 30 mL). The combined ethereal phases were washed with
cold water (15 mL) and dried over sodium sulfate. The reaction
was checked by silica gel TLC (hexane/ethyl acetate 2:1). The ni-
trated product was visualized by UV light and also by p-dimethyl-
aminobenzaldehyde solution. After some hours subsequent to the
heating of the plate, the compound was visualized as a yellow spot;
Rf (hexane/ethyl acetate 2:1) = 0.57. Column chromatography over
silica gel (hexane/ethyl acetate 10:1) of the evaporation residue
gave 10 as a pale yellow solid (yield: 2.2 g, 35%). Identification
Relative energies (B3LYP/6-31G(d) + ZPE) (in kcal molꢀ1) and dihedral angles C1 -C2
-
0
0
0
0
C
3 -C4 (in degree).
Diene
Gas-phase
Benzene
D
E
Dihedral angle
D
E
Dihedral angle
1
2
3
4.1
4.2
5
Butadiene
3.4
5.1
3.0
2.7
3.7
3.1
3.5
31.1
29.7
33.2
28.6
34.1
26.0
30.3
3.7
5.3
2.6
3.2
3.8
3.3
3.5
30.4
29.2
33.1
27.9
34.6
23.7
29.2
Therefore, these conformations were used for the computational
studies.
2.2. General experimental details
data: IR (KBr)
m
(cmꢀ1): 1343, 1534, 1717; 1H NMR (300 MHz,
NMR spectra were recorded at 298 K in CDCl3, using TMS as the
internal standard. GC–MS analyses were performed in an instru-
ment equipped with a 100% polydimethylsiloxane column. IR spec-
tra were recorded from KBr pellets (as in the case of solids) and
from thin films over KBr disks (as in the case of liquids). Silica
gel (70–230 mesh) and alumina (150 mesh) were used for chroma-
tography. The reaction solvent (benzene) was first dried over cal-
cium chloride and then, over sodium wires. Finally, it was
refluxed over metallic sodium for some days immediately before
use. Diazomethane (in ether) was prepared in situ starting from
N-nitroso-N-methylurea [27], this precursor was synthesized from
urea and methylamine following the literature methods [28].
CDCl3) d (ppm): 8.28 (1H, d, J = 1.8 Hz), 8.24 (1H, d, J = 1.8 Hz),
3.91 (3H, s); 13C NMR (200 MHz, CDCl3) d (ppm): 51.6, 131.3,
134.8, 142.7, 153.2, 160.0; MS (EI) m/z 187 (M+), 156 (100), 141,
110, 82.
Dienes 1 and 3 are commercially available [31], whereas diene 4
was prepared following the procedure proposed by Oppolzer et al.
[32] without isolation of the imine intermediate, and with subse-
quent purification by column chromatography over silica gel using
hexane/ethyl acetate [33,34].
The DA reactions were performed under conditions similar to
those reported for nitronaphthalenes [33,35]. The reaction temper-
ature was 160 °C using benzene as solvent. The molar diene/dieno-
phile ratio was 2:1 for 1; 2.5:1 for 4 and 6:1 for 3.
General procedure for the thermal DA reactions: All reactions
were carried out in oven-dried glassware. An ampoule containing
a solution of 1.0 mmol of the dienophile and the required amount
of the diene in 0.5 mL of dry benzene was cooled in liquid nitrogen,
sealed and heated in an oil bath. After completion of the reaction, it
was cooled once more in liquid nitrogen and opened. The solvent
was evaporated in vacuo to give the crude product, which was sub-
jected to TLC and GC–MS spectrometry. For the case in which the
reaction yield was moderate (i.e. DA reaction between 10 and 1),
column chromatography and NMR analysis were also performed.
Methyl benzo[b]thiophene-3-carboxylate (27). Detected by GC–
MS of the reaction crude. MS (EI) m/z: 192 (M+), 177, 161, 133,
45, 89.
2.3. Synthetic procedure
Compound 10 was prepared by a sequence of reactions starting
from the commercially available 3-thiophenecarboxylic acid [29].
First of all, a derivatization reaction employing diazomethane
was done in order to obtain the methyl ester. Since ester substitu-
ents deactivate the aromatic rings towards electrophilic substitu-
tion reactions, fumic nitric acid in acetic anhydride was
employed to nitrate the heterocyclic compound.
2.4. Methyl 5-nitro-3-thiophenecarboxylate (10)
An ethereal solution of diazomethane (prepared by literature
methods) [27] was slowly added to a cold mixture of 3-thiophen-
ecarboxylic acid (5.0 g, 39 mmol) in ether (10 mL) (caution: diazo-
methane is explosive and highly toxic. Avoid using sharp
materials). When the evolution of the nitrogen liberated in the
reaction finished and the excess of diazomethane was noted (yel-
low color), no more diazomethane was added. The reaction mix-
ture was stirred for 2 h in an ice-water bath and for 2 h at room
temperature to insure complete reaction. The solution was filtered
and the ether and excess of diazomethane were evaporated under
reduced pressure. The viscous residue was dissolved in dichloro-
methane and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated to give an oil. The complete disappear-
ance of the substrate was checked by silica gel TLC. In the TLC plate
the product was visualized by UV light and also by p-dimethylami-
nobenzaldehyde solution [30] (color of the spot: reddish); Rf (hex-
Methyl 7-(N-propylacetamido)-4,7-dihydrobenzo[b]thiophene -3-
carboxylate (25). Detected by GC–MS of the reaction crude. MS
(EI) m/z: 293 (M+), 278, 262, 250, 218, 193.
Methyl 5-hydroxybenzo[b]thiophene-3-carboxylate (28). Detected
by GC–MS of the reaction crude. MS (EI) m/z: 208 (M+), 193, 179,
178, 177, 149. Column chromatography over alumina (hexane/
ethyl acetate mixtures) of the crude product gave 28 (42%). IR
(KBr)
m
(cmꢀ1): 3369 (br), 1712, 1358; 1H NMR (300 MHz, CDCl3)
d (ppm): 3.96 (3H, s), 5.91 (1H, br s), 7.03 (1H, dd, J = 8.4, 2.4 Hz),
7.72 (1H, d, J = 8.4 Hz), 8.13 (1H, d, J = 2.4 Hz), 8.39 (1H, s); 13C
NMR (200 MHz, CDCl3) d (ppm): 51.9, 109.6, 115.3, 123.4, 126.1,
132.2, 138.1, 138.2, 154.5, 163.6.
3. Results and discussion
ane/ethyl acetate 2:1) = 0.72. Identification data: IR (KBr)
m
(cmꢀ1):
3.1. Selection of the dienes and dienophiles
1718, 1352; 1H NMR (300 MHz, Cl3CD) d (ppm): 8.10 (dd, 1H,
J = 3.0, 1.2 Hz), 7.52 (dd, 1H, J = 5.1, 1.2 Hz), 7.30 (dd, 1H, J = 5.1,
3.1 Hz); 3.87 (s, 3H). 13C NMR (200 MHz, Cl3CD) d (ppm): 163.2,
132.6, 130.8, 128.8, 127.8, 52.8.
Thiophene derivatives were chosen in view of examining its
reactivity towards electron-rich 1,3-butadienes. Therefore, in order
to test the efficacy of this kind of compounds to undergo DA

R. Brasca et al. / Journal of Molecular Structure 1010 (2012) 158–168
161
reactions, the following dienes (Fig. 2), commonly used in polar DA
reactions, were selected.
For that reason (lacking a H atom neighboring the NO2 group)
and/or low electrophilicity, compounds 8 and 11–19 are discarded.
On the other hand, thiophenes 6, 7, 9 and 10 are potential can-
didates to act as electrophiles in polar DA reactions. Due to dissim-
ilar positional relation of the substituents in these compounds, two
classes of benzo[b]thiophenes will be obtained after nitrous acid
elimination and aromatization from the cycloadducts (i.e. 2-substi-
tuted and 3-substituted benzo[b]thiophenes). The substitution pat-
tern that could allow the construction of simple 3-substituted
benzo[b]thiophenes, which have important applications [4,55,56]
is the one displayed in compound 10 (Fig. 3). In contrast, the other
3 dienophiles could allow obtaining the basic benzo[b]thiophene
skeleton that is part of more complex structures in which the 2
position is substituted by different groups (Fig. 4) [57–59].
Considering Figs. 3 and 4, we decided to analyze compound 10
that allows obtaining the heterocyclic structure of simple
benzo[b]thiophenes through DA reactions and then, just by means
of functional group transformations on the methyl ester fragment,
important compounds could be obtained in a simple way. On the
other hand, the compounds depicted in Fig. 4 are more complex
in structure. Hence, not only functional group transformations will
be required in the synthetic strategies.
So, compound 10 was chosen to be investigated in polar DA
reactions with a variety of dienes. This substitution pattern is suit-
able in order to guarantee a good electrophilic behavior of the die-
nophile and to allow the aromatization process to take place.
Moreover, this dienophile can be easily synthesized starting with
the carboxylic ester or with the carboxylic acid (both commercially
available).
Considering the substitution pattern of the reacting pairs (i.e.
dienes with electron-releasing groups and dienophile with elec-
tron-withdrawing groups), it can be clearly seen that these DA
reactions have a polar nature [15b], in which the thiophene deriv-
ative acts as a strong electrophile, and the dienes as strong nucle-
ophiles. In fact, the dienophile, with an electrophilicity power of
2.84 eV, can be classified as a strong electrophile within the scale
of electrophilicity proposed by Domingo et al. [40], and the dienes
(N = 3.67–4.31 eV, Table 3, Fig. 5) can be classified as strong nucle-
ophiles [18].
They have been demonstrated to undergo DA reactions with a
wide range of dienophiles with complete regiocontrol [36].
Another feature that makes them especially useful in organic syn-
thesis is the possibility to obtain aromatic products under certain
experimental conditions, by losing the substituents that are ini-
tially placed in strategic positions of the 1,3-butadiene system
and in the dienophile as well (Scheme 1) [33,37].
1-N-acylamino-1,3-butadienes are very convenient synthetic
equivalents for the parent 1-amino-1,3-butadienes. These elec-
tron-rich dieneamides undergo DA reactions with high regio- and
stereoselectivity [38].
The electrophilic activation of the thiophene ring towards DA
reactions can be achieved by the incorporation of electron-with-
drawing substituents. Since nitro is one of the most powerful elec-
tron-withdrawing groups, it is an opportune substituent to induce
polar DA reaction towards electrophilic activation of the
p system
to which it is directly attached. Therefore, substitutions with a ni-
tro group exclusively and in combination with other electron-
withdrawing substituents were considered.
The substitution patterns concerning the dienophile were cho-
sen based on published synthetic procedures and commercial
availability (Refs. [41–54] in Table 2). Nitroethylene, a well known
powerful dienophile is included in Table 2 as a reference dieno-
phile [39,40]. Thiophene is also considered in order to do
comparisons.
As expected, the substitution of one hydrogen atom in the thi-
ophene ring (20) by one nitro group increases the electrophilicity
character. A larger effect is found in the 2-nitro-substituted hetero-
cycle (13) compared with the 3-nitro-substituted derivative (18).
The disubstitutions considered in Table 2 are also suitable in order
to enhance the reactivity of the dienophiles.
The thiophene rings substituted with two different electron-
withdrawing groups (i.e. methyl carboxylate/cyano/bromine and
nitro at C2) show the highest values in electrophilicity power
(x = 2.83–3.65 eV). Consequently, these strong electrophiles are
tentatively considered as possible dienophiles.
It is important to notice that subsequent HNO2 elimination from
the cycloadducts is necessary to promote aromatization. This step
requires an H atom as neighbor to the NO2 (i.e. adjacent to the
nitro-substituted carbon of the thiophene ring). Therefore,
substitution by two groups in adjacent positions (e.g. C2 and C3
or C4 and C5) will prevent subsequent aromatization of the
cycloadducts.
On the other hand, the electronic chemical potential of the
diene series (Table 3) is higher than that of the dienophile
(ꢀ5.23 eV), thereby suggesting that the net charge transfer will
take place from the diene towards the thiophene derivative. This
also indicates that the dienes will more likely behave as electron
donor species (i.e. as nucleophile).
Fig. 2. Selected 1,3-butadienes.

162
R. Brasca et al. / Journal of Molecular Structure 1010 (2012) 158–168
Scheme 1. Aromatization of the cycloadduct in the thermal DA reaction between 1-nitronaphthalene and 1-methoxy-3-trimethylsiloxy-1,3-butadiene [33].
Table 2
B3LYP/6-31G(d) calculated global reactivity indexes, electronic chemical potential
l
, chemical hardness
g
, and electrophilicity
x
, for the considered dienophiles.
Molecule
Global properties (eV)
l
g
x
Methyl 2-cyano-5-nitrothiophene [41] (6)
Methyl 5-nitrothiophene-2-carboxylate [42] (7)
Methyl 2-nitrothiophene-3-carboxylate [43] (8)
2-Bromo-5-nitrothiophene [44] (9)
Methyl 5-nitrothiophene-3-carboxylate [45] (10)
2-Nitro-3-bromothiophene [46] (11)
ꢀ5.66
ꢀ5.34
ꢀ5.19
ꢀ5.02
ꢀ5.23
ꢀ5.06
ꢀ5.04
ꢀ4.90
ꢀ5.09
ꢀ5.33
ꢀ4.86
ꢀ4.84
ꢀ4.88
ꢀ4.62
ꢀ4.08
4.39
4.50
4.61
4.32
4.81
4.51
4.70
4.62
4.98
5.44
4.70
4.83
4.95
4.78
4.35
3.65
3.16
2.92
2.91
2.84
2.83
2.70
2.66
2.60
2.61
2.51
2.42
2.40
2.23
2.07
Methyl 3-nitrothiophene-2-carboxylate [47] (12)
2-Nitrothiophene [48,49] (13)
Methyl 4-nitrothiophene-2-carboxylate [50] (14)
Nitroethylene [40] (reference dienophile) (15)
2-Nitro-3-methylthiophene [51] (16)
Methyl 4-nitro-5-methylthiophene-2-carboxylate [52] (17)
3-Nitrothiophene [48,53] (18)
2-Methyl-3-nitrothiophene [54] (19)
Thiophene (20)
Fig. 3. Construction of simple benzo[b]thiophenes through functional group transformations on the expected DA reaction products. R1 is any group coming from the diene.
R2 = F; Amine is piperazine and Ar is 1-naphthyl. R = alkyl, cycloalkyl, aryl.
As can be seen, the structural and electronic effects induced by
the chemical substitution on the butadiene system produce differ-
ent responses in the electrophilicity and nucleophilicity power. In
fact, different trends are obtained regarding these two properties.
For example, when analyzing the nucleophilicity index (Table 3),
butadiene is suggested to be the poorest nucleophile as expected,
whereas dieneamide 4.2 (N = 3.71 eV) is predicted to be a strong
nucleophile when analyzing the nucleophilicity scale [18].
In order to characterize the nature of the DA reactions involving
the dienophile 10, the polarity of the process was assessed compar-
ing the electrophilicity index of the diene/dienophile interacting
pairs [40,60]. The marked differences in electrophilicity power be-
tween the thiophene derivative and the diene series (1.70–2.29 eV)
indicate the polar character of these reactions. Moreover, for the
pairs dienophile/Danishefsky’s diene, dienophile/dieneamine and
dienophile/Rawal’s diene a higher regioselectivity is indicated
On the other hand, dienes 1, 2 and 5 are predicted to be good
(D
x
= 2.16, 2.24 and 2.29 eV, respectively, compared with 1.70–
nucleophiles using both scales (low
x value and high N value).
2.11 eV for the other dienes) [17a].

R. Brasca et al. / Journal of Molecular Structure 1010 (2012) 158–168
163
Fig. 4. Construction of complex benzo[b]thiophenes. R1 is any group coming from the diene. R2 = CO2Me, CN, Br.
Table 3
functions, the local indexes account properly for the observed reg-
ioselectivity in all the analyzed cases.
B3LYP/6-31G(d). Global properties such as
polarizability, in a.u.
l, g, x and N are shown in eV and
Methyl 5-nitrothiophene-3-carboxylate (10) displays the high-
est electrophilic activation at C4 for all levels of theory (Table 4).
In contrast, analysis of the regional Fukui function for this dieno-
phile in gas-phase reveals a different reactivity tendency depend-
ing on the basis set used (Table S1, Supplementary material).
Diene
l
g
x
N
hai
5
2
ꢀ2.41
ꢀ2.36
ꢀ2.69
ꢀ3.33
ꢀ2.79
ꢀ3.01
ꢀ3.45
4.83
5.08
5.33
4.85
5.33
4.80
5.67
0.60
0.55
0.68
1.14
0.73
0.94
1.05
4.31
4.22
3.77
3.71
3.67
3.59
2.83
78.05
164.79
116.08
111.86
101.16
112.47
41.12
1
4.2a
0
All dienes show their maximum nucleophilicity value at the C4
3
site regardless of the media (gas phase/benzene) or the level of the-
ory (Table 5, see also Tables S2–S4 of Supplementary material).
Hence, in the case of the thiophene derivative the preferred
addition is to the nitro-substituted double bond. The nitro group,
as a stronger electron-withdrawing moiety than the ester substitu-
ent, acts as a regiodirector orienting the DA reaction towards the
double bond to which it is directly attached. As a result, the cyc-
4.1a
Butadiene
a
Four conformations were analyzed for this dieneamide (Fig. 5). The pair of
conformers in which the propyl substituent is at the same side of the conjugated
system (i.e. 4.1 and 4.2) have the lowest relative energy (B3LYP/6-31G(d) + ZPE:
D
E = 0.96 kcal molꢀ1). Therefore, these two conformers are considered thereafter.
0
loadduct resulting from the C4 (dienophile)–C4 (diene) interaction
is expected to be formed.
3.2. Identification of reactive sites on the dienophile and dienes
Taking into consideration the large difference in the values of
To identify the most reactive site of the dienophile and dienes,
0
0
NC1 and NC4 for dienes 1 and 4 (Table 5), a good regiocontrol is
likely for the DA reactions involving these dienes. However, due
to the substitution pattern of both dienes, the expected products
will have similar substituents in the same positions of the
benzo[b]thiophene ring (i.e. CO2Me at C3 and OH at C5 for the prod-
uct originated with diene 1, and CO2Me at C3 and OTBS at C5 for the
product of the reaction with diene 2) [62]. Moreover, diene 2 has to
be synthesized [63] whereas diene 1 is commercially available
[31]. Therefore, for simplicity we chose Danishefsky’s diene as an
electron-rich component (Table 3) in order to continue with this
investigation.
0
the Fukui functions at C2, C3, C4, and C5 of the dienophile; and C1
0
and C4 of the dienes as well as local electrophilicity and nucleophi-
licity indexes derived therefrom, were evaluated [17a].
The results obtained from solvent calculations are gathered in
Tables 4 and 5 (see Fig. 2 for atom numbering). The highest local
electrophilicity (nucleophilicity) value for the dienophile (dienes)
is in bold. The results for gas-phase calculations are included in
Supplementary Material.
Different levels of theory were included based on preliminary
studies concerning DA reactions between furan derivatives and
Danishefsky’s diene [61]. There it was found that only when the
LANL2DZ basis set is used (at HF or B3LYP levels) and the solvent
(benzene, CPCM) is considered in the calculations of regional Fukui
Several dieneamines were demonstrated to be unstable under
thermal conditions when they were tested with a variety of
dienophiles, preventing the DA reaction [64]. For this reason the
Fig. 5. Different conformers for the dieneamide 4. Relative energies (kcal molꢀ1):
E (4.4) = 3.8 (gas-phase) and 3.3 (benzene).
DE (4.2) = 1.0 (gas-phase) and 0.6 (benzene), DE (4.3) = 2.4 (gas-phase) and 2.0 (benzene),
D

164
R. Brasca et al. / Journal of Molecular Structure 1010 (2012) 158–168
Table 4
Generally, the effect of the solvent benzene as obtained by
CPCM single-point calculations leads to a preferential stabilization
of the reactants and transition states with a concomitant decrease
Local electrophilicity values for the dienophile (benzene, CPCM). Levels of theory:
B3LYP/6-31G(d); B3LYP/LANL2DZ; HF/LANL2DZ.
Molecule
Site k
xk (eV)
of
D
Ereact (Tables S5 and S6, Supplementary material).
On the other hand, an increase of the reaction barriers is ob-
served when considering entropic corrections (Table 6,
Gꢁact). It
is also clear tꢁhat the formation of all the cycloadducts is endergonic
(Table 6, Greac). In spite of these main differences between ZPE
2
3
4
0.42; 0.42; 0.23
0.01; 0.00; 0.01
0.43; 0.50; 0.24
D
D
10
5
0.11; 0.07; 0.06
corrected energies and Gibbs free energies, the general conclusion
for each diene/dienophile pair is the same as the one obtained by
analyzing the energetic data.
The incorporation of the corresponding thermal corrections in-
Table 5
creases the relative free energies (Table 6,
values in brackets). Moreover, the formation of all the cycloadducts
is endergonic by 8–19 kcal molꢀ1 (Table 6, Grꢁeac, see the values in
D D
Gꢁact and Gꢁreac, see the
Local nucleophilicity values for dienes 1–5 (benzene, CPCM). Levels of theory: B3LYP/
6-31G(d); B3LYP/LANL2DZ; HF/LANL2DZ.
D
Diene
Site k
Nk (eV)
brackets). Nevertheless, the expected aromatization of the cycload-
ducts (i.e. HNO2 elimination) should lead to considerably more sta-
ble products (see Section 3.4).
161
10
40
10
40
10
40
10
40
10
40
10
40
0.51; 0.51; 0.66
1.33; 1.31; 1.29
0.37; 0.33; 0.50
1.07; 1.08; 1.18
0.73; 0.73; 0.88
0.90; 0.89; 0.98
0.49; 0.49; 0.68
0.78; 0.77; 0.87
0.56; 0.56; 0.75
0.83; 0.82; 0.95
0.47; 0.43; 0.66
1.00; 1.01; 1.10
2
The ꢁreasons fꢁor the deꢁcrease in the Gibbs free energy barriers
3
(i.e.
DG10þ1
<
DG10þ4
< DG10þ3) when comparing the four favorable
reactions (Table 6, in bold) may derive from the fact that diene 1
has the largest polarizability (Table 3) which favors the electronic
transfer between the two partners (i.e. transfer of charge from do-
nor diene to acceptor dienophile). Moreover, this diene has a con-
venient substitution pattern that cause a synergic increase in the
4.1
4.2
5
0
nucleophilic character of C4 (Table 5) and a good nucleophilicity
power (Table 3).
According to the observed trend in
D
Gꢁact values, it is expected
that the DA reaction between 10 and diene 1 is more favorable
than with diene 3. The formation of the cycloadduct generated
by the reaction of 10 + 3 is kinetically very unfavorable.
As a complement of the theoretical study, in order to corrobo-
rate this predicted trend, we performed the corresponding thermal
reactions. The experimental results are presented and discussed
below.
dieneamine 5 is discarded in spite of being an activated nucleo-
phile (Table 3).
Finally, dienes 3 and 4 are chosen as moderately activated com-
ponents towards polar DA reactions.
3.3. Mechanism of the DA reactions
The mechanistic aspects of the DA reactions that are initialized
0
by the nucleophilic attack of C4 of the diene to C4 of the dienophile
3.4. Experimental verification
will be considered in detail. For each reaction, two stereoisomeric
channels are feasible (endo and exo, with respect to nitro). The
possible modes of addition are depicted in Scheme 2 .
In the three reactions studied here, 10 + 1, 10 + 4, and 10 + 3,
the attack by the diene occurs at the C4–C5 double bond of the
thiophene ring in accordance with the results based on the local in-
dexes. Thermal extrusion of the nitro group from the cycloadducts
and the formation of aromatic products took place during the
reaction time (Scheme 3). The isolation of the nitro-substituted
cycloadduct could not be achieved under the reaction conditions
used.
For the thermal reaction between 10 and 3, only traces of the
aromatic product 28 (i.e. methyl benzo[b]thiophene-3-carboxyl-
ate), which was originated from the DA cycloadduct, were experi-
mentally detected by GC–MS of the reaction crude (Scheme 3).
On the other hand, diene 4 afforded a dihydrobenzo[b]thio-
phene derivative in very low yield. Based on the local indexes
analysis, the expected product in this reaction is methyl 7-(N-
propylacetamido)-4,7-dihydrobenzo[b]thiophene-3-carboxylate 26.
Traces of an aromatic compound originated from the DA cycload-
duct (i.e. methyl benzo[b]thiophene-3-carboxylate 28) were also
detected by GC–MS of the reaction crude (Scheme 3).
Finally, according to the theoretical predictions described
above, the DA reaction of 10 with the highly functionalized diene
1 gave the aromatic alcohol 27, originated from the DA cycload-
duct, in moderate yield (42%). In this case, the DA cycloadduct lost
the nitro group as nitrous acid (21 ? 24, Scheme 3) followed by
hydrolysis of the silyl group and methanol elimination, giving the
corresponding aromatic product during the reaction time
(24 ? 27, Scheme 3). A completely similar behavior was also
The calculations show that both TS are highly asymmetric
(
D
rendo = 1.19 Å and
1.07 Å for 4.1; rendo = 1.04 Å and
1.15 Å and
D
rexo = 1.03 Å for 3;
D
rendo = 1.21 Å and
D
rendo
rexo
=
=
D
D
rexo = 0.99 Å for 4.2; D
D
rexo = 1.22 Å for 1) [65]. In all the cases, the formation
0
of one of the new sigma bonds (i.e. C4 of the diene and C4 of the
dienophile) is more advanced because it involves the interaction
between the most nucleophilic and electrophilic sites of the
reactive pair diene/dienophile. The TS structures for both channels
are shown in Fig. 6.
Domingo et al. suggested to denote reactions that proceed in a
single kinetic step through highly asynchronous TSs as two-stage
one-step mechanisms [66].
Calculated activation and reaction energies including ZPE cor-
rections in benzene as solvent are summarized in Table 6 (
DEact
and Ereact). The values at 433 K (the temperature used in the ac-
D
tual syntheses) are similar to those obtained at 298 K. In two cases
(reactions with 3 and 4.2) the endo-stereoisomer is preferentially
formed (channel 1), being the activation energies lower than for
the exo-addition. In contrast, with diene 4.1 the exo approach is fa-
vored over the endo. For the reaction with 1 a quite small differ-
ence is found between the endo and exo reaction barriers
suggesting that both mechanisms could be operating in this case.
Except for the reaction between 10 and the dieneamide (i.e. 4.1
and 4.2), the exo-cycloadducts are more stable than the endo
products.

R. Brasca et al. / Journal of Molecular Structure 1010 (2012) 158–168
165
Scheme 2. Possible modes of addition that involve the participation of the reactive sites indicated by the local indexes in the DA process.
Table 6
Energetic and thermodynamic results at 298 K (433 K). B3LYP/6-31G(d), benzene, SP/
CPCM. The data is organized in ascending order of DGꢁact values.
ꢁ
ꢁ
DGreac
a
a
Diene
Mode
D
Eact
DEreac
D
Gact
1
Endo
Exo
Endo
Exo
Endo
Exo
Endo
Exo
15.5
15.7
20.1
17.9
17.7
19.7
19.6
21.6
ꢀ9.1
ꢀ10.5
ꢀ3.0
28.9 (35.2)
28.9 (35.1)
32.7 (38.3)
30.3 (36.2)
30.7 (36.8)
32.4 (38.3)
32.1 (38.0)
33.9 (39.7)
4.3 (10.8)
2.4 (8.5)
4.1
4.2
3
10.8 (17.4)
12.2 (18.7)
7.5 (14.1)
9.4 (15.9)
4.4 (10.7)
3.4 (10.2)
ꢀ1.3
ꢀ6.2
ꢀ4.1
ꢀ8.5
ꢀ10.5
a
Standard state conversion from gas-phase to solution-phase for a DA reaction:
D
Giꢁ
¼
D
Goi ꢀ X. The subscript i stands for act or reac; the superscript open circle
indicates the use of a standard-state gas-phase pressure of 1 atm and the correction
factor X is equal to 1.9 and 2.8 kcal molꢀ1 at 298 and 433 K, respectively.
DFT methods and it was shown that the elimination step, leading
to stable elimination products (
6-31(G)d level, relative to the reactive pair), was the responsible
factor for the feasibility of the overall process [68].
D
Gꢁreac ꢃ ꢀ22kcal molꢀ1 at B3LYP/
Therefore, in an analogous manner to the reactions involving
nitropyrroles, nitroselenophenes and nitrofurans under thermal
conditions, elimination of HNO2 from the DA cycloadducts and
conversion of the elimination products into benzo[b]thiophene
derivatives contribute to the overall domino processes (Scheme 3)
that are initialized by nucleophilic attacks of electron-rich dienes
to the electron-deficient dienophiles in polar DA reactions, with
two-stage one-step mechanisms [66].
For the reliable DA reaction to synthesize benzo[b]thiophene
derivatives under thermal conditions (i.e. 10 and 1), the reaction
product was characterized (see experimental section) and the reg-
iochemistry was elucidated. The obtained result is in agreement
with the theoretical outcome (Scheme 3) that predicts the reaction
to take place regiospecifically at the nitro substituted C@C double
bond.
Fig. 6. Optimized TS structures.
As shown in Fig. 3, the benzo[b]thiophene system could be sub-
sequently manipulated, thus extending its utility in synthesis.
Moreover, the ester is a versatile unit because of the large variety
of chemical transformations it allows on the reaction products.
observed in a variety of other DA reactions with the same diene
[6a,6c,33,67].
For comparable DA reactions using nitropyrroles [6a], nitrose-
lenophenes [6b] and nitrofurans [6c] with substituted 1,3-butadi-
enes, it was experimentally demonstrated that the nitrated
cycloadducts suffered cis-extrusion of the nitro group as nitrous
acid and subsequent aromatization. Moreover, the mechanism for
the reactions involving nitrofurans was fully characterized using
The tendency concerning the
D
Gꢁact values that was established
previously (Table 6) is in agreement with the experimental results
shown here (i.e. the highest yield was obtained for the reaction
which was calculated to be kinetically favored and only traces of
the product were detected in the kinetically disfavored reaction).

166
R. Brasca et al. / Journal of Molecular Structure 1010 (2012) 158–168
Scheme 3. These results are based on DFT computations and experimental work.
3.5. Summary of methodology
4. Conclusion
We showed how DFT methods can help in the work of synthetic
organic chemists in order to plan a certain reaction (polar DA reac-
tion in this case) considering a variety of available reagents. The
suggested procedure consists of the following steps:
A variety of synthetically and commercially available nitrothi-
ophenes were proposed as strong electrophiles in order to partici-
pate in polar DA reactions. The series was analyzed in detail with
the aim of selecting a potential dienophilic candidate.
The reactive counterparts which consist of a variety of dienes
substituted with electron-releasing groups were also investigated
using DFT-based indexes.
The feasibility of methyl 5-nitrothiophene-3-carboxylate (10) to
act as electrophile in polar DA reactions towards the electron-rich
dienes 1, 3 and 4 was established using the TS framework and cor-
roborated in an experimental way.
(1) Analyze the global DFT-based indexes (i.e.
x and N) taking
into consideration that the reaction feasibility depends on
the electrophilic and nucleophilic character of the reacting
pairs. The best combinations are between strong electro-
philes and strong nucleophiles.
(2) Pre-select the most promising electrophile/nucleophile pairs
and analyze the local DFT-based indexes (i.e. xk and Nk) in
order to predict the regiochemistry of the cycloadduct. Here
it will be possible to discard the reagents that do not provide
the required regioisomer.
The global properties of the diene/dienophile pairs illustrate the
polar character of the DA reactions.
It was found that the attack of the dienes should take place at the
nitro substituted double bond of the dienophile to give the DA cyc-
loadducts. The use of a high nucleophilically activated diene and an
electron-deficient dienophile (i.e. 1 and 10) should allow the reac-
tion to proceed with a total regiocontrol, as indicated by the local
nucleophilicity index and the difference in electrophilicity power.
Danishefsky’s diene (1) is indicated to be the most reactive
diene of the series, being the feasibility of the polar reaction with
10 the most favorable. In a kinetically controlled reaction this
cycloaddition should proceed through both channels (i.e. endo
and exo) because there is no difference between the barriers asso-
ciated to the cycloadduct formation in benzene at 433 K. The reac-
tion mechanism is two-stage one-step which proceeds through a
highly asynchronous TS.
(3) Once the potential reactive pairs are selected (at this point
the list of reagents is probable more reduced than the initial
one), a final selection can be done by using thermodynamic
criterions based on TS computations (i.e. the reactions with
the lowest
D
Gꢁact values are preferred in this step).
(4) The last part consists of carrying out the reactions that were
indicated to be promising in the previous step.
This methodology is not only limited to the rational selection of
reacting pairs in polar DA reactions, it can also be used to explain
experimental tendencies and get insights into the reaction
mechanisms.

R. Brasca et al. / Journal of Molecular Structure 1010 (2012) 158–168
167
[9] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman,
J.A. Montgomery Jr., T. Vreven, K. N. Kudin, J.C. Burant, J.M. Millam, S.S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G.A. Petersson,
H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J.E. Knox, H.P. Hratchian,
J.B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A. J.
Austin, R. Cammi, C. Pomelli, J.W. Ochterski, P.Y. Ayala, K. Morokuma, G.A.
Voth, P. Salvador, J.J. Dannenberg, V.G. Zakrzewski, S. Dapprich, A.D. Daniels,
M.C. Strain, O. Farkas, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman,
J.V. Ortiz, Q. Cui, A.G. Baboul, S. Clifford, J. Cioslowski, B.B. Stefanov, G. Liu, A.
Liashenko, P. Piskorz, I. Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-
Laham, C.Y. Peng, A. Nanayakkara, M. Challacombe, P.M.W. Gill, B. Johnson, W.
Chen, M.W. Wong, C. Gonzalez, J.A. Pople, Gaussian 03, Revision B.04, Gaussian
Inc., Pittsburgh, PA, 2003.
All the computational predictions are in good agreement with
the experimental results.
Acknowledgments
R. Brasca thanks the European Commission for the Erasmus
Mundus External Cooperation Window (EMECW) Lot 16 Scholar-
ship and CONICET for the Doctoral Grant Programme.
We thank Dr. M.A. Romero (Instituto de Desarrollo Tecnológico
para la Industria Química, CONICET) for his help in computations.
[10] (a) J. Soto-Delgado, L.R. Domingo, R. Araya-Maturana, R. Contreras, J. Phys. Org.
Chem. 22 (2009) 578;
(b) C.N. Alves, A.S. Carneiro, J. Andrés, L.R. Domingo, Tetrahedron 62 (2006)
5502;
Appendix A. Supplementary material
(c) P. Arroyo, M.T. Picher, L.R. Domingo, F. Terrier, Tetrahedron 61 (2005) 7359;
(d) K. Geetha, T.C. Dinadayalane, G.N. Sastry, J. Phys. Org. Chem. 16 (2003) 298;
(e) R. Vijaya, T.C. Dinadayalane, G.N. Sastry, J. Mol. Struct. (Theochem) 589
(2002) 291;
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2011.11.050.
(f) L.R. Domingo, M.T. Picher, M.J. Aurell, J. Phys. Chem. A 103 (1999) 11425;
(g) L.R. Domingo, M. Arnó, J. Andrés, J. Am. Chem. Soc. 120 (1998) 1617;
(h) V. Branchadell, Int. J. Quantum Chem. 61 (1997) 381.
[11] C. Gonzalez, H.B. Schlegel, J. Phys. Chem. 94 (1990) 5523.
[12] J. Tomasi, M. Persico, Chem. Rev. 94 (1994) 2027.
[13] (a) A. Klamt, V. Jonas, T. Buerger, J.C.W. Lohrenz, J. Phys. Chem. A 102 (1998)
5074;
(b) A. Klamt, G. Schüürmann, J. Chem. Soc. Perkin Trans. 2 (1993) 799.
[14] (a) C.P. Kelly, C.J. Cramer, D.G. Truhlar, J. Phys. Chem. B 111 (2007) 408;
(b) M.A. Kastenholz, H. Hünenberger, J. Chem. Phys. 124 (2006) 224501/1–
224501/20;
References
[1] (a) H-F. Guo, H-Y. Shao, Z-Y. Yang, S-T. Xue, X. Li, Z-Y. Liu, X-B. He, J-D. Jiang,
Y-G. Zhang, S-Y. Si, Z.R. Li, J. Med. Chem 53 (2010) 1819;
(b) A.M. Isloor, B. Kalluraya, K.S. Pai, Eur. J. Med. Chem 45 (2010) 825;
(c) K. Ester, M. Hranjec, I. Piantanida, I. Caleta, I. Jarak, K. Pavelic, M. Kralj, G.
Karminski-Zamola, J. Med. Chem. 52 (2009) 2482;
(d) Z. Qin, I. Kastrati, R.E.P. Chandrasena, H. Liu, P. Yao, P.A. Petukhov, J.L.
Bolton, G.R.J. Thatcher, J. Med. Chem. 50 (2007) 2682;
(e) G.J. Cullinan, US patent 6 096 781, 2000;
(c) A. Ben-Naim, Solvation Thermodynamics, Plenum, New York, 1987.
[15] (a) P.K. Chattaraj, S. Giri, S. Duley, Chem. Rev. 111 (2011) PR43;
(b) L.R. Domingo, J.A. Sáez, Org. Biomol. Chem. 7 (2009) 3576;
(c) L.R. Domingo, P. Pérez, R. Contreras, Eur. J. Org. Chem. (2006) 498;
(d) S. Noorizadeh, H. Maihami, J. Mol. Struct. (Theochem) 763 (2006) 133;
(e) D.H. Ess, G.O. Jones, K.N. Houk, Adv. Synth. Catal. 348 (2006) 2337;
(f) P.K. Chattaraj, U. Sarkar, D.R. Roy, Chem. Rev. 106 (2006) 2065;
(g) L.R. Domingo, P. Pérez, R. Contreras, Lett. Org. Chem. 2 (2005) 68;
(h) P. Pérez, L.R. Domingo, M.J. Aurell, R. Contreras, Tetrahedron 59 (2003)
3117.
[16] (a) R.G. Parr, W. Yang, Density Functional Theory of Atoms and Molecules,
Oxford University Press, UK, 1989;
(b) R.G. Parr, R.G. Pearson, J. Am. Chem. Soc. 105 (1983) 7512;
(c) R.G. Pearson, J. Am. Chem. Soc. 85 (1963) 3533.
[17] (a) L.R. Domingo, M.J. Aurell, P. Pérez, R. Contreras, J. Phys. Chem. A 106 (2002)
6871;
(f) D.J. Sall, J.A. Bastian, S.L. Briggs, J.A. Buben, N.Y. Chirgadze, D.K. Clawson,
M.L. Denney, D.D. Giera, D.S. Gifford-Moore, R.W. Harper, K.L. Hauser, V.J.
Klimkowski, T.J. Kohn, H-S. Lin, J.R. McCowan, A.D. Palkowitz, G.F. Smith, K.
Takeuchi, K.J. Thrasher, J.M. Tinsley, B.G. Utterback, S-C.B. Yan, M. Zhang, J.
Med. Chem. 40 (1997) 3489;
(g) L.J. Black, H.U. Bryant, G.J. Cullinan, US patent 5 482 949, 1996;
(h) T. Bosin, R.S. Bitner, T.M. Gadbois, V.C. Yu, S.S. Bowersox, US patent 5 462
949, 1995;
(i) A. Shafiee, M.A. Hedayati, M.M. Salimi, S.M. Faghihi, J. Pharm. Sci. 72 (1983)
198;
(j) C.D. Jones, US patent 4 418 068, 1983;
(k) C.D. Jones, T. Suarez, US patent 4 133 814, 1979;
(l) T.R. Bosin, E.E. Campaigne, Adv. Drug Res. 11 (1977) 191.
[2] (a) P.J. Kurtz, Pharmacol. Biochem. Behav. 6 (1977) 303;
(b) C.H. Williams, J.L. Casterline Jr., K.H. Jacobson, Toxicol. Appl. Pharm. 11
(1967) 302.
[3] (a) B. Ettinger, D.M. Black, B.H. Mitlak, R.K. Knickerbocker, T. Nickelsen, H.K.
Genant, C. Christiansen, P.D. Delmas, J.R. Zanchetta, J. Stakkestad, C.C. Glüer, K.
Krueger, F.J. Cohen, S. Eckert, K.E. Ensrud, L.V. Avioli, L. Lips, S.R. Cummings,
JAMA J. Am. Med. Assoc. 282 (1999) 637;
(b) P.D. Delmas, N.H. Bjarnason, B.H. Mitlak, A.C. Ravoux, A.S. Shah, W.J. Huster,
M. Draper, C.N. Christiansen, Engl. J. Med. 337 (1997) 1641;
(c) L.J. Black, M. Sato, E.R. Rowley, D.E. Magee, A. Bekele, D.C. Williams, G.J.
Cullinan, R. Bendele, R.F. Kauffman, W.R. Bensch, J. Clin. Invest. 93 (1994) 63.
[4] T. Eicher, S. Hauptmann, The Chemistry of Heterocycles: Structures, Reactions,
Synthesis and Applications, Wiley-VCH, New York, 2003.
[5] (a) T. Cordes, C. Elsner, T. Herzog, C. Hoppmann, T. Schadendorf, W. Summerer,
K. Rück-Braun, W. Zinth, Chem. Phys. 358 (2009) 103;
(b) L.R. Domingo, Tetrahedron 58 (2002) 3765;
(c) R.G. Parr, L. Von Szentpaly, S. Liu, J. Am. Chem. Soc. 121 (1999) 1922.
[18] (a) L.R. Domingo, E. Chamorro, P. Pérez, J. Org. Chem. 73 (2008) 4615;
(b) P. Jaramillo, L.R. Domingo, E. Chamorro, P. Pérez, J. Mol. Struct. (Theochem)
865 (2008) 68.
[19] H. Kurtz, D. Dudis, Quantum mechanical methods for predicting nonlinear
optical properties, in: K.B. Lipkowitz, D.B. Boyd (Eds.), Reviews in
Computational Chemistry, Wiley-VCH, New York, 1998.
[20] R.G. Parr, W. Yang, J. Am. Chem. Soc. 106 (1984) 4049.
[21] P. Fuentealba, P. Pérez, R. Contreras, J. Chem. Phys. 113 (2000) 2544.
[22] R.R. Contreras, P. Fuentealba, M. Galván, P. Pérez, Chem. Phys. Lett. 304 (1999)
405.
[23] P. Fuentealba, R.R. Contreras, Reviews of Modern Quantum Chemistry, World
Scientific, Singapore, 2002.
[24] We are very grateful to M. Bergallo and J. Bonazza (Departament of
Mathematics, Facultad de Ingeniería Química, Universidad Nacional del
Litoral) for providing us with the program which performed the required
calculations concerning the Fukui function.
(b) V.A. Bren, A.D. Dubonosov, L.L. Popova, V.P. Rybalkin, I.D. Sadekov, E.N.
Shepelenko, A.V. Tsukanov, ARKIVOC (2005) 60;
(c) M. Irie, K. Uchida, Bull. Chem. Soc. Jpn. 71 (1988) 985.
[6] (a) C. Della Rosa, M.N. Kneeteman, P.M.E. Mancini, Tetrahedron Lett. 48 (2007)
1435;
(b) C. Della Rosa, M.N. Kneeteman, P.M.E. Mancini, Tetrahedron Lett. 48 (2007)
7075;
(c) C. Della Rosa, C.M.N. Keeteman, P.M.E. Mancini, Tetrahedron Lett. 46 (2005)
8711;
[25] (a) E. Chamorro, P.K. Chattaraj, P. Fuentealba, J. Phys. Chem. A 107 (2003)
7068;
(b) P.K. Chattaraj, B. Maiti, U. Sarkar, J. Phys. Chem. A 107 (2003) 4973;
(c) P. Pérez, A. Toro-Labbé, A. Aizman, R. Contreras, J. Org. Chem. 67 (2002)
4747.
(d) C. Della Rosa, M.N. Kneeteman, P.M.E. Mancini, in: 9th International
Electronic Conference on Synthetic Organic Chemistry (ECSOC-9), 2005;
(e) G.W. Gribble, M.G. Saulnier, E.T. Pelkey, T.L.S. Kishbaugh, Y. Liu, J. Jiang, H.A.
Trujillo, D.J. Keavy, D.A. Davis, S.C. Conway, F.L. Switzer, S. Roy, R.A. Silva, J.A.
Obaza-Nutaitis, M.P. Sibi, N.V. Moskalev, T.C. Barden, L. Chang, W.N. Habeski, B.
Pelcman, W.R. Sponholtz, R.W. Chau, B.D. Allison, S.D. Garaas, M.S. Sinha, M.A.
McGowan, M.R. Reese, K.S. Harpp, Curr. Org. Chem. 9 (2005) 1493;
(f) T.L.S. Kishbaugh, G.W. Gribble, Tetrahedron Lett. 42 (2001) 4783.
[7] (a) E. Paredes, R. Brasca, M.N. Kneeteman, P.M.E. Mancini, Tetrahedron 63
(2007) 3790;
[26] (a) P. Pérez, L.R. Domingo, M. Duque-Noreña, E. Chamorro, J. Mol. Struct.
(Theochem) 895 (2009) 86;
(b) R. Contreras, J. Andres, V.S. Safont, P. Campodonico, J.G. Santos, J. Phys.
Chem. A 107 (2003) 5588.
´
[27] (a) A.I. Vogel, B.S. Furniss, Vogels Textbook of Practical Organic Chemistry, fifth
ed., Longman Scientific & Technical, England, 1989;
(b) F. Arndt, Org. Synth. 15 (1935) 3; Org. Synth. 2 (1943) 165 (Coll.).
[28] (a) L.I. Smith, Organic Reactions, vol. 1, John Wiley and Sons, Inc., New York,
1942;
(b) F. Arndt, Org. Synth. 15 (1935) 48; Org. Synth. 2 (1943) 461 (Coll.).
[29] Product Number: 247766; Sigma–Aldrich.
(b) A. Chrétien, I. Chataigner, S.R. Piettre, Chem. Commun. (2005) 1351;
(c) E. Wenkert, S. Piettre, J. Org. Chem. 53 (1988) 5850;
(d) E. Wenkert, P.D.R. Moeller, S.R. Piettre, J. Am. Chem. Soc. 110 (1988) 7188.
[8] (a) A.D. Becke, J. Chem. Phys. 98 (1993) 5648;
[30] (a) E. Stahl, Thin-Layer Chromatography: A Laboratory Handbook, Academic
Press, New York, 1965;
(b) A.D. Becke, Phys. Rev. A. 38 (1988) 3098;
(c) C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1988) 785.
(b) E. Stahl, U. Kaltenbach, J. Chromatogr. 5 (1961) 351.

168
R. Brasca et al. / Journal of Molecular Structure 1010 (2012) 158–168
[31] Product number: 227226 (1-trimethylsiloxy-1,3-butadiene), 212830 (1-
methoxy-3-trimethylsiloxy-1,3-butadiene); Sigma–Aldrich.
[32] (a) W. Oppolzer, L. Bieber, E. Francotte, Tetrahedron Lett. 11 (1979) 981;
(b) K. Taguchi, F.H. Westherimer, J. Org. Chem. 36 (1971) 1570;
(c) L.E. Overman, G.F. Taylor, P.J. Jessup, Tetrahedron Lett. 17 (1976) 3089;
(d) M. Petrzilka, J.I. Grayson, Synthesis (1981) 753.
[33] E. Paredes, B. Biolatto, M.N. Kneeteman, P.M.E. Mancini, Tetrahedron Lett. 41
(2000) 8079.
[34] B. Biolatto, M.N. Kneeteman, P.M.E. Mancini, Tetrahedron Lett. 40 (1999) 3343.
[35] E. Paredes, B. Biolatto, M.N. Kneeteman, P.M.E. Mancini, Tetrahedron Lett. 43
(2002) 4601.
[50] K.K. Venter, M.A. Trushule, V.P. Litvinov, É.G. Ostapenko, É.É. Liepinsh, Chem.
Heterocycl. Compd. 14 (1978) 490.
[51] (a) M.D. Threadgill, P. Webb, P. O’Neill, M.A. Naylor, M.A. Stephens, I.J.
Stratford, S. Cole, G.E. Adams, E.M. Fielden, J. Med. Chem. 34 (1991) 2112;
(b) I.J. Rinkes, Recl. Trav. Chim. Pays-Bas 52 (1933) 1052.
[52] E. Campaigne, H.G. Grose, J. Am. Chem. Soc. 73 (1951) 3812.
[53] J.M. Barker, P.R. Huddleston, M.L. Wood, Synth. Commun. 25 (1995) 3729.
[54] H.R. Snyder, L.A. Carpino, J.F. Zack Jr., J.F. Mills, J. Am. Chem. Soc. 79 (1957)
2556.
[55] A. Shafiee, M. Vossoghi, J. Wossooghi, S. Yazdani, J. Pharm. Sci. 70 (1981)
566.
[36] (a) S.A. Kozmin, M.T. Green, V.H. Rawal, J. Org. Chem. 64 (1999) 8045;
(b) F. Fringuelli, A. Taticchi, Dienes in the Diels–Alder Reaction, Wiley, New
York, 1990;
[56] S. Pérez-Silanes, L. Berrade, R.N. García–Sánchez, A. Mendoza, S. Galiano, B.M.
Pérez-Solórzano, J.J. Nogal-Ruiz, A.R. Martínez-Fernández, I. Aldana, A. Monge,
Molecules 14 (2009) 4120.
(c) B.M. Trost, W.C. Vladuchick, A.J. Bridges, J. Am. Chem. Soc. 102 (1980) 3554;
(d) L.E. Overman, G.F. Taylor, K.N. Houk, L.N. Domelsmith, J. Am. Chem. Soc.
100 (1978) 3182;
[57] (a) E. Israel, J. Cohn, L. Dubé, J.M. Drazen, J. Am. Med. Assoc. 275 (1996) 931;
(b) M.C. Liu, L.M. Dubé, J. Lancaster, J. Allergy Clin. Immunol. 98 (1996) 859.
[58] K. Koike, Z. Jia, T. Nikaido, Y. Liu, Y. Zha, D. Guo, Org. Lett. 1 (1999) 197.
[59] T.R. Kelly, Y. Fu, J.T. Sieglen Jr., H. De Silva, Org. Lett. 2 (2000) 2351.
[60] (a) A. Benmeddah, S.M. Mekellesche, W. Benchouk, B. Mostefa-Kara, D.
Villemin, J. Mol. Struct. (Theochem) 821 (2007) 42;
(e) S. Danishefsky, T. Kitahara, J. Org. Chem. 40 (1975) 538;
(f) P. Beslin, R. Bloch, G. Moinet, J.M. Conia, Bull. Soc. Chim. Fr. (1969) 508.
[37] (a) B.J.D. Wright, J. Hartung, F. Peng, R. Van de Water, H. Liu, Q-H. Tan, T-C.
Chou, S.J. Danishefsky, J. Am. Chem. Soc. 130 (2008) 16786;
(b) R.A. Tapia, A. Bau, C. Salas, Synth. Commun. 36 (2006) 771;
(c) J.A. Valderrama, C. Astudillo, R.A. Tapia, E. Prina, E. Estrabaud, R. Mahieux,
A. Fournet, Chem. Pharm. Bull. 50 (2002) 1215;
(b) P. Pérez, L.R. Domingo, A. Aizman, R.A. Contreras, in: A. Toro-Labbé (Ed.),
Theoretical Aspects of Chemical Reactivity, Elsevier Science, New York, 2006;
(c) P. Arroyo, M.T. Picher, L.R. Domingo, J. Mol. Struct. (Theochem) 709 (2004)
45.
(d) R.A. Tapia, C. Lizama, C. López, J.A. Valderrama, Synth. Commun. 31 (2001)
601;
[61] R. Brasca, M.N. Kneeteman, P.M.E. Mancini, W.M.F. Fabian, J. Mol. Struct.
(Theochem) 911 (2009) 124.
(e) J. Paquet, P. Brassard, Can. J. Chem. 67 (1989) 1354.
[38] (a) L.E. Overman, R.L. Freerks, C.B. Petty, L.A. Clizbe, R.K. Ono, G.F. Taylor, P.J.
Jessup, J. Am. Chem. Soc. 103 (1981) 2816;
[62] For similar cycloadditions that support this fact see: Ref. 6(a,b,c) and C. Della
Rosa, M.N. Kneeteman, P.M.E. Mancini, in: 13th International Electronic
Conference on Synthetic Organic Chemistry (ECSOC-13)
(b) L.E. Overman, C. Fukaya, J. Am. Chem. Soc. 102 (1980) 1454;
(c) W. Oppolzer, L. Bieber, E. Francotte, Tetrahedron Lett. 20 (1979) 4537;
(d) L.E. Overman, P.J. Jessup, J. Am. Chem. Soc. 100 (1978) 5179.
[39] D. Ranganathan, C.B. Rao, S. Ranganathan, A.K. Mehrotra, R. Iyengar, J. Org.
Chem. 45 (1980) 1185.
[40] L.R. Domingo, M. Aurell, R. Contreras, P. Pérez, Tetrahedron 58 (2002) 4417.
[41] Product number: 07517, Fluka.
[42] Product number (5-nitrothiophene-2-carboxylic acid): N6898, Sigma–Aldrich.
[43] H. Satonaka, Bull. Chem. Soc. Jpn. 56 (1983) 3337.
[63] S. Kozmin, S. He, V.H. Rawal, Org. Synth. 78 (2002) 152.
[64] B. Biolatto, M.N. Kneeteman, E. Paredes, P.M.E. Mancini, J. Org. Chem. 66 (2001)
3906.
[65]
D
r = (r1–r2) where: r1 is the C5–C10 distance and r2 is the C4–C40 distance.
[66] (a) L.R. Domingo, J.A. Sáez, R.J. Zaragozá, M. Arnó, J. Org. Chem. 73 (2008) 8791
(more references concerning two-stage mechanisms are: 15b);
(b) S. Berski, J. Andrés, B. Silvi, L.R. Domingo, J. Phys. Chem. A 110 (2006)
13939;
(c) L.R. Domingo, J. Org. Chem. 66 (2001) 3211;
[44] Product number: 544531, Sigma–Aldrich.
(d) M.J. Goldstein Jr., G.L. Thayer, J. Am. Chem. Soc. 87 (1965) 1933.
[67] (a) C.D. Donner, M. Gill, L.M. Tewierik, Molecules 9 (2004) 498;
(b) E.M. Beccalli, F. Clerici, M.L. Gelmi, Tetrahedron 59 (2003) 4615;
(c) Y. Motoyama, Y. Koga, H. Nishiyama, Tetrahedron 57 (2001) 853;
(d) S. Danishefsky, T. Kitahara, C.F. Yan, J. Morris, J. Am. Chem. Soc. 101 (1979)
6996;
(e) S. Danishefsky, T. Kitahara, J. Am. Chem. Soc. 96 (1974) 7807;
(f) S. Danishefsky, C.F. Yan, R.K. Singh, R.B. Gammill, P.M. McCurry Jr., N.
Fritsch, J. Clardy, J. Am. Chem. Soc. 101 (1979) 7001.
[68] R. Brasca, M.N. Kneeteman, P.M.E. Mancini, W.M.F. Fabian, Eur. J. Org. Chem.
(2010) 721.
[45] Product number: 645559 (methyl 3-thiophenecarboxylate), Sigma–Aldrich.
[46] A.R. Katritzky, E.F.V. Scriven, S. Majumder, R.G. Akhmedova, N.G. Akhmedov,
A.V. Vakulenko, ARKIVOC (2005) 179.
[47] S.A. Shackelford, M.B. Anderson, L.C. Christie, T. Goetzen, M.C. Guzman, M.A.
Hananel, W.D. Kornreich, H. Li, V.P. Pathak, A.K. Rabinovich, R.J. Rajapakse, L.K.
Truesdale, S.M. Tsank, H.N. Vazir, J. Org. Chem. 68 (2003) 267.
[48] S. Gronowitz, A-B. Hörnfeldt, Thiophenes: Best Synthetic Methods, Elsevier,
Academic Press, UK, 2004.
[49] V.S. Babasinian, Org. Synth. 14 (1934) 76;
V.S. Babasinian, Org. Synth. 2 (1943) 466 (Coll.).