Investigation into the regiochemistry of some pyrazoles derived from 1,3-dipolar cycloaddition of methyl methacrylate with some nitrilimines: A combined theoretical and experimental study

Article abstract of DOI:10.1002/cjoc.201190218

1,3-Dipolar cycloaddition between methyl methacrylate as dipolarophile and some nitrilimines which were generated in situ afforded the new pyrazoles. The regiochemistry and reactivity of these reactions has been investigated on the basis of density functi

Full text of DOI:10.1002/cjoc.201190218

FULL PAPER
Investigation into the Regiochemistry of Some Pyrazoles
Derived from 1,3-Dipolar Cycloaddition of Methyl Meth-
acrylate with Some Nitrilimines: A Combined
Theoretical and Experimental Study
Bakavoli, Mehdi
Moeinpour, Farid*
Davoodnia, Abolghasem
Morsali, Ali
Department of Chemistry, Islamic Azad University-Mashhad Branch, Mashhad, Iran
1,3-Dipolar cycloaddition between methyl methacrylate as dipolarophile and some nitrilimines which were
generated in situ afforded the new pyrazoles. The regiochemistry and reactivity of these reactions has been investi-
gated on the basis of density functional theory (DFT)-based reactivity indexes and activation energy calculations.
The theoretical 13C NMR chemical shifts of the cycloadducts which were obtained by GIAO method were compa-
rable with the observed values.
Keywords regioselectivity, cycloaddition, density functional calculations
Introduction
dipoles which were generated in situ by base treatment
of the corresponding hydrazonoyl chlorides 1a and 1b
in order to synthesize the new methyl 1-(4-bromo-
phenyl)-4-methyl-3-(4-nitrophenyl)-4,5-dihydro-1H-py-
razole-4-carboxylate (4a) and methyl 3-(4-chlorophenyl)-
4-methyl-1-(4-nitrophenyl)-4,5-dihydro-1H-pyrazole-4-
carboxylate (4b) (Scheme 1). In addition, we found it
worthwhile to analyze the regioselectivity of these
1,3-DC reactions by several theoretical approaches,
namely, activation energy calculations and DFT-based
reactivity indexes. Finally, the gauge-invariant atomic
orbital (GIAO) method9 was used to calculate NMR
chemical shifts, to help the experimental cycloadduct
determination, because it has shown to yield data com-
parable to those of the experiment.10
A useful simplification for the study of the regiose-
lectivity in reactions may be obtained by looking at
those processes having a markedly polar character,
where the transition structure associated with the
rate-determining step mostly involves the formation of
one single bond between the most electrophilic and
other nucleophilic sites. According to the model re-
cently proposed by Domingo,11,12 during an electro-
phile-nucleophile interaction process, when two reac-
tants approach each other from a large distance, they
feel only the effect of the global electrophilicity ω of
each other and not its local counterpart. The molecule
with the larger ω value will act as an electrophile, and
the other will be acting as the nucleophile. The preferred
interaction will be through the most electrophilic site of
the former and the most nucleophilic site of the latter.
Local philicity indexes (for definition, see computa-
The cycloaddition of 1,3-dipolar species to an alkene
for the synthesis of five-membered rings is a classic and
important reaction in organic chemistry.1 These 1,3-
dipolar cycloaddition (1,3-DC) reactions are used for
both academia and industrial purposes.2 These reactions
are one of the most important processes with both syn-
thetic and mechanistic interest in organic chemistry.
Current understanding of the underlying principles in
the Diels-Alder (DA) reactions and the 1,3-DCs has
grown from a fruitful interplay between theory and ex-
periment.2-4 Two major factors (i.e. the steric and elec-
tronic effects) can influence the regioselectivity of these
reactions.2 Although transition state theory remains the
most widely used and the most rigorous approach for
the study of the mechanism and the regiochemistry of
these reactions, the localization of transition states is not
always easy. Furthermore, transition state calculations
are often very time-consuming when bulky substituents
are present in reactive systems. Recently, reactivity de-
scriptors based on the density functional theory (DFT),
such as Fukui indexes, local softnesses and local elec-
trophilicity, have been extensively used for the predic-
tion of the regioselectivity. For instance, several treat-
ments of 1,3-DC reactions of nitrilimines with various
dipolarophiles can be found in the literature.5-7 1,3-DC
reactions of nitrilimines to olefins have been utilized
extensively to synthesize pyrazoles and pyrazolidines.8
In this context, we became interested in the reactivity of
methyl methacrylate 3 as dipolarophile towards N-(4-
bromophenyl)-C-(4-nitrophenyl)nitrilimine (2a) and N-
(4-nitrophenyl)-C-(4-chlorophenyl)nitrilimine (2b) as
*
E-mail: f.moeinpour@gmail.com; Tel.: 0098 511 879 7022; Fax: 0098 511 879 6416
Received September 20, 2010; revised November 30, 2010; accepted February 12, 2011.
Chin. J. Chem. 2011, 29, 1167— 1172
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Bakavoli et al.
FULL PAPER
Scheme 1
tional details) are therefore expected to be useful de-
scriptor of regional electrophilicity/nucleophilicity pat-
terns that may account for the observed regioselectivity
in two-center reactions with a significant polar charac-
ter.
electrophilic ( fk－ ) and nucleophilic attack ( fk+ ) can
be written as
fk－ ＝[ρ (N)－ρ (N－1)]
(4)
(5)
k
k
f + ＝[ρ (N＋1)－ρ (N)]
Computational details
k
k
k
All calculations were performed with the Gaussian
98 program suite.13 For DFT calculations, the
B3LYP/6-31G(d) level of theory was employed. The
optimizations of equilibrium geometries of reactants and
products were performed using the Berny analytical
gradient optimization method.14 The transition states
(TSs) for the 1,3-DC reactions have been localized at
the B3LYP/6-31G(d) level of theory. The stationary
points were characterized by frequency calculations in
order to verify that the TSs had one and only one
imaginary frequency. The atomic electronic populations
were evaluated according to Merz-Kollman scheme
(MK option).15,16 The global electrophilicity ω for di-
poles and dipolarophile was evaluated using Eq. (1):17
where ρ (N), ρ (N－1) and ρ (N＋1) are the gross elec-
k
k
k
tronic populations of the site k in neutral, cationic, and
anionic systems, respectively.
The local electrophilicity index, ω , condensed to
k
atom k is easily obtained by projecting the global quan-
tity onto any atomic center k in the molecule by using
the electrophilic Fukui function (i.e. the Fukui function
23
for nucleophilic attack, fk+
)
ωk＝ω fk+
(6)
Recently, Domingo et al.24 has introduced an em-
pirical (relative) nucleophilicity index, N, based on the
HOMO energies obtained within the Kohn-Sham
scheme,19 and defined as EHOMO(Nu)－EHOMO(TCE).
This nucleophilicity scale is referred to tetracyano-
ethylene (TCE) as a reference. Local nucleophilicity
index,25 Nk, was evaluated using the following equation:
2
ω＝ µ / 2 η
(1)
In Eq. (1) µ and η are the electronic chemical potential
and the chemical hardness of the ground state (GS) of
atoms and molecules, respectively.
The electronic chemical potential µ and chemical
hardness η were evaluated in terms of the one electron
energies of the HOMO and LUMO, using Eqs. (2) and
(3), respectively:18,19
Nk＝Nfk−
(7)
where fk− is the Fukui function for an electrophilic at-
tack.22
µ
(ε ε )/2
(2)
(3)
≈
≈
＋
H
L
The 13C NMR chemical shifts were calculated by
means of the GIAO method,9 using the tetramethylsi-
lane (TMS) as 13C reference, at the B3LYP/6-31G (d)
η
(ε ε )
－
L
H
As usual, local indexes are computed in atomic con-
densed form.20 The well-known Fukui function21,22 for
level of theory (reference value of δ ＝184.5307).
C
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Chin. J. Chem. 2011, 29, 1167— 1172

Regiochemistry of Some Pyrazoles Derived from Methyl Methacrylate
Experimental
refluxing in chloroform. 1,3-DC of nitrilimines 2 with
the dipolarophile proceeded smoothly in a selective
manner to give a single regioisomer of each pair 4a—5a
and 4b—5b in good yields (Scheme 1). The assignment
of the regiochemistry of these products was based upon
i) comparing the theoretical 13C NMR spectral data ob-
tained by GIAO method with the observed values for
both regioisomers; ii) activation energy calculations and
iii) DFT-based reactivity indexes.
i) For further cycloadduct characterization, we ob-
tained the theoretical 13C chemical shifts values for the
products through the GIAO method and compared it
with the observed values. As it can be seen in Table 1
and Scheme 1, the observed values for C(1) and C(2) in
each of the isolated products (δ 53.3 and 69.6, 53.5 and
68.5 in compounds 4a and 4b; respectively) are in
closer proximity to the theoretical values for compounds
4a and 5b. It seems that the isolated regioisomers are
structurally similar to 4a and 5b. Further proofs came
from activation energy and DFT studies as followings.
The melting points were recorded on an Electro-
thermal type 9100 melting point apparatus. The H
1
NMR (400 MHz) spectra were recorded on a Bruker AC
400 spectrometer. 13C NMR spectra were determined
using the Bruker AM-400 instrument operating at 100
MHz. IR spectra were determined as KBr pellets on a
Shimadzu model 470 spectrophotometer. The mass
spectra were scanned on a Varian Mat CH-7 instrument
at 70 eV. Hydrazonoyl chlorides 1, the precursors of
nitrilimines 2 are known compounds and were prepared
according to generally used methods.26
General procedure for the synthesis of cycloadducts
4a and 4b
To a solution of methyl methacrylate 3 (5 mmol) and
hydrazonoyl chlorides 1a, 1b (5 mmol) in chloroform
(20 mL) was added triethylamine (0.7 mL, 5 mmol).
The reaction mixture was refluxed for 8—10 h till the
hydrazonoyl chloride disappeared as indicated by TLC
analysis. The solvent was evaporated and the residue
was treated with methanol. The solid that formed was
collected and crystallized from suitable solvent to afford
the pure products 4a and 4b respectively in good yields.
Methyl 1-(4-bromophenyl)-4-methyl-3-(4-nitro-
phenyl)-4,5-dihydro-1H-pyrazole-4-carboxylate (4a)
Brown solid, yield 86%, m.p. 142 ℃; 1H NMR (CDCl3,
400 MHz) δ: 1.72 (s, 3H, CH3), 3.34 (d, J＝16.8 Hz, 1H,
CHAHB), 3.75 (d, J＝17.2 Hz, 1H, CHAHB), 3.81 (s, 3H,
OCH3), 7.03 (d, J＝8.8 Hz, 2H, CH, 4-bromophenyl
ring), 7.40 (d, J＝8.8 Hz, 2H, CH, 4-bromophenyl ring),
7.81 (d, J＝8.8 Hz, 2H, CH, 4-nitrophenyl ring), 8.26 (d,
J＝8.8 Hz, 2H, CH, 4-nitrophenyl ring); 13C NMR
(CDCl3, 100 MHz) δ: 21.4 (CH3), 47.6 (OCH3), 53.3
(CH2), 69.6 (C-CH3), 113.5, 116.3, 124.1, 126.0, 132.1,
138.1, 141.3, 143.1 (CPh), 147.3 (C＝N), 173.2 (C＝O);
IR (KBr) ν: 1734 (C＝O), 1589 (C＋＝N), 1557 (NO2)as,
Table 1 The comparison of theoretical 13C NMR chemical
shifts data (δ) of C-1 and C-2 of each pair of regioisomers with
those obtained from the experimental 13C NMR spectroscopy
Atom
number
Calculated
chemical shift
Experimental
chemical shift
Compound
4a
C-1
C-2
54.3
70.3
53.3
69.6
5a
4b
5b
C-1
C-2
39.7
61.5
C-1
C-2
52.8
67.0
53.5
68.5
C-1
C-2
45.5
49.6
－1
＋
1338 (NO2)s cm ; MS m/z: 417 (M ), 419 (M ＋2).
Methyl 3-(4-chlorophenyl)-4-methyl-1-(4-nitro-
phenyl)-4,5-dihydro-1H-pyrazole-4-carboxylate (4b)
Yellow solid, yield 87%, m.p. 195 ℃; 1H NMR (CDCl3,
400 MHz) δ: 1.79 (s, 3H, CH3), 3.37 (d, J＝17.2 Hz, 1H,
CHAHB), 3.76 (d, J＝16.5 Hz, 1H, CHAHB), 3.81 (s, 3H,
OCH3), 7.11 (d, J＝9.2 Hz, 2H, CH, 4-nitrophenyl ring),
7.43 (d, J＝8.8 Hz, 2H, CH, 4-chlorophenyl ring), 7.68
(d, J＝8.4 Hz, 2H, CH, 4-chlorophenyl ring), 8.17 (d,
J＝9.2 Hz, 2H, CH, 4-nitrophenyl ring); 13C NMR
(CDCl3, 100 MHz) δ: 21.5 (CH3), 48.6 (OCH3), 53.5
(CH2), 68.5 (C-CH3), 112.3, 125.9, 127.4, 129.1, 129.6,
135.9, 139.8, 147.4 (CPh), 147.7 (C＝N), 172.7 (C＝O);
IR (KBr) ν: 1725 (C＝O), 1580 (C＋＝N), 1558 (NO2)as,
ii) Activation energy calculations. The transition
states have been localized for both cyclization modes.
The corresponding activation energies and structures are
given in Table 2 and Figure 1 respectively. An analysis
of the geometries at the TSs given in Figure 1 indicates
that they correspond to an asynchronous bond formation
processes. The extent of bond formation along a reac-
tion pathway is provided by the concept of bond order
(BO).27 The BO (Wiberg indexes) values of the N—C
and C—C forming bonds at TSs are shown in brackets
in Figure 1. These values are within the range of 0.12 to
0.28. Therefore, it may be suggested that these TSs cor-
respond to early processes. In general, the asynchronic-
ity shown by the geometrical data is accounted for by
the BO values. A qualitative reactivity can be estimated
by applying Hammond’s postulate.28 All of the reactions
proceeded exothermically with large ∆Er (relative ener-
gies between products and reactants) energy values.
According to Hammond’s postulate, the TSs should
－1
＋
1336 (NO2)s cm ; MS m/z: 373 (M ), 375 (M ＋2).
Results and discussion
Nitrilimines 2 were generated in situ from base
treatment of corresponding hydrazonoyl chlorides 1 by
Chin. J. Chem. 2011, 29, 1167— 1172
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Bakavoli et al.
FULL PAPER
－1
Table 2 Energies of reactants, transition states and cycloadducts 4 and 5, E (a.u.), relative activation energies ∆Ea (kJ•mol ) and rela-
－1
tive energies between products and reactants, ∆Er (kJ•mol )
a
a
Reaction
System
Nitrilimine 2a
E
∆Ea
∆Er
－1274.91217
－345.78703
－1620.69205
－1620.68701
－1620.77412
－1620.76306
2a＋3
Methyl methacrylate 3
TS 4a
TS 5a
4a
18.4
31.4
－204.2
－167.8
5a
Nitrilimine 2b
－3386.41812
－345.78703
－3732.19001
－3732.18221
－3732.28004
－3732.26910
2b＋3
Methyl methacrylate 3
TS 4b
TS 5b
4b
38.1
58.6
－196.6
－169.9
5b
a To reactants; ∆Ea＝ETS－(ENitrilimine＋Edipolarophile); ∆Er＝EProduct－(ENitrilimine＋Edipolarophile).
Figure 1 Optimized geometries for transition state structures at the B3LYP/6-31G(d) level of theory. Hydrogen atoms have been omit-
ted for clarity. Distances of forming bonds are given in angstroms. The bond orders are given in brackets.
then be closer to the reactants. The activation energy
values, ∆Ea, also favor the formation of the cycload-
ducts 4a and 4b against their regioisomers 5a and 5b
respectively.
iii) DFT-based reactivity indexes. Prediction of re-
giochemistry by using DFT-based reactivity indexes:
The chemical hardnesses η, global electrophilicity ω and
global nucleophilicity N of the nitrilimines and dipola-
rophile are given in Table 3. The Fukui indexes for the
atoms N(1) and C(3) of the dipoles (nitrilimines) and for
the atoms C(4) and C(5) of the dipolarophile (methyl
methacrylate), calculated with MK population analysis,
are given in Table 4 (see Scheme 2 for atom number-
ing).
As it can be seen in Table 3, the electronic chemical
potentials of nitrilimines (dipoles) 2a and 2b are greater
than that of methyl methacrylate 3 (dipolarophile),
which indicates the charge transfer is taking place from
nitrilimines to methyl methacrylate. Note that even
though nitrilimine 2a and 2b has a larger electrophilicity
value ω than methyl methacrylate 3, the latter has a
lower chemical potential, which is the index that deter-
mines the direction of the electronic flux along the
cycloaddition.29 For better visualization we have de-
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Chin. J. Chem. 2011, 29, 1167— 1172

Regiochemistry of Some Pyrazoles Derived from Methyl Methacrylate
Table 3 HOMO, LUMO energies in a.u., electronic chemical
potential (µ in a.u.), chemical hardness (η, in a.u.), global elec-
trophilicity (ω, in eV) and global nucleophilicity (N, in eV) for
dipoles and dipolarophile systems
4b regioisomer. As it can be seen in Scheme 2, the local
philicity indexes (ω , Nk) seem to be a reliable tool for
k
the prediction of the most favored interaction in a
two-center polar process. It turns out that the two-center
polar model, based on electrostatic charges, predicts
correctly the experimental regioselectivity.
Reactant HOMO LUMO
µ
η
ω
Na
2a －0.205 －0.090 －0.148 0.115 2.591 3.541
2b －0.210 －0.083 －0.147 0.127 2.315 3.405
Conclusion
3
－0.268 －0.038 －0.153 0.230 1.385 1.827
a
The regioselectivity for the 1,3-DC reactions of ni-
trilimines 2 with methyl methacrylate 3 has been inves-
tigated using experimental and theoretical 13C NMR
studies together with the activation energy calculations
and the DFT-based reactivity indexes at the B3LYP/6-
31G(d) level of theory. The results obtained in this work
clearly predict the regiochemistry of the isolated
cycloadducts.
The HOMO energy of tetracyanoethylene is －0.33514 a.u. at
the same level of theory.
Table 4 Fukui indexes for the N(1) and C(3) atoms of the ni-
trilimines and for atoms C(4) and C(5) of the methyl methacrylate
System
Nitrilimine 2a
Atom number
N(1)
fk＋
fk－
0.116
0.064
C(3)
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Chin. J. Chem. 2011, 29, 1167— 1172