Investigation into the regiochemistry of some pyrazoles derived from 1, 3-dipolar cycloaddition of acrylonitrile with some nitrilimines: Theoretical and experimental studies

Article abstract of DOI:10.4067/S0717-97072011000400010

1,3-dipolar cycloaddition between acrylonitrile and two N-(4-substituted)phenyl-C-(4-chlorophenyl)nitrilimines which were generated in situ afforded the new pyrazoles. The regiochemistry and reactivity of these reactions has been investigated on the basis

Full text of DOI:10.4067/S0717-97072011000400010

J. Chil. Chem. Soc., 56, Nº 4 (2011)
INVESTIGATION INTO THE REGIOCHEMISTRY OF SOME PYRAZOLES DERIVED FROM 1,
3-DIPOLAR CYCLOADDITION OF ACRYLONITRILE WITH SOME NITRILIMINES: THEORETICAL AND
EXPERIMENTAL STUDIES
FARID MOEINPOUR1*, MEHDI BAKAVOLI2, ABOLGHASEM DAVOODNIA2 and ALI MORSALI2
1Department of Chemistry, Islamic Azad University- Bandar Abbas Branch, Bandar Abbas, Iran
2Department of Chemistry, Islamic Azad University- Mashhad Branch, Mashhad, Iran
(Received: January 12, 2011 - Accepted: September 7, 2011)
ABSTRACT
1,3-dipolar cycloaddition between acrylonitrile and two N-(4-substituted)phenyl-C-(4-chlorophenyl)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 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 comparable with
the observed values.
INTRODUCTION
1,3-Dipolar cycloaddition reactions of nitrilimines with dipolarophiles
containing a carbon-carbon double bond represent an important synthetic
route to substituted pyrazoles and pyrazolidines 1. These reactions are one
of the most important processes with both synthetic and mechanistic interest
2
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 experiment 2-4. Two major factors i.e. the steric
2
and electronic effects can influence the regioselectivity of these reactions .
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 easier.
Furthermore, transition state calculations are often very time-consuming
when bulky substituents are present in reactive systems. Recently, reactivity
descriptors based on the density functional theory (DFT), such as Fukui
indexes, local softnesses and local electrophilicity, have been extensively
used for the prediction of the regioselectivity. For instance, several treatments
of 1,3-DC reactions of nitrilimines with various dipolarophiles can be found
in the literature 5-8. In this context, we became interested in the reactivity of
acrylonitrile 3 as dipolarophile towards two N-(4-substituted)phenyl-C-(4-
chlorophenyl)nitrilimines 2 as dipoles which were generated in situ by base
treatment of the corresponding hydrazonoyl chlorides 1 in order to synthesize
the new 3-(4-chlorophenyl)-1-(4-nitrophenyl)-4,5-dihydro-1H-pyrazole-4-
carbonitrile 4a and 1-(4-bromophenyl)-3-(4-chlorophenyl)-4,5-dihydro-1H-
pyrazole-5-carbonitrile 5b (Scheme1). 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
Scheme 1. The regioisomeric pathways for 1,3-DC of nitrilimines 2 and
dipolarophile 3.
3. COMPUTATIONAL DETAILS
All calculations were performed with the Gaussian98 program suite
16
.
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 17. 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) 18,19. The global
9
indexes. Finally, the gauge-invariant atomic orbital (GIAO) method was
used to calculate NMR chemical shifts, to help the experimental cycloadduct
determination, because it has shown to yield data comparable to those of the
experiment 10
.
electrophilicity w for dipoles and dipolarophile was evaluated using Eq. (1) 20
:
Regioselectivity criteria for two-center reactions
According to the model recently proposed by Domingo
regioselectivity of a polar cycloaddition reaction could be explained by the
most favorable two-center interactions between the highest nucleophilic
and electrophilic sites of the reagents. The corresponding reaction channel
favors the maximum CT from the nucleophilic to the electrophilic reagent
µ2
11,
12, the
(1)
ω =
2η
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,
in the course of the polar cycloaddition reaction. Local electrophilicity and
13-15
nucleophilicity indexes
(for definition, see Eqs. 6 and 7) are expected to
using Eqs. (2) and (3), respectively 21,22
:
be useful descriptor of regional electrophilicity/nucleophilicity patterns that
may account for the observed regioselectivity in two-center reactions with a
significant polar character.
(εH +εL )
µ ≈
2
(2)
e-mail: f.moeinpour@gmail.com
870

J. Chil. Chem. Soc., 56, Nº 4 (2011)
4-bromophenyl ring), 7.48 (2H, dd, CH, J = 8 Hz, 4-chlorophenyl ring), 7.64
(2H, dd, CH, J = 8 Hz, 4-chlorophenyl ring);13C NMR (100 MHz, CDCl ), dC
38.8 (CH2), 50.0 (CH), 116.7 (C ≡ N), 114.1, 115.1, 127.3, 129.1, 132.2, 1335.9,
142.5 (C, phenyl rings), 147.7 (C = N). Anal. Calcd for C H11Br ClN3: C,
53.29; H, 3.07; N, 11.65. Found: C, 53.33; H, 3.09;N, 11.67).16
η ≈ (εL − εH )
(3)
As usual, local indexes are computed in atomic condensed form 23. The
24,25
well-known Fukui function
for electrophilic (f k-) and nucleophilic attack
(f k+) can be written as
RESULTS AND DISCUSSION
fk− = [ρk (N) − ρk (N −1)]
fk+ = [ρk (N +1) − ρk (N)]
(4)
(5)
Nitrilimines 2 were generated in situ from base treatment of corresponding
hydrazonoyl chlorides 1 by 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 90% and 88% yields respectively
(scheme 1). For each one of these cycloaddition reactions, two cyclization
modes have been investigated. They are related to the two regioisomeric
approaching modes of nitrilimines 2 to the acrylonitrile 3 mentioned as 4a - 5a
and 4b - 5b. The assignment of the regiochemistry of these products was based
upon i) comparing the theoretical 13C NMR spectral data obtained by GIAO
method with the observed values for both regioisomers; ii) activation energy
calculations and iii) DFT-based reactivity indexes.
Where ρ (N), ρk (N - 1) and ρk (N + 1) are the gross electronic populations
of the site k ikn neutral, cationic, and anionic systems, respectively.
The local electrophilicity index14, 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 function (i.e. the Fukui function for
14
nucleophilic attack, f +
)
k
i) For further cycloadduct characterization, we obtained 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 C1 and C2 in each of the isolated products (48.7
and 39.0, 38.8 and 50.0 ppm in compounds 4 and 5, respectively) are in closer
proximity to the theoretical values for compounds 4a and 5b. It seems likely
that the isolated regioisomers are structurally similar to 4a and 5b. Further
proofs came from activation energy and DFT studies as followings:
ωk = ωfk+
(6)
Recently, Domingo et al. has introduced an empirical (relative)
nucleophilicity index 13, N, based on the HOMO energies obtained within
the Kohn–Sham scheme 22, and defined as E
(Nu) - E
(TCE). This
nucleophilicity scale is referred to tetracyanHoOeMthOylene (THCOEM)O taken as a
reference. Local nucleophilicity index 26, Nk, was evaluated using the following
equation 26
:
Table 1. The comparison of theoretical 13C NMR chemical shifts data (δ,
ppm) of C-1 and C-2 of each pair of regioisomers with those obtained from the
experimental 13C NMR spectroscopy.
Nk =
(7)
Experimental
chemical shift
Calculated chemical
shift
where fk− is the Fukui function for an electrophilic attack 25
.
Atom number
Compound
The 13C NMR chemical shifts were calculated by means of the GIAO
method 9, using the tetramethylsilane (TMS) as 13C reference, at the B3LYP/6-
311+G (d) level of theory (reference value of 13C = 184.5307 ppm).
48.7
39.0
48.4
38.7
33.2
47.5
45.2
31.3
38.5
49.4
C-1
C-2
C-1
C-2
C-1
C-2
C-1
C-2
4a
5a
4b
5b
EXPERIMENTAL
The melting points were recorded on an Electrothermal type 9100 melting
1
point apparatus. The H 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
38.8
50.0
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. As it can be seen in Table 2, in the reaction between 2a and 3,
TS 4a is located 1.6 kcal below TS 5a and in the reaction between 2b and 3 TS
5b is located 0.5 kcal below TS 4b. The activation energies corresponding to
the two cyclization modes of the reactions are: 8.5, 10.1 for 2a+3, and 7.9, 7.2
for 2b+3. Thus, in 2a+3 reaction pathway, 4a regioisomer is kinetically more
favored than the 5a. In reaction between 2b + 3, 5b regioisomer is kinetically
more favored than the 4b. The presence of the nitro group in nitrilimine 2a
not only changes the regioselectivity but also slightly increases the barrier.
An analysis of the geometries at the TSs given in Figure1 indicates that they
correspond to an asynchronous bond formation processes. The extent of bond
formation along a reaction pathway is provided by the concept of bond order
(BO) 28. The BO (Wiberg indexes) values of the N – C and C – C forming bonds
at TSs are shown in brackets in Figure1. These values are within the range
of 0.17 to 0.26. Therefore, it may be suggested that these TSs correspond to
early processes. In general, the asynchronicity shown by the geometrical data
is accounted for by the BO values. A qualitative reactivity can be estimated by
applying Hammond’s postulate 29. All the reactions proceeded exothermically
with large ΔEr (relative energies between products and reactives) energy
values which make them irreversible processes (see Table 2). According to
Hammond’s postulate, the TSs should then be closer to the reactives. The
activation energy values, ΔE , also favor the formation of the cycloadducts 4a
and 5b against their regioisoamers 5a and 4b respectively. The polar nature of
the two cyclization modes can be estimated by a charge transfer (CT) analysis
at the TSs. The CT from nitrilimine 2a to acrylonitrile 3 is 0.19 e at TS 4a and
0.16 e at TS 5a. Therefore the CT calculations show a NED (normal electron
demand) character for this reaction. For 2b + 3, The CT from nitrilimine 2b to
according to generally used methods 27
.
Typical experimental procedure for 4a and 5b
To a solution of acrylonitrile 3 (5 mmol) and hydrazonoyl chlorides 1a,b
(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 5b
respectively in good yields.
3-(4-chlorophenyl)-1-(4-nitrophenyl)-4,5-dihydro-1H-pyrazole-4-
carbonitrile (4a): This compound was obtained as brown solid (90%). m.p.
182 °C. IR (KBr) (nmax/cm-1):1395, 1493,1597 cm-1. MS (EI, 70 eV) m/z: 326
(M+), 328(M++2). 1H NMR (400 MHz, CDCl ) dH 3.88 (1H, d, J = 16 Hz,
CHAHB), 4.01 (1H, d, J = 16 Hz, CHAHB), 5.932 (1H, t, CH, J= 8 Hz), 7.39
(2H, dd, CH, J = 8 Hz, 4-nitrophenyl ring), 7.58 (2H, dd, CH, J = 8 Hz,
4-chlorophenyl ring), 7.85 (2H, dd, CH, J = 8 Hz, 4-chlorophenyl ring), 8.27
(2H, dd, CH, J = 8 Hz, 4-nitrophenyl ring). 13C NMR (100 MHz, CDCl3) dC
39.0 (CH), 48.7 (CH2), 115.9 (C ≡ N), 113.0, 127.6, 128.2, 128.5, 129.3, 136.8,
147.2 (C, phenyl rings), 149.9 (C = N). Anal. Calcd for C16H11N4O2: C, 58.82;
H, 3.39; N, 17.15. Found: C, 58.85; H, 3.43; N, 17.19.
1-(4-bromophenyl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-5-
carbonitrile (5b): This compound was obtained as light pink solid (88%). m.p.
165 °C. IR (KBr) (nmax/cm-1):1336, 1558, 1580 cm-1. MS (EI, 70 eV) m/z: 359
(M+), 361(M++2), 363 (M++4). 1H NMR (400 MHz, CDCl ) dH 3.64 (1H, d, J
= 12 Hz, CHAHB), 3.66 (1H, d, J = 12 Hz, CHAHB), 4.98 (13H, t, CH, J= 8 Hz),
7.13 (2H, dd, CH, J = 8 Hz, 4-bromophenyl ring), 7.42 (2H, dd, CH, J = 8 Hz,
871

J. Chil. Chem. Soc., 56, Nº 4 (2011)
acrylonitrile 3 is 0.13 e at TS 4b and 0.17 e at TS 5b. Thus the CT calculations
show a NED character for this process.
Table 2. Energies of reactives, transition states and cycloadducts 4 and 5,
E (a.u.), relative activation energies ΔEa (kcal mol−1) relative energies between
products and reactives, ΔEr (kcal mol−1) and charge transfer (CT, in e) at TSs
a
a
Reaction
System
E
ΔEa
ΔEr
CT
Nitrilimine 2a -3386.446204
2a+3
Acrylonitrile 3
-170.831848
-3357.264112
-3357.261021
-3357.337234
-3357.336012
TS 4a
TS 5a
4a
8.5
0.19
0.16
10.1
-37.3
-36.7
5a
Nitrilimine 2b -3641.523112
2b+3
Acrylonitrile 3
-170.831848
-3812.342220
-3812.343012
-3812.431102
-3812.432241
TS 4b
TS 5b
4b
7.9
7.2
0.13
0.17
-47.9
-48.5
5b
a to reactives
4(b)
4(a)
(5a)
872

J. Chil. Chem. Soc., 56, Nº 4 (2011)
Table 4. Fukui indexes for the N1 and C3 atoms of the nitrilimines and for
atoms C4 and C5 of the acrylonitrile
Atom
number
System
fk+
fk-
ωk
Nk
N1
0.136
0.100
0.163
0.215
0.465
0.340
0.591
0.781
Nitrilimine 2a
Nitrilimine 2b
Acrylonitrile 3
C3
N1
C3
C4
0.359
0.201
0.625
0.350
C5
As it can be seen in Table 3, the electronic chemical potentials of
nitrilimines (dipoles) 2a and 2b are greater than that of acrylonitrile 3
(dipolarophile), which indicates the charge transfer is taking place from
nitrilimines to acrylonitrile. Note that even though nitrilimine 2a has a larger
electrophilicity value w than acrylonitrile 3, the latter has a lower chemical
potential, which is the index that determines the direction of the electronic flux
along the cycloaddition. These results are in agreement with CT calculations at
the TSs. For better visualization we have depicted these interactions in Scheme
2. In the reaction between 2a and 3, the most favorable two-center interaction
takes place between N1 of nitrilimine 2a and C4 of the acrylonitrile 3 leading
to the formation of the 4a regioisomer. In the reaction between 2b and 3, the
most favorable two-center interaction takes place between C3 of nitrilimine 2b
and C4 of the acrylonitrile 3 leading to the formation of the 5b regioisomer.
The replacement of Br group in 2b (or 5b in Scheme 2) by NO2 in 2a (or 4a in
Scheme 2) changes the N1 and C3 values. This fact is the responsible for the
changes in the calculated regioselectivity. As it can be seen in Scheme 2, the
local philicity indexes (ωk, Nk) seem to be a reliable tool for 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.
(5b)
Figure 1. Optimized geometries for transition state structures at the
B3LYP/6-31G (d) level of theory. Hydrogen atoms have been omitted for
clarity. Distances of forming bonds are given in angstroms. The bond orders
are given in brackets.
iii) DFT-based reactivity indexes
Prediction of regiochemistry by using DFT-based reactivity indexes
The chemical hardnesses η, global electrophilicity
w and global
nucleophilicity N of the nitrilimines and dipolarophile are given in Table 3.
The Fukui indexes for the atoms N1 and C3 of the dipoles (nitrilimines) and for
the atoms C4 and C5 of the dipolarophile (acrylonitrile), calculated with MK
population analysis, are given in Table 4 (see Scheme 2 for atom numbering).
Table 3. HOMO, LUMO energies in a.u., electronic chemical potential (µ
in a.u.), chemical hardness (η, in a.u.), global electrophilicity (ω, in eV) and
global nucleophilicity (N, in eV) for dipole and dipolarophile systems.
Na
ω
η
µ
LUMO HOMO
Reactants
3.416
3.625
1.250
2.309
1.891
1.744
0.126
0.133
0.233
-0.146
-0.136
-0.173
-0.083
-0.069
-0.056
-0.210
-0.202
-0.289
2a
2b
3
Scheme 2. Illustration of the favorable interactions using Local
nucleophilicities, Nk, for dipole centers and local electrophilicities, ωk, for the
acrylonitrile centers calculated with MK population analysis.
a
In conclusion the regioselectivity for the 1,3-DC reactions of nitrilimines
2 with acrylonitrile 3 has been investigated 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.
873

J. Chil. Chem. Soc., 56, Nº 4 (2011)
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B.
Cross, V. Bakken, 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 and J. A. Pople,
GAUSSIAN 98, Revision A.7; Gaussian: Wallingford, CT, 1998.
17. H. B. Schlegel, J. Comput. Chem. 3 (1982) 214.
18. U. C. Singh, P. A. Kollman, J. Comput. Chem. 5 (1984) 129.
19. B. H. Besler, K. M. Merz and P. A. Kollman, J. Comput. Chem. 11 (1990)
431.
20. R. G. Parr, L. V. Szentpály and S. Liu, J. Am. Chem. Soc. 121 (1999) 1922.
21. R. G. Parr, W. Yang, Density Functional Theory of Atoms and Molecules,
Oxford University Press: New York, 1989.
REFERENCES
1. K.V. Gothelf, K.A. Jorgensen, Chem. Rev. 98 (1998) 863.
2. A. Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley: New York,
1984.
3. A.Wasserman Diels–Alder Reactions; Elsevier: NewYork, 1965.
4. I. Fleming Pericyclic Reactions; Oxford University: Oxford, 1999.
5. G. Krajsovszky, A. N. Haider, J. Mol. Struc (Theochem) 528 (2000) 13.
6. G. Molteni, A. Ponti, J. Org. Chem. 66 (2001) 5252.
7. G. Molteni, A. Ponti, Tetrahedron 59 (2003) 5225.
8. G. Molteni, ARKIVOC ii (2007) 224.
9. K. Wolinski, J.F. Hilton and P. Pulay, J. Am. Chem. Soc. 112 (1990) 8251.
10. A. Garc´ıa-Granados, E. Melguizo and A. Parra, J. Org. Chem. 65 (2000)
8214.
11. L. R. Domingo, M. J. Aurell, P. Pérez and R. Contreras, Tetrahedron 58
(2002) 4417.
12. P. Pérez, L. R. Domingo, M. J. Aurell and R. Contreras, Tetrahedron 59
(2003) 3117.
22. R. G. Parr, R. G. Pearson, J. Am. Chem. Soc. 105 (1983) 7512.
23. W. Yang, W.J. Mortier, J. Am. Chem. Soc. 108 (1986) 5708.
24. K. Fukui, Science 218 (1982) 747.
13. L. R. Domingo, E. Chamorro, P. Pérez, J. Org. Chem. 73 (2008) 4615.
14. L. R. Domingo, M. J. Aurell, P. Pérez and R. Contreras, J. Phys. Chem. A
106 (2002) 6871.
25. R. G. Parr, W. Yang, J. Am. Chem. Soc. 106 (1984) 4049.
26. P. Pérez, L. R. Domingo, M. Duque-Noreña, E. Chamorro, J. Mol. Struc.
(Theochem) 895 (2009) 86.
27. R. Huisgen, M. Seidel, G. Wallbillich and H. Knupffer, Tetrahedron 17
(1962) 3.
15. G. Bentabed-Ababsa, A. Derdour, T. Roisnel, J. A. Sa´ez, P. Pe´rez, E.
Chamorro, L. R. Domingo and F. Mongin, J. Org. Chem. 74 (2009) 2120.
16. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J.
R. Cheeseman, J. A. Montgomery, 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,
28. K. B. Wiberg, Tetrahedron 24 (1968) 1083.
29. G. S. Hammond, J. Am. Chem. Soc. 77 (1955) 334.
874