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Journal of the Chilean Chemical Society

On-line version ISSN 0717-9707

J. Chil. Chem. Soc. vol.60 no.2 Concepción June 2015

http://dx.doi.org/10.4067/S0717-97072015000200022 

 

THE TAUTOMERISM OF PYRAZOLINES (DIHYDROPYRAZOLES)

 

I. ALKORTA* AND J. ELGUERO

Instituto de Química Médica (CSIC), Juan de la Cierva, 3, E-28006 Madrid, Spain Dedicated to Professor Josep Castells on the occasion of his 90th Birthday


ABSTRACT

The exception to the rule that Δ3-pyrazolines are not stable unless both nitrogen atoms are substituted that has been recently published, Tetrahedron Lett. 55, 2208, (2014), has been proved false. By means of GIAO/B3LYP/6-311++G(d,p) calculations, it has been shown that the product is a pyrazole formed by rearrangement.

Keywords: pyrazolines, dihydropyrazoles, rearrangement, NMR, DFT calculations, GIAO


 

1. INTRODUCTION

There exists a clear imbalance in tautomeric studies of heterocycles between the much studied aromatic compounds and the seldom studied non-aromatic compounds. A clear example is the pyrazole/pyrazoline pair. There are hundreds of publications dealing with pyrazoles,1,2 while there is only one paper where a theoretical study of the tautomerism of pyrazolines (dihydropyrazoles) is reported.3 This is not due to the relative importance of both heterocycles, at least, not only, but more probably to the fact that pyrazole tautomers have similar energies while in the case of pyrazoline one tautomer is clearly more stable than the others. Pyrazolinones (pyrazolones) occupy an intermediate situation having both aromatic and non-aromatic tautomers, and they have been also much studied.1,4

According to our calculations carried out at the B3LYP/6-311++G(d,p) level for compounds 1a-1c,3 that we have completed for the present work for compounds 2b-2d (Scheme 1), the Δ2-pyrazolines (4,5-dihydro-1H-pyrazoles, 1b and 2b) are more stable than the Δ'-pyrazolines (4,5-dihydro-3H-pyrazoles, 1a). By far, the Δ3-pyrazolines (2,3-dihydro-1H-pyrazoles, 1c, 2c, 2d) are the less stable. It is interesting to note that the methyl group stabilizes the Δ3 tautomers.

 

Scheme 1. The different pyrazolines and their relative
energies in kJ·mol-1.

 

Pyrazolines tautomerize one into another by mere heating and by acid catalysis. Thus 1-unsubstituted Δ2-pyrazolines, like 1b, thermally isomerizes into A1-pyrazolines, like 1a, that lose N2 to yield cyclopropanes.5 The Δ1 to Δ2 isomerization is also known.6

N1-H or N2-H Δ3-pyrazolines (1c, 2c, 2d) are so unstable that they are not isolated and transform spontaneously into Δ2-pyrazolines (1b, 2b) and, with some exceptions, only 1,2-disubstituted Δ3-pyrazolines are known.

In 1970, Wittig and Hutchison,7 reported the following sequence of reactions (3 → 4 → 5, Scheme 2) where a N1-H Δ3-pyrazoline 5 was isolated.

 

Scheme 2. Formation of a Δ2-pyrazoline 7 and not of a Δ3-pyrazoline 5.

 

We demonstrated afterwards that the product of rearrangement of the pyrazolenine 3 was not the pyrazole 4 but the isopyrazole 6 that was reduced by lithium aluminium hydride to a Δ2-pyrazoline 7, therefore disproving an example of N1-H Δ3-pyrazoline stable. However, we described that these compounds could be stable when they carry special substituents (Scheme 3).8

 

Scheme 3. The structure of a true N1-H Δ3-pyrazoline.

 

When hexafluoroacetone azine (8) reacted with one alkene, compound 9 was isolated. The presence of a geminal trifluoromethyl group at position 5 prevented the isomerization of 9 to a Δ2-pyrazoline.8

The situation seemed clear until recently a counterexample was published.

2. RESULTS AND DISCUSSION

In 2009, Ashton T. Hamme II and co-workers published a paper that contains the following sequence (Scheme 4). When 2-methylene-1,3,3-trimethylindoline (10) reacts with a nitrile imine (generated in situ from 11a) a spiro-Δ2-pyrazoline 12a was formed that rearranged into the pyrazole 13a (characterized by X-ray crystallography: Figure 1, refcode CORTEJ).9 The authors propose that the rearrangement involves the Δ3-pyrazoline 14a.10

 

Scheme 4. Hamme's results of 2009.

 

Figure 1. Left side: X-ray structure of 2-(2- 1,3-diphenyl-1H-pvrazol-
5-yl)-N-methylaniline (13a).10 Right side: optimized B3LYP/6-311++G
(d,p) structure of 13a.

 

The X-ray structure shows a N–H···π hydrogen bond involving the aromatic electrons of the pyrazole ring. They also reported the 1H and 13C chemical shifts but without assigning them. We have used the atom numbering of Scheme 5 to prepare Table 1 where a tentative assignment was made using GIAO/B3LYP/6-311++G(d,p) calculated chemical shifts (see Computational Methods).

 

Scheme 5. Atom numbering of
pyrazole 13a.

 

Table 1: Calculated and experimental chemical shifts (ppm) of
compound 13a.

 

In 2014, the same authors published for R = OMe, the study of the equilibrium 12b/14b.11 They reported the X-ray structure of 12b, but the CCDC deposition number 701051 actually corresponds to 13a although the Figure that appears in their paper is that of 12b. They described the properties of both tautomers that depend on the solvent: in benzene (12b, yellow solution) and in chloroform (14b, pink solution). They used trifluoroacetic acid (TFAA) to transform tautomer 12b into tautomer 14b (Scheme 6). The latter one was stable in these conditions.

 

Scheme 6. Equilibrium 12b/14b and protonated pyrazolinium salts.

 

The results reported in Scheme 6 are in total contradiction to what we have summarized in the introduction. We have calculated at the B3LYP/6-311++G(d,p) level the energies of the compounds of Scheme 6 (Table 2).

 

Table 2: Energies (hartrees) and relative energies (kJ·mol-1) of the
compounds of Scheme 5.

 

It is clear that, consistently with our previous calculations (Scheme 1), a solvent effect cannot account for the existence of 14b in chloroform.

We have calculated the absolute shieldings of the compounds of Table 1 (σ, ppm) at the GIAO/B3LYP/6-311++G(d,p) level and transformed them into chemical shifts (δ, ppm) by means of empirical equations we have established previously (see Computational Methods).

We will first discuss the case of 12b because there is no doubt about its structure. Unfortunately, the authors reported its chemical shifts without assignment and with only the number of protons and some coupling JHH values, that we have used to build up Table 3 using the numbering of Scheme 7.

 

Table 3: Calculated and experimental chemical shifts (ppm) of
compound 12b.

 

Scheme 7. Numbering of 12b used for NMR.
Methyl 7 is close to C4 and the methyl 8 is
close to the N1-phenyl group; Ha is close to
C6 and Hb is close
to N15.

 

The assignment was done by analogy and some errors between close signals are possible. That of Table 3 corresponds to Exp. = (1.002±0.003) Calcd., n = 37, R2 = 0.999.

In Table 4 we have reported the other compound of Table 1, the Δ3-pyrazoline 14b while its numbering is in Scheme 8.

 

Table 4: Calculated and experimental chemical shifts (ppm) of compound 14b.

 

Scheme 8. Numbering of 14b used for NMR the
methyl 8 is close to the N1-phenyl group.

 

It is clear that the experimental values do not correspond to 14b. Besides, there is an important experimental 1H NMR datum: the N-Me group at 2.70 ppm is a doublet with J = 5 Hz, this is typical of a NHMe;12 Obviously the compound is the pyrazole 13b [13b and 14b have the same mass (C26H27N3O)]. It differs from pyrazole 13a in the fact that the coupling between the methyl group Me16 and the NH (a 3JHH) is only observed for the second one, but it is known that observing these couplings depends on the exchange rate of the amino proton.13 The calculated chemical shifts for pyrazole 13b (Scheme 8) are also reported in Table 4.

Using all the available data of Tables 1 and 4 for the pyrazoles 13a and 13b an excellent correlation is found: Exp. = (1.000±0.003) Calcd., n = 69, R2 = 0.9998. Note that the 15N chemical shifts are very different for compounds 13b and 14b.

 

Scheme 9. Left side: Atom numbering of pyrazole 13b. Right side:
optimized B3LYP/6-311++G(d,p) structure of 13b.

 

3. CONCLUSIONS

The availability of standard theoretical calculations of absolute shieldings (σ, ppm) and the robustness of the empirical equations to transform them into chemical shifts (δ, ppm) has allowed to correct an structural error of the literature,11 and confirm that Δ3-pyrazolines are stable only when both N atoms are substituted.

Computational Methods

DFT calculations were carried out using the B3LYP13 functional, together with the 6-311++G/d,p) basis set.14 Absolute shieldings were calculated within the GIAO approximation. All the calculations were carried out using the Gaussian 09 package.15 Empirical equations were used to transform the 1H, 13C and 15N absolute shieldings into chemical shifts.16

ACKNOWLEDGMENTS

This work has been supported by the Spanish Ministerio de Economía y Competitividad (CTQ2012-35513-C02-02) and Comunidad Autónoma de Madrid (S2013/MIT-2841, Fotocarbon). Computer, storage and other resources from the CTI (CSIC) are gratefully acknowledged.

 

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