A theoretical study of the mechanism of oxidation of 1 H -pyrazolines to 1 H -pyrazoles by molecular bromine

The bromine oxidation of NH-pyrazolines to pyrazoles involves a bromo substituted 2-or 1-pyrazoline. The present paper explores theoretically the different possibilities comparing the published NMR results to the experimental ones. Besides, geometries and energies are reported and discussed.


Introduction
2][3][4] Several oxidizing agents have been used, amongst them bromine in different solvents.Bromine is an efficient and inexpensive agent but in some cases the resulting pyrazole is further brominated on the ring or in a substituent, for instance an aryl group.If one of the C4 or C5 carbon atoms is disubstituted the oxidation to pyrazole is accompanied by a retropinacol rearrangement with migration of one of the substituents to the adjacent position (Scheme 1).1a,2a,4a In what concerns bromination of 1-substituted-2-pyrazolines, the accepted mechanism is represented in Scheme 2. If the position 3 is unsubstituted a 3-bromopyrazoline is obtained that can be further oxidized to a 3-bromopyrazole.When there is a substituent at position 3, then two molecules of hydrogen bromide are eliminated and a pyrazole was isolated.The behavior depicted in Scheme 2 was referred to "enamine-like" 5 and the kinetic parameters determined (order 2, k = 2.2x10 6 l.mol -1 .s -1 for 1-phenyl-2-pyrazoline). 6 When in position 1 there is an H atom, 1H-2-pyrazolines, there is another possibility, that the bromination occurs on the N1 nitrogen atom, somewhat related to the bromination of succinimide to affords NBS (N-bromosuccinimide). 7 In Scheme 3 we have represented two possible mechanisms.
In the present paper we will report our results concerning the mechanisms of Scheme 3.
In 1962 and then, in more detail, in 1963 we proposed a mechanism involving an Nbromination. 8,9We maintain this mechanism in subsequent papers of 1964 and 1965, 10,11 and corrected it in 1967. 5In the meantime, in 1966 a paper by Closs and Heyn appeared in which they prove conclusively that the intermediate was a 3-bromo-1-pyrazoline 5 and not a 1-bromo-2-pyrazoline 2. 12 The experiments were carried out on 3,5,5-trimethyl-2-pyrazoline (7, Scheme 4) and on 5methyl (11) and 3-methyl-2-pyrazoline (13, Scheme 5).The brominated pyrazoline 8 was isolated (Bp0.5 = 58 ºC, m.p. 16 ºC) and characterized by its reactivity with potassium iodide, silver nitrate and sulfur dioxide.In IR, there is no NH band and presents a doublet at 1360-1370 cm -1 characteristic of a gem-dimethyl group.Its 1 H NMR in CDCl3 at 56.4 MHz shows bands at  1.45 (s, gem-dimethyl), 2.14 (s, 3-methyl) and a quartet centered at 1.99 ppm (J = 14.7 Hz) corresponding to the protons of the 4-position.In the same papers we reported that the bromination of 5-methyl-2-pyrazoline (11) affords 12 because the coupling between the 5-methyl and the 5-H disappears (in 11, 3 J55 = 6.8 Hz) while a signal appears at 2.68 that we assigned to a 3-methyl group (in 13, 3-methyl at 1.97 ppm).Thus, the bromination was accompanied by an isomerization of 11 to 13.It was verified that the bromination of 13 affords 12.
In 1966, Closs and Heyn working at 60 MHz in CCl4 interpreted the NMR spectrum of the compound obtained by bromination of 7 as belonging to structure 18 (Scheme 6).The signals appeared at  1.41 (s, gem-dimethyl), 2.09 (s, 3-methyl) and an AB system at 2.26 and 1.65 ppm (J = 14.6 Hz) corresponding to the protons of the 4-position.They concluded that the molecule does not have a plane of symmetry and therefore cannot be 8. Besides, in toluene the methyl groups of the gem-dimethyl displays two signals ( = 0.08 ppm) and also in pyridine ( = 0.02 ppm). 12Additional evidence against the N-bromo structure 8 was the lack of coupling between the methyl protons at position 3 and the methylene protons at C-4 that in other pyrazolines amount to approximately 1 Hz. 12

7
Br 2 These arguments are convincing; we have also reported the small 4 J34 coupling of about 1 Hz, for instance for 13, the methyl group appears as a triplet with a J of 0.9 Hz. 11 Afterwards, we reported that this coupling is dependent on the 1-substituent and that in some cases vanished. 13It cannot be excluded that the bromine substituent affects 4 J34 to the point to be not observable.
However, the main argument was that 8 was planar on average leading to the isochrony of the protons of the 4-position and of that of the methyl groups.At about the same time that these papers appeared, the very slow inversion process for N-halogenoaziridines was discovered [14][15][16][17] providing a possible explanation based on structure 8.

The structure of the products of direct bromination of 2-pyrazolines
We have published papers concerning the NMR properties of 2-pyrazolines, 1 H, 18-20 13 C, 21,22 and 15 N. 23 Results from other authors can be found in references 4,24,25 .Also the geometries of these five-membered heterocycles related to the envelope of cyclopentane have been discussed and compared with crystallographic data from the CSD.In Table 1 are some data of the calculated geometries of pyrazolines and in Figure 1 a view of 8 and 18 showing that the bromine atoms are clearly out-of-plane.The only structure related to 18 found in the CSD, BHXMPZ (3-bromo-4,5-dihydro-5-hydroperoxy-4,4-dimethyl-3,5diphenyl-3H-pyrazole), 27,28 is also represented.Unsubstituted  2 -pyrazoline and  1 -pyrazoline have folding angles of  = 28º and 13.5º, respectively, in perfect agreement with the data of Table 1. 26The NBr derivatives are more folded than the NH-ones, by about 4º.The X-ray structure, BHXMPZ, differs but it has special substituents like OOH.
The inversion barriers, ZPE (Zero-point energy) corrected, are much smaller for N-H than for N-Br, the first are between 11 and 14 kJ mol -1 while the second are between 32 and 39 kJ mol -1 (factor between 2.2 and 3.6).In any case, barriers in the range between 30-40 kJ mol -1 are too low to justify the distereotopicity of methylene and methyl protons of the positions 4 and 5 in 8. 29,30 We have calculated the inversion barriers including the ZPE correction of 1H-aziridine (62.9 kJ mol -1 ), 1-chloroaziridine (101.8 kJ mol -1 ) and 1-bromoaziridine (91.7 kJ mol -1 ) corresponding to an increase of the barriers by halogenation of 1.6 (Cl) and 1.5 times (Br).Another calculation (cc-pVDZ, cc-pVTZ and cc-pVQZ extrapolated to focal-point) for the barrier of 1H-aziridine affords 79 kJ mol -1 . 31Experimental values are 73 kJ mol -1 for 1H-aziridine (CCl4) 32 and much higher than 90 kJ mol -1 for N-chloro and N-bromoaziridines. 33Other authors estimate the barriers of these last compounds to 105-115 kJ mol -1 . 34Our barrier for 1H-aziridine is underestimated (73/62.9= 1.16), using this factor of proportionality, the values for N-chloro and N-bromoaziridines can be estimated to 118 and 107 kJ mol -1 , respectively, consistent with the experimental results previously discussed.In any case, the barriers of aziridines are much larger than those of pyrazolines.Therefore, the disterotopicity cannot be due to a N-Br blocked inversion.
Table 3. 1 H, 13 C and N chemical shifts (ppm) and some selected SSCC (Spin-Spin Coupling Constants, Hz). 1 H NMR values of reference 35 that differ from those of references 8,9  12 ppm; b In the cited publication only the center of the AB system was reported while AB was not given; c In toluene the methyl groups of the gemdimethyl appear different ( = 0.08 ppm) as well as in pyridine ( = 0.02 ppm). 12e calculations reproduce fairly well the known experimental values for NH-pyrazolines.Thus, we can be confident that in the case of 8 and 18 the predictions are accurate.The 1 H NMR data agree much better with 18 than with 8 even assuming no N-Br inversion in the latter.At that time (1962-1966), 13 C and 15 N NMR were not accessible preventing a straightforward identification.Although, the information on 12/22 is scarce (only 1 H NMR) it appears that the structure should be 22.
We have calculated all the couplings involving the compounds of Tables 3 and 5, but we will report here only the 1 H-1 H SSCC of compounds 7, 8 and 18 (Scheme 7).
2 J gem = -14.6 4 J MeH4 = -0.95 4 J MeH4' = -1.90Simultaneous NH inversion and ring inversion in the case of 7 transform the AB system of the 4-CH2 into an A2 system preventing the observation of the geminal 2 J44'.At the same time, the 4 J is averaged to a -1.4 Hz, which compares well with the experimental J34 = |1.2|Hz.In the case of the hypothetical 8 the values are very similar eliminating the possibility that the bromine atom at N1 could substantially reduce 4 J.On the contrary, as assumed by Closs and Heyn, 12 J34 is almost zero for 18.

The structure of the products formed after the direct bromination of 2-pyrazolines
We will obviate the geometrical aspects of pyrazoles 9, 10, 14, 15, 16 and 17, because the geometry of pyrazoles has been discussed many times, [36][37][38][39] and report in Figure 2   In what concerns the energies (Table 4) only three products have the same molecular formula and can be compared.Note that for pyrazolium salts, the anion bromide was not included in the calculations.Of the three compounds with C6H10N2 formula, the 1H-pyrazole 10 is by far the most stable; the exo tautomer 20 is slightly less stable than the 3H-pyrazole 19 (14.9 kJ mol -1 ).
Concerning NMR, in general, we will report in Table 5 only the chemical shifts that have experimental counterparts.Taking into account that data measured in the solid state deviate from those in solution, 44,45 and that 13 C C-Br signals need to be corrected, 46,47 the results of Table 5 are satisfactory to the point that the predictions for 19 should be close to reality.The more similar structure found in the literature is 22. 48Its 13 C chemical shifts are very similar to the calculated ones of Table 5

Conclusions
Theoretical calculations at the B3LYP/6-311++G(d,p) level for geometries, energies and coupling constants and GIAO (Gauge-Independent Atomic Orbital) over these geometries for chemical shifts provide a complete and consistent picture of the processes involved in the bromination of 1H-2-pyrazolines.Obviously the Closs and Heyn mechanism of 1966 was confirmed as we already recognized in 1967.

Computational Details
The geometry of the molecules has been fully optimized with the hybrid HF/DFT B3LYP (Becke, three-parameter, Lee-Yang-Parr) [49][50][51] computational method and the 6-311++G(d,p) basis set [52][53][54] in gas phase.Frequency calculations have been carried out at the same computational level to verify that the structures obtained correspond to energetic minima and transition state (zero and one imaginary frequency, respectively).These geometries have been used for the calculations of coupling constants, SSCC, as well as for the absolute chemical shieldings with the GIAO method 55,56 and the B3LYP/6-311++G(d,p) computational level.All the calculations have been carried out with the Gaussian-09 package. 57he following equations obtained by atatistical analysis of a great number of data have been used to transform absolute shieldings into chemical shifts:  1 H = 31.0-0.97 *  1 H eq. 1 (reference TMS, 0.00 ppm) 58  13 C = 175.7 -0.963 *  13 C eq. 2 (reference TMS, 0.00 ppm) 59  15 N = -152.0-0.946 *  15 N eq. 3 (reference ext.neat MeNO2, 0.00 ppm) 59 The chemical shifts and all the coupling constants not discussed in this manuscript are available from one of us (I.A.) on request.

Scheme 4 .
Scheme 4. The mechanism we proposed for the bromination of 7.

Scheme 5 .
Scheme 5.The mechanism we proposed in 1962-1963 for the bromination of 11 and 13.

Scheme 6 .
Scheme 6.The mechanism proposed by Closs and Heyn in 1966 for the bromination of 7.

Table 1 .
Some geometrical data of pyrazolines.X is the atom, H or Br, of the substituent on the out-of-plane atom, N or C, of the envelope

Table 5 .
(Continued) a In solid state (CPMAS, Cross Polarization Magic Angle Spinning); b Due to prototropy, these products are mixtures of 3-and 5-methyl tautomers except in some solvents like HMPA (Hexamethylphosphoramide) or in the solid state.