An Example of Polynomial Expansion: The Reaction of 3(5)-Methyl-1H-Pyrazole with Chloroform and Characterization of the Four Isomers.

The reaction in phase-transfer catalyzed conditions of 3(5)-methyl-1H-pyrazole with chloroform affords four isomers 333, 335, 355 and 555 in proportions corresponding to the polynomial expansion (a + b)³, with a = 0.6 and b = 0.4, a and b being 3-methyl and 5-methyl proportions. The up (u) and down (d) conformation of the pyrazolyl rings with regard to the Csp³⁻H atom was established by X-ray crystallography and by ¹H-, 13C- and 15N-NMR in solution combined with gauge-including atomic orbitals (GIAO)/B3LYP/6-311++G(d,p) calculations. A comparison with other X-ray structures of tris-pyrazolylmethanes was carried out.

1. Introduction

N-unsubstituted pyrazoles, and in general N-unsubstituted azoles, react with chloroform in phase-transfer catalysis (PTC) conditions to afford trispyrazolylmethanes [1], the neutral equivalents of anionic scorpionates [2]. The reaction of 3(5)-methyl-1H-pyrazole (1) with chloroform was reported in 1984 and the only compound isolated in a pure state was the tris(3-methylpyrazol-1-yl)methane 333 derivative (1H, CDCl3, Csp3-H: 8.11 ppm) (Figure 1) [3]. We have used a double nomenclature, 3 or 5 to define the position of the methyl group (3 precedes 5) and down (d) and up (u) to define the position of N2 (N4, N6) with regard to the H of the Csp3–H group (down on opposite sides, up on the same side). For instance, structure types 335 duu and 355 duu should be read 3Me-d, 3Me-u, 5Me-u and 3Me-d, 5Me-u, 5Me-u. We have used this nomenclature in previous papers [4,5,6].

Figure 1

The four tris [3(5)-methyl]pyrazol-1-ylmethanes and the (0.6 + 0.4)3 proportions.

The reaction was reported again in 1999 and, surprisingly, the only isolated isomer (17% yield) was the 335 isomer (1H, CDCl3, Csp3-H: 8.21 ppm) [7]. In 2012 the more hindered 555 derivative was prepared from tri(pyrazol-1-yl)methane (tpzm) by alkylation of the lithium derivative (1H, CDCl3, Csp3-H: 8.31 ppm) [8].

Finally, the reaction was repeated again in 2012 and, although the yields of different isomers were not discussed, using the information concerning the 1H-NMR of the Csp3-H proton from this and others papers the relative yields of the four isomers can be determined (Figure 2) [8,9]. The authors also demonstrated that the mixture of the four isomers could be isomerized under the action of p-toluenesulfonic acid to a mixture of 333 and 335 in a 2:1 ratio (crude yield 82%), proving that they are the most stable isomers. The utility of the 333 ligand prompted Anwander et al. to prepare it from the mixture and isolate it by recrystallization [10].

Figure 2

The 1H-NMR spectrum in CDCl3 of the Csp3-H proton of the crude mixture (integration in the vertical scale) [8].

The authors point out that the 333 isomer, δ = 8.13 ppm, represents approximately 22% of the crude. From the data of Figure 2 reported and from the integration (total 2.324) it is easy to determine the proportions: 333, δ = 8.13 ppm, 22%; 335, δ = 8.21 ppm, 43%; 355, δ = 8.26 ppm, 28.5%; and 555, δ = 8.32 ppm, 6.5%.

We have shown that in the reaction of polyhaloalkanes, such as dichloromethane, and chloroform with non-symmetrical 1H-pyrazoles (different substituents at position 3 and 5), the proportion of isomers in the crude always follows a binomial expansion, in this case (a + b)3, where a + b = 1 [11,12].

Figure 1 shows the results obtained with a = 0.6 and b = 0.4, i.e., more 3-methyl than 5-methyl isomers, a ratio consistent with the proportions obtained by alkylation of 3(5)-methyl-1H-pyrazole [13,14,15,16,17,18].

The calculated values (21.6%, 43.2%, 28.8% and 6.4%) are remarkably consistent, indicating that at every step the ratio 0.6/0.4 is constant. The accuracy is so remarkable that it is possible to conclude that a = 0.603, b = 0.397 yields better results: 21.9%, 28.5%, 43.3% and 6.3%.

The 333 compound prepared as in [3] was used to prepare complexes with Fe(II) to study their spin-transition temperatures [19]. The few relevant data concerning these compounds are 13C-NMR data (unassigned) of 555 [, and the crystal structure of 333 (obtained by the general procedure followed by the isomerization of the mixture using p-toluenesulfonic acid) [20]. The structure of 333 (TUYZEU, Figure 3) [21] corresponds to a uud conformation. These isomerization experiments, together with those reported previously [9], prove that the stability decreases in the order 333 > 335 > 355 or 555.

Figure 3

A view of the structure of (a) the 333 isomer (Cambridge Structural Database (CSD) [21] refcode: TUYZEU) and (b) the 335 isomer (bis(3-methylpyrazolyl, 5-methylpyrazolyl)methane). Displacement ellipsoids are drawn at 50% probability level. Hydrogen atoms are represented as spheres of 0.1Å radii.

The melting points of three isomers were known: 333, 107–109 °C [3], 335, 114–115 °C [7], and 555, 145–148 °C [8].

2. Results and Discussion

We decided to repeat the reaction shown in Figure 1 to determine if it was possible to isolate other isomers and establish their structures, and to discuss their conformations.

2.1. Chemistry

The synthesis of N,N’,N”-3(5)-trimethylpyrazolylmethanes was performed following the protocol described by Juliá et al. for the synthesis of N,N’,N”-triazolylmethanes (see Section 3.2) [3]. The percentages were determined by 1H-NMR using the signals of the Csp3-H atom in CDCl3 at 400 MHz (Table 1): 21.8% 333, 47.8% 335, 25.2% 355 and 5.2% 555. These percentages correspond to (a + b)3 for a = 0.60 and b = 0.40 (21.6%; 43.2%; 28.8%; 6.4%) with a little worse agreement than the literature results [8].

Table 1

1H-NMR data of trispyrazolylmethanes at 400.13 MHz. Solvent CDCl3. Chemical shifts (δ, ppm) in ppm; 1H-1H spin-spin coupling constants J (Hz).

Isomer	3-Methyl	5-Methyl	CH
333	H4: 6.11 (d, 3JH4H5 = 2.5)H5: 7.38 (d, 3JH5H4 = 2.5)CH3: 2.27 (s)	----	8.128.11 [8]
335	H4: 6.11 (d, 3JH4H5 = 2.5)H5: 7.33 (d, 3JH5H4 = 2.5)CH3: 2.27 (s)	H3: 7.55 (d, 3JH3H4 = 1.5)H4: 6.11 (dq, 3JH4H3 = 1.5, 4JH4Me = 0.4)CH3: 2.39 (d, 4JMeH4 = 0.4)	8.218.21 [8]
355	H4: 6.12 (dq, 3JH4H5 = 2.5, 4JMeH4 = 0.4)H5: 7.33 (d, 3JH5H4 = 2.5)CH3: 2.29 (d)	H3: 7.37 (dq,3JH3H4 = 1.7, 5J H3Me = 0.4)H4: 5.72 (dq, 3JH4H3 = 1.7, 4JH4Me = 0.8)CH3: 2.23 (dd, 4JMeH4 = 0.8, 5JMeH3 = 0.4)	8.26 (s)8.26 [8]
555	----	H3: 7.51 (ddq, 3JH3H4 = 1.6, 5JMeH3 = 0.4)H4: 5.80 (dq, 3JH4H3 = 1.7, 4JH4Me = 0.8)CH3: 2.09 (dd, 4JMeH4 = 0.8, 5JMeH3 = 0.4)	8.31 (s)8.33 [8]

2.2. NMR Studies

Table 1 (CDCl3) and Table 2 (C6D6) contain all the NMR information concerning the four isomers. The calculated values are in the Electronic Supplementary Information (ESI), Supplementary Materials Tables S1 to S4. In CDCl3 equilibration between isomers occurs that can be due to the presence of DCl, although we keep the solvent over Ag wire. For this reason, only the “fast” 1H-NMR experiments are reported in this solvent (see later). To avoid the problems encountered with deuterochloroform we move to another solvent. We select hexadeuterobenzene because in this solvent (in earlier work C6H6 was used) the methyl groups of pyrazoles have rather different 1H-NMR chemical shifts [22,24].

Table 2

1H (400.13 MHz), 13C (100.62 MHz) and 15N (40.54 MHz) NMR data of trispyrazolylmethanes. Solvent C6D6. Chemical shifts (δ, ppm) in ppm; 1H-1H and 1H-13C spin-spin coupling constants J (Hz).

Isomer	3-Methyl	5-Methyl	CH
333	N1: –173.3 N2: –79.5	----	----
	C3: 150.9C4: 107.1, 1J = 175.3, 2J = 6.8, 3J = 3.4C5: 130.6, 1J = 188.5, 2J = 9.5, 3J = 2.5CH3: 14.0, 1J = 127.3	----	83.81J = 166.4
	H4: 5.76 (d, 3JH4H5 = 2.5)H5: 7.27 (d, 3JH5H4 = 2.5)CH3: 2.08 (s)	----	8.22
335	N1: –172.8 N2: –77.9	N1: –171.4N2: –80.4	----
	C3: 150.5C4: 107.3, 1J = 175.0, 2J = 8.3, 3J = 3.3C5: 130.3, 1J = 189.3, 2J = 9.5, 3J = 2.6CH3: 13.9, 1J = 127.2	C3: 141.2, 1J = 185.2, 2J = 5.7C4: 107.0, 1J = 175.1, 2J = 10.6, 3J = 3.8C5: 140.3 CH3: 10.5, 1J = 128.5	81.41J = 164.2
	H4: 5.82 (d, 3JH4H5 = 2.5)H5: 7.56 (d, 3JH5H4 = 2.5)CH3: 2.11 (s)	H3: 7.36 (d, 3JH3H4 = 1.7)H4: 5.62 (dq, 3JH4H3 = 1.7, 4JH4Me = 0.8)CH3: 1.82 (d, 4JMeH4 = 0.8)	8.40 (s)
355	N1: –175.6N2: –78.8	N1: –171.3N2: –76.5	----
	C3: 151.0C4: 106.8, 1J = 175.3C5: 131.3,1J = 190.3, 2J = 9.9CH3: 14.0, 1J = 127.3	C3: 140.7, 1J = 185.1, 2J = 5.8C4: 107.8, 1J = 174.8C5: 140.5CH3: 10.9, 1J = 129.1	81.61J = 164.6
	H4: 5.82 (3JH4H5 = 2.5)H5: 7.28 (3JH5H4 = 2.5)CH3: 2.14(s)	H3: 7.37 (3JH3H4 = 1.7)H4: 5.72 (dq, 3JH4H3 = 1.7, 4JH4Me = 0.8)CH3: 1.87 (m)	8.46 (s)
555	----	N1: –173.4N2: –75.4	----
	----	C3: 140.1, 1J = 185.0, J = 5.8C4: 108.1, 1J = 174.7 (m)C5: 140.5CH3: 10.9, 1J = 128.6	82.11J = 163.1
	----	H3: 7.37 (3JH3H4 = 1.7, H3)H4: 5.80 (dq, 3JH4H3 = 1.7, 4JH4Me = 0.8)CH3: 1.84 (m)	8.43 (s)

The methyl groups appear in C6D6 at ~2.10 (3-methyl) and ~1.85 ppm (5-methyl), very close to the values reported in the literature, 2.25 and 1.80 ppm, respectively [22,23,24]. These values together with the relative intensities allow an immediate identification of the four isomers by 1H-NMR.

Another useful criterion is that 3JHH has a value of 1.8 Hz between H3 and H4 protons and 2.6 Hz between H3 and H4 protons. When a methyl group was involved, then 4JH4Me5 > 4JH4Me3 [22,23,24].

The GIAO calculated chemical shifts reported in the ESI agree well with the experimental values. To determine the major conformers, the problem is that the variation of chemical shift inter-conformers are small compared with the variation within each isomer that results in correlation coefficients R = 1.000 or 0.999 in most cases (correlation coefficient matrix). However, considering not only R2, but also an intercept as small as possible and a slope as close to 1.00 as possible, the results of Table 3 were obtained.

Table 3

Best conformers according to the method. 1H in CDCl3; 13C and 15N in C6D6.

Comp	Conformation	Erel	1H	13C	15N	X-ray
333	ddd	37.1	ddd
	udd	11.2			udd
	uud	0.0	uud	uud	uud	uud: TUYZEU
	uuu	2.4		uuu
335	ddd	37.4
	ddu	15.1	ddu
	duu	17.3	duu
	udd	12.6		udd	udd
	uud	0.0		uud	uud	uud: this work
	uuu	12.1
355	ddd	23.2
	ddu	0.0	ddu		udd
	duu	2.5	duu
	udd	4.1		udd
	uud	9.9
	uuu	10.7		uuu
555	ddd	19.3
	udd	0.0	udd	udd	udd
	uud	5.9	uud	uud	uud
	uuu	18.5

They are not all consistent but clear preferences are observed. We have tried a mixture of the conformations of lower energy; for the 335 isomer we have preferred the udd (12.6 kJ·mol–1) to the uuu (12.1 kJ·mol–1).

In the case of the 555 isomers, the regression leads to a negative coefficient for the uud isomer that does not have a physical meaning, which indicates that the only isomer present is the udd isomer.

The mixtures (sum ≈ 1.00) correspond to about 3/4 of the lower energy isomers and 1/4 of the higher energy ones for 335 and 355; in the case of the 333 isomer there is 95% of the uud isomer.

We found that a solution of an almost pure sample of the 335 isomer in CDCl3 slowly isomerizes into the more stable 333 isomer (Figure 4). This could be due to the presence of DCl in the solvent produced by photodecomposition of CDCl3, and is related to the already reported isomerization in acid media [9]. The mechanism should proceed by protonation of one of the pyrazoles (formation of a pyrazolium salt), leaving this ring as neutral 3(5)-methyl-1H-pyrazole, and the resulting carbocation reacting with 3(5)-methyl-1H-pyrazole.

Figure 4

Evolution of the 333/335 ratio with time. (a) Recorded after 1 h in CDCl3, about 95% of 335 isomer and 5% of 333 isomer; (b) recorded after one night in CDCl3, about 50/50 of 335 and 333 isomer.

2.3. Crystallography

The crystal structure of 335 presents one independent molecule in its asymmetric unit with two of their pyrazole N2 atoms pointing to the CH direction and the third one pointing into the opposite direction; therefore, these molecules present an uud conformation displaying HCN1N2 dihedral angles of 39.0(6)°, 17.6(7)° and −168.1(3)°. As the crystal space group contains inversion centers, both enantiomers coexist in a 1:1 ratio.

A summary of the crystal data and structure refinement is included in the ESI as Table S1. Table 4 contains geometrical parameters of 3(5)-methylpyrazolylmethane isomers, the one recorded in the Cambridge Structural Database (CSD) [21] and the new one reported in this manuscript. A view of their molecule structure with their atom labeling is depicted in Figure 3.

Table 4

Selected geometrical parameters for 333 and 335.

	333uud (TUYZEU)			335uud
	pz_A	pz_B	pz_C	pz_A	pz_B	pz_C
N1-N2	1.359	1.362	1.355	1.359(5)	1.364(5)	1.346(6)
N2-C3	1.330	1.328	1.335	1.328(6)	1.332(5)	1.351(7)
C3-C4	1.401	1.402	1.395	1.375(7)	1.383(6)	1.338(8)
C4-C5	1.361	1.362	1.357	1.360(7)	1.343(6)	1.339(7)
N1-C5	1.349	1.351	1.347	1.326(5)	1.350(5)	1.402(6)
C1-N1	1.445	1.444	1.440	1.453(5)	1.455(5)	1.483(6)
C5-N1-N2	111.8	112.1	112.5	111.2(4)	111.8(3)	112.0(4)
N1-N2-C3	104.8	104.6	104.3	105.1(4)	104.1(3)	105.0(4)
N2-C3-C4	110.9	111.0	110.7	110.5(4)	110.9(4)	108.8(5)
C3-C4-C5	105.5	105.8	106.2	106.1(4)	106.9(4)	112.1(5)
C4-C5-N1	107.0	106.5	106.2	107.2(4)	106.4(4)	102.1(5)
C1-N1-N2	117.5	117.4	121.5	117.0(3)	118.3(3)	119.6(3)
N2/1-C3/5-C6	120.2	120.4	120.6	120.8(5)	120.5(4)	120.5(5)
C4-C3/5-C6	128.9	128.5	128.7	128.6(5)	128.7(4)	137.5(5)
H1-C1-N1-N2	24.5	28.0	−170.9	39.0(6)	17.6(7)	−168.1(3)
H1-C1-N1-C5	−164.8	−160.0	10.8	−150.3(5)	−163.4(5)	15.3(5)
C1-N1-N2-C3	173.4	173.6	−178.4	172.6(4)	179.9(4)	−177.7(4)

There are no significant differences in the observed geometry parameters for the pyrazole rings for the 3-methyl rings in both 333 and 335 isomers; however, the 5-methyl ring in 335 presents unusual geometries, especially for the intra-ring bond angles, N2-C3-C4, C3-C4-C5 and C4-C5-N1, and also for the N1-C5-C6 and C4-C5-C6 angles. There is not any apparent reason to justify this, but X-ray data collected for other crystals showed a possible occupancy disorder of the two isomers, 335 and 333. Therefore, pz_C can, overall, be of 5-methylpyrazolyl with high occupancy and 3-methylpyrazolyl at low occupancy. It also justifies the difference peaks observed around the pz_C ring (Figure 5). A disorder model has been able to be refined with a crystal collected at low temperature but, due to the problems in reaching refinement convergence with the data, and the many geometrical restraints and constraints that were necessary, we do not think that it adds any knowledge to the results presented in this manuscript.

Figure 5

A view of the molecular structure of compound 335 showing the highest difference peaks (e Å−3). Dotted lines joining these peaks mimic the disorder model observed and refined for the other crystal collected at low temperature.

Both compounds present a twist of the pz-planes describing a propeller structure independently of the N2 position (up or down).

Compound 335 forms dimers through weak CH···N hydrogen bonds (C1-H···N2(B), C6(B)-H···N2(A)) that expand into chains along (1–10) axis by C5(B)-H···N2(C) contacts. Saturating the three N-acceptors in the molecules, these chains join to form (001) layers by C-H···π-pz non-bonded interactions (C3(C)-H···π-pz(A), C4(C)-H···π-pz(B)). Methyl groups of pyrazoles A and B point out of these layers forming lines along the b-direction with an a-axis separation between methyl lines where a methyl line, from a consecutive layer, fits as a zipper to pack the layers and to build the crystal. C6(A)-H···π-pz(C) and van der Waal interactions glue the layers (Figure 6).

Figure 6

Three views of the structure of compound 335.

In the Cambridge Structural Database (CSD, Version 5.39, updates to Feb 2018) [21], 19 structures of 17 trispyrazolylmethane compounds are recorded (Figure 7). Five of these structures contain 3(5)-pyrazoles, and the observed isomers are 333 in four cases (AKUSAA, DUDFUF, TUYZEU, XIVVAA) and 335 in the remaining one (XIVVEE). The one we report here is the second example of a 335 isomer.

Figure 7

Molecular diagram of 17 trispyrazolylmethane derivatives recorded in the CSD version 5.39, updates to Feb 2018. ( cocrystallized with tmeda, benzene and n-hexane solvates).

All trispyrazolylmethane molecules display a propeller structure with a wide range of twisting in their pyrazole planes, from 3° to 68°. The most frequent conformations are udd (observed in 10 structures) and uud (observed in seven structures).

2.4. Theoretical Calculations

The geometries of the two most relevant isomers are depicted in Figure 8 while the energies are reported in Table 5.

Figure 8

The most relevant calculated structures (the geometries of all the structures are to be found in the ESI).

Table 5

Energies (kJ·mol–1). The minimum energy conformation in black; the crystallographic structure, TUYZEU, in italics.

Compound	Conformation	Relative Energy, Conformations	Relative Energy, Isomers
333	ddd	37.1
	udd	11.2
	uud	0.0	0.0
	uuu	2.4
TUYZEU	uud	0.0
335	ddd	37.4	39.1
	ddu	15.1	16.8
	duu	17.3	19.0
	udd	12.6	14.2
	uud	0.0	1.7
	uuu	12.1	13.8
355	ddd	23.2	41.0
	ddu	0.0	17.9
	duu	2.5	20.4
	udd	4.1	22.0
	uud	9.9	27.8
	uuu	10.7	28.6
555	ddd	19.3	43.1
	udd	0.0	23.8
	uud	5.9	29.7
	uuu	18.5	42.3

The isomers’ stability decreases in the order 333 (0.0) > 335 (1.7) > 355 (17.9) > 555 (23.8 kJ·mol−1), in agreement with the experimental results; this is the thermodynamic order that is unrelated to the kinetic order of the percentages measured on the crude. The acid-catalyzed isomerization from the crude leads to a mixture of 333 and 335 which have very close energies (Figure 7) [8]. Concerning the up/down isomerism, the most stable are the ones (333, 335), the one (355) and the one (555). The 355 uud is 9.9 kJ·mol−1 above the 355 ddu and the 555 uud is 5.9 kJ·mol−1 above the 555 one.

Concerning the calculated geometries, the most interesting parameters are the torsion angles (Table 6).

Table 6

Torsions (°). The minimum energy conformation in black; the crystallographic structure, TUYZEU, in italics.

Compound	Conformation	8-7-1-23	13-12-1-23	3-2-1-23
333	ddd	145.3	145.3	145.3
	udd	−5.5	177.7	159.1
	uud	−32.9	−28.1	174.4
	uuu	−40.5	−40.5	−40.5
TUYZEU	uud	−32.9	−28.2	174.4
X-ray	uud	−27.97	−24.48	170.87
335	ddd	−143.4	−149.9	−136.1
	ddu	−173.0	−85.7	12.3
	duu	145.3	−38.6	−26.9
	udd	−170.1	4.7	−151.7
	uud	−31.7	−26.7	174.9
	uuu	−52.1	−41.1	−29.0
X-ray	uud	−39.0(6)	−17.4(7)	168.2(3)
355	ddd	−136.2	−147.6	−139.6
	ddu	−173.0	−85.7	12.3
	duu	145.3	−38.6	−26.9
	udd	−170.1	4.7	−151.7
	uud	−57.9	162.3	−22.9
	uuu	−43.3	−43.1	−34.4
555	ddd	139.2	139.2	139.2
	udd	−18.4	129.3	151.6
	uud	−24.2	−50.0	156.1
	uuu	−40.2	−40.2	−40.2

The chemical shifts we have used for the interpolations (Equations (1–3)) have been obtained transforming the absolute shielding calculated with the B3LYP/6-311++G(d,p)/GIAO methods for the gas phase and then transformed through empirical equations to chemical shifts (see Section 3.5). These δ values do not correspond to the gas phase but to solution, because the empirical equations were established using gas phase σ and solution δ.

When comparing the experimental chemical shifts in solution to the GIAO calculated ones, remember that the four 3/5 isomers correspond to different molecules that are stable in the NMR time scale. On the other hand, the up/down rotational isomers are separated by low rotational barriers and in solution only averaged signals will be observed.

3. Materials and Methods

3.1. Experimental

High-resolution mass spectra were recorded on a Quadrupole Time-of-Flight (QTOF) mass spectrometer under Electrospray Ionization (ESI) conditions.

3.2. Chemistry

A mixture of 3(5)-methyl-1H-pyrazole (1.93 mL, 24 mmol), anhydrous K2CO3 (16.58 g, 120 mmol) and (Bu)4NHSO4 (0.41 g, 1.2 mmol) was vigorously stirred and refluxed in dry CHCl3 (25 mL) for 24 h. Then the mixture was filtered and the residue washed with hot CHCl3 (3 × 25 mL). The organic solution was evaporated and the crude product was purified by column chromatography (using silica 1:130) and then by crystallization using a mixture of diethyl ether/hexane. Four isomers of N,N’,N”-3(5)-trimethylpyrazolylmethanes were formed: the 3,3,3-trimethylpyrazolylmethane (333), the 3,3,5-trimethylpyrazolylmethane (335), which was the major isomer, the 3,5,5-trimethylpyrazolylmethane (355) and the 5,5,5-trimethylpyrazolylmethane (555), which was the minor isomer. The overall reaction yield calculated as the sum of all the isomers isolated by column chromatography was 46% (0.94 g), corresponding to 0.20 g of 333, 0.45 g of 335, 0.24 g of 355 and 0.05 g of 555. Melting points were determined under microscope.

Only the 335 isomer was isolated pure in enough quantity; the 355 was isolated in a very small amount only enough to measure its melting point and record its exact mass; the two other isomers, 333 and 555 only as mixtures of two isomers enriched in one of them.

Tris(3-methyl-1H-pyrazol-1-yl)methane (333): Not isolated pure. According to literature it melts at 107–109 °C [3].

Bis(3-methyl-1H-pyrazol-1-yl)(5-methyl-1H-pyrazol-1-yl)methane (335): M.p. = 109–111 °C, literature: 114–115 °C [7]. HRMS (ESI) [M + H]+ Calcd for [C13H17N6+] 257.1509, found 257.1506.

Bis(5-methyl-1H-pyrazol-1-yl)(3-methyl-1H-pyrazol-1-yl)methane (355): M.p. = 55–57 °C. HRMS (ESI) [M + H]+ Calcd for [C13H17N6+] 257.1509, found 257.1512.

Tris(5-methyl-1H-pyrazol-1-yl)methane (555): Not isolated pure. According to literature it melts at 145–148 °C [8].

3.3. NMR Spectroscopy

Solution NMR spectra were recorded on a 9.4 Tesla Bruker spectrometer (Bruker Española S.A., Madrid, Spain), 400.13 MHz for 1H, 100.62 MHz for 13C and 40.54 MHz for 15N) at 300 K with a 5-mm inverse detection H-X probe equipped with a z-gradient coil. Chemical shifts (δ in ppm) are given from internal solvents: CDCl3 7.26 for 1H; C6D6 7.16 for 1H and 128.39 for 13C. Nitromethane was used as external reference for 15N. Coupling constants (J in Hz) are accurate to ±0.2 Hz for 1H and ±0.6 Hz for 13C. CDCl3 contains 0.5 wt% silver wire as stabilizer.

Typical parameters for 1H-NMR spectra were spectral width 4000 Hz and pulse width 9.5 μs at an attenuation level of 0 dB. Typical parameters for 13C-NMR spectra were spectral width 21 kHz, pulse width 10.6 μs at an attenuation level of −6 dB and relaxation delay 2 s. WALTZ 16 was used for broadband proton decoupling; the FIDs were multiplied by an exponential weighting (lb = 2 Hz) before Fourier transformation. In some cases, for resolution enhancement processing a Gaussian multiplication of the FID prior to Fourier transformation was applied.

2D (1H-13C) gs-HMQC, (1H-13C) gs-HMBC and (1H-15N) gs-HMBC, were acquired and processed using Bruker NMR software suite (Bruker, Karlsruhe, Germany) in non-phase-sensitive mode. Gradient selection was achieved through a 5% sine truncated shaped pulse gradient of 1 ms.

Selected parameters for (1H-13C) gs-HMQC and gs-HMBC spectra were: spectral width 4000 Hz for 1H and 20 kHz for 13C, 1024 × 256 data set, number of scans 2 (HMQC) or 4 (HMBC) and relaxation delay 1s. In the gs-HMQC experiments GARP modulation of 13C was used for decoupling. The FIDs were processed using zero filling in the F1 domain and a sine-bell window function in both dimensions was applied prior to Fourier transformation.

Selected parameters for gs-HMBC spectra were: spectral width 4000 Hz for 1H and 15 kHz for 15N, 2048 × 1024 data set, number of scans 4, relaxation delay 1s. In the gs-HMBC delays of 60 and 100 ms for the evolution of the 15N-1H long-range coupling were used. The FIDs were processed using zero filling in the F1 domain and a sine-bell window function in both dimensions was applied prior to Fourier transformation.

3.4. Crystallography

For compound 335 [bis(3-methylpyrazolyl)(5-methylpyrazolyl)methane], X-ray single crystal diffraction data were collected on a Bruker APEX-II CCD diffractometer (Bruker Española S.A., Madrid, Spain) [25].

From initial data collected at room temperature, a possible occupancy disorder of the two isomers, 335 and 333 was identified. Data collected at 150 K of a different crystal allowed us to build a disorder model that showed a mixture of these two isomers. Due to the many problems to refine this disordered model and to reach convergence, we kept the best data for the work presented in this manuscript. It corresponds to data collected at room temperature and it shows the lowest proportion of the 333 isomer (so it could be omitted).

Using Olex2 (v1.2, Durham University, Durham, UK) [26], the structure was solved with the ShelXS (v4-2016, Universität Göttingen, Göttingen, Germany) [27] structure solution program using Direct Methods and refined with the ShelXL (v4-2016, Universität Göttingen, Göttingen, Germany) [28] refinement package using Least Squares minimization. A summary of the crystal data and structure refinement is included in Table S5. For the visualization and analysis of crystal structures the Mercury program was used [29].

3.5. Theoretical Calculations

Density Functional Theory (DFT) calculations were carried out using the Becke, three-Parameter, Lee, Yang and Parr (B3LYP) Gaussian 09 (Version D.01, Wallingford, CT, USA, 2009) [30,31,32], together with the 6-311++G/(d,p) basis set [33,34]. Absolute shieldings were calculated within the GIAO approximation [35,36]. All the calculations were carried out using the Gaussian 09 package (Version D.01, Wallingford, CT, USA, 2009) [37]. Empirical equations were used to transform the 1H, 13C and 15N absolute shieldings into chemical shifts [38,39].

4. Conclusions

The accuracy of the polynomial expansion (a + b)3 is extraordinary because it was unexpected. It implies that the ratios of the reactivity of the chlorine atoms with 3(5)-methyl-1H-pyrazole are the same for CHCl3, CH(Mepz)Cl2 and CH(Mepz)2Cl. This work reported the first systematic study of the structure of the four tris[3(5)-methyl]pyrazol-1-ylmethanes, a series of ligands used in coordination chemistry.

The solid-solution [40] structure of the 335 isomer, actually a mixture of 335 (major) and 333 (minor) isomers, results from the isomerization of the 335 isomer into the 333 isomer during the crystallization process. In the crystallization batch there are different crystals but a clear predominance of the 335 isomer is always found by crystallography.