Order versus disorder in two isomorphous pyrazolone-substituted diethyl propanedioates prepared using a three-component one-pot reaction under solvent-free conditions

Two new substituted propanedioate esters have been synthesized using a three-component solvent-free thermal reaction. The products, which are isomorphous, differ only in the presence of a bromophenyl group in one, where the molecules are fully ordered, as compared with a chlorophenyl group in the other, where the molecules exhibit two types of disorder.


Chemical context
Pyrazoles exhibit a very wide range of pharmacological and other biological activities, which have recently been extensively reviewed (Ansari et al., 2017;Karrouchi et al., 2018). In a continuation of a broadly based study of the synthesis and structures of novel pyrazole derivatives (Asma et al., 2018;Kiran Kumar et al., 2020;Shaibah et al., 2020a,b), we have now investigated a three-component reaction between diethylpropanedioate (diethylmalonate), 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde and some aryl azides. Our expectation was that the methylene group of the ester component would undergo a condensation reaction with the carbaldehyde function to provide a new electron-deficient alkene system, which would then undergo a 1,3-dipolar cycloaddition with the aryl azide to provide pyrazole-substituted 1,2,3-triazoles. The reactions, carried out under thermal and solvent-free conditions, turned out to take an entirely different course, in which the azide group was lost and giving, instead of the anticipated products, the highly substituted esters diethyl (RS)-2-[(4-bromophenyl)(5-methyl-3-oxo-2phenyl-2,3-dihydro-1H-pyrazol-4-yl)methyl]propanedioate (I) (Figs. 1 and 2) and diethyl (RS)-2-[(4-chlorophenyl)(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)methyl]propanedioate (II) (Figs. 3 and 4). The yields were fairly low, in the range 35-40%, and the course of the reaction is unclear: the by-products must include HCl and HN 3 , and the H atoms in these by-products may well arise from thermal degradation of one or more of the reactants, particularly the ester component. However, despite the modest yields, compounds (I) and (II) are formed from readily accessible precursors in a very rapid process in which two new C-C bonds are formed in a single step. Here we report the synthesis of compounds (I) and (II), the reaction sequence for which is summarized in Fig. 5, and their molecular and supramolecular structures.

Structural commentary
Compounds (I) and (II) both crystallize with Z 0 = 2 in space group P2 1 /n, and they are isomorphous. However, while the molecules in (I) are both fully ordered (Figs. 1 and 2), albeit with some evidence for large librational motion in one of the ethoxy groups, both of the independent molecules exhibit disorder in (II). In the type 1 molecule of (II), containing atom C121 (Fig. 3), the unsubstituted phenyl ring is disordered over two sets of atomic sites having occupancies 0.635 (10) and 0.365 (10), and in the type 2 molecule, containing atom C221 (Fig. 4), the whole diethylmalonate fragment is disordered over two sets of atomic sites having occupancies 0.690 (5) and 0.310 (5).
All of the molecules contain a stereogenic centre, at atom C121 in the type 1 molecules (Figs. 1 and 3) and at atom C221 in the type 2 molecules (Figs. 2 and 4), and all of the reference molecules were selected to have the R-configuration. The centrosymmetric space group confirms that both compounds have crystallized as racemic mixtures.
In both molecules of compound (I), the substituents on the The structure of the type 2 molecule of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 3
The structure of the type 1 molecule of (II), showing the atom-labelling scheme and the disorder. The major disorder component is drawn using full lines and the minor disorder component is drawn using broken lines. Displacement ellipsoids are drawn at the 30% probability level.

Figure 1
The structure of the type 1 molecule of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level. conformation that is almost fully staggered, with the two H atoms antiperiplanar (Table 1); the same applies to compound (II) (Figs. 3 and 4), including both of the disorder components in the type 2 molecule. However, comparison of other aspects of the molecular conformations of the two independent molecules in the ordered structure of (I) shows some marked differences between the two molecules (Table 1; Figs. 1 and 2). In particular, the components of the diester function in the two molecules are very different, as exemplified by the values of the torsional angles Cx21-Cx2-Cx1-Ox2 and Cx21-Cx2-Cx3-Ox4 (Figs. 1 and 2). Of the atoms in the ethoxy groups, only atom C14 participates in the hydrogen bonding (Table 2); while this may influence the conformation of the ethoxy group O12/C14/C15, the other ethoxy groups are most probably adopting conformations that reflect their efficient accommodation in the spaces available in the supramolecular assembly generated by the hydrogen bonds (cf. Section 3 below). Similar remarks apply to the conformations of the disordered ester units in compound (II), below. Similarly, the orientations of the aryl group in the two molecules differ, as shown by the torsional angles Cx2-Cx21-Cx31-Cx32 and Nx41-Nx42-Cx51-Cx52 (where x = 1 or 2; Figs. 1 and 2). These differences may be associated with the different hydrogen-bonding behaviour of the two molecules. Thus, different ester units in the two molecules are involved in hydrogen bonding (Table 2). The aryl groups in both molecules are involved in hydrogen bonding; the substituted ring provides donors in both molecules, in a C-HÁ Á ÁO hydrogen bond in the type 1 molecule and in a C-HÁ Á Á(arene) hydrogen bond in the type 2 molecule, but only in the type 1 molecule does the unsubstituted aryl ring act as a hydrogenbond acceptor.
In compound (II), the conformations of the major disorder components are very similar to those of the corresponding molecules of compound (I), but those of the minor disorder components in the type 2 molecule differ significantly (Table 1; Fig. 4), but the conformations of the two disorder components in the type 1 molecule of (II) differ only modestly (Table 2; Fig. 3).
In compound (II) there is a rather short HÁ Á ÁH contact, 1.79 Å , between the minor occupancy atom H163 in the reference molecule 1 at (x, y, z) and the idealized riding site of the major occupancy atom H25A in molecule 2 at (1 + x, y, z). However, the atom H25A forms part of a methyl group, and such methyl groups are likely to be undergoing extremely rapid rotations about the adjacent C-C bonds, particularly at ambient temperature (Riddell & Rogerson, 1996, 1997 Table 1 Selected torsional angles ( ).

Figure 4
The structure of the type 2 molecule of (II), showing the atom-labelling scheme and the disorder. The major disorder component is drawn using full lines and the minor disorder component is drawn using broken lines. Displacement ellipsoids are drawn at the 30% probability level and, for the sake of clarity, a few of the atom labels have been omitted.
suggest that if the minor-occupancy form of molecule 1 is present at (x, y, z), then molecule 2 at (1 + x, y, z) will probably also be the minor-occupancy form. However, this does not imply any longer-range correlation between the disorder components, nor require any relationship between the disorder occupancy factors for the two independent molecules. Compounds (I) and (II) were crystallized under identical conditions, and their crystals thus obtained are isomorphous (Table 3); it is therefore surprising to find that while the structure of compound (I) is ordered, that of compound (II) is disordered in two different ways, so that although these compounds are isomorphous, they cannot be regarded as strictly isostructural (cf. Acosta et al., 2009;Yé pes et al., 2012). It is also surprising to note that the unit-cell volume, and hence the molar volume, is smaller for the bromo compound (I) than for the chloro compound (II), although the reverse relationship would be expected (Hofmann, 2002). The larger molar volume for (II) is almost certainly associated with the disorder, but this does not shed any light on the underlying reasons for this disorder, as compared with the ordered structure of (I). Whether the larger volume is a consequence of the disorder or whether the disorder is actually a consequence of the larger molar volume, itself the result of some other factors, remains in doubt. In the absence of a systematic study of the effects of the crystallization regime on relationship between unit-cell volume and the order/disorder question, which we currently have no plans to undertake, any further comments could not be more than pure speculation.

Supramolecular features
The hydrogen bonds formed by compounds (I) and (II) are very similar (Table 2), so that it is necessary only to discuss in detail the supramolecular assembly in compound (I). Within the selected asymmetric unit of (I), the two molecules are linked by an N-HÁ Á ÁO hydrogen bond, and bimolecular units of this type that are related by the n-glide plane at y = 0.75 are linked by a second, almost linear N-HÁ Á ÁO hydrogen bond to form a C 2 2 (10) (Etter, 1990;Etter et al., 1990;Bernstein et al., 1995) chain running parallel to the [101] direction. The formation of this chain is augmented by a C-HÁ Á ÁO hydrogen bond between bimolecular units related by the n-glide plane at y = 0.75, resulting in a chain of rings running parallel to the [101] direction (Fig. 6). There is also a C-HÁ Á Á(arene) interaction within the selected asymmetric unit. Inversionrelated pairs of chains of this type are further linked, albeit fairly weakly (Wood et al., 2009), by a second C-HÁ Á ÁO hydrogen bond to form a complex sheet lying parallel to (101). Entirely similar remarks apply to the supramolecular assembly of compound (II) ( Table 2).

Refinement
Crystal data, data collection and refinement details are summarized in Table 3. For compound (I), all H atoms were located in difference maps. The H atoms bonded to C atoms were then treated as riding atoms in geometrically idealized positions with C-H distances of 0.95 Å (aromatic), 0.98 Å (CH 3 ), 0.99 Å (CH 2 ) or 1.00 Å (aliphatic C-H), and with U iso (H) = 1.2U eq (C). For the H atoms bonded to N atoms, the atomic coordinates were refined with U iso (H) = 1.2U eq (N) giving the N-H distances shown in Table 2. A search for possible additional crystallographic symmetry found none. For compound (II), the initial refinement used the atomic coordinates of compound (I), with exactly the same treatment for the H atoms, but it was immediately apparent that both of the independent molecules in (II) exhibited disorder. In molecule 1, containing atom C121, the unsubstituted phenyl ring was disordered, while in molecule 2, containing atom C221, the diethylmalonate fragment was disordered. In each molecule, the bonded distances and the 1,3-non-bonded distances in the minor disorder component were restrained to be the same of the corresponding distances in the major component, subject to s.u. values of 0.01 and 0.02 Å , respectively. In addition, the anisotropic displacement parameters for the atoms in the disordered portions of the molecules were subjected to a similarity restraint, while the C221-C22 and C221-C32 distances were restrained to be equal, subject to an s.u. of 0.02 Å , as were all of the O-C distances and all of the C-C distances in the ethoxy units. Subject to these conditions, the N-H distances are as shown in Table 2, and the refined disorder occupancies are 0.635 (10) and 0.365 (10) in molecule 1, and 0.690 (5) and 0.310 (5) in molecule 2.    SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics: PLATON (Spek, 2020); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015b) and PLATON (Spek, 2020).