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The quest for concepts of isostructurality in organic crystals has been long and mostly based on geometric data, even with the development of modern software. This field of study is of great interest to the pharmaceutical industry and for the prediction of crystal structures. Despite this, there is still no methodology that provides broad quantitative and comparable similarity data between two complete crystalline structures. The present study demonstrated that the similarity between two crystalline structures could be estimated from the similarity between the two “supramolecular clusters”. Quantitative indexes for similarity comparisons of crystal structures were shown using nine 5-aryl-1-(1,1-dimethylethyl)-1 H -pyrazoles as a model. This proposal includes the quantitative data of a geometric parameter ( I D ), a contact area parameter ( I C ), and an energetic parameter ( I G ). The proposed indexes exhibited good perspective regarding the similarity data and distinct regions of similarity. The range of similarity was set at I X ≥ 0.80, 0.80 > I X > 0.60, and I X ≤ 0.60 (X = D, C, or G). Indexes with a value near 1.0 indicate systems with isostructural, isocontact, and isoenergetic behavior. The results indicated that supramolecular structures with high similarity must have high values for all three indexes ( I D , I C , and I G ).

Polymorphs have been widely studied since different crystalline phases of the same compound may have distinct properties. Macromolecules are an area of major study with just a few polymorphs reported. This investigation presents the first case of polymorphism in a [2]rotaxane molecule. This rotaxane contains a succinamide station bearing nonsymmetric stoppers and a tetralactam macrocycle. A different polymorphic phase is achieved by varying the crystallization solvent. These polymorphs presented relevant differences at the molecular level and were classified as conformational polymorphs. At the supramolecular level, polymorph I is −21 kcal mol −1 more stable than polymorph II. Crystallization mechanisms to assess the stages of the crystallization process were proposed. Similar stabilization of the first nuclei formed was observed to be responsible for the possibility of both forms to coexist. The large differences observed between the polymorphs were not significantly reflected in the types and contribution of the intermolecular interactions, in which a high resemblance was observed.

A series of seven N -phenylamides [R–C(O)NHPh, in which R: CH 3 , C(CH 3 ) 3 , Ph, CF 3 , CCl 3 , CBr 3 , and H] were used as models in this study. Molecular packing and intermolecular interactions were evaluated by theoretical calculations, solution NMR, and quantum theory of atoms in molecules analyses. Crystallization mechanisms were proposed based on the energetic and topological parameters using the supramolecular cluster as demarcation. Concentration-dependent 1 H NMR experiments corroborated the proposed interactions between molecules. For all compounds (except for R: H, which initially formed tetramers), layers (two-dimensional) or chains (one-dimensional) were formed in the first stage of the proposed crystallization mechanisms. The presence of strong intermolecular NH···O=C interactions promoted the first stages. The study in solution provided different values of association constant ( K ass ) governed by the hydrogen bond NH···O=C, showing that the stronger interactions are directly influenced by the substituent steric hindrance. A correlation between K ass(NH···O=C) from the solution and the NH···O=C interaction energy in the crystal showed a good trend.

The first Quantum Theory of Atoms in Molecules (QTAIM) analysis of [2]­rotaxanes was used in combination with quantum mechanical calculations and variable temperature NMR experiments. The study shows all the intramolecular interactions of tetraalkylsuccinamide[2]­rotaxanes with different templates. The threads have different stoppers [R1R2NC­(O)-CH2CH2-C­(O)­NR2R1, in which R2/R1 = CH2 cy-Hex/CH2Ph, i-Bu, Bu, and Pr]. The different threads used allowed us verify that the contact area between the submolecular components (C Mcy···Thr) is closely correlated with the interaction energy (G Mcy···Thr) in the [2]­rotaxanes studied. Furthermore, the QTAIM data and quantum mechanical calculations confirmed that, in all of the compounds, the hydrogen bonds are responsible for most of the energy from the intramolecular interactions that follow the C–H···π and H···H interactions, independent of the thread used. In the liquid state, using NMR 1H some intramolecular interactions were observed, which is in agreement with the data obtained in the solid state, thus making possible a comparison between the energy data obtained via the quantum mechanical calculations and the molecular movements of the [2]­rotaxanes in solution. Consequently, a new way of understanding the intramolecular interactions in [2]­rotaxanes and the influence they have on the movement of molecular machines is presented.

A synthetic strategy to obtain a series of 3-heteroalkyl-4,5-dihydroisoxazoles, which is based on the cyclocondensation reaction of 5-heteroalkyl-1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones 1a-g, 2a-g with hydroxylamine has been developed. The preparation of 1,1,1-trichloro-5-heteroalkyl-4-methoxy-3-penten[hexen]-2-ones in good yields is also described.Isoxazole derivatives possess very interesting pharmacological properties, especially some heteroalkylisoxazoles such as semi-synthetic penicillins and cephalosporins that were prepared from 2-(3-chloroisoxazole-5-il)acetic acid, 1 muscimol an analog of g-aminobutiric acid (GABA), 2 the 3-aminomethylisoxazole and the furtetronium (2-trimethylamonium methylfurane) a GABA A receptor. 3As part of our research program, we have developed general synthesis of 1,1,1-trihalo-4-methoxy-3-alken-2-ones 4,5 and demonstrated their usefulness in the preparation of heterocycles. 4,6-8 In general, the presence of a trihalomethyl group in the precursor is a determining factor to establish the regiochemistry of the heterocyclic ring 5-8 and increases its biological activity. 9-12 The transformation of the trichloromethyl group under mild conditions 8 into carboxylic groups prompted us to devote special attention to these substrates. Despite extensive studies on the applications of 1,1,1-trihalo-4-alkoxy-3-alken-2-ones in heterocyclic chemistry 4,6-8,13-16 , the strategy to synthesize 5-heteroalkyl substituted 1,1,1-trihalo-4-alkoxy-3-alken-2-ones and their usefulness in the synthesis of heterocycles has not yet been developed. These compounds are highly functionalized intermediates, which may be useful for further synthetic conversions.In this paper we report a new and efficient synthetic approach for the preparation of a series 5-heteroalkyl-1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-one intermediates. 1-3 In a second step, we show a cyclocondensation reaction of 5-heteroalkyl-1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones with hydroxylamine to obtain the related 3-heteroalkyl-4,5-dihydroisoxazoles (Scheme 1).The compounds 1a, 2a were obtained from the reaction of 1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones with bromine in the presence of pyridine. The 1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones were synthesized from the reaction of the enol ethers or acetals with trichloroacetyl chloride. 4,5The allyl nucleophilic substitution reaction for the synthesis of 1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones 1b, 1f, 1g, 2b, 2f and 2g were carried out in acetone at 25°C for 2-96 h (Table 1). In the case of 1c and 2c, under the same conditions, we obtained only starting materials. To obtain compounds 1c and 2c it was necessary to use potassium carbonate (1 equiv) in acetone under reflux for 10-16 h.Compounds 1d, 1e, 2d and 2e were obtained by the reaction of 1a and 2a, respectively, with the appropriate nucleophile in benzene and triethylamine (1 equiv) at 25°C for 2 h. Table 1 shows the reaction conditions used for the synthesis of compounds 1b-g and 2b-g. Scheme 1 i)...

Bis-ureas are generally associated with strongly bifurcated hydrogen bonds (NH···OC interactions). For this reason, a series of trisubstituted bis-ureas (TBU) with bulk substituents were designed and used as a study model to gain a better understanding of the persistence of NH···OC interactions as driving interactions of the crystallization process. The TBU molecules possess different substituents (isopropyl, benzyl, and 4-nitro-benzyl) and variations in the methylene spacer. The TBU self-assembly, through crystallization mechanism proposals, is discussed related to the role of intermolecular interactions that drive and participate in the crystallization process. The intermolecular interactions present in the proposed first nuclei of crystallization were studied by concentration-dependent 1H NMR experiments and QTAIM analysis. Our findings showed that even with bulky substituents, the NH···OC interactions in most compounds played an important role in stabilizing the first nuclei formed during the crystallization process. However, in one case the molecular topology prevented the formation of NH···OC as the driving interaction in the first crystallization nuclei. In this case, the crystallization was mainly governed by a set of “weaker” interactions, showing that a subtle molecular change in the methylene spacer favored H···H interactions over directional N–H···O interactions. For some of the compounds studied, we propose both when the symmetry-independent molecules observed in the crystal lattice could be formed and when the water molecules are probably trapped during the crystallization to form the hydrate crystalline phases. This study contributes to the better understanding of issues related to modulating NH···OC hydrogen bonds using bulky substituents in the self-assembly of flexible TBU molecules.

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