Alajos Kálmán

Classification of the isostructurality of organic molecules in the crystalline state

Since its discovery by Mitscherlich in 1819, the isomorphism of crystals has been interpreted in various, sometimes controversial ways. This can be attributed to the fact that the word isomorphous refers only to the external similarities between crystalline substances. Identical or quasi-identical packing motifs of related organic substances should therefore be distinguished by a more appropriate terminology. For organic substances, in contrast with inorganic crystals, where the recommended term is isotypic, the term isostructural is unambiguous. The present work attempts to classify the main forms as isostructural and homeostructural. Within the former class, there are two subclasses distinguished by the degree of isostructurality

Volumetric measure of isostructurality

The numerical descriptors of isostructurality are critically reviewed and to overcome their limitations a new volumetric measure is proposed. It is defined as the percentage ratio of the overlapping volume of molecules in the analyzed structures to the average of the corresponding molecular volumes. For the calculation of this index a numerical approach is presented, which is also capable of treating disordered structures. The use of isostructurality calculations is demonstrated using a series of examples. Homologous 9-alkylthiophenanthrenes are used as simple illustrations of the necessity and applicability of the new descriptor. The structural changes in the inclusion compounds of 5-methoxysulfadiazine with chloroform, dioxane and tetrahydrofuran are analyzed and rationalized with the aid of isostructurality indices. The diverse relationships among a series of helical tubuland diols cocrystallized with simple phenols are also characterized. The modifications in molecular and crystal structures are correlated with the calculated degree of isostructurality.

Isostructurality in one and two dimensions: Isostructurality of polymorphs

A set of polymorphic crystal structures was retrieved from the Cambridge Structural Database in order to estimate the frequency of isostructurality among polymorphs. Altogether, 50 structures, the polymorphs of 22 compounds, were investigated. It was found that one-, two- or three-dimensional isostructurality is exhibited by approximately half of the compounds analyzed. Among the isostructural polymorphs, the frequency of one-, two- and three-dimensional isostructurality is similar. From the examples, it appears that three-dimensional isostructurality is connected to the gradual ordering of crystal structures, while one- and two-dimensional isostructurality can often be related to specific packing interactions. The possibility of many similar interactions seems to decrease the probability of the occurrence of isostructural polymorphs. Conformational polymorphs do not exhibit isostructurality.

Comparison of the polymorphic modifications of famotidine

The polymorphic modifications of famotidine are described and characterized by their spectroscopic (infrared, X-ray) and some physico-chemical data. In addition to the standard physico-chemical data (melting point, solubility, bulk density) some further properties influencing its use in pharmaceutical technology are also characterized. The methods used to prepare the morphologically homogeneous modifications are also given.

Stereochemical studies-XXXIII.1 Saturated heterocycles-IX2: Synthesis and conformations of stereoisomeric cis- and troans-tetramethylene- and pentamethylenedihydro-1,3-oxazines

Abstract By the reaction of cis- and trans-2-aminomethylcyclohexanol (1, 2), cis- and trans-2-hydroxymethyl-cyclohexylamine (3,4) and the homologous cycloheptane derivatives (5-8) with ethyl p-chlorobenzimidate (11), cis- and trans-5,6-tetramethylene- and pentamethylene-2,3,5,6-tetrahydro-4H-1,3-oxazines (12,13,16,17) and cis- and trans-4,5-tetramethylene- and pentaimethylene-4,5-dihydro-6H-1,3-oxazines (14, 15, 18, 19) were prepared. The amidine intermediate of the ring-closure reaction was isolated, and the mechanism of the acid-catalysed reaction is discussed. It follows from the 1H NMR data that in the preferred conformations of the cis-tetramethylene-tetrahydrooxazines the methylene group of the hetero ring is equatorial and the hetero atom (O or N) axial. In contrast, the conformation equilibria of the cis pentamethylene derivatives, in accordance with earlier X-ray analysis, are shifted towards the conformer containing the methylene group in isoclinal and the hetero atom in equatorial position. The preferred conformations 12a and 14a of the tetramethylene derivatives 12 and 14 were also determined by X-ray crystal analysis.

Inclusion compounds containing a drug: structure and thermal stability of the first clathrates of nitrazepam and isothiocyanato ethanol complexes of Co(II) and Ni(II)

Abstract Syntheses, crystal structures and comparative analytical investigations on the first two inclusion compounds of an antiepileptic drug, nitrazepam (1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one) are reported. The biologically active molecule forms isostructural clathrates with diaquadiethanolbis(isothiocyanato) complexes of both cobalt(II) and nickel(II) in molar ratios of 1:2 [M(NCS)2(C2H5OH)2(H2O)2]·2C15H11N3O3 (M=Co2+, 1, and M=Ni2+, 2). Detailed analyses of the structures, the secondary interactions, the neutral drug conformations, the FTIR spectra and thermal stabilities of the clathrates, in comparison with those of the crystalline nitrazepam, have been carried out. In the crystal structures there are only host–guest hydrogen bonds of O⋯H, N⋯H and S⋯H type. Owing to the comparable size of the two constituents neither host–host nor guest–guest secondary interactions occur. In the first thermal decomposition step a parallel release of ethanol and water was observed by simultaneous thermogravimetric and differential thermal analysis measurements. This indicates that some bonds of the metal complex unit and the host–guest secondary interactions in 1 and 2 are weaker than interactions in the pure drug. If an easy release of ethanol and water occurs during dissolution of 1 and 2, it might result in an improved bioavailability of the drug, which is soluble only in aqueous ethanol.

Reaction of copper(II) with 1-carboxamide-3,5-dimethylpyrazole, 1-carboxamidine-3,5-dimethylpyrazole, 4-acetyl-3-amino-5-methylpyrazole and 5-amino-4-carboxamide-1-phenylpyrazole ☆

Abstract Complex formation of copper(II) bromide and acetate with 1-carboxamide-3,5-dimethylpyrazole (HL3) and copper(II) bromide with 5-amino-4-carboxamide-1-phenylpyrazole (L2), 4-acetyl-3-amino-5-methylpyrazole (HL4) and 1-carboxamidine-3,5-dimethylpyrazole (HL5), was studied. The obtained compounds, CuBr2(L2)2, Cu(L3)2, CuBr2(HL4)2, CuBr2(HL5)2 and [CuBr(HL1)(L3)]2 (HL1 denotes the 3,5-dimethylpyrazole), are characterized by elemental analysis, FT-IR spectrometry, molar conductivity, TG-MS and DSC. The X-ray structure of [CuBr(HL1)(L3)]2 and Cu(L3)2 is discussed. For [CuBr(HL1)(L3)]2 a dimeric penta-co-ordinated structure has been found; the co-ordination around the metal in Cu(L3)2 is trans-square planar. To CuBr2(L2)2 and CuBr2(HL4)2 a nearly tetrahedral, while for CuBr2(HL5)2 an octahedral geometry may be assumed. It means that the geometry of the compounds in the first place depends on the ligand substituents. The course of the complex formation reaction is anion-dependent and may be explained on the basis of Pearsons theory, taking into account the steric factors. A low stability intermediate formation was observed in the thermal decomposition of Cu(L3)2.

Stereochemical studies—76 saturated heterocycles—63 : synthesis of cis- and trans-n-methyl- and n-benzyl-4.5- and 5,6-tetramethylenetetrahydro-1,3-oxazines; an x-ray study of n-benzyl-cis-4,5-tetramethylenetetrahydro-1,-3-oxazinium- picrate

Abstract - The corresponding cis - and trans-N -methyl- and N -benzyl-5,6- and 4,5-tetramethylenetetrahydro-l,3-oxazines (5a,b-8a,b) were synthesized from cis - and trans-N -methyl and N -benzyl-2- aminomethyl-1-cyclohexanols 1a,b,2a,b , from cis - and trans-N -methyl- and N benzyl -2-hydroxymethyl-1-cyclohexylamines (3a,b,4a,b) by reaction with formaldehyde. The aminoalcohols 1a,2a,3a,b and 4a,b were prepared in considerably higher yields than in earlier procedures. NMR spectroscopy showed that the cis isomers of the synthesized oxazines were conformationally homogeneous in solution, and their preferred conformation (inside or outside) depended on the steric requirement of the groups attached to the anellation points, whereas a bulky C-2 substituent had no influence on the predominant conformation. The structure of N -benzyl- cis -4,5-tetramethylenetetrahydro-1,3-oxaziniumpicrate (7b) . determined by X-ray diffraction analysis, was in agreement with the predominant N-outside conformation of the corresponding base, established by means of NMR spectroscopy.

Crystal structures of ecdysteroids: the role of solvent molecules in hydrogen bonding and isostructurality.

Three crystal forms of the steroid 20-hydroxyecdysone were identified by single-crystal X-ray diffraction analysis: a solvent-free modification, a methanol solvate hydrate and a trihydrate. The structure of a closely related steroid, polypodine B (the 5,20-dihydroxy derivative of ecdysone), was determined in its monohydrate form. Since the unit-cell volume of unsolvated 20-hydroxyecdysone was found to be considerably smaller than that of ecdysone [Huber & Hoppe (1965). Chem. Ber. 98, 2403-2424], a new structure determination of ecdysone was performed, which confirmed the unexpected difference between the unit-cell volumes. The crystals of ecdysone and 20-hydroxyecdysone are isostructural, while the mixed solvate of 20-hydroxyecdysone is homostructural with the hydrate of polypodine B. A detailed analysis of the hydrogen-bond networks in these closely related crystal pairs highlights their packing similarities, demonstrates the role of solvent molecules, and explains the unexpectedly small cell volume of 20-hydroxyecdysone.

Intramolecular sulphur(IV)-oxygen interaction in sulphoxides and sulphilimines with 2-methoxycarbonyl-phenyl and 2-nitrophenyl groups: an X-ray study

Abstract The molecular structures of methyl 2-(methylthio)benzoate, dimethyl 2,2′-dithiodibenzoate, dimethyl 2,2′-thiodibenzoate, methyl 2-(2-nitrophenylthio)benzoate, 2,2′-dinitrodiphenyl sulphide and methyl 2-(2-nitrophenylthio)phenylacetate exhibiting S(II)⋯O(carbonyl) or S(II)⋯O—(nitro) close contact have been investigated by X-ray diffreaction. Planar (ArSMe), equatorial (Ar 2 S 2 ) and skew (Ar 2 S) conformations are explained by steric and conjugative effects and sulphur(II)—oxygen interaction. Linear and non-linear X—S⋯O close contacts resulting from favourable “bond direction” and unfavouralbe “lone-pair direction” approaches (2.619–2.722 and 2.900–3.402 A, respectively) are discussed in detail. Possible aryl ring positions, the geometry of rings with S⋯O contact and the nature of counter-atom (X = C, S) are considered as decisive factors. The results are consistent with different neighbouring group effects found earlier for o -CO 2 Me, o -CH 2 CO 2 Me and o -NO 2 groups. Data support the mutual dependence of S—S and S⋯O distances in compounds with a linear S—S⋯O arrangement. Other bond lenghts, e.g. CO, NO and S(II)—C ar are not affected significantly by sulphur—oxygen interaction.