Does the exception prove the rule? - A comparative study of supramolecular synthons in a series of lactam esters

In this paper a series of simple lactam esters and carboxylic acids is studied with respect to their overall conformation and hydrogen bonding patterns. In total, eight lactams featuring Nα-substitution have been synthesized. Additionally, the molecular structures of related lactam esters have been considered. The length of the amide bonds does not seem to be majorly influenced by different substituents unless the electron withdrawing N-Boc-protection group is introduced, resulting in a higher susceptibility towards hydrolytic ring opening. As known from other lactams, the Nα ester moiety of the title compounds can be in an axial or equatorial conformation. Smaller ester groups were found to prefer equatorial positions, while larger ones occupy axial sites. N-substitution seems to promote axial conformations of the respective Nα group, with enantholactams being the only studied exception. In addition to the two common amide packing motifs, i.e. the R22(8) amide dimer (NH∙∙∙O/NH∙∙∙O) and the C(4) amide chain, a third graph-set was found: the R22(8) NH∙∙∙O/CH∙∙∙O=C heterodimers. In general, there seems to be a tendency for medium- sized lactams as well as lactams with small esters to form R22(8) amide dimers. Larger esters and enantholactam esters lead to C(4) amide chains. In this respect the formation of R22(8) N-H∙∙∙O/C-H∙∙∙O=C heterodimers should be seen as a remarkable exception

First steps for the direct purification of L-Leu-L-Leu dipeptide through co-crystallisation

Trifluoroacetate salt contamination of peptides represents a challenging issue related to solid phase peptide synthesis and purification because it affects the chemical and biological properties of peptides. Purification of such materials is typically performed through a two-step post-synthetic procedure based on chromatography followed by ion exchange. For the first time, co-crystallization is presented in this study as a possible alternative and advantageous single-step method for the obtaining of TFA-free crystals of a dipeptide. A trifluoroacetate-contaminated L-Leu-L-Leu dipeptide has been used for co-crystallization experiments along with different solid coformers. New multicomponent crystals containing only the title compound and the second co-crystal formers are described in this work. Such results represent a novelty in the field of peptide chemistry and a valid proof for the use of crystal engineering-based method for a combined purification and crystallization strategy

The missing link in the homologous series of lactams: the X-ray structure of valerolactam

Lactams are an important class of heterocyclic compounds and are widely used for industrial and pharmaceutical purposes. Even decades after initial lactam syntheses, research on their physical and chemical properties is still rewarding. It delivers valuable information on the reactivity of lactams and their conformational behavior. For the small and medium-sized parent lactams the X-ray structures have been well known, except for the ‘missing link’ the 6-membered valerolactam. An X-ray structure of valerolactam is described here for the first time stimulating a comparative discussion of the homologous lactam series. The experimental solid state conformation of valerolactam differs significantly from the calculated and energy-minimized ones reported in the literature. The amide bond length in valerolactam is more or less equal to other lactams. A comparison with the structure of cyclohexene revealed striking similarities arising from the partial C-N double bond in valerolactam caused by amide resonance

First Comparative Study of the Three Polymorphs of Bis(isonicotinamide) Citric Acid Cocrystals and the Concomitant Salt 4‑Carbamoylpyridinium Citrate Isonicotinamide

This contribution presents a previously unreported example and comparative study of a binary crystalline adduct that exhibits concomitant salt and cocrystal forms. Specifically, three new polymorphs (α, β, γ) of a novel 2:1 cocrystal of bis(isonicotinamide) citric acid are reported, and the route to isolating each polymorph from aqueous solution is presented and the crystal chemistry of the system is characterized. In addition, the metastable 2:1 salt (ionic adduct) isolated as a transient (overlapping) phase under crystallization conditions identical to the polymorphs is also presented. As far as the authors can ascertain, this may be the first reported example of a salt−cocrystal−polymorphic concomitant system. A comparative study of the solid form landscape is presented, wherein mapping reveals the unique structural complexity of this multiple form salt−cocrystal concomitant system. The α and β forms are structurally very similar, where comparisons of packing behavior are shown to only be different outside the glide plane. The γ form is very different in structure, where supramolecular chirality is present. In addition, further characterization of the isolated solid-state forms includes thermal, spectroscopic, and computational analysis, all of which are employed to further verify the solid form landscape of the isonicotinamide−citric acid adduct and were found to have an order of stability of β, α, γ, salt, the salt being the metastable form

Synthesis of a bicyclic oxo-gamma-lactam from a simple caprolactam derivative

The synthesis of the 6-azabicyclo[3.2.1]octane ring system, via Dieckmann cyclization, is described. Ring closure involves reaction of a caprolactam enolate with a C-6 ester, the reactive axial conformation of which is promoted by the presence of an N-tert-butyloxycarbonyl group on the lactam nitrogen. The results will enable the synthesis of new bridged caprolactams for testing as antibacterials and nucleophilic enzyme inhibitors

Fine-tuning of a thermosalient phase transition by solid solutions

Thermosalient crystals are solids that exhibit motion at the macroscale as a consequence of a thermally induced phase transition. They represent an interesting scientific phenomenon and could be useful as actuators for the conversion of thermal energy into motion or mechanical work. The potential utilization of these miniature transducers in real-world devices requires a controllable phase transition (i.e. a predetermined temperature). While it is difficult to control these performances with a single-component molecular crystal, “tunable” properties could be accomplished by solid solutions. To verify this hypothesis, the thermosalient material [Zn(bpy)Br2] (bpy = 2,2′-bipyridine) was selected and its synthesis was performed in the presence of chloride ions. The resulting mixed crystals ([Zn(bpy)Br2xCl2(1−x)]) show that the product undergoes the expected thermosalient phase transition, and the temperature of the onset of the phase transition and the transition enthalpy depend on the Cl/Br ratio

Crystalline forms of selected agrochemical actives : design and synthesis of cocrystals

The research described in this disseration covers the crystal form screening of two analogous agrochemical actives, thiophanate-methyl and thiophanate-ethyl, as well as the discovery of seven 4-hydroxybenzoic acid cocrystals of selected agrochemical actives. Polymorphs are crystal forms of a compound that have the same composition, but a different arrangement of molecules. Cocrystals are molecular crystals composed of two or more compounds, and refer mainly to crystals which contain compounds that are solids at standard conditions. Solvates are forms that have molecules of solvent in the crystal lattice and these include hydrates, in which the solvent is water. The crystal forms of organic compounds are investigated especially in the pharmaceutical and other specialty chemical industries for better processing and activity of the compounds as well as for intellectual property reasons. Thiophanate-methyl was found to crystallize as two polymorphs and fourteen solvates, while thiophanate-ethyl was found to crystallize as four polymorphs and seven solvates. Identification of the forms was achieved mostly with powder X-ray diffraction, but methods such as IR spectroscopy, solid state NMR spectroscopy and thermogravimetric analysis were also used. The crystal structures of most of the crystal forms were determined by single crystal X-ray diffraction, allowing the inspection of intermolecular interactions such as hydrogen bonding. Reliable hydrogen bonding motifs were identified and used as supramolecular synthons in the design of new cocrystal forms. Three cocrystals of thiophanate-methyl and eight cocrystals of thiophanateethyl were found. The seven cocrystal forms of agrochemical actives with 4- hydroxybenzoic acid show better properties in comparison to the pure forms, and highlight the importance of cocrystallization in industrial applications. The design and synthesis of cocrystals as well as the analysis of packing and hydrogen bonding in crystal structures is reviewed in the literature part of this thesis

“Predicting” polymorphs of pharmaceuticals using hydrogen bond propensities: probenecid and Its two single-crystal-to-single-crystal phase transitions

The recently developed hydrogen-bonding propensity tool in the Cambridge Structural Database software package (Mercury) was tested to predict polymorphs. The compounds for the study were chosen from a list of approximately 300 pharmaceutically important compounds, for which multiple crystal forms had not been previously reported. The hydrogen-bonding propensity analysis was carried out on approximately 60 randomly selected compounds from this list. Several compounds with a high probability for exhibiting polymorphism in the analysis were chosen for a limited experimental crystal form screening. One of the compounds, probenecid, did not yield polymorphs by traditional solution crystallization screening, but differential scanning calorimetry revealed three polymorphs. All of them exhibit the same hydrogen bonding and transform via two reversible single-crystal-to single-crystal transformations, which have been characterized in detail through three single-crystal structure determinations at appropriate temperatures

“Predicting” crystal forms of pharmaceuticals using hydrogen bond propensities: two test cases

The Cambridge Structural Database incorporates an algorithm, based on data mining and statistical analysis of the structures in the database, for evaluating the “risk of polymorphism” in any compound. We have applied that algorithm to a number of pharmaceutically important compounds from the European Pharmacopoeia for which multiple crystal forms have not been reported. The survey suggested the possibility of polymorphism in at least two compounds, bufexamac and meglumine. The statistical analysis and the subsequent experimental search for polymorphism are reported here. While polymorphism was detected and characterized in both cases, the structural results were not necessarily compatible with the basis for the measure of the “risk of polymorphism”