A theoretical and NMR lanthanide-induced shift (LIS) investigation of the conformations of lactams.

Molecular mechanics (MM) with MMFF94 and MMX force fields and ab initio (RHF/6-31G*,RHF/6-311G**, and B3LYP/6-311G**) calculations are used with lanthanide-induced shift (LIS) to investigate the conformations of N-methyl-2-pyrrolidone 1, N-methyl-2-piperidone 2, ε-caprolactam 3, γ-valerolactam (1,5-dimethyl-2-pyrrolidone) 4, 2-azetidinone 5, 4-methyl azetidinone 6, 4-phenyl azetidinone 7, and N-methyl-4-phenyl azetidinone 8. The Yb(fod)3 paramagnetic induced shifts of all the 1 H and 13 C nuclei are measured and the corresponding diamagnetic complexation shifts obtained by the addition of Lu(fod)3 . The complexation model (two-, three-, or four-site) used depends on the relative rates of the processes involved. The amide inversion is the same order as that of the 5- and 6-membered lactam rings and much faster than the lanthanide complexation and the inversion of the 7-membered ring. Both MM and ab initio calculations give an envelope conformation for 1 with C-4 out of the ring plane in agreement with the LIS analysis. For the piperidone ring of 2, the half-chair is calculated as the most stable form. The LIS analysis confirms this but cannot exclude a small amount (<2%) of the boat conformation. For 3, the LIS analysis gives a minimum for 90:10% chair to boat conformation, and 4 exists in two envelope conformations with the C5 -Me ps-eq and ps-ax in an eq/ax ratio of 94:6%. In 2-azetidinone 5, the ab initio calculations gave both ring and nitrogen planar, but the MMFF94 calculations give a butterfly ring and pyramidal nitrogen. The LIS analysis for 5 gave good agreement (Rcryst 0.46%) for the MMFF94 geometry with endo NH but the planar ab initio geometries worse agreement (Rcryst = 1.1%). For 4-methyl-2-azetidinone 6, the MMFF94 geometry gave good agreement (Rcryst 0.96%) with two butterfly conformations with axial and equatorial methyl groups in 1:1 ratio. All the planar geometries gave worse agreement (Rcryst >1.5%). In 4-phenyl azetidinone 7, the MMFF94 geometry with 60% of the axial conformer gave Rcryst 1.2% but the other geometries Rcryst >1.5%. In contrast the N-methyl-4-phenyl-2-azetidinone 8 gave good agreement for all the geometries. The butterfly conformation gave Rcryst 1.1% for 80% of the axial conformer and the planar geometries Rcryst 0.98%. The LIS results confirm the ab initio and MM optimised geometries, but the conformer energies at times differ from the calculated values. They also differ considerably from the corresponding values for the lactones studied previously, and possible reasons for this are discussed.

Reversibly changing a painkiller structure: a hot topic for a cold case--ibuprofen lysine salt.

Ibuprofen lysine salt can undergo a fully reversible, thermally induced phase transition into a different enantiotropically related polymorphic form. The structures of both the high and low temperature phases were solved using state-of-the-art X-ray powder diffraction methods, showing many similarities both in the molecular conformation and in the crystal packing. The full structural analysis and comparison of the two crystal structures allowed to understand the mechanism of the phase transition and explain its reversible nature in what appears to be a rare case of isosymmetric temperature-driven phase transformation of an organic solid.

A structural powder diffraction study of two polymorphic forms of nortriptyline hydrochloride.

Nortriptyline hydrochloride, a tricyclic antidepressant, appears in two different polymorphic forms, only one of which (hereafter, form ß) has been previously characterized by single-crystal analysis. Form ß is monoclinic, P2(1)/c, with a = 5.070(2), b = 34.088(5), c = 9.976(1) Å, and ß = 90.74(2)°. A second crystalline form (the α form) has now been characterized by structural powder diffraction methods (using both laboratory and synchrotron radiation diffraction data). Form α crystallizes in the monoclinic P2/c space group, a = 9.99126(6), b = 5.10021(3), c = 34.1636(1) Å, and ß = 98.684(6)°. The thermodynamic relationship between the two forms has been determined by differential scanning calorimetry analysis and variable-temperature thermodiffractometric experiments, revealing that the two forms are monotropically related and form α is more stable. Both phases are characterized by a sequence of hydrogen-bonded N-protonated molecules, which, in the two crystalline environments, adopt the same conformation. The difference between the two crystals can be traced back to the supramolecular arrangement characterized by one-dimensional chains, built by homochiral molecules (for conformationally driven chirality) in the α form, and by enantiomeric ones in the ß form. This observation nicely explains why, upon heating, solid-solid interconversion between the two forms does not occur.

Polymorphism of linezolid: a combined single-crystal, powder diffraction and NMR study.

Linezolid (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl] acetamide is one of the first commercially available (and most widely used) oxazolidinone antibiotics. It was selectively prepared as two anhydrous polymorphic forms, labelled form II and IV in accordance with preliminary reports in the patent literature. Form II has been characterized by single-crystal X-ray diffraction methods (orthorhombic, P2 1 2 1 2 1, a=6.536(1), b=9.949(1), c=24.807(3)A, V=1613.1(3)A3, Z=4, Z'=1), while powders of form IV could be fully characterized by employing ab initio powder diffraction methods (triclinic, P1, a=6.5952(7)A, b=10.9875(10)A, c=12.9189(14)A, alpha=110.683(4) degrees , beta=88.186(6) degrees , gamma=105.826(6) degrees , V=840.5(2)A(3), Z=Z'=2). The interconversion of form II into form IV was studied by TG, DSC and thermodiffractometry, which indicated a quantitative (endothermic and irreversible) transformation (in air) just above 160 degrees C. On cooling from the melt, linezolid gives an oily material, stable at RT, which can be crystallized into form IV by controlled heating near 100 degrees C. These materials were further characterized by high-resolution 1H and 13C NMR studies, as well as by 13C solid-state NMR.