Polymorphs and Polymorphic Cocrystals of Temozolomide

Crystal polymorphism in the antitumor drug temozolomide (TMZ), cocrystals of TMZ with 4,4′‐bipyridine‐N,N′‐dioxide (BPNO), and solid‐state stability were studied. Apart from a known X‐ray crystal structure of TMZ (form 1), two new crystalline modifications, forms 2 and 3, were obtained during attempted cocrystallization with carbamazepine and 3‐hydroxypyridine‐N‐oxide. Conformers A and B of the drug molecule are stabilized by intramolecular amide N? H???N_imidazole and N? H???N_tetrazine interactions. The stable conformer A is present in forms 1 and 2, whereas both conformers crystallized in form 3. Preparation of polymorphic cocrystals I and II (TMZ?BPNO 1:0.5 and 2:1) were optimized by using solution crystallization and grinding methods. The metastable nature of polymorph 2 and cocrystal II is ascribed to unused hydrogen‐bond donors/acceptors in the crystal structure. The intramolecularly bonded amide N–H donor in the less stable structure makes additional intermolecular bonds with the tetrazine C?O group and the imidazole N atom in stable polymorph 1 and cocrystal I, respectively. All available hydrogen‐bond donors and acceptors are used to make intermolecular hydrogen bonds in the stable crystalline form. Synthon polymorphism and crystal stability are discussed in terms of hydrogen‐bond reorganization.     

An Internal Fluorescent Probe Based on Anthracene to Evaluate Cation–Anion Interactions in Imidazolium Salts

A series of fluorescent imidazolium‐based salts containing the cation [AnCH₂MeIm]⁺ (in which An=anthracene and Im=the imidazolium cation) with Cl^?, BF₄^?, PF₆^?, SO₃CF₃^?, [N(CN)₂]^?, [N(SO₂CF₃)₂]^?, or PhBF₃^? anions have been prepared and characterized. X‐ray diffraction analysis of four of the salts reveals a number of C? H???X‐type (X=O, N, F) hydrogen bonds between the hydrogen atoms from the imidazolium ring and in some cases from the anthracene ring with the electronegative atoms of the anions. Additionally, C? H???π interactions can be found in all the salts analyzed by X‐ray diffraction, whereas π–π stacking is observed only in the salt containing the phenyltrifluoroborate anion. Fluorescence emission analysis in acetonitrile shows that the fluorescence of these salts varies significantly according to the nature of the anion, and correlates to the extent of ion pairing present in solution. Photodimerization of these salts was observed, and in one case a dimer has been isolated and characterized by X‐ray crystallography.     

δ‐Sulfanilamide

The δ polymorph of sulfanilamide (or 4‐aminobenzenesulfonamide), C₆H₈N₂O₂S, displays an overall three‐dimensional hydrogen‐bonded network that is dominated by a two‐dimensional substructure with R²₂(8) rings; these result from dimeric N—H...O interactions between adjacent sulfonamide groups. This study shows how the polymorphism of sulfanilamide is linked to its versatile hydrogen‐bonding capabilities.     

Chloromethane–Water Adduct: Rotational Spectrum,Weak Hydrogen Bonds,and Internal Dynamics

The rotational spectra of four isotopologues of the 1:1 complex between chloromethane and water revealed the presence of only one rotamer in a pulsed jet expansion. The two subunits are linked through two weak hydrogen bonds, O? H???Cl (R_H???Cl=2.638(2) Å) and C? H???O (R_H???O=2.501(2) Å), forming a five‐membered ring. All transitions display the hyperfine structure due to the ³⁵Cl (or ³⁷Cl) nuclear quadrupole effects. Dynamical features in the spectrum are caused by two large‐amplitude motions. Each component line appears as an asymmetric doublet with a relative intensity ratio of 1:3. The splittings led to the determination of barrier to internal rotation of water around its symmetry axis, V₂=320(10) cm^?1. Finally, an unexpected small value of the inertial defect (?0.96 uŲ rather than ?3.22 uŲ) allowed the estimation of the barrier to the internal rotation of the CH₃ group, V₃≈8 cm^?1.     

The 1:1 inclusion compounds zolmitriptan–benzene and zolmitriptan–phenol

In the benzene and phenol solvates of (S)‐4‐{3‐[2‐(dimethylamino)ethyl]‐1H‐indol‐5‐ylmethyl}oxazolidin‐2‐one, viz. C₁₆H₂₁N₃O₂·C₆H₆, (I), and C₁₆H₂₁N₃O₂·C₆H₅OH, (II), the host molecule has three linked residues, namely a planar indole ring system, an ethylamine side chain and an oxazolidinone system. It has comparable features to that of sumatriptan, although the side‐chain orientations of (I) and (II) differ from those of sumatriptan. Both (I) and (II) have host–guest‐type structures. The host molecule in (I) and (II) has an L‐shaped form, with the oxazolidinone ring occupying the base and the remainder of the molecule forming the upright section. In (I), each benzene guest molecule is surrounded by four host molecules, and these molecules are linked by a combination of N—H...N, N—H...O and C—H...O hydrogen bonds into chains of edge‐fused R₄⁴(33) rings. In (II), two independent molecules are present in the asymmetric unit, with similar conformations. The heterocyclic components are connected through N—H...N, N—H...O and C—H...O interactions to form chains of edge‐fused R₆⁴(38) rings, from which the phenol guest molecules are pendent, linked by O—H...O hydrogen bonds. The structures are further stabilized by extensive C—H...π interactions.     

Hydrogen Bonding of Fluorinated Saccharides in Solution: F Acting as H‐Bond Acceptor in a Bifurcated H‐Bond of 4‐Fluorinated Levoglucosans

4‐Fluorinated levoglucosans were synthesised to test if OH???F H‐bonds are feasible even when the O???F distance is increased. The fluorinated 1,6‐anhydro‐β‐D ‐glucopyranoses were synthesised from 1,6 : 3,4‐dianhydro‐β‐D ‐galactopyranose ( 8 ). Treatment of 8 with KHF₂ and KF gave 43% of 4‐deoxy‐4‐fluorolevoglucosan ( 9 ), which was transformed into the 3‐O‐protected derivatives 13 by silylation and 15 by silylation, acetylation, and desilylation. 4‐Deoxy‐4‐methyllevoglucosan ( 19 ) and 4‐deoxylevoglucosan ( 21 ) were prepared as reference compounds that can only form a bivalent H‐bond from HO? C(2) to O? C(5). They were synthesised from the ⁱPr₃Si‐protected derivative of 8 . Intramolecular bifurcated H‐bonds from HO? C(2) to F? C(4) and O? C(5) of the 4‐fluorinated levoglucosans in CDCl₃ solution are evidenced by the ¹H‐NMR scalar couplings ^h1J(F,OH) and ³J(H,OH). The OH???F H‐bond over an O???F distance of ca. 3.0 Å is thus formed in apolar solvents, at least when favoured by the simultaneous formation of an OH???O H‐bond.     

trans‐Diaquabis(3‐hydroxybenzoato‐κO1)bis(nicotinamide‐κN1)copper(II)

The title compound, [Cu(C₇H₅O₃)₂(C₆H₆N₂O)₂(H₂O)₂], is a two‐dimensional hydrogen‐bonded supramolecular complex. The Cu^II ion resides on a centre of symmetry and is in an octahedral coordination environment comprising two pyridine N atoms, two carboxylate O atoms and two O atoms from water molecules. Intermolecular N—H...O and O—H...O hydrogen bonds produce R₂²(4), R₂²(8) and R₂²(15) rings which lead to one‐dimensional polymeric chains. An extensive two‐dimensional network of N—H...O and O—H...O hydrogen bonds and C—H...π interactions are responsible for crystal stabilization.     

Diamine‐Catalyzed Addition of ZnEt2 to PhC(O)CF3: Two Mechanisms and Autocatalytic Asymmetric Enhancement

NMR spectroscopic studies of the catalytic addition reaction of ZnEt₂ to PhC(O)CF₃ in the presence of three very efficient catalysts [TMEDA, tBuBOX, and L ; where L is a chiral diamine synthesized from optically pure (R,R)‐1,2‐diphenylethylenediamine and (S)‐2,2′‐bis‐(bromomethyl)‐1,1′‐binaphthalene] reveal large differences in their behavior. For the ligands TMEDA and tBuBOX, the catalysis shows no unusual features and proceeds via [(N?N)Zn(Et){OC(CF₃)(Et)Ph}]. For N?N? L , the observation of autocatalytic asymmetric enhancement during the catalysis, and unusual inverse concentration dependence on the reaction rate, indicate the participation of an additional novel catalytic cycle that goes through a dinuclear intermediate containing one ZnEt₂ and one ZnEt fragment connected by N?N and OR bridges. Interestingly, the ¹⁹F NMR signals of the main product of the reaction ([Zn(Et){OC*(CF₃)(Et)Ph}]₂) allowed us to assess the enantioselectivity of the processes in situ without the assistance of chiral chromatography.     

trans‐Diaquabis(nicotinamide‐κN)bis(salicylato‐κO)cobalt(II)

The title compound, [Co(C₇H₅O₃)₂(C₆H₆N₂O)₂(H₂O)₂], forms a three‐dimensional hydrogen‐bonded supramolecular structure. The Co^II ion is in an octahedral coordination environment comprising two pyridyl N atoms, two carboxylate O atoms and two O atoms from water molecules. Intermolecular N—H...O and O—H...O hydrogen bonds produce R₂²(8), R₂²(12) and R₂²(14) rings, which lead to two‐dimensional chains. An extensive three‐dimensional supramolecular network of C—H...O, N—H...O and O—H...O hydrogen bonds and C—H...π interactions is responsible for crystal structure stabilization. This study is an example of the construction of a supramolecular assembly based on hydrogen bonds in mixed‐ligand metal complexes.     

Anion‐, Solvent‐, Temperature‐, and Mechano‐Responsive Photoluminescence in Gold(I) Diphosphine‐Based Dimers

A series of [Au₂(nixantphos)₂](X)₂ (nixantphos=4,6‐bis(diphenylphosphino)‐phenoxazine; X=NO₃, 1 ; CF₃COO, 2 ; CF₃SO₃, 3 ; [Au(CN)₂], 4 ; and BF₄, 5 ) complexes that exhibit intriguing anion‐switchable and stimuli‐responsive luminescent photophysical properties have been synthesized and characterized. Depending on their anions, these complexes display yellow ( 3 ), orange ( 4 and 5 ), and red ( 1 and 2 ) emission colors. They exhibit reversible thermo‐, mechano‐, and vapochromic luminescence changes readily perceivable by the naked eye. Single‐crystal X‐ray studies show that the [Au₂(nixantphos)₂]²⁺ cations with short intramolecular Au ??? Au interactions are involved as donors in an infinite N?H ??? X (X=O and N) hydrogen‐bonded chain formation with CF₃COO^? ( 2 C ) and aurophilically linked [Au(CN)₂]^? counterions ( 4 C ). Both crystals show thermochromic luminescence; their room temperature red ( 2 C ) and orange ( 4 C ) emission turns into yellow upon cooling to 77 K. They also exhibit reversible mechanochromic luminescence by changing their emission color from red to dark ( 2 C ), and orange to red ( 4 C ). Compounds 1 – 5 also display reversible mechanochromic luminescence, altering their emission colors between orange ( 1 ) or red ( 2 ) to dark, as well as between yellow ( 3 ) or orange ( 4 and 5 ) to red. Detailed photophysical investigations and correlation with solid‐state structural data established the significant role of N?H ??? X interactions in the stimuli‐responsive luminescent behavior.     

A Combined Experimental and Theoretical Electron Density Study of Intra‐ and Intermolecular Interactions in Thiourea S,S‐Dioxide

The thiourea S,S‐dioxide molecule is recognized as a zwitterion with a high dipole moment and an unusually long C? S bond. The molecule has a most interesting set of intermolecular interactions in the crystalline state—a relatively strong O???H? N hydrogen bond and very weak intermolecular C???S and N???O interactions. The molecule has C_s symmetry, and each oxygen atom is hydrogen‐bonded to two hydrogen atoms with O???H? N distances of 2.837 and 2.826 Å and angles of 176.61 and 158.38°. The electron density distribution is obtained both from Xray diffraction data at 110 K and from a periodic density functional theory (DFT) calculation. Bond characterization is made in terms of the analysis of topological properties. The covalent characters of the C? N, N? H, C? S, and S? O bonds are apparent, and the agreement on the topological properties between experiment and theory is adequate. The features of the Laplacian distributions, bond paths, and atomic domains are comparable. In a systematic approach, DFT calculations are performed based on a monomer, a dimer, a heptamer, and a crystal to see the effect on the electron density distribution due to the intermolecular interactions. The dipole moment of the molecule is enhanced in the solid state. The typical values of ρ_b and H_b of the hydrogen bonds and weak intermolecular C???S and N???O interactions are given. All the interactions are verified by the location of the bond critical point and its associated topological properties. The isovalue surface of Laplacian charge density and the detailed atomic graph around each atomic site reveal the shape of the valence‐shell charge concentration and provide a reasonable interpretation of the bonding of each atom.     

The anilinium chloride adduct of 4‐bromo‐N‐phenylbenzene­sulfonamide

The title compound anilinium chloride–4‐bromo‐N‐phenyl­benzene­sulfonamide (1/1), C₆H₈N⁺·Cl⁻·C₁₂H₁₀BrNO₂S, displays a hydrogen‐bonded ladder motif with four independent N—H⋯Cl bonds in which both the NH group of the sulfonamide molecule and the NH₃ group of the anilinium ion [N⋯Cl = 3.135 (3)–3.196 (2) Å and N—H⋯Cl = 151–167°] are involved. This hydrogen‐bonded chain contains two independent R₄²(8) rings and each chloride ion acts as an acceptor of four hydrogen bonds.     

Strong N−X⋅⋅⋅O−N Halogen Bonds: A Comprehensive Study on N‐Halosaccharin Pyridine N‐Oxide Complexes

A study of the strong N?X???^?O?N⁺ (X=I, Br) halogen bonding interactions reports 2×27 donor×acceptor complexes of N‐halosaccharins and pyridine N‐oxides (PyNO). DFT calculations were used to investigate the X???O halogen bond (XB) interaction energies in 54 complexes. A simplified computationally fast electrostatic model was developed for predicting the X???O XBs. The XB interaction energies vary from ?47.5 to ?120.3 kJ mol^?1; the strongest N?I???^?O?N⁺ XBs approaching those of 3‐center‐4‐electron [N?I?N]⁺ halogen‐bonded systems (ca. 160 kJ mol^?1). ¹H NMR association constants (K_XB) determined in CDCl₃ and [D₆]acetone vary from 2.0×10⁰ to >10⁸ m ^?1 and correlate well with the calculated donor×acceptor complexation enthalpies found between ?38.4 and ?77.5 kJ mol^?1. In X‐ray crystal structures, the N‐iodosaccharin‐PyNO complexes manifest short interaction ratios (R_XB) between 0.65–0.67 for the N?I???^?O?N⁺ halogen bond.     

Resonance Character of Copper/Silver/Gold Bonding in Small Molecule⋅⋅⋅MX (X=F,Cl, Br,CH3, CF3) Complexes

The resonance character of Cu/Ag/Au bonding is investigated in B???M?X (M=Cu, Ag, Au; X=F, Cl, Br, CH₃, CF₃; B=CO, H₂O, H₂S, C₂H₂, C₂H₄) complexes. The natural bond orbital/natural resonance theory results strongly support the general resonance‐type three‐center/four‐electron (3c/4e) picture of Cu/Ag/Au bonding, B:M?X?B⁺?M:X^?, which mainly arises from hyperconjugation interactions. On the basis of such resonance‐type bonding mechanisms, the ligand effects in the more strongly bound OC???M?X series are analyzed, and distinct competition between CO and the axial ligand X is observed. This competitive bonding picture directly explains why CO in OC???Au?CF₃ can be readily replaced by a number of other ligands. Additionally, conservation of the bond order indicates that the idealized relationship b_B???M+b_MX=1 should be suitably generalized for intermolecular bonding, especially if there is additional partial multiple bonding at one end of the 3c/4e hyperbonded triad.     

A novel tubular hydrogen‐bond pattern in a new diazaphosphole oxide: a combination of X‐ray crystallography and theoretical study of hydrogen bonds

In the structure of 2‐(4‐chloroanilino)‐1,3,2λ⁴‐diazaphosphol‐2‐one, C₁₂H₁₁ClN₃OP, each molecule is connected with four neighbouring molecules through (N—H)₂…O hydrogen bonds. These hydrogen bonds form a tubular arrangement along the [001] direction built from R ³₃(12) and R ₄³(14) hydrogen‐bond ring motifs, combined with a C (4) chain motif. The hole constructed in the tubular architecture includes a 12‐atom arrangement (three P, three N, three O and three H atoms) belonging to three adjacent molecules hydrogen bonded to each other. One of the N—H groups of the diazaphosphole ring, not co‐operating in classical hydrogen bonding, takes part in an N—H…π interaction. This interaction occurs within the tubular array and does not change the dimension of the hydrogen‐bond pattern. The energies of the N—H…O and N—H…π hydrogen bonds were studied by NBO (natural bond orbital) analysis, using the experimental hydrogen‐bonded cluster of molecules as the input file for the chemical calculations. In the ¹H NMR experiment, the nitrogen‐bound proton of the diazaphosphole ring has a high value of 17.2 Hz for the ²J _H–P coupling constant.     

The Intermolecular S?H⋅⋅⋅Y (Y=S,O) Hydrogen Bond in the H2S Dimer and the H2S–MeOH Complex

The nature of the S? H???S hydrogen‐bonding interaction in the H₂S dimer and its structure has been the focus of several theoretical studies. This is partly due to its structural similarity and close relationship with the well‐studied water dimer and partly because it represents the simplest prototypical example of hydrogen bonding involving a sulfur atom. Although there is some IR data on the H₂S dimer and higher homomers from cold matrix experiments, there are no IR spectroscopic reports on S? H???S hydrogen bonding in the gas phase to‐date. We present experimental evidence using VUV ionization‐detected IR‐predissociation spectroscopy (VUV‐ID‐IRPDS) for this weak hydrogen‐bonding interaction in the H₂S dimer. The proton‐donating S? H bond is found to be red‐shifted by 31 cm^?1. We were also able to observe and assign the symmetric (ν₁) stretch of the acceptor and an unresolved feature owing to the free S? H of the donor and the antisymmetric (ν₃) SH stretch of the acceptor. In addition we show that the heteromolecular H₂S–MeOH complex, for which both S? H???O and O? H???S interactions are possible, is S‐H???O bound.     

Two polymorphs of 5‐cyclohexyl‐5‐ethylbarbituric acid and their packing relationships with other barbiturates

Polymorph (Ia) (m.p. 474 K) of the title compound, C₁₂H₁₈N₂O₃, displays an N—H...O=C hydrogen‐bonded layer structure which contains R₆⁶(28) rings connecting six molecules, as well as R₂²(8) rings linking two molecules. The 3‐connected hydrogen‐bonded net resulting from these interactions has the hcb topology. Form (Ib) (m.p. 471 K) displays N—H...O=C hydrogen‐bonded looped chains in which neighbouring molecules are linked to one another by two different R₂²(8) rings. Polymorph (Ia) is isostructural with the previously reported form II of 5‐(2‐bromoallyl)‐5‐isopropylbarbituric acid (noctal) and polymorph (Ib) is isostructural with the known crystal structures of four other barbiturates.     

Hydrogen‐Bond Cooperativity in Formamide2–Water: A Model for Water‐Mediated Interactions

The rotational spectrum of formamide₂–H₂O formed in a supersonic jet has been characterized by Fourier‐transform microwave spectroscopy. This adduct provides a simple model of water‐mediated interaction involving the amide linkages, as occur in protein folding or amide‐association processes, showing the interplay between self‐association and solvation. Mono‐substituted ¹³C, ¹⁵N, ¹⁸O, and ²H isotopologues have been observed and their data used to investigate the structure. The adduct forms an almost planar three‐body sequential cycle. The two formamide molecules link on one side through an N?H???O hydrogen bond and on the other side through a water‐mediated interaction with the formation of C=O???H?O and O???H?N hydrogen bonds. The analysis of the quadrupole coupling effects of two ¹⁴N‐nuclei reveals the subtle inductive forces associated to cooperative hydrogen bonding. These forces are involved in the changes in the C=O and C?N bond lengths with respect to pure formamide.     

Chiral Fluorinated α‐Sulfonyl Carbanions: Enantioselective Synthesis and Electrophilic Capture,Racemization Dynamics,and Structure

Enantiomerically pure triflones R¹CH(R²)SO₂CF₃ have been synthesized starting from the corresponding chiral alcohols via thiols and trifluoromethylsulfanes. Key steps of the syntheses of the sulfanes are the photochemical trifluoromethylation of the thiols with CF₃Hal (Hal=halide) or substitution of alkoxyphosphinediamines with CF₃SSCF₃. The deprotonation of RCH(Me)SO₂CF₃ (R=CH₂Ph, iHex) with nBuLi with the formation of salts [RC(Me)? SO₂CF₃]Li and their electrophilic capture both occurred with high enantioselectivities. Displacement of the SO₂CF₃ group of (S)‐MeOCH₂C(Me)(CH₂Ph)SO₂CF₃ (95 % ee) by an ethyl group through the reaction with AlEt₃ gave alkane MeOCH₂C(Me)(CH₂Ph)Et of 96 % ee. Racemization of salts [R¹C(R²)SO₂CF₃]Li follows first‐order kinetics and is mainly an enthalpic process with small negative activation entropy as revealed by polarimetry and dynamic NMR (DNMR) spectroscopy. This is in accordance with a C_α? S bond rotation as the rate‐determining step. Lithium α‐(S)‐trifluoromethyl‐ and α‐(S)‐nonafluorobutylsulfonyl carbanion salts have a much higher racemization barrier than the corresponding α‐(S)‐tert‐butylsulfonyl carbanion salts. Whereas [PhCH₂C(Me)SO₂tBu]Li/DMPU (DMPU = dimethylpropylurea) has a half‐life of racemization at ?105 °C of 2.4 h, that of [PhCH₂C(Me)SO₂CF₃]Li at ?78 °C is 30 d. DNMR spectroscopy of amides (PhCH₂)₂NSO₂CF₃ and (PhCH₂)N(Ph)SO₂CF₃ gave N? S rotational barriers that seem to be distinctly higher than those of nonfluorinated sulfonamides. NMR spectroscopy of [PhCH₂C(Ph)SO₂R]M (M=Li, K, NBu₄; R=CF₃, tBu) shows for both salts a confinement of the negative charge mainly to the C_α atom and a significant benzylic stabilization that is weaker in the trifluoromethylsulfonyl carbanion. According to crystal structure analyses, the carbanions of salts {[PhCH₂C(Ph)SO₂CF₃]Li? L }₂ ( L =2 THF, tetramethylethylenediamine (TMEDA)) and [PhCH₂C(Ph)SO₂CF₃]NBu₄ have the typical chiral C_α? S conformation of α‐sulfonyl carbanions, planar C_α atoms, and short C_α? S bonds. Ab initio calculations of [MeC(Ph)SO₂tBu]^? and [MeC(Ph)SO₂CF₃]^? showed for the fluorinated carbanion stronger n_C→σ* and n_O→σ* interactions and a weaker benzylic stabilization. According to natural bond orbital (NBO) calculations of [R¹C(R²)SO₂R]^? (R=tBu, CF₃) the n_C→σ*_{S? R} interaction is much stronger for R=CF₃. Ab initio calculations gave for [MeC(Ph)SO₂tBu]Li ? 2 Me₂O an O,Li,C_α contact ion pair (CIP) and for [MeC(Ph)SO₂CF₃]Li ? 2 Me₂O an O,Li,O CIP. According to cryoscopy, [PhCH₂C(Ph)SO₂CF₃]Li, [iHexC(Me)SO₂CF₃]Li, and [PhCH₂C(Ph)SO₂CF₃]NBu₄ predominantly form monomers in tetrahydrofuran (THF) at ?108 °C. The NMR spectroscopic data of salts [R¹(R²)SO₂R³]Li (R³=tBu, CF₃) indicate that the dominating monomeric CIPs are devoid of C_α? Li bonds.