The 2:1 complex of 1-piperidineacetic acid with perchloric acid, (PAA)2H·ClO4, has been prepared and characterized by X-ray diffraction at 130 K and refined to the R=0.041 (I>2σ(I)). The crystals are monoclinic, space group C2/c, a=11.663(2), b=12.844(3), c=12.512(3)Å, β=103.35(3)°, V=1823.6(7)Å3, Z=4. An asymmetric unit comprises one 1-piperidiniumacetate zwitterion and a half of the perchlorate anion. Two such species are related by the two-fold axes and the zwitterions form a homoconjugated cation through a short and probably symmetrical hydrogen bond with the O⋯H⋯O distance of 2.441(3)Å. These homoconjugated cations related by the symmetry centre are connected by N–H⋯O hydrogen bonds (2.766(2)Å). In the structure of complex (PAA)2H·ClO4 optimized by the PM3 and SAM1 methods one molecule of the 1-piperidineacetic acid exists as a zwitterion, whereas the other is in cationic form. In the powder FTIR spectrum of (PAA)2H·ClO4 the N–H⋯O and O⋯H⋯O hydrogen bonds are manifested by two well separated broad absorption bands in the 3030–2690 cm−1 and 1500–400 cm−1 regions, respectively.

The molecular and crystal structure of N-methylpiperidine betaine hydrobromide, MPBHBr, has been solved by X-ray diffraction methods at 100K and refined to the R=0.017 (I>2σ(I)). The crystals are monoclinic, space group P21/c, a=6.193(1), b=13.275(3), c=13.056(3)Å, β=103.38(3)°, V=1044.2(4)Å3, Z=4. Piperidine ring adopts a chair conformation with the CH2COOH group in an axial and the CH3 group in an equatorial position. The carboxylic group is engaged in a weak hydrogen bond with the bromide ion, O–H⋯Br− (Br−⋯O 3.130(1)Å). Powder FTIR spectrum was measured and assignments of the observed bands to vibrations of the hydrogen bond are proposed. In the crystal, the hydroxy proton in the COOH group is in syn conformation relative to the CO bond, while in the PM3-optimized structure it is in anti.

CMTI-I, a small-protein trypsin inhibitor, has been crystallized as a 4:1 protein-zinc complex. The metal is coordinated in a symmetric tetrahedral fashion by glutamate/glutamic acid side chains. The structure was solved by direct methods in the absence of prior knowledge of the special position metal centre and refined with anisotropic displacement parameters using diffraction data extending to 1.03 A. In the final calculations, the main-chain atoms of low B(eq) values were refined without restraint control. The two molecules in the asymmetric unit have a conformation that is very similar to that reported earlier for CMTI-I in complex with trypsin, despite the Met8Leu mutation of the present variant. The only significant differences are in the enzyme-binding epitope (including the Arg5 residue) and in a higher mobility loop around Glu24. The present crystal structure contains organic solvent molecules (glycerol, MPD) that interact with the inhibitor molecules in an area that is at the enzyme-inhibitor interface in the CMTI-I-trypsin complex. A perfectly ordered residue (Ala18) has an unusual Ramachandran conformation as a result of geometrical strain introduced by the three disulfide bridges that clamp the protein fold. The results confirm deficiencies of some stereochemical restraints, such as peptide planarity or the N-C(alpha)-C angle, and suggest a link between their violations and hydrogen bonding.

The crystal structure of a novel non-peptidic HIV-1 protease inhibitor derived by simple solid-state dimerization of 4-aryl-1,4-dihydropyridines, reveals a strained central cage and the conformation of its phenyl, benzyl, and hydroxymethylene substituents. The polycyclic cage includes two nearly flat cyclobutane rings and four fused piperidine rings in boat conformations. The cage geometry reveals two unexpected features, namely marked distortions of the valence angles in every second piperidine and a shortening of one of the cyclobutane bonds. The molecule displays exact centrosymmetry, but the central cage and the hydroxymethylene substituents also approximate the C2-symmetry of the target enzyme. The two independent hydroxyl groups are involved in intermolecular hydrogen bonding, one as a donor, the other as an acceptor. The disposition of the hydroxyl groups in the molecular framework is compatible with the dual role of the inhibitor in the active-site cavity of HIV-1 protease, whereby one OH group is hydrogen-bonded to the catalytic aspartates, whereas another one provides an interface to the locked flaps of the enzyme.

Crystalline complex of I-piperidineacetic acid with perchloric acid, PAAH.ClO4, has been prepared and characterised by X-ray diffraction method at 100 K and refined to the R = 0.022 (I > 2sigma(I)). The crystals are orthorhombic, space group P2(1)2(1)2(1), with a = 6.607(1), b = 8.171(2), c = 18.651(4) Angstrom, Z = 4, V = 1006.9(4) Angstrom(3). The N-H proton is in an axial position and the CH2COOH substituent in an equatorial one. The COOH group is involved in two hydrogen bonds; one with the ClO4- anion, O(2)-H(2)O-...(1') = 2.664(1) Angstrom, and the second with the N+-H proton of a neighbouring molecule, related by the twofold screw axis parallel to x; O(1)H-...(11)-N(1) = 2.957(1) Angstrom. The N+-H proton forms a trifurcated (four-centre) hydrogen bond. The two contacts of the N+-H hydrogen atom, an intermolecular with the ClO4- anion and an intramolecular with the O=C group are formed. Each ClO4- anion is surrounded by five 1-piperidiniumacetic acid molecules and each oxygen atom interacts electrostatically with three positively charged nitrogen atoms. Powdered spectra of PAAH.ClO4 and its deuterated analogue were measured and assignment of the observed bands to vibrations of the hydrogen bonds and internal vibrations are proposed. The (NHO)-O-... and (OHO)-O-... hydrogen bonds are manifested by superimposition of a broad and smooth absorption in the 3300-2800 cm(-1) region with a maximum at 3120 cm(-1). (C) 2002 Elsevier Science B.V. All rights reserved.

The HIV-1 protease is essential for replication of infective virus HIV, and therefore is an attractive target for the design of specific inhibitors. In search for new inhibitors, substantial effort is devoted to understanding the nature of the inhibitor binding modes in the active site, using X-ray diffraction on crystals as the primary source of structural information. This paper describes the crystallization and preliminary diffraction study of HIV-1 (BRU) protease complexed with the Boc-Phe[(S)-CH(OH)CH2NH]-Phe-Ile-Phe-NH2 inhibitor (SI). The SI is a four-amino-acid pseudopeptidic inhibitor, where the scissile peptide bond is replaced by the (2-hydroxyethyl)amine (HEA) isostere. Current state of crystallization of HIV-1 protease complexed with RI, (Boc-Phe[(R)-CH(OH)CH2NH]-Phe-Ile-Phe-NH2), which is a stereoisomer of SI, is also reported. First crystallization trials were based on crystallization studies performed with complexes of HIV-1 PR with inhibitors SE, RE, RQ. These inhibitors differ from SI in the amino acid at P2’ position, carrying Glu or Gln instead of Ile, and in configuration at C4, the carbon bearing hydroxygroup of the HEA group. The hanging-drop vapor diffusion technique has been used in all experiments. In the case of Glu/Gln containing inhibitors protein-inhibitor mixture of 3 mg/ml HIV PR, 0.544 mM inhibitor (four-fold molar excess over protease) in 50 mM sodium acetate pH 5.6, 1 mM EDTA, 0.05% 2-sulfonylethan-1-ol ( -mercaptoethanol, 5% DMSO was used. The optimum crystallization conditions found for these crystals are: 1M NH4H2PO4, 100 mM sodium citrate, pH 4.5, temperature 6 8 C [1]. In contrast to Glu/Gln containing inhibitors, SI inhibitor addition caused protein precipitation even in the absence of a salt precipitant. A probable reason is higher hydrophobicity of SI inhibitor. Addition of ammonium phosphate under the conditions described above produced no crystal growth and no additional precipitation. Crystals of maximum dimensions 0.5x0.05x0.05 mm were grown at pH 6-8, 25 C and low precipitant concentration (0.1 M NH4H2PO4, 5 mM sodium citrate, 50 mM sodium acetate), but reproducibility of the crystal growth was very low and crystals often coexisted with precipitate. Good reproducibility has not been achieved until the following measures have been undertaken to decrease protease precipitation by inhibitor: 1) decreasing the inhibitor concentration to a two-fold molar excess over protease 2) increasing the concentration of DMSO in protease-inhibitor mixture to 10% 3) avoiding an abrupt decrease in DMSO concentration in the hanging drop after mixing protein solution with the reservoir liquid 4) including 0.05% TritonX-100 in drop as well as in reservoir solution helped to prevent the crystal twinning that elsewhere became a problem at this stage 5) increasing the protein concentration resulted in a major improvement of reproducibility These measures lead to two different crystal forms (needles and platelets). NaCl was used as precipitant in all but initial experiments.

refolded protein from inclusion bodies. A purification procedure comprising three chromatography steps yielded scFv 1696 in the purity necessary for crystallization trials. The complex was prepared by mixing scFv1696 with an excess of the epitope peptide corresponding to the N-terminus of HIV-2 PR (PQFSLWKR). Monomeric and dimeric forms of the complex were separated by FPLC on a Mono-Q column. In contrast to free scFv 1696 these forms are stable and do not interchange. In a series of crystallization trials crystals of the complex have been obtained. For crystallization trials by vapour diffusion method (hanging drop) only monomeric complex of the scFv1696 with epitope peptide was used. Crystals grew spontaneously at 25C in ammonium sulfate (concentrations: 1.8 2.0 M) at pH 4.6. These crystals were very sensitive and flaws on their surface appeared in few days. However, this spontaneous crystallization could not be reproduced with a new batch of the complex, therefore, a streak seeding technique was applied and single crystals of size up to 0.3 x 0.3 x 0.2 mm were obtained. Solving of 3D structure of the scFv 1696 epitope peptide complex is expected to lead to antibodystructurebased design of a new class of HIV protease non-active site inhibitors, possibly of different HIV resistance characteristics.

N-(omega -carboxyalkyl)morpholine hydrochlorides, OC4H8N(CH2)(n)COOH . HCl, n = 1-5, were obtained and analyzed by C-13 cross polarization (CP) magic angle spinning (MAS) NMR, FTIR and PM3 calculations. The structure of N-(3-carboxypropyl)-morpholine hydrochloride (n = 3) has been solved by X-ray diffraction method at 100 K and refined to the R = 0.031. The crystals are monoclinic, space group P2(1)/c, a = 14.307(3), b = 9.879(2), c = 7.166(1) Angstrom, beta = 93.20(3)degrees, V = 1011.3(3) Angstrom (3), Z = 4. In this compound the nitrogen atom is protonated and two molecules form a centrosymmetric dimer, connected by two N+-H . . . Cl- (3.095(1) Angstrom) and two O-H . . . Cl- (3.003(1) Angstrom) hydrogen bonds. C-13 CP MAS NMR spectra, contrary to the solution, showed non-equivalence of the ring carbon atoms. The PM3 calculations predict a molecular dimer without proton transfer for an HCl complex, while for an HBr complex an ion pairs with proton transfer, and reproduces correctly the conformation of both dimers but overestimates H-bond distances. Shielding constants calculated from the PM3 geometry of ion pairs gave a linear correlation with the C-13 chemical shifts in solids. (C) 2001 Elsevier Science B.V. All rights reserved.

Complex of 4-dimethylamino-2,6-dimethylpyridine N-oxide with 4-toluenesulphonic acid (4-NMe2–2,6–Me2–PyO·HOTs) was studied by X-ray diffraction, FTIR spectroscopy and ab initio HF calculations. The crystal is monoclinic, space group P21/c with a=8.527(2), b=26.200(5), c=7.4910(10)Å, β=91.22(3)°. The proton is transferred from the acid to the N-oxide and oxygen atoms of the SO3 group show strongly elongated ellipsoids. The average O⋯O distance is 2.539(10)Å and the O(4)–H⋯O(1) angle is 168(8)°. The HF/6-31G(d,p) method predicts hydrogen bonded ion pair with slightly longer hydrogen bond than that in the crystal. The FTIR spectrum of the complex shows a broad band at ca. 2360cm−1 caused by the OH stretching vibration. Relations between geometrical parameters of the OHO bridge, based on the results of X-ray diffraction studied for 93 hydrogen bonded complexes of N-oxides with phenols and carboxylic acids, acids salts of carboxylic acids, and basic salts of N-oxides and betaines covering a broad ΔpKa range from −11.56 to 5.0, are proposed.

The following crystalline complexes of trimethylamine N-oxide (TMAO) with pentachlorophenol (PCP): TMAO.PCP, TMAO.PCP . H2O and TMAO.2PCP have been prepared and characterized by FTIR spectroscopy, quantum-mechanical calculations with DFT and semiempirical methods and X-ray diffraction (two complexes). The crystals of TMAO.PCP are orthorombic, space group Peen with a = 27.621(6), b = 13.642(3), c = 7.191(1) Angstrom, V = 2709.6(9) Angstrom(3), Z = 8. The proton is transferred from PCP to TMAO and both residues are linked by an O-H ... O hydrogen bond of length 2.464(3) Angstrom and an angle of 168(4)degrees. The crystals of TMAO.PCP . H2O are monoclinic, space group C2/c with a = 20.388(3), b = 10.314(2), c = 14.300(2) Angstrom, beta = 105.43(2)degrees, V = 2898.6(8) Angstrom(3), Z = 8. The proton is transferred from PCP to TMAO. Two pentachlorophenolates are bridged by two water molecules to form an eight membered ring with four O-H . O hydrogen bonds of 2.663(3) and 2.647(3) Angstrom, respectively. Each water molecule, in turn, additionally forms a hydrogen bond of 2.497(3) Angstrom to protonated TMAO.BLYP, SAM1 and PM3 calculations have been carried out of the most stable structures. In the case of TMAO.PCP and TMAO.PCP . H2O a good agreement between the calculated and X-ray data are obtained. FTIR spectra of the investigated complexes are consistent with the O ... O distances. TMAO.2PCP in acetonitrile solution exists as a mixture of TMAO.PCP and solvated PCP. The observed shifts of the centre of gravity of the broad absorption in TMAO.PCP toward higher wavenumbers relative to those in complexes of pyridine N-oxides with comparable Delta pK(a) can be explained by the resonance interaction between the N-oxide group and aromatic ring. (C) 1999 Elsevier Science B.V. All rights reserved.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A complex of pyridine N-oxide (PyO) with 2,6-dichloro-4-nitrophenol (DCNP) was studied by X-ray diffraction, FT-IR spectroscopy and quantum-mechanical calculations with the DFT and semiempirical methods. The crystals of the PyO . DCNP are triclinic, space group P (1) over bar, a = 6.833(1) Angstrom, b = 8.717(2) Angstrom, c = 11.482(2) Angstrom, alpha = 98.93(2)degrees, beta = 93.63 (1)degrees, gamma = 109.12(2)degrees, V = 633.6(3) Angstrom(3), Z = 2. The molecules of the complex are joined by the N-O ... H-O hydrogen bond with the O ... O distance of 2.476(2) Angstrom, and the O(4)... H(1)-O(1) angle of 165.1 degrees. The dihedral angle between the planes of the bridged pyridine and phenyl rings is 71.8 degrees. The weak C-H ... O, C-H ... Cl interactions and stacking forces stabilize three dimensional packing pattern. The SAM1 and DFT methods predict one minimum for B ... H-A form, while the PM3 method predicts two minima, the deeper one for B ... H-A complex and the shallower one for B+-H ... A(-) form. For the most stable complexes the predicted O ... O distances are longer than the experimental value by 0.141, 0.067 and 0.231 Angstrom, respectively for the DFT, SAM1 and PM3 methods. The calculated bond lengths, except N(1)-O(4), are longer than those fi om the X-ray as results of intermolecular interactions in the crystal. The SAM1 geometry of PyO . DCNP is slightly better than this obtained by the PM3 method and it is recommended as input in nb initio calculations. The protonic broad absorption in the 1500-250 cm(-1) region is typical for such a short hydrogen bond and the proton motion may be described by a potential curve with an asymmetric double minimum. Proton motion in the bridge is faster than the time range of IR spectroscopy.

Crystals of bis(2,6-dimethylpyridine-N-oxide) sulphate are monoclinic, space group P2(1)/c, a = 14.098(2) Angstrom, b = 7.855(1) Angstrom, c = 15.203(3) Angstrom, beta = 104.84(1)degrees. The crystal structure has been refined to R = 0.0373 (2052 reflections). The disordered SO42- anion accepts hydrogen bonds from two protonated 2,6-dimethylpyridine-N-oxides and two alternative conformations of the SO42- group are distinguished. The occupancy factor of the predominant orientation is 0.63 and the O...O distances are 2.445(2) and 2.453(4) Angstrom; in the second form (fraction, 0.37), these distances are 2.345(2) and 2.544(9) Angstrom.The PM3 and AM1 methods predict three minima for the title complex, whereas the SAM1 and BLYP/6-31G methods predict only one. All methods predict that molecular complex 3 is the most stable. The SAM1 geometry is very close to that of BLYP/6-31G.The Fourier transform IR (FTIR) spectrum shows a very intense and broad (continuum) absorption within the 1600-400 cm(-1) region, typical of short hydrogen bonds. There is no absorption in the 3000-2000 cm(-1) region expected for the longer hydrogen bond (2.544(9) Angstrom) in the less populated orientation. Isotope and solvent effects are discussed. (C) 1997 Elsevier Science B.V.

Pyridine N-oxides form two types of crystalline complexes with phentachlorophenol, with 1:1 and 1:2 base-to-acid ratios. The 1:2 complex of 2,6-dimethylpyridine N-oxide with pentachlorophenol crystallizes in space group P1̄ with a = 7.335(1) Å, b = 11.324(2) Å, c = 15.824(2) Å, α = 100.38(1)°, β = 94.63(1)°, γ = 106.60(1)°, V = 1226.7(6) Å3 and Z = 2. The structure has been refined to R = 0.046 for 3408 observed Mo Kα reflections. The oxygen atom of the N-oxide group accepts hydrogen bonds from two molecules of pentachlorophenol, with Otctdot;O distances of 2.639(5) and 2.642(5) Å and OHO angles of 141.2° and 157.6°, respectively. Both NOtctdot;HO bridges are formed in, or near, the directions of the electron lone-pairs of the N-oxygen atom. The two pentachlorophenol rings (A and B) are nearly parallel to each other and they are almost perpendicular to the pyridine ring. FTIR spectra of eleven 1:2 complexes in the solid state are similar and independent of the proton acceptor properties of the N-oxides. Five lines in the 35Cl NQR spectra of the 1:2 complexes provide evidence that both molecules of pentachlorophenol are equivalent. In CHCl3 solution, all the 1:2 complexes exist as a mixture of the 1:1 complex and pentachlorophenol.

A close structural relationship between - and -santenones, occuring in Indian sandalwood (Santalum album), results in serious difficulties in the preparation of their derivatives in a pure form.1,2

Complexes of five pyridines and nine pyridine N-oxides with 2,6-dichloro-4-nitrophenol (DCNP) in solution and the solid state were studied by Fourier transform IR and UV spectroscopy, by quantum-mechanical calculations with the semiempirical parametric method 3 (PM3) and by X-ray analysis.The crystals of the 1 : 1 complex of 4-methoxy-2,6-dimethylpyridine N-oxide with DCNP are monoclinic, space group P2(1)/n, a = 4.5936(5) Angstrom, b = 21.953(3) Angstrom, c = 15.664(2) Angstrom, beta = 92.87(1)degrees, V = 1577.6(8) Angstrom(3), Z = 4. The molecules of the complex are joined together by an N+O-H ... O- hydrogen bond with an O ... O distance of 2.425(3) Angstrom, a C-O- distance of 1.286(3) Angstrom and a (N+O)-H ... O- angle of 152.9 degrees.The PM3 method predicts for all the investigated complexes two minima, the deeper one for B ... HA complexes and the shallower one for the B+-H ... A(-) forms. For the 4-methylpyridine complex the N+-H ... O- distance is reproduced correctly but for the 4-methoxy-2,6-dimethylpyridine N-oxide complex the N+-H ... O- distance is too long, The predicted hydrogen-bond angles differ from the experimental values by more than 10 degrees.In solid state complexes of pyridines the N ... O distances and the broad absorption due to a protic vibration are not directly related to Delta pK(a). This is due to the crystal packing forces. In solution the broad absorption varies with Delta pK(a). A band in the 3500 cm(-1) region due to the solvated phenol is present in all investigated complexes in solution. Absorption in the 3000-2000 cm(-1) region of pyridine complexes is more intense than that of the pyridine N-oxides, in agreement with the difference in N ... O and N-O ... O distances. The broad absorption in the spectra of pyridine complexes is more influenced by solvent effects than in the pyridine N-oxide complexes.The UV spectra of the pyridine complexes show two bands due to B ... H-A (305-315 nm) and B+-H ... A(-) (382-395 nm) forms. The UV spectra of complexes of pyridine N-oxides of intermediate strengths in CH2Cl2 are not combinations of the spectra of phenol and phenolate, The band in the intermediate position denotes that neither species close to phenol nor to phenoxide ion is present. In these complexes the proton is probably localized in a single minimum and the minimum moves from the donor to the acceptor or, what is more probable, reorganization of the solvent molecules around the complex is faster than the time range of UV spectroscopy. In acetonitrile the situation is quite different as two bands are present, in agreement with a prototropic equilibrium. Effects of solvent, concentration and stoichiometry on interactions of DCNP with pyridines and pyridine N-oxides are compared and discussed. An extended mechanism of the proton-transfer reaction is proposed.

The crystal structure of the 4-methoxy-2,6-dimethylpyridine N-oxide·pentachlorophenol complex has been determined by X-ray analysis. The O ··· O distance is 2.439(6) Å, the OHO angle is 152.3° and the hydrogen-bonded proton is close to the phenol molecule. The FT-IR spectra of pentachlorophenol complexes with some substituted pyridine N-oxides in the solid state and seven aprotic solvents of different polarity (ϵ from 2.27 to 37.5) show a broad absorption. The broad absorption shows weak dependence upon solvent polarity and is classified as type (ii). UV spectra show that in the investigated complexes protons are not transferred from the phenol to the N-oxides. Formamide (ϵ = 111) is a much stronger proton acceptor than the pyridine N-oxides. Pentachlorophenol in formamide is converted to the phenolate ion.

The rules governing the amidine cis-trans configuration are developed. In amidines the most bulky groups bonded to N1, N2 or C1 tend always to be in the trans position and the molecular configuration depends on the relative sizes of these substituents.

The crystal structure of 1-benzyloxy-4-methoxypyridinium perchlorate has been deduced from single-crystal X-ray diffraction data. The crystals are monoclinic, space group P2(1)/a, with a = 9.254 0(7), b = 21.532(2), c = 7.335 2(8) angstrom, beta = 102.69(1)-degrees and Z = 4. The final R value is 0.084 for 1593 observed reflections. The molecule is extended with a trans conformation around the central C(1)-O(1) bond linking the phenyl and pyridine residues. The aromatic ring planes are almost perpendicular to the linking C(1)-O(1) bond and the rings are twisted 9.1 (2)-degrees to each other. The N-O distance [1.401(7) angstrom] is much longer than that found in pyridine N-oxides and is typical for an N-O single bond. Both the PM3 and AM1 methods predict that the trans conformer is less stable (by ca. 3 kcal mol-1) than the gauche conformer in the gas phase. The problem of the conformation of the phenyl group (D) and pyridinium group (A) in compounds of the type DCH(R1)CHR2A (R1 = R2 = H or alkyl) is reviewed.

The reaction of dichloroketene and 3β-acetoxy-20a-homopregna-5,20-diene 1 is shown to give one diastereoisomeric cycloadduct 2 arising from attack at the rear side of the preferred rotamer 1b of the steroid skeleton. The structure of dichlorocyclobutanone 2 was determined by X-ray crystallography. Reduction of 2 gives chlorocyclobutanone 3 and cyclobutanone 4. Examination of the cyclobutanones by CD, 1H and 13C NMR spectroscopy demonstrates that these techniques can be used for the determination of the configuration of 2 and 3.