Three-center Hydrogen Bonds Research Articles

Hollow Crescents, Helices, and Macrocycles from Enforced Folding and Folding-Assisted Macrocyclization

This Account reviews the progress made by us on creating porous molecular crescents, helices, and macrocycles based on aromatic oligoamides. Inspired by natural pore- or cavity-containing secondary structures, work described in this Account stemmed from the development of foldamers consisting of benzene rings linked by secondary amide groups. Highly stable, three-center intramolecular hydrogen bonds involving the amide linkages are incorporated into these aromatic oligoamides, which, along with meta-linked benzene units that introduce curvatures into the corresponding backbones, leads to tape-like, curved backbones. Depending on their chain lengths, aromatic oligoamides that fold into crescent and helical conformations have been obtained. Combining results from modeling and experimentally measured data indicates that the folding of these oligomers is readily predictable, determined by the localized intramolecular three-center H-bonds and is independent of side-chain substitution. As a result, a variety of reliably folded, modifiable scaffolds can now be constructed. The well-defined crescent or helical conformations contain noncollapsible internal cavities having multiple introverted amide oxygen atoms. Changing the backbone curvature by tuning the ratio of meta- to para-linked benzene units leads to crescents or helices with cavities of tunable sizes. For example, oligoamides consisting of meta-linked units contain cavities of approximately 9 A across, while those with alternating meta- and para-linked units have cavities of over 30 A across. The generality of such a folding and cavity-creating strategy has also been demonstrated by the enforced folding of other types of aromatic oligomers such as oligo(phenylene ethynylene)s, aromatic oligoureas, and aromatic oligosulfonamides. More recently, the folding of aromatic oligoamides was found to assist efficient macrocyclization reactions, which has provided a convenient method for preparing a new class of large shape-persistent macrocycles in high yields. The folded and cyclic structures were extensively characterized based on multiple techniques such as one- and two-dimensional NMR, mass spectrometry, and X-ray crystallography, as well as theoretical calculations. The enforced folding and folding-assisted cyclization of oligomers have provided a predictable strategy for developing crescent, helical, and cyclic structures containing nanosized voids that are mostly associated with the tertiary and quaternary structures of proteins. The availability of these porous molecules has supplied a new class of nanosized building blocks that provide both opportunities and challenges for creating the next-generation nanostructures capable of presenting multiple introverted functional groups, forming various pores and channels, and finally, developing protein-like pockets.

Synthesis, X-ray structures, and magnetic properties of heterometal dinuclear Cr(III)–M(II) complexes

New 3,5-bis(2-pyridyl)pyrazolato (bpypz) bridged heterometal dinuclear complexes [(nta)Cr(μ-bpypz)M II(picen)] + (M = Mn(II), Ni(II)) and [(acac) 2Cr(μ-bpypz)Ni II(picen)] 2+ (nta = nitrilotriacetate, picen = N, N′-bis(2-pyridylmethyl)ethylenediamine, acac = acetylacetate) were synthesized and characterized by the X-ray analysis, ESI-MS and the magnetic measurements, and/or 2H NMR spectra. The molecular structures were compared from a viewpoint of the conformation of the picen depending on M II ionic radii or different modes of hydrogen bonds. The picen in [(nta)Cr(μ-bpypz)Mn II(picen)]BF 4 takes an abnormal conformation with intramolecular bifurcated three-center hydrogen bonds between two carboxylate oxygens of nta and an amine proton of the picen as found for the previously reported corresponding Fe(II) complex [K. Ni-iya, A. Fuyuhiro, T. Yagi, S. Nasu, K. Kuzushita, S. Morimoto, S. Kaizaki, Bull. Chem. Soc. Jpn. 74 (2001) 1891]. On the other hand, for both Ni(II)-nta and Ni(II)-acac complexes, the picen takes a normal conformation with only a two-center hydrogen bond between non-bridging ligands. The magneto-structural relation is discussed for the Cr(III)–Ni(II) complexes in connection with the orthogonality or orbital overlap arising from the difference in distortion around Cr(III) moiety.

2-(2-Benzyloxyphenyl)-1H-benzimidazole

The asymmetric unit of the title compound, C20H16N2O, contains two mol­ecules. The dihedral angles between the benzimidazole ring systems and the attached benzene rings are 10.6 (5) and 13.7 (5)°. The conformers are linked by bifurcated three-centre hydrogen bonds, forming chains along the diagonal of the a b plane. The packing is further stabilized by π–π and C—H⋯π inter­actions.

Three-centre hydrogen bonds in triphenyl-phosphine oxide-hydro-quinone (1/1).

The title cocrystal, C18H15OP·C6H6O2, belongs to a series of mol­ecular systems based on triphenyl­phosphine P-oxide. The O atom of the oxide group acts as an acceptor for hydrogen bonds from OH groups of two hydro­quinone mol­ecules which lie on inversion centres [O⋯O = 2.7451 (17) and 2.681 (2) Å]. The crystal structure is stabilized by weak C—H⋯O hydrogen bonds, forming a C 2 1(8) chain which runs parallel to the [100] direction.

(3E)-5-Hydroxy-3-[5-(hydroxymethyl)furan-2-ylmethylene]-1-benzofuran-2(3H)-one

The title compound, C14H10O5, was isolated from Senecio cannabifolius Less var. integrifolius aqueous extract. The structure was elucidated on the basis of spectroscopic data, including MS, 1H NMR and 13C NMR, and the relative configuration was confirmed by X-ray crystallographic analysis. The benzofuran ring is almost coplanar with the furan ring [dihedral angle = 10.47 (15)°]. A chain is formed through supramolecular R 2 2(10) synthons and three-centre hydrogen bonds.

Probing the Nature of Three-Centered Hydrogen Bonds in Minor-Groove Ligand−DNA Interactions: The Contribution of Fluorine Hydrogen Bonds to Complex Stability

Double-stranded DNA sequences have been prepared in which single atoms (the O2-carbonyls of selected thymines) have been replaced by fluorine or methyl. To maintain normal Watson-Crick hydrogen bonding with the complementary purines, these analogue derivatives have been prepared as C-nucleosides. The O2-carbonyls of interest for this study are those involved in a bifurcated (or three-centered) hydrogen bond with the minor groove binding ligand 4',6-diamidino-2-phenylindole (DAPI). TM studies of the duplexes illustrate that the DNA duplexes are destabilized when fluorine or methyl replaces one or both of the minor groove O2-carbonyls, which can in part be explained by changes in minor groove hydration. In the presence of DAPI, most of the duplexes exhibit an increased TM due to the presence of DAPI bound in the minor groove. The extent of helix overstabilization negatively correlates with the presence of one or both methyl groups in the minor groove, suggesting that ligand binding is weakened in the presence of the non-carbonyl functional groups. The presence of single fluorine appears to promote helix stabilization, and native-like stabilization occurs when both fluorines are present. KD values quantitate binding effects between DAPI and the native and analogue sequences. Sequences with one or both methyl groups exhibit very poor binding with DAPI, while those containing a single fluorine behave essentially like native carbonyl-containing sequences. With both fluorines present, KD values were observed to increase by a moderate 3-fold at 100 mM NaCl and somewhat more at 200 mM NaCl. Binding affinities with both methyl groups present were 500-1000-fold weaker than native. The results suggest that organofluorines can function as hydrogen-bond acceptors, at least in the bifurcated interaction that contributes to minor groove binding by DAPI.

Structure−Function Studies of Modular Aromatics That Form Molecular Organogels

Three urea-based aromatics 1-3, each with distinct steric and electronic characteristics, have been synthesized and their ability to undergo hierarchical assembly and gel organic solvents investigated. We have found that compound 1 promotes the sol-gel phase transition in primary alcohols (from CH3OH to C10H21OH; CGC < 15 mg/mL), while 2 and 3 do not. IR spectroscopy, X-ray powder diffraction (XRPD), and transmission electron microscopy (TEM) measurements show that 1 organizes into "cylinders" in primary alcohols, using three-centered hydrogen bonds and pi-pi aromatic interactions. The cylinders further organize into pairs through interdigitation of the methyl groups of the adjacent aromatic rings. Importantly, the lateral packing of the cylinders is enhanced as the bulk solvent polarity increases providing a mechanism for controlling the material's morphology via the solvophobic effect. Molecular mechanics (Amber) and semiempirical (AM1) calculations suggested similar conformational behavior but distinct electronic properties of 1-3. Thus, pi-deficient 2 without the methyl groups and pi-rich 3 without aromatic nitrogen fail to promote the sol-gel phase transition in alcohols due to their inability to undergo effective hierarchical assembly, which is necessary for the formation of a 3D fibrillar network. In addition, we have found that the ultrasonication of a supersaturated solution of 1 is necessary for the gelation. Presumably, a fast exchange of the aggregates of 1 is assisted with sonic waves to allow for the effective and "error free" assembly wherein an entangled net of fibers capable of encapsulating solvent molecules is formed.

Basicity of isomeric ditetrazolylbenzenes and their N-tert-butyl derivatives

The basicity constants \((pK_{BH^ + } ,pK_{BH^{2 + } } )\) of 1,2-, 1,3-, and 1,4-bis(tetrazol-5-yl)benzenes and their N-tert-butyl derivatives in aqueous sulfuric acid and the dissociation constants (pKHB) of the corresponding H-complexes with p-fluorophenol in carbon tetrachloride were determined by UV and IR spectroscopy. Mono-and diprotonation of isomeric ditetrazolylbenzenes is observed in the acidity range (H0) from −1 to −5 (\(pK_{BH^ + } \) −2.5 to −3.0; \(pK_{BH^{2 + } } \) −3.8 to −4.9). Introduction of a tert-butyl group into the 2-position of the heteroring almost does not affect the basicity of ditetrazolyl benzenes. Among the examined compounds, 1,2-bis(2-tert-butyltetrazol-5-yl)benzene is the strongest proton acceptor with respect to p-fluorophenol as standard proton donor, presumably due to formation of a complex with bifurcated (three-center) hydrogen bond.

Dynamic [2]Catenanes Based on a Hydrogen Bonding-Mediated Bis-Zinc Porphyrin Foldamer Tweezer: A Case Study

This paper describes the self-assembly of a new class of three-component dynamic [2]catenanes, which are driven or stabilized by intramolecular hydrogen bonding, coordination, and electrostatic interaction. One of the component molecules 2, consisting of an aromatic oligoamide spacer and two peripheral zinc porphyrin units, was designed to adopt a folded preorganized conformation, which is stabilized by consecutive intramolecular three-centered hydrogen bonds. Component molecule 3 is a linear secondary ammonium bearing two peripheral pyridine units, which was designed to form a 1:1 complex with 24-crown-8 (5). The 1H NMR and UV-vis experiments in CDCl3-CD3CN (4:1 v/v) revealed that, due to the preorganized U-shaped feature, 2 could efficiently bind 3 through the cooperative zinc-pyridine coordination to generate highly stable 1:1 complex 2.3. Adding 5 to the 1:1 solution of 2 and 3 led to the formation of dynamic three-component [2]catenane 2.3.5 as a result of the threading of 3 through 5. 1H NMR studies indicated that in the 1:1:1 solution (3 mM) [2]catenane 2.3.5 was generated in 55% yield at 25 degrees C. The yield was increased with the reduction of the temperature and [2]catenane could be produced quantitatively in a 1:1:2 solution ([2]=3 mM) at -13 degrees C. Replacing 3 with 1,2-bis(4,4'-bipyridinium)ethane (4) in the three-component solution could also give rise to similar dynamic [2]catenane 2.4.5 albeit in slightly lower yield.

Three-centre hydrogen bonds in 4-picolineN-oxide–hydroquinone (1/1)

The title compound, C6H7NO·C6H6O2, belongs to a series of mol­ecular systems based on methylpyridine N-oxides. The N-oxide molecule is located on a crystallographic twofold rotation axis, while the hydroquinone molecule is located on an inversion centre. The two components are linked by an O—H⋯O hydrogen bond with a distance of 2.675 (2) Å. In the crystalline environment, three-centre hydrogen bonds involving the N-oxide O atom with two hydro­quinone mol­ecules related by symmetry in the [001] direction are observed.

The 1:1 cocrystals of the proton-transfer compound dilituric acid–phenylbiguanide monohydrate

A proton-transfer compound, 1-phenylbiguanidium 5-nitro-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate monohydrate, C(8)H(12)N(5)(+) x C(4)H(2)N(3)O(5)(-) x H(2)O, has been synthesized by a reaction between dilituric acid (5-nitro-2,4,6-trihydroxypyrimidine, Dilit) and phenylbiguanide (N-phenylimidocarbonimidic diamide, Big). This compound cocrystallized as a 1:1 adduct, and the asymmetric unit consists of two dilituric amino-oxo planar tautomeric anions (Dilit(-)), two monoprotonated phenylbiguanidium cations (BigH(+)) and two water molecules of crystallization (Z' = 2). Protonation occurs at the N atom attached to the phenyl ring of Big as a result of the proton-transfer process from the acidic hydroxy group of Dilit. In the crystal structure, the hydrated 1:1 adduct is stabilized by 25 two- and three-center hydrogen bonds.

Solvatochromism of heteroaromatic compounds: XXX. N-Methyltrifluoromethanesulfonamide as hydrogen-bond donor

In two-centered H-complexes with protophilic solvents, the monomer of N-methyltrifluoromethanesulfonamide I behaves as a strong H-bond donor, stronger than 4-fluorophenol and ranking second after 4-nitrophenol. In protophilic media, amide I exists as monomeric H-complexes with a two-centered H-bond and 1:2 H-complexes of the open-chair dimer with a bifurcated (three-centered) hydrogen bond. The formation of a strong bifurcated H-bond weaken the bridging N-H.‥O=S bond.

Conformational study and electron density analysis of 9-[tetrahydropyran-3-yl]purine derivatives

A conformational analysis was carried out on cis-6-chloro-9-[2-(2-hydroxyethyl)-2,3,5,6-tetrahydro-4 H-pyran-3-yl]purine and several related model compounds at the HF/6-31++G(d,p) and B3LYP/6-311++G(2d,2p) levels, and also using the semiempirical methods AM1 and PM3. The result of this analysis shows that the molecule prefers an axial disposition of the purine ring, with an approximate cis orientation of C4–N9–C1′–H1′ dihedral angle. The stability of this conformation comes mainly from the formation of a C–H⋯O⋯H–O intramolecular three-center hydrogen bond. In this structure, the tetrahydropyran oxygen acts as an acceptor, while both H8 of the purine ring and the hydroxylic hydrogen of the hydroxyethyl group act as donors. Also, the equatorial disposition of the hydroxyethyl group in this conformer reduces its repulsions with the purine ring and the tetrahydropyran hydrogens. The quantum theory of atoms in molecules was applied to study the electronic effects produced by the conformational changes, bonding between tetrahydropyran and purine rings, chlorine substitution, and intramolecular hydrogen bonding.

2-(2-Methoxyphenyl)-1H-benzimidazole

The asymmetric unit of the title compound, C14H12N2O, contains two different conformational isomers of 2-(2-methoxy­phen­yl)-1H-benzimidazole. The dihedral angles between the benzimidazole ring systems and the 2-methoxy­phenyl substituents are 26.9 (3) and −13.3 (3)°. The conformers are linked by bifurcated three-centre hydrogen bonds, forming chains running along the a axis. The packing is further stabilized by offset and edge-to-face π–π inter­actions.

Supramolecular amide and thioamide synthons in hydrogen bonding patterns of N-aryl-furamides and N-aryl-thiofuramides

The supramolecular synthon of amide group in the primary and secondary amides is well recognized to be infinite chains of the C(4) type formed by the intermolecular hydrogen bond of the type N–H $${\cdots}$$ O=C. On the other hand, there is a lack of structural data for the thioamides. Three compounds belonging to the class of N-aryl-fura-mides (N-(4-bromophenyl)-5-bromo-2-furancarboxamide, N-(4-chlorophenyl)-5-bromo-2-furancarboxamide) and to the class of N-aryl-thiofuramide (N-(4-methoxyphenyl)-2-furanthiocarboxamide) are prepared and characterized by the NMR spectroscopy in solution; molecular and crystal structures in the solid state have been determined by X-ray single crystal diffractometry and the structures in the gas phase by DFT and AM1 calculations. The investigation is carried out in order to establish supramolecular amide and thioamide synthons of hydrogen bonding patterns in these crystal structures. The geometry of the N–H $${\cdots}$$ O=C and the N–H $${\cdots}$$ S=C type of hydrogen bonds are compared due to the possibility of the N–H amide group to form intramolecular hydrogen bond with the furan oxygen atom, thus, commonly, leading to the three-center hydrogen bond pattern. The competition between the S=C proton acceptor of thioamides and the other proton acceptors (such as methoxy group) for the amide N–H proton donor group has been investigated. In that context, the above-mentioned compounds are correlated with the others of this class, structurally determined, so far.

Subpyriporphyrin—A [14]Triphyrin(1.1.1) Homologue with an Embedded Pyridine Moiety

Short and to the point: A three-centered hydrogen bond is present in 6,16-dimesityl-11-phenylsubpyriporphyrin, a non-aromatic free-base triphyrin(1.1.1)-related molecule. X-ray crystal structural analysis shows this compound contains the shortest known N⋅⋅⋅N distance (2.370 Å) for two N atoms involved in hydrogen bonding. The molecule also acts as a ligand, as shown by the formation of a boron complex.

Formation and Dissociation of Intra−Intermolecular Hydrogen-Bonded Solute−Solvent Complexes: Chemical Exchange Two-Dimensional Infrared Vibrational Echo Spectroscopy

2-Methoxyphenol (2MP) solutes form weak complexes with toluene solvent molecules. The complexes are unusual in that the 2MP hydroxyl has an intramolecular hydrogen bond and simultaneously forms an intermolecular hydrogen bond with toluene and other aromatic solvents. In the equilibrated solute-solvent solution, there exists approximately the same concentration of 2MP-toluene complex and free 2MP. The very fast formation and dissociation (chemical exchange) of this type of three-centered hydrogen bond complex were observed in real time under thermal equilibrium conditions with two-dimensional (2D) infrared vibrational echo spectroscopy. Chemical exchange is manifested in the 2D spectrum by the growth of off-diagonal peaks. Both the formation and dissociation can be characterized in terms of the dissociation time constant, which was determined to be 3 ps for the 2MP-toluene complex. The intra-intermolecular hydrogen bond formation is influenced by subtle details of the molecular structure. Although 2MP forms a complex with toluene, it is demonstrated that 2-ethoxyphenol (2EP) does not form complexes to any significant extent. Density functional calculations at the B3LYP/6-31+G(d,p) level suggest that steric effects caused by the extra methyl group in 2EP are responsible for the difference.

L-Prolinamidium hydrogensquarate

Cations of the title compound, C5H11N2O+·C4HO4−, are connected by inter­molecular N(amide)—H⋯O(amide) hydrogen bonds into helical chains, whereas anions are inter­linked by strong O(hydrox­yl)—H⋯O hydrogen bonds into chains. These two distinct chains are interconnected by both N(amide)—H⋯O and N(ammonium)—H⋯O hydrogen bonds into a three-dimensional framework. One of the ammonium protons is involved in a three-centre hydrogen bond.

Hydrogen bonding in dimers of tritolyl and tritosylurea derivatives of triphenylmethanes

The crystal structure of the homodimer formed by the tritolylurea 3a proves the existence of a belt of six bifurcated hydrogen bonds between both NH and the O=C groups of the adjacent urea residues. For the tritosylurea 3b, four additional three-center hydrogen bonds, also involving the SO2 oxygen, are found in the crystalline state. Molecular dynamics simulations in a chloroform box confirm these patterns of the hydrogen bonds and the resulting elongation of the dimer 3b. 3b in comparison to 3a x 3a. The calculated complexation energies for the three dimeric combinations are nearly identical in agreement with the simultaneous formation of heterodimer 3a x 3b in a mixture of 3a and 3b.

Molecular Structure of Complexes with Bifurcated Hydrogen Bond: III. Solvate H-Complexes Formed by Trifluoromethanesulfonamide and Its Cyclic Dimer

According to the data of IR spectroscopy, dielcometry, and B3LYP/6-31G* quantum-chemical calculations, trifluoromethanesulfonamide homoassociates in weakly basic protophilic media are converted into 2 : 1 solvate H-complexes. Cyclic trifluoromethanesulfonamide dimer decomposes in heteroassociate with dioxane with a composition of 1 : 3. Cyclic trifluoromethanesulfonamide dimer with dioxane forms a 1 : 4 H-complex with bifurcated (three-center) hydrogen bond involving the bridging hydrogen atom of the NH group (NH⋯O).