XB Donor Research Articles

ChemInform Abstract: Halogen‐Bonding‐Induced Hydrogen Transfer to C=N Bond with Hantzsch Ester.

Several bidentate dihydroimidazolines were prepared and investigated as catalysts for hydrogen transfer reduction of C═N bond with Hantzsch ester. Highly efficient reactions were observed for quinolines and imines with low catalyst loading of 2 mol %. The presence of halogen bonding was elucidated using NMR studies and isothermal calorimeric titrations. Binding constants of the XB donors were also measured using isothermal calorimeric titrations (ITC).

Discriminating halogen-bonding from other noncovalent interactions by a combined NOE NMR/DFT approach.

Herein a combined NOE NMR/DFT methodology to discriminate between adducts held together by halogen bonding (XB) and other noncovalent interactions (non-XB, such as lone pair/π), based on the determination of the XB donors' and acceptors' relative orientation, is proposed. In particular, (19) F,(1) H HOESY NMR spectroscopy experiments and DFT calculations on different XB donors, such as perfluorohexyl iodide (I1), iodopentafluorobenzene (I2) and bromopentafluorobenzene (Br), combined with different Lewis bases, such as 1,4-diazabicyclo[2.2.2]octane (DABCO) and 2,4,6-trimethylpyridine (Me3 Py), were performed. The results clearly show that in the case DABCO/I1 the XB adduct is practically the only one present in solution, whereas for the other pairs a certain amount of non-XB adduct is present. Combining DFT and HOESY results, the amount of non-XB adducts can be roughly quantified under our experimental conditions as 4 % for DABCO/I2, between 10 and 20 % for Me3 Py/I1 and Me3 Py/I2, and 44 % for DABCO/Br.

N···I halogen bonding interactions: influence of Lewis bases on their strength and characters.

Halogen bonding (XB) as an emerging noncovalent interaction, due to its highly directional and devisable properties, has given rise to considerable interest for constructing supramolecular assemblies. In this work, the newly developed density functional M06-2X calculations and the quantum theory of "atoms in molecules" (QTAIM) studies were carried out on a series of N···I halogen bonding to investigate the influence of Lewis bases (XB acceptors) on the XB. For the Lewis base C6-nH6-nNn (n = 1, 2, 3), with the increasing number of nitrogen atom in the aromatic ring, the most negative electrostatic potentials (VS,min) outside the nitrogen atom becomes less negative and the XB becomes weaker. The positive cooperativity exists in the Y(-)-C6H5N···C6F5I, Y(-)-C4H4N2···C6F5I, and Y(-)-C3H3N3···C6F5I (Y(-) = Cl(-), Br(-), I(-)) termolecular complexes: the H bond or anion-π interactions have the ability to enhance the N···I halogen bond and vice versa. With the addition of halogen anions to the XB acceptor, the XB become more covalent, more electronic charge transfer from the XB acceptors to donors, the XB acceptors become more energetically stabilized and XB donors become more destabilized, and the atomic volume attraction of both the nitrogen and iodine atoms become more obvious. From the view of the Laplacian of electron density function, for the XB acceptor, the reactivity zone is the region of valence shell charge concentration (VSCC), where it is a (3, -3) critical point (CP) and referred to as a lump, thus the XB interaction can be classified as a lump-hole interaction. The more negative VS,min outside the nitrogen atom, the stronger the XB, resulting in the greater distance between the (3, -3) CP and the nitrogen nucleus.

Halogen-bonding-induced hydrogen transfer to C═N bond with Hantzsch ester.

Several bidentate dihydroimidazolines were prepared and investigated as catalysts for hydrogen transfer reduction of C═N bond with Hantzsch ester. Highly efficient reactions were observed for quinolines and imines with low catalyst loading of 2 mol %. The presence of halogen bonding was elucidated using NMR studies and isothermal calorimeric titrations. Binding constants of the XB donors were also measured using isothermal calorimeric titrations (ITC).

The 1:1 co-crystal of triphenyl(2,3,5,6-tetrafluorobenzyl)phosphonium bromide and 1,1,2,2-tetrafluoro-1,2-diiodoethane

The title compound, C25H18F4P+·Br−·C2F4I2, is a 1:1 co-crystal of triphen­yl(2,3,5,6-tetra­fluoro­benz­yl)phospho­nium (TTPB) bromide and 1,1,2,2-tetra­fluoro-1,2-di­iodo­ethane (TFDIE). The crystal structure consists of a framework of TTPB cations held together by C—H⋯Br inter­actions. In this framework, infinite channels along [100] are filled by TFDIE mol­ecules held together in infinite ribbons by short F⋯F [2.863 (2)–2.901 (2)Å] inter­actions. The structure contains halogen bonds (XB) and hydrogen bonds (HB) in the bromide coordination sphere. TFDIE functions as a monodentate XB donor as only one I atom is linked to the Br− anion and forms a short and directional inter­action [I⋯Br− 3.1798 (7) Å and C—I⋯Br− 177.76 (5)°]. The coordination sphere of the bromide anion is completed by two short HBs of about 2.8 Å (for H⋯Br) with the acidic methyl­ene H atoms and two longer HBs of about 3.0 Å with H atoms of the phenyl rings. Surprisingly neither the second iodine atom of TFDIE nor the H atom on the tetra­fluoro­phenyl group make any short contacts.

Supramolecular Hierarchy among Halogen‐Bond Donors

Through a combination of structural chemistry, vibrational spectroscopy, and theory, we have systematically examined the relative structure-directing importance of a series of ditopic halogen-bond (XB) donors. The molecular electrostatic potential surfaces of six XB donors were evaluated, which allowed for a charge-based ranking. Each molecule was then co-crystallized with 21 XB acceptors and the results have made it possible to map out the supramolecular landscape describing the competition between I/Br-ethynyl donors, perfluorinated I/Br donors, and I/Br-phenyl based donors. The results offer practical guidelines for synthetic crystal engineering driven by robust and directional halogen bonds.

A catenane assembled through a single charge-assisted halogen bond.

Getting connected: The formation of pseudorotaxane assemblies between a designed macrocyclic halogen bonding (XB) acceptor (red in scheme) and a series of XB donor threading components was templated by a single halogen bond. The strength of the XB assembly between the pyridine macrocycle and iodopyridinium thread was utilized in the ring-closing metathesis clipping synthesis of a [2]catenane.

The halogen-bonded adduct 1,4-bis(pyridin-4-yl)buta-1,3-diyne–1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-hexadecafluoro-1,8-diiodooctane (1/1)

In the crystal structure of the title compound, C8F16I2·C14H8N2, the mol­ecules form infinite chains parallel to [2-11] through two symmetry-independent C—I⋯N halogen bonds (XBs). As commonly found, the perfluoro­alkyl mol­ecules segregate from the hydro­carbon ones, forming a layered structure. Apart from the XBs, the only contact below the sum of van der Waals radii is a weak H⋯F contact. The topology of the network is a nice example of the paradigm of the expansion of ditopic starting modules; the XB leads to the construction of infinite supramolecular chains along [2-11] formed by alternating XB donors and acceptors.

4,4′‐Azobis(halopyridinium) Derivatives: Strong Multidentate Halogen‐Bond Donors with a Redox‐Active Core

Halopyridiniums also do the trick: An easily accessible class of highly potent bis(pyridinium)-based multidentate halogen-bond (XB) donors is introduced, which, in addition to their inherent XB acidity, also include a built-in redox option (see scheme). These XB donors function as activating reagents for the carbon–bromine bond in benzhydryl bromide. During the reaction, bromide is oxidized to elemental bromine, which forms the basis of a parallel activation mechanism.

Neutral Organometallic Halogen Bond Acceptors: Halogen Bonding in Complexes of PCPPdX (X = Cl, Br, I) with Iodine (I(2)), 1,4-Diiodotetrafluorobenzene (F4DIBz), and 1,4-Diiodooctafluorobutane (F8DIBu).

The behavior of a sterically crowded neutral pincer {2,6-bis[(di-t-butylphosphino)methyl]-phenyl}palladium (PCPPd) halides, PCPPdX (X = Cl, Br or I), as XB acceptors with strong halogen bond (XB) donors, iodine (I2), 1,4-diiodotetrafluorobenzene (F4DIBz), and 1,4-diiodooctafluorobutane (F8DIBu) were studied in the solid state. The co-crystallization experiments afforded high-quality single crystals of XB complexes PCPPdCl–I2 (1a), PCPPdBr–I2 (2a), PCPPdI–I2(3a), PCPPdCl–F4DIBz (1b), PCPPdBr–F4DIBz (2b), and PCPPdBr–F8DIBu (2c). The 1:1 iodine complexes (1a, 2a, and 3a) all showed a strong halogen bonding interaction, the reduction of the sum of the van der Waals radii of halogen to iodine being 24.6 (1a), 23.9 (2a), and 19.4% (3a) with X···I–I angles of 177, 176, and 179°, respectively. While the pincer palladium chloride 1 and bromide 2 were crystallographically isomorphous and showed similar XB behavior, the palladium iodide complex, 3, exhibited markedly different properties, and unlike 1 and 2 it does not, under similar conditions, result in XB complexes with the weaker XB donors F4DIBz and F8DIBu. The results indicate that PCPPdI is not nucleophilic enough to have XB interactions with other donors than iodine. However, the weaker XB donors F4DIBz and F8DIBu form XB complexes with the chloride 1 and especially with the bromide 2. The prevalence of the halogen bonding with 2 is probably not only electronic in origin, and it seems to offer the best balance between electron poorness and steric availability. The XB interactions with F4DIBz and F8DIBu are much weaker than with iodine, the reduction of the sum of the van der Waals radii of halogen to iodine being 13.5, 12.3, and 14.6% with C–I···X angles between 163 and 179° for 1b, 2b, and 2c, respectively, and results in polymeric (···1···F4DIBz···1···F4DIBz···)n, (···2···F4DIBz···2···F4DIBz···)n, and (···2···F8DIBu···2···F8DIBu···)n one-dimensional zigzag chains in the solid state.

Halogen Bonding at the Active Sites of Human Cathepsin L and MEK1 Kinase: Efficient Interactions in Different Environments

In two series of small-molecule ligands, one inhibiting human cathepsin L (hcatL) and the other MEK1 kinase, biological affinities were found to strongly increase when an aryl ring of the inhibitors is substituted with the larger halogens Cl, Br, and I, but to decrease upon F substitution. X-ray co-crystal structure analyses revealed that the higher halides engage in halogen bonding (XB) with a backbone C=O in the S3 pocket of hcatL and in a back pocket of MEK1. While the S3 pocket is located at the surface of the enzyme, which provides a polar environment, the back pocket in MEK1 is deeply buried in the protein and is of pronounced apolar character. This study analyzes environmental effects on XB in protein-ligand complexes. It is hypothesized that energetic gains by XB are predominantly not due to water replacements but originate from direct interactions between the XB donor (Caryl-X) and the XB acceptor (C=O) in the correct geometry. New X-ray co-crystal structures in the same crystal form (space group P2(1)2(1)2(1)) were obtained for aryl chloride, bromide, and iodide ligands bound to hcatL. These high-resolution structures reveal that the backbone C=O group of Gly61 in most hcatL co-crystal structures maintains water solvation while engaging in XB. An aryl-CF3-substituted ligand of hcatL with an unexpectedly high affinity was found to adopt the same binding geometry as the aryl halides, with the CF3 group pointing to the C=O group of Gly61 in the S3 pocket. In this case, a repulsive F2C-F⋅⋅⋅O=C contact apparently is energetically overcompensated by other favorable protein-ligand contacts established by the CF3 group.

Tetrahedral Oxyanions in Halogen-Bonded Coordination Networks

The deliberate construction of (6,3) networks via halogen bond-driven self-assembly of tetra-n-butylammonium perchlorate, periodate, and perrhenate with 1,4-diiodotetrafluorobenzene is reported. The mononegative oxyanions sit at network nodes and work as tridentate halogen bond (XB) acceptors, the diiodobenzene derivative spaces the nodes and function as a bidentate XB donor, while the ammonium cations occupy the space encircled by the supramolecular (6,3) frames. Mixed crystals wherein two different oxyanions statistically occupy the network nodes have also been obtained and show geometrical parameters intermediate to the corresponding pure crystals containing only one of the two oxyanions. Mononegative tetrahedral oxyanions are thus demonstrated to behave as general and effective tectons in anion coordination and anion-templated assembly driven by halogen bonding.

Modulation of N···I and +N−H···Cl−···I Halogen Bonding: Folding, Inclusion, and Self-Assembly of Tri- and Tetraamino Piperazine Cyclophanes

The acidity of the crystallization conditions was successfully employed in modulating the balance between the robust intramolecular hydrogen bonding (HB) and intermolecular halogen bonding (XB) observed in large tri- (1) and tetraamino (2) piperazine cyclophanes. A careful crystallization of the title XB acceptor cyclophanes with a strong bidentate XB donor 1,4-diiodotetrafluorobenzene (F4DIB) from CHCl3:MeOH, dimethylformamide (DMF), or HCl:H2O:EtOH resulted in X-ray quality crystals of 1·F4DIB, 2@DMF, 2·2@F4DIB, [1H3]Cl3·(F4DIB)6, and [2H6]Cl6·(F4DIB)2. The intramolecular hydrogen bonding pattern in 1 and 2 was retained in neutral protic and aprotic solvents, and regular N−H···N hydrogen and C−I···N halogen bonding synthons were observed for 1·F4DIB, 2@DMF, and 2·2@F4DIB. Because of its unaffected Pac-Man (alias Pacman) motif, cyclophane 2 manifested a size-selective complexation of DMF over F4DIB under neutral conditions. Acidic conditions led to the protonation of the cyclophanes, and +N−H···Cl−, CPFC...

Halogen bonding: Recent advances

Halogen bonding (XB), as a directional interaction between covalently bound halogen atoms (XB donor) and Lewis bases (A, XB acceptor), has been recently intensively investigated as a powerful tool in crystal engineering. After a short review on the origin and general features of halogen bonding, current developments towards (i) the elaboration of three-dimensional networks, (ii) the interaction with anionic XB acceptors, (iii) its identification in biological systems and (iv) the formation of liquid crystal phases will be described. Theoretical analyses, statistical studies and experimental electron density determinations converge to describe halogen bonding as a relatively weak structure directing tool, when compared with hydrogen bonding. However, when the halogen atom is strongly activated as in iodoperfluorinated molecules or cationic aromatic systems can halogen bonding act as an efficient and reliable structure directing tool.

Highly Interpenetrated Supramolecular Networks Supported by N⋅⋅⋅I Halogen Bonding

Halogen bonding (XB) has been used to assemble tetrakis(4-pyridyl)pentaerythritol (tetradentate XB acceptor) with different alpha,omega-diiodoperfluoroalkanes (bidentate XB donors) or tetrakis(4-iodotetrafluorophenyl)pentaerythritol (tetradentate XB donor). The remarkable linearity of the XB formed, the rodlike character of alpha,omega-diiodoperfluoroalkanes and the mutual complementarities of pentaerythritol partners, translate the three-dimensional character of the XB acceptor into open primary networks, which interpenetrate to avoid the presence of voids and to ensure segregation of the modules. Two-dimensional (2D) square 4(4) layers (sql) with fourfold and fivefold interpenetration, as well as an eightfold diamondoid network (dia) of class Ia and a remarkable tenfold dia network of class IIIa, have been obtained.