Taming Molecular Folding: Anion-Templated Foldamers with Tunable Quaternary Structures.

Higher-order foldamers represent a unique class of supramolecules at the forefront of molecular design. Herein we control quaternary folding using a novel approach that combines halogen bonding (XBing) and hydrogen bonding (HBing). We present the first anion-templated double helices induced by halogen bonds (XBs) and stabilized by "hydrogen bond enhanced halogen bonds" (HBeXBs). Our findings demonstrate that the number and orientation of hydrogen bond (HB) and XB donors significantly affect the quaternary structure and guest selectivity of two similar oligomers. This research offers new design elements to engineer foldamers and tailor their quaternary structure for specific guest binding.

Cucurbit[8]uril Binds Nonterminal Dipeptide Sites with High Affinity and Induces a Type II ß-Turn.

In an effort to target polypeptides at nonterminal sites, we screened the binding of the synthetic receptor cucurbit[8]uril (Q8) to a small library of tetrapeptides, each containing a nonterminal dipeptide binding site. The resulting leads were characterized in detail using a combination of isothermal titration calorimetry, 1H NMR spectroscopy, electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS), and X-ray crystallography. The equilibrium dissociation constant values determined for the binding of Q8 to nonterminal dipeptide sites Lys-Phe (KF) and Phe-Lys (FK) were 60 and 86 nm, respectively. These are to the best of our knowledge the highest affinities reported to date for any synthetic receptor targeting a nonterminal site on an unmodified peptide. A 0.79 Å resolution crystal structure was obtained for the complex of Q8 with the peptide Gly-Gly-Leu-Tyr-Gly-Gly-Gly (GGLYGGG) and reveals structural details of the pair-inclusion motif. The molecular basis for recognition is established to be the inclusion of the side chains of Leu and Tyr residues, as well as an extensive network of hydrogen bonds between the peptide backbone, the carbonyl oxygens of Q8, and proximal water molecules. In addition, the crystal structure reveals that Q8 induces a type II ß-turn. The sequence-selectivity, high affinity, reversibility, and detailed structural characterization of this system should facilitate the development of applications involving ligand-induced polypeptide folding.

The interplay between hydrogen and halogen bonding: substituent effects and their role in the hydrogen bond enhanced halogen bond.

The hydrogen bond enhanced halogen bond (HBeXB) has recently been used to effectively improve anion binding, organocatalysis, and protein structure/function. In this study, we present the first systematic investigation of substituent effects in the HBeXB. NMR analysis confirmed intramolecular HBing between the amine and the electron-rich belt of the XB donor (N-H⋯I). Gas-phase density functional theory studies showed that the influence of HBing on the halogen atom is more sensitive to substitution on the HB donor ring (R1). The NMR studies revealed that the intramolecular HBing had a significant impact on receptor performance, resulting in a 50-fold improvement. Additionally, linear free energy relationship (LFER) analysis was employed for the first time to study the substituent effect in the HBeXB. The results showed that substituents on the XB donor ring (R2) had a competing effect where electron donating groups strengthened the HB and weakened the XB. Therefore, selecting an appropriate substituent on the adjacent HB donor ring (R1) could be an alternative and effective way to enhance an electron-rich XB donor. X-ray crystallographic analysis demonstrated that intramolecular HBing plays an important role in the receptor adopting the bidentate conformation. Taken together, the findings imply that modifying distal substituents that affect neighboring noncovalent interactions can have a similar impact to conventional para substitution substituent effects.

Pushing the limits of the hydrogen bond enhanced halogen bond-the case of the C-H hydrogen bond.

C-H hydrogen bonds have remarkable impacts on various chemical systems. Here we consider the influence of C-H hydrogen bonds to iodine atoms. Positioning a methyl group between two iodine halogen bond donors of the receptor engendered intramolecular C-H hydrogen bonding (HBing) to the electron-rich belt of both halogen bond donors. When coupled with control molecules, the role of the C-H hydrogen bond was evaluated. Gas-phase density functional theory studies indicated that methyl C-H hydrogen bonds help bias a bidentate binding conformation. Interaction energy analysis suggested that the charged C-H donors augment the halogen bond interaction-producing a >10 kcal mol-1 enhancement over a control lacking the C-H⋯I-C interaction. X-ray crystallographic analysis demonstrated C-H hydrogen bonds and bidentate conformations with triflate and iodide anions, yet the steric bulk of the central functional group seems to impact the expected trends in halogen bond distance. In solution, anion titration data indicated elevated performance from the receptors that utilize C-H Hydrogen Bond enhanced Halogen Bonds (HBeXBs). Collectively, the results suggest that even modest hydrogen bonds between C-H donors and iodine acceptors can influence molecular structure and improve receptor performance.

Halogen bonding organocatalysis enhanced through intramolecular hydrogen bonds.

Recent results indicate a halogen bond donor is strengthened through direct interaction with a hydrogen bond to the electron-rich belt of the halogen. Here, this Hydrogen Bond enhanced Halogen Bond (HBeXB) plays a clear role in a catalyst. Our HBeXB catalyst improves product conversion in a halide abstraction reaction over a traditional halogen bonding derivative.

Modulating photoswitch performance with halogen, coordinative and hydrogen bonding: a comparison of relative bond strengths.

The behavior of an enediyne photoswitch is modulated with halogen bonding, coordinative bonding and hydrogen bonding. Through NMR and computational studies we demonstrate that the relative strength of the secondary bonding directly influences the rate of photoisomerization and the photostationary state.

Theoretical, Solid-State, and Solution Quantification of the Hydrogen Bond-Enhanced Halogen Bond.

Proximal noncovalent forces are commonplace in natural systems and understanding the consequences of their juxtaposition is critical. This paper experimentally quantifies for the first time a Hydrogen Bond-Enhanced Halogen Bond (HBeXB) without the complexities of protein structure or preorganization. An HBeXB is a halogen bond that has been strengthened when the halogen donor simultaneously accepts a hydrogen bond. Our theoretical studies suggest that electron-rich halogen bond donors are strengthened most by an adjacent hydrogen bond. Furthermore, stronger hydrogen bond donors enhance the halogen bond the most. X-ray crystal structures of halide complexes (X- =Br- , I- ) reveal that HBeXBs produce shorter halogen bonds than non-hydrogen bond analogues. 19 F NMR titrations with chloride highlight that the HBeXB analogue exhibits stronger binding. Together, these results form the foundation for future studies concerning hydrogen bonds and halogen bonds in close proximity.

Helical Anion Foldamers in Solution.

Using anions to induce molecular structure is a rapidly growing area of dynamic and switchable supramolecular chemistry. The emphasis of this review is on helical anion foldamers in solution, and many of the beautiful complexes described herein are accentuated by their crystal structures. Anion foldamers are defined as single- or multistrand complexes-often helical-that incorporate one or more anions. The review begins by discussing foldamer structure and nomenclature and follows with discourse on the anions which are employed. Recent advances in functional foldamers that bind a single anion are examined, including: induced chirality, stimuli-responsive dynamics, fluorescence changes, organocatalysis, anion transport, and halogen bonding. The review then inspects multianion foldamers, and this section is organized by the number of strands within the foldamer-from single- to triple-strand foldamers. Finally, the review is punctuated by recent hydrogen- and halogen-bonding triple-strand anion foldamers.

Hydrogen Bond Enhanced Halogen Bonds: A Synergistic Interaction in Chemistry and Biochemistry.

The halogen bond (XB) has become an important tool for molecular design in all areas of chemistry, including crystal and materials engineering and medicinal chemistry. Its similarity to the hydrogen bond (HB) makes the relationship between these interactions complex, at times competing against and other times orthogonal to each other. Recently, our two laboratories have independently reported and characterized a synergistic relationship, in which the XB is enhanced through direct intramolecular HBing to the electron-rich belt of the halogen. In one study, intramolecular HBing from an amine polarizes the iodopyridinium XB donors of a bidentate anion receptor. The resulting HB enhanced XB (or HBeXB) preorganizes and further augments the XB donors. Consequently, the affinity of the receptor for halogen anions was significantly increased. In a parallel study, a meta-chlorotyrosine was engineered into T4 lysozyme, resulting in a HBeXB that increased the thermal stability and activity of the enzyme at elevated temperatures. The crystal structure showed that the chlorine of the noncanonical amino acid formed a XB to the protein backbone, which augmented the HB of the wild-type enzyme. Calorimetric analysis resulted in an enthalpic contribution of this Cl-XB to the stability of the protein that was an order of magnitude greater than previously determined in biomolecules. Quantum mechanical (QM) calculations showed that rotating the hydroxyl group of the tyrosine to point toward rather than away from the halogen greatly increased its potential to serve as a XB donor, equivalent to what was observed experimentally. In sum, the two systems described here show that the HBeXB concept extends the range of interaction energies and geometries to be significantly greater than that of the XB alone. Additionally, surveys of structural databases indicate that the components for this interaction are already present in many existing molecular systems. The confluence of the independent studies from our two laboratories demonstrates the reach of the HBeXB across both chemistry and biochemistry and that intentional engineering of this enhanced interaction will extend the applications of XBs beyond these two initial examples.

Structural and Computational Characterization of a Bridging Zwitterionic-Amidoxime Uranyl Complex.

A bridging (µ2) neutral zwitterionic amidoxime binding mode previously unobserved between amidoximes and uranyl is reported and compared to other uranyl amidoxime complexes. Density functional theory computations show the dinuclear complex exhibits a shallow potential energy surface allowing for facile inclusion of a nonbonding water molecule in the solid-state.

Anion Influence on the Packing of 1,3-Bis(4-Ethynyl-3-Iodopyridinium)-Benzene Halogen Bond Receptors.

Rigid and directional arylethynyl scaffolds have been widely successful across diverse areas of chemistry. Utilizing this platform, we present three new structures of a dicationic 1,3-bis(4-ethynyl-3-iodopyridinium)-benzene halogen bonding receptor with tetrafluoroborate, nitrate, and hydrogen sulfate. Structural analysis focuses on receptor conformation, anion shape, solvation, and long range packing of these systems. Coupled with our previously reported structures, we conclude that anions can be classified as building units within this family of halogen bonding receptors. Two kinds of antiparallel dimers are observed for these dicationic receptors. An off-centered species is most frequent, present among geometrically diverse anions, and assorted receptor conformations. In contrast, the centered antiparallel dimers are observed with receptors adopting a bidentate conformation in the solid-state. While anions support the solid-state formation of dimers, the molecular geometry and characteristics (planarity, rigidity, and directionality) of arylethynyl systems increases the likelihood of dimer formation by limiting efficient packing arrangements. The significantly larger cation may have considerable influence on the solid-state packing, as similar cationic arylethynyl systems also display these dimers, suggesting.

Co-crystals of an organic triselenocyanate with ditopic Lewis bases: recurrent chalcogen bond interactions motifs.

Organic selenocyanates R-Se-CN can act as an amphoteric chalcogen bond (ChB) donor (through the Se atom) and acceptor (through the N atom lone pair). Co-crystallization of tri-substituted 1,3,5-tris(selenocyanatomethyl)-2,4,6-trimethylbenzene (1) is investigated with different ditopic Lewis bases acting as chalcogen bond (ChB) acceptors to investigate the outcome of the competition, as ChB acceptor, between the nitrogen lone pair of the SeCN group and other Lewis bases involving pyridinyl or carbonyl functions. In the presence of tetramethylpyrazine (TMP), benzoquinone (BQ) and para-dinitrobenzene (pDNB) as ditopic Lewis bases, a recurrent oligomeric motif stabilized by six ChB interactions is observed, involving six SeCN groups and the ChB acceptor sites of TMP, BQ and pDNB in the 2:1 adducts (1)2·TMP, (1)2·BQ and (1)2·pDNB.

Solvatochromism and fluorescence response of a halogen bonding anion receptor.

Herein, we present on two 2,6-bis(4-ethynylpyridinyl)-4-fluoroaniline receptors that display solvatochromic absorption and emission. Neutral derivatives displayed opposite solvatochromic behavior as compared to the alkylated receptors. Adding anions induced changes in the absorption and emission spectra. In general, the fluorescence of the halogen bonding receptor was quenched less efficiently when compared to the hydrogen bonding receptor.

Correction: The intramolecular hydrogen bonded-halogen bond: a new strategy for preorganization and enhanced binding.

[This corrects the article DOI: 10.1039/C8SC01973H.].

A Long-Lived Halogen-Bonding Anion Triple Helicate Accommodates Rapid Guest Exchange.

Anion-templated helical structures are emerging as a dynamic and tractable class of supramolecules that exhibit anion-switchable self-assembly. We present the first kinetic studies of an anion helicate by utilizing halogen-bonding m-arylene-ethynylene oligomers. These ligands formed high-fidelity triple helicates in solution with surprisingly long lifetimes on the order of seconds even at elevated temperatures. We propose an associative ligand-exchange mechanism that proceeded slowly on the same timescale. In contrast, intrachannel anion exchange occurred rapidly within milliseconds or faster as determined by stopped-flow visible spectroscopy. Additionally, the helicate accommodated bromide in solution and the solid state, while the thermodynamic stability of the triplex favored larger halide ions (bromide≈iodide≫chloride). Taken together, we elucidate a new class of kinetically stable helicates. These anion-switchable triplexes maintain their architectures while accommodating fast intrachannel guest exchange.

The intramolecular hydrogen bonded-halogen bond: a new strategy for preorganization and enhanced binding.

Natural and synthetic molecules use weak noncovalent forces to preorganize structure and enable remarkable function. Herein, we introduce the intramolecular hydrogen bonded-halogen bond (HB-XB) as a novel method to preorganize halogen bonding (XBing) molecules, while generating a polarization-enhanced XB. Positioning a fluoroaniline between two iodopyridinium XB donors engendered intramolecular hydrogen bonding (HBing) to the electron-rich belt of both XB donors. NMR solution studies established the efficacy of the HB-XB. The receptor with HB-XBs (G2XB) displayed a nearly 9-fold increase in halide binding over control receptors. Gas-phase density functional theory conformational analysis indicated that the amine stabilizes the bidentate conformation. Furthermore, gas-phase interaction energies showed that the bidentate HB-XBs of G2XBme2+ are more than 3.2 kcal mol-1 stronger than the XBs in a control without the intramolecular HB. Additionally, crystal structures confirm that HB-XBs form tighter contacts with I- and Br- and produce receptors that are more planar. Collectively the results establish the intramolecular HB-XB as a tractable strategy to preorganize XB molecules and regulate XB strength.

Steric Effects of pH Switchable, Substituted (2-pyridinium)urea Organocatalysts: a Solution and Solid Phase Study.

The study of hydrogen bonding organocatalysis is rapidly expanding. Much research has been directed at making catalysts more active and selective, with less attention on fundamental design strategies. This study systematically increases steric hindrance at the active site of pH switchable urea organocatalysts. Incorporating strong intramolecular hydrogen bonds from protonated pyridines to oxygen stabilizes the active conformation of these ureas thus reducing the entropic penalty that results from substrate binding. The effect of increasing steric hindrance was studied by single crystal X-ray diffraction and by kinetics experiments of a benchmark reaction.

Experimental investigation of halogen-bond hard-soft acid-base complementarity.

The halogen bond (XB) is a topical noncovalent interaction of rapidly increasing importance. The XB employs a `soft' donor atom in comparison to the `hard' proton of the hydrogen bond (HB). This difference has led to the hypothesis that XBs can form more favorable interactions with `soft' bases than HBs. While computational studies have supported this suggestion, solution and solid-state data are lacking. Here, XB soft-soft complementarity is investigated with a bidentate receptor that shows similar associations with neutral carbonyls and heavy chalcogen analogs. The solution speciation and XB soft-soft complementarity is supported by four crystal structures containing neutral and anionic soft Lewis bases.

A Halogen-Bond-Induced Triple Helicate Encapsulates Iodide.

The self-assembly of higher-order anion helicates in solution remains an elusive goal. Herein, we present the first triple helicate to encapsulate iodide in organic and aqueous media as well as the solid state. The triple helicate self-assembles from three tricationic arylethynyl strands and resembles a tubular anion channel lined with nine halogen bond donors. Eight strong iodine⋅⋅⋅iodide halogen bonds and numerous buried π-surfaces endow the triplex with remarkable stability, even at elevated temperatures. We suggest that the natural rise of a single-strand helix renders its linear halogen-bond donors non-convergent. Thus, the stringent linearity of halogen bonding is a powerful tool for the synthesis of multi-strand anion helicates.

Anion-directed self-assembly of a 2,6-bis(2-anilinoethynyl)pyridine bis(amide) scaffold.

Bis(sulfonamide) receptors based on the 2,6-bis(2-anilinoethynyl)pyridine scaffold form persistent dimers with water and halides in solution and in the solid-state. The structurally related bis(amide) receptor derived from 3,5-dinitrobenzoyl chloride is a dimer in the solid-state with two HCl molecules directing the self-assembly. The 2+2 dimer, with a twisted "S"-shaped backbone, is held together by six hydrogen bonds. Dissolution of the (H2+·Cl- )2 adduct in CHCl3 results, however, in a monomeric structure. DOSY and 1H NMR experiments were used to identify the dominance of monomer in solution for both 2 and H2+·Cl- . The 'OFF-ON' fluorescence response of 2, 6-bis(2-anilinoethynyl)pyridine is retained with amide arms.