Transition Metal Catalysis Controlled by Hydrogen Bonding in the Second Coordination Sphere.

Transition metal catalysis is of utmost importance for the development of sustainable processes in academia and industry. The activity and selectivity of metal complexes are typically the result of the interplay between ligand and metal properties. As the ligand can be chemically altered, a large research focus has been on ligand development. More recently, it has been recognized that further control over activity and selectivity can be achieved by using the "second coordination sphere", which can be seen as the region beyond the direct coordination sphere of the metal center. Hydrogen bonds appear to be very useful interactions in this context as they typically have sufficient strength and directionality to exert control of the second coordination sphere, yet hydrogen bonds are typically very dynamic, allowing fast turnover. In this review we have highlighted several key features of hydrogen bonding interactions and have summarized the use of hydrogen bonding to program the second coordination sphere. Such control can be achieved by bridging two ligands that are coordinated to a metal center to effectively lead to supramolecular bidentate ligands. In addition, hydrogen bonding can be used to preorganize a substrate that is coordinated to the metal center. Both strategies lead to catalysts with superior properties in a variety of metal catalyzed transformations, including (asymmetric) hydrogenation, hydroformylation, C-H activation, oxidation, radical-type transformations, and photochemical reactions.

Chirality-Driven Self-Assembly of Discrete, Homochiral FeII 2 L3 Cages.

Coordination chemistry is a powerful method to synthesize supramolecular cages with distinct features that suit specific applications. This work demonstrates the synthesis of discrete, homochiral FeII 2 L3 cages via chirality-driven self-assembly. Specifically, the installation of chirality - at both the vertices and ligand backbones - allows the formation of discrete, homochiral FeII 2 L3 cages of different sizes via stereochemical control of the iron(II) centers. We observed that larger cages require multiple chiral centra (chiral ligands and vertices). In contrast, the formation of smaller cages is stereoselective with solely chiral ligands. The latter cages can also be formed from two chiral subcomponents, but only when they have matching chirality. Single-crystal X-ray diffraction of these smaller FeII 2 L3 cages revealed several non-covalent interactions as a driving force for narcissistic chiral self-sorting. This expected behavior was confirmed utilizing the shorter ligands in racemic form, yielding discrete, homochiral FeII 2 L3 cages formed in enantiomeric pairs.

A High-Affinity "Synthavidin" Receptor for Squaraine Dyes.

Strong-binding host-guest pairings in aqueous media have potential as "supramolecular glues" in biomedical techniques, complementing the widely-used (strept)avidin-biotin combination. We have previously found that squaraine dyes are bound very strongly by tetralactam macrocycles possessing anthracenyl units as cavity walls. Here we show that replacing the anthracenes with pentacyclic 5,7,12,14-tetrahydro-5,7,12,14-tetraoxapentacene (TOP) units generates receptors which bind squaraines with increased affinities (around Ka =1010  m-1 ) and improved selectivities. Binding can be followed through changes to squaraine fluorescence and absorbance. The TOP units are easy to prepare and potentially variable, while the TOP-based receptor shows improved photostability, both in itself and in complex with squaraines. The results suggest that this system could prove valuable in the further development of practical "synthavidin" chemistry.

Importance of Cu and Ag regium-π bonds in supramolecular chemistry and biology: a combined crystallographic and ab initio study.

Identifying and characterizing new binding events between electron donor and acceptor counterparts represents a crucial step to complete the molecular recognition and aggregation picture, which is key to chemistry and biology. In this study we interrogated both the PDB (Protein Data Bank) and CSD (Cambridge Structural Database) for the presence of Cu and Ag regium-π (Rg-π) bonds (an attractive noncovalent force between elements from group 11 and π-systems). Concretely, we found evidence of the plausible biological role of the interaction in protein-DNA systems, bacterial Ag extrusion processes and Heme group redox functionality. Furthermore, we also highlighted the implications of Rg-π bonds in the crystal packing of two host-guest systems, where this interaction is key for the binding and recognition of small organic molecules as well as for the encapsulation of organometallic complexes. Theoretical models were used to analyse the strength of the interaction (RI-MP2/def2-TZVP level of theory) together with QTAIM (Quantum Theory of Atoms in Molecules), NBO (Natural Bonding Orbital) and NCIplot (Non Covalent Interactions plot) analyses, which further assisted in the characterization of the regium-π interactions described herein. We expect the results from this study will be useful to attract the attention of chemical biologists as well as to expand the potential of the interaction to the supramolecular chemistry and crystal engineering communities.

A Water Soluble Pd2 L4 Cage for Selective Binding of Neu5Ac.

The sialic acid N-acetylneuraminic acid (Neu5Ac) and its derivatives are involved in many biological processes including cell-cell recognition and infection by influenza. Molecules that can recognize Neu5Ac might thus be exploited to intervene in or monitor such events. A key obstacle in this development is the sparse availability of easily prepared molecules that bind to this carbohydrate in its natural solvent; water. Here, we report that the carbohydrate binding pocket of an organic soluble [Pd2 L4 ]4+ cage could be equipped with guanidinium-terminating dendrons to give the water soluble [Pd2 L4 ][NO3 ]16 cage 7. It was shown by means of NMR spectroscopy that 7 binds selectively to anionic monosaccharides and strongest to Neu5Ac with Ka =24 M-1 . The cage had low to no affinity for the thirteen neutral saccharides studied. Aided by molecular modeling, the selectivity for anionic carbohydrates such as Neu5Ac could be rationalized by the presence of charge assisted hydrogen bonds and/or the presence of a salt bridge with a guanidinium solubilizing arm of 7. Establishing that a simple coordination cage such as 7 can already selectively bind to Neu5Ac in water paves the way to improve the stability, affinity and/or selectivity properties of M2 L4 cages for carbohydrates and other small molecules.

Frustrated Lewis Pairs Based on Carbon⋠⋠⋠Carbon+ Tetrel Bonds: A DFT Study.

The ability of Triangulenium (TA+ ) compounds to form Frustrated Lewis Pairs (FLPs) with N-HeteroCycle Carbenes (NHCs) is analysed in this manuscript at the PBE0-D3/def2-TZVP level of theory. We have used six TA+ -based moieties, three presenting similar bridging groups (O (trioxo), -CH2 (triaryl) and -NH (triaza)) and another three mixing, O, -CH2 and NH moieties. In addition, several aryl-substituted NHCs have been used as electron donor moieties to undergo carbon⋅⋅⋅carbon+ tetrel bonds with the TA+ derivatives. More precisely, -Me,-iPr, -tBu and -Ph groups were used. Finally, we have used Bader's quantum theory of "atoms in molecules" (QTAIM) and Natural Bonding Analysis (NBO) to characterize the carbon⋅⋅⋅carbon+ tetrel bonds described herein. We expect the results gathered herein will be useful for further exploitation of carbon⋅⋅⋅carbon+ bonds in the formation of FLPs as well as to expand the current knowledge of tetrel bonds to the fields of synthetic chemistry and catalysis.

An Octa-Urea [Pd2 L4 ]4+ Cage that Selectively Binds to n-octyl-α-D-Mannoside.

Designing compounds for the selective molecular recognition of carbohydrates is a challenging task for supramolecular chemists. Macrocyclic compounds that incorporate isophtalamide or bisurea spacers linking two aromatic moieties have proven effective for the selective recognition of all-equatorial carbohydrates. Here, we explore the molecular recognition properties of an octa-urea [Pd2 L4 ]4+ cage complex (4). It was found that small anions like NO3- and BF4- bind inside 4 and inhibit binding of n-octyl glycosides. When the large non-coordinating anion 'BArF ' was used, 4 showed excellent selectivity towards n-octyl-α-D-Mannoside with binding in the order of Ka ≈16 M-1 versus non-measurable affinities for other glycosides including n-octyl-ß-D-Glucoside (in CH3 CN/H2 O 91 : 9).

Comparison of [Pd2L4][BF4]4 cages for binding of n-octyl glycosides and nitrate (L = isophthalamide or dipicolinamide linked dipyridyl ligand).

Two dipyridyl ligands were synthesized, where the pyridyl donor fragments were separated by an isophthalamide (1) or a dipicolinamide moiety (2). Both ligands formed [Pd2(Ligand)4][BF4]4 complexes in CD2Cl2 containing 5% dmso-d6. It was found that while [Pd2(1)4][BF4]4 readily binds to n-octyl glycosides and to nitrate anions, [Pd2(2)4][BF4]4 did not. The difference in binding properties could be rationalized based on the reduced flexibility and size of the [Pd2(2)4]2+ cage and/or stronger interior binding of a BF4- counter anion.

A Synthetic Galectin Mimic.

Galectins are a galactoside specific subclass of carbohydrate binding proteins (lectins) involved in various cellular activities, certain cancers, infections, inflammations, and many other biological processes. The molecular basis for the selectivity of galectins is well-documented and revolves around appropriate interaction complementarity: an aromatic residue for C-H⋅⋅⋅π interactions and polar residues for (charge assisted) hydrogen bonds with the axial hydroxyl group of a galactoside. However, no synthetic mimics are currently available. We now report on the design and synthesis of the first galectin mimic (6), and show that it has a higher than 65-fold preference for n-octyl-ß-galactoside (8) over n-octyl-ß-glucoside (7) in CD2 Cl2 containing 5 % [D6 ]DMSO (with Ka ≥4500 M-1 for 6:8). Molecular modeling informed by nOe studies reveal a high degree of interaction complementarity between 6 and galactoside 8, which is very similar to the interaction complementarity found in natural galectins.

A [Pd2L4]4+ cage complex for n-octyl-ß-d-glycoside recognition.

The cage complex [Pd294]4+ (3') binds n-octyl glycosides in DCM/DMSO (9 : 1) solution with Ka ≈ 51 M-1 for n-Oct-ß-d-Glc and Ka ≈ 29 M-1 for n-Oct-ß-d-Gal.

Intramolecular Spodium Bonds in Zn(II) Complexes: Insights from Theory and Experiment.

Two new dinuclear zinc(II) complexes, [Zn2(µ1,3-OAc)(L1)2]I·MeOH (1) and [Zn2(µ1,3-OAc)(L2)(NCS)] (2), (where HL1 = 2-(((3-(dimethylamino)propyl)amino)methyl)-6-methoxy-phenol and H2L2 = 2,2'-[(1-Methyl-1,2-ethanediyl)bis(iminomethylene)]bis[6-ethoxyphenol]) have been synthesized and characterized by elemental and spectral analysis. Their X-ray solid state structures have been determined, revealing the existence of intramolecular Zn···O spodium bonds in both complexes due to the presence of methoxy (1) or ethoxy (2) substituents adjacent to the coordinated phenolic O-atom. These noncovalent interactions have been studied using density functional theory (DFT) calculations, the quantum theory of "atoms-in-molecules" and the noncovalent interaction plot. Moreover, a search in the Cambridge structure database (CSD) has been conducted in order to investigate the prevalence of intramolecular spodium bonds in Zn complexes. To our knowledge this is the first investigation dealing with intramolecular spodium bonds.

Spodium Bonds: Noncovalent Interactions Involving Group†12 Elements.

The term spodium (Sp) bond is proposed to refer to a net attractive interaction between any element of Group 12 and electron-rich atoms (Lewis bases or anions). These noncovalent interactions are markedly different from coordination bonds (antibonding Sp-ligand orbital involved). Evidence is provided for the existence of this interaction by calculations at the RI-MP2/aug-cc-pVTZ level of theory, atoms-in-molecules, and natural bond orbital analyses and by examining solid-state structures in the Cambridge Structure Database.

Intermolecular Non-Covalent Carbon-Bonding Interactions with Methyl Groups: A CSD, PDB and DFT Study.

A systematic evaluation of the CSD and the PDB in conjunction with DFT calculations reveal that non-covalent Carbon-bonding interactions with X-CH3 can be weakly directional in the solid state (P ≤ 1.5) when X = N or O. This is comparable to very weak CH hydrogen bonding interactions and is in line with the weak interaction energies calculated (≤ -1.5 kcal·mol-1) of typical charge neutral adducts such as [Me3N-CH3···OH2] (2a). The interaction energy is enhanced to ≤-5 kcal·mol-1 when X is more electron withdrawing such as in [O2N-CH3··O=Cdme] (20b) and to ≤18 kcal·mol-1 in cationic species like [Me3O+-CH3···OH2]+ (8a).

Disaggregation is a Mechanism for Emission Turn-On of ortho-Aminomethylphenylboronic Acid-Based Saccharide Sensors.

ortho-Aminomethylphenylboronic acid-based receptors with appended fluorophores are commonly used as molecular sensors for saccharides in aqueous media. The mechanism for fluorescence modulation in these sensors has been attributed to some form of photoinduced electron transfer (PET) quenching, which is diminished in the presence of saccharides. Using a well-known boronic acid-based saccharide sensor (3), this work reveals a new mechanism for fluorescence turn-on in these types of sensors. Compound 3 exhibits an excimer, and the associated ground-state aggregation is responsible for fluorescence modulation under certain conditions. When fructose was titrated into a solution of 3 in 2:1 water/methanol with NaCl, the fluorescence intensity increased. Yet, when the same titration was repeated in pure methanol, a solvent in which the sensor does not aggregate, no fluorescence response to fructose was observed. This reveals that the fluorescence increase is not fully associated with fructose binding, but instead disaggregation of the sensor in the presence of fructose. Further, an analogue of the sensor that does not contain a boronic acid (4) responded nearly identically to 3 in the presence of fructose, despite having no functional group with which to bind the saccharide. This further supports the claim that fluorescence modulation is not primarily a result of binding, but of disaggregation. Using an indicator displacement assay and isothermal titration calorimetry, it was confirmed that fructose does indeed bind to the sensor. Thus, our evidence reveals that while binding occurs with fructose in the aqueous solvent system used, it is not related to the majority of the fluorescence modulation. Instead, disaggregation dominates the signal turn-on, and is thus a mechanism that should be investigated in other ortho-aminomethylphenylboronic acid-based sensors.

σ-Hole Opposite to a Lone Pair: Unconventional Pnicogen Bonding Interactions between ZF3 (Z=N, P, As, and Sb) Compounds and Several Donors.

The ability of several pnicogen sp(3) derivatives ZF3 (Z=N, P, As, Sb) to interact with electron-rich entities by means of the opposite face to the lone pair (lp) is investigated at the RI-MP2/aug-cc-pVQZ level of theory. The strength of the interaction ranges from -1 to -87 kJ mol(-1) , proving its favorable nature, especially when the lp is coordinated to a metal center, whereby the strength of the interaction is significantly enhanced. NBO analysis showed that orbital effects are modest contributors to the global stabilization of the pnicogen σ-hole bonded complexes studied. Finally, a selection of Cambridge Structural Database examples are shown that demonstrate the impact of this counterintuitive binding mode in the solid state.

Tetrel Bonding Interactions.

Tetrel (Tr) bonding is first placed into perspective as a σ-hole bonding interaction with atoms of the Tr family. An sp(3) R4Tr unit has four σ-holes with which a Lewis base can form a complex. We then highlight some inspiring crystal structures where Tr bonding is obvious, followed by an account of our own work. We have shown that Tr bonding is ubiquitous in the solid state and we have highlighted that Tr bonding with carbon is possible when C is placed in the appropriate chemical context. We hope that this account serves as an initial guide and source of inspiration for others wishing to exploit this vastly underexplored interaction.

Synthesis and evaluation of a desymmetrised synthetic lectin: an approach to carbohydrate receptors with improved versatility.

A new synthetic lectin features apolar surfaces provided by two different aromatic components (biphenyl and pyrenyl). Affinities up to 260 M(-1) are recorded for carbohydrates in water. The desymmetrised design has potential for variation to give receptors with a broadened range of capabilities.

1,1,2,2-Tetracyanocyclopropane (TCCP) as supramolecular synthon.

The 1,1,2,2-tetracyanocyclopropane (TCCP) unit presents a synthetically accessible and versatile synthon that can interact with lone-pair or π-electrons by 'non-covalent carbon bonding'. Complexes of TCCP with common small molecules, anions, aromatics like fullerenes, amino acids and nucleobases were computed at the DFT BP86-D3/def2-TZVP level of theory. Binding energies vary between about -10 kcal mol(-1) for neutral guests and -15 to -50 kcal mol(-1) for anionic species. This is comparable to strong and very strong hydrogen bonding respectively. Thus, in addition to synthons that contain polarized hydrogen or halogen atoms, TCCP presents a new supramolecular synthon that awaits experimental exploitation.

Platform Synthetic Lectins for Divalent Carbohydrate Recognition in Water.

Biomimetic carbohydrate receptors ("synthetic lectins") have potential as agents for biological research and medicine. However, although effective strategies are available for "all-equatorial" carbohydrates (glucose, etc.), the recognition of other types of saccharide under natural (aqueous) conditions is less well developed. Herein we report a new approach based on a pyrene platform with polar arches extending from aryl substituents. The receptors are compatible with axially substituted carbohydrates, and also feature two identical binding sites, thus mimicking the multivalency observed for natural lectins. A variant with negative charges forms 1:2 host/guest complexes with aminosugars, with K1 >3000 m(-1) for axially substituted mannosamine, whereas a positively charged version binds the important α-sialyl unit with K1 ≈1300 m(-1) .

Synthetic Receptors for the High-Affinity Recognition of O-GlcNAc Derivatives.

The combination of a pyrenyl tetraamine with an isophthaloyl spacer has led to two new water-soluble carbohydrate receptors ("synthetic lectins"). Both systems show outstanding affinities for derivatives of N-acetylglucosamine (GlcNAc) in aqueous solution. One receptor binds the methyl glycoside GlcNAc-ß-OMe with Ka ≈20,000 m(-1), whereas the other one binds an O-GlcNAcylated peptide with Ka ≈70,000 m(-1). These values substantially exceed those usually measured for GlcNAc-binding lectins. Slow exchange on the NMR timescale enabled structural determinations for several complexes. As expected, the carbohydrate units are sandwiched between the pyrenes, with the alkoxy and NHAc groups emerging at the sides. The high affinity of the GlcNAcyl-peptide complex can be explained by extra-cavity interactions, raising the possibility of a family of complementary receptors for O-GlcNAc in different contexts.