PI by NMR: Probing CH–π Interactions in Protein–Ligand Complexes by NMR Spectroscopy

While CH–π interactions with target proteins are crucial determinants for the affinity of arguably every drug molecule, no method exists to directly measure the strength of individual CH–π interactions in drug–protein complexes. Herein, we present a fast and reliable methodology called PI (π interactions) by NMR, which can differentiate the strength of protein–ligand CH–π interactions in solution. By combining selective amino‐acid side‐chain labeling with ¹H‐¹³C NMR, we are able to identify specific protein protons of side‐chains engaged in CH–π interactions with aromatic ring systems of a ligand, based solely on ¹H chemical‐shift values of the interacting protein aromatic ring protons. The information encoded in the chemical shifts induced by such interactions serves as a proxy for the strength of each individual CH–π interaction. PI by NMR changes the paradigm by which chemists can optimize the potency of drug candidates: direct determination of individual π interactions rather than averaged measures of all interactions.     

N‐Confused Phlorin‐Prodigiosin Chimera: meso‐Aryl Oxidation and π‐Extension Triggered by Peripheral Coordination

An N‐confused phlorin isomer bearing a dipyrrin moiety at the α‐position of the confused pyrrole ring ( 1 ) was synthesized. Pd^II and B^III coordination at the peripheral prodigiosin‐like moiety of 1 afforded the corresponding complexes 2 and 3 . Reflux of 2 in triethylamine (TEA) converted the meso‐phenyl into the Pd^II‐coordinating phenoxy group to afford 4 . Under the same reaction conditions, TEA was linked to the α‐position of the dipyrrin unit in 3 as an N,N‐diethylaminovinyl group to afford 5 . Furthermore, peripheral coordination of B^III in 3 and 5 improved the planarity of the phlorin macrocycle and thus facilitated the coordination of Ag^III at the inner cavity to afford 3‐Ag and 5‐Ag , respectively. These results provide an effective approach for developing unique porphyrinoids through peripheral coordination.     

Interplay between Cation–π and Coinage‐Metal–Oxygen Interactions: An Ab Initio Study and Cambridge Structural Database Survey

The interplay between cation–π and coinage‐metal–oxygen interactions are investigated in the ternary systems N???PhCCM???O (N=Li⁺, Na⁺, Mg²⁺; M=Ag, Au; O=water, methanol, ethanol). A synergetic effect is observed when cation–π and coinage‐metal–oxygen interactions coexist in the same complex. The cation–π interaction in most triads has a greater enhancing effect on the coinage‐metal–oxygen interaction. This effect is analyzed in terms of the binding distance, interaction energy, and electrostatic potential in the complexes. Furthermore, the formation, strength, and nature of both the cation–π and coinage‐metal–oxygen interactions can be understood in terms of electrostatic potential and energy decomposition. In addition, experimental evidence for the coexistence of both interactions is obtained from the Cambridge Structural Database (CSD).     

Synthesis,X‐ray characterization and density functional theory studies of N6‐benzyl‐N6‐methyladenine–M(II) complexes (M = Zn,Cd): The prominent role of π–π, C–H···π and anion–π interactions

We report the synthesis and X‐ray characterization of the N⁶‐benzyl‐N⁶‐methyladenine ligand (L) and three metal complexes, namely [Zn(HL)Cl₃]·H₂O ( 1 ), [Cd(HL)₂Cl₄] ( 2 ) and [H₂L]₂[Cd₃(μ‐L)₂(μ‐Cl)₄Cl₆]·3H₂O ( 3 ). Complex 1 consists of the 7H‐adenine tautomer protonated at N3 and coordinated to a tetrahedral Zn(II) metal centre through N9. The octahedral Cd(II) in complex 2 is N⁹‐coordinated to two N⁶‐benzyl‐N⁶‐methyladeninium ligands (7H‐tautomer protonated at N3) that occupy apical positions and four chlorido ligands form the basal plane. Compound 3 corresponds to a trinuclear Cd(II) complex, where the central Cd atom is six‐coordinated to two bridging μ‐L and four bridging μ‐Cl ligands. The other two Cd atoms are six‐coordinated to three terminal chlorido ligands, to two bridging μ‐Cl ligands and to the bridging μ‐L through N3. Essentially, the coordination patterns, degree of protonation and tautomeric forms of the nucleobase dominate the solid‐state architectures of 1 – 3 . Additionally, the hydrogen‐bonding interactions produced by the endocyclic N atoms and NH groups stabilize high‐dimensional‐order supramolecular assemblies. Moreover, energetically strong anion–π and lone pair (lp)–π interactions are important in constructing the final solid‐state architectures in 1 – 3 . We have studied the non‐covalent interactions energetically using density functional theory calculations and rationalized the interactions using molecular electrostatic potential surfaces and Bader's theory of atoms in molecules. We have particularly analysed cooperative lp–π and anion–π interactions in 1 and π⁺–π⁺ interactions in 3 .     

Unexpectedly strong anion–π interactions on the graphene flakes

Interactions of anions with simple aromatic compounds have received growing attention due to their relevancy in various fields. Yet, the anion–π interactions are generally very weak, for example, there is no favorable anion–π interaction for the halide anion F^? on the simplest benzene surface unless the H‐atoms are substituted by the highly negatively charged F. In this article, we report a type of particularly strong anion–π interactions by investigating the adsorptions of three halide anions, that is, F^?, Cl^?, and Br^?, on the hydrogenated‐graphene flake using the density functional theory. The anion–π interactions on the graphene flake are shown to be unexpectedly strong compared to those on simple aromatic compounds, for example, the F^?‐adsorption energy is as large as 17.5 kcal/mol on a graphene flake (C₈₄H₂₄) and 23.5 kcal/mol in the periodic boundary condition model calculations on a graphene flake C₁₁₃ (the supercell containing a F^? ion and 113 carbon atoms). The unexpectedly large adsorption energies of the halide anions on the graphene flake are ascribed to the effective donor–acceptor interactions between the halide anions and the graphene flake. These findings on the presence of very strong anion–π interactions between halide ions and the graphene flake, which are disclosed for the first time, are hoped to strengthen scientific understanding of the chemical and physical characteristics of the graphene in an electrolyte solution. These favorable interactions of anions with electron‐deficient graphene flakes may be applicable to the design of a new family of neutral anion receptors and detectors. © 2012 Wiley Periodicals, Inc.     

CH–π and CF–π Interactions Lead to Structural Changes of N‐Heterocyclic Carbene Palladium Complexes

The role of CH–π and CF–π interactions in determining the structure of N‐heterocyclic carbene (NHC) palladium complexes were studied using ¹H NMR spectroscopy, X‐ray crystallography, and DFT calculations. The CH–π interactions led to the formation of the cis‐anti isomers in 1‐aryl‐3‐isopropylimidazol‐2‐ylidene‐based [(NHC)₂PdX₂] complexes, while CF–π interactions led to the exclusive formation of the cis‐syn isomer of diiodobis(3‐isopropyl‐1‐pentafluorophenylimidazol‐2‐ylidene) palladium(II).     

Self‐Assembly and Disassembly of Vesicles as Controlled by Anion–π Interactions

Anion–π interactions have been widely studied as new noncovalent driving forces in supramolecular chemistry. However, self‐assembly induced by anion–π interactions is still largely unexplored. Herein we report the formation of supramolecular amphiphiles through anion–π interactions, and the subsequent formation of self‐assembled vesicles in water. With the π receptor 1 as the host and anionic amphiphiles, such as sodium dodecylsulfate (SDS), sodium laurate (SLA), and sodium methyl dodecylphosphonate (SDP), as guests, the sequential formation of host–guest supramolecular amphiphiles and self‐assembled vesicles was demonstrated by SEM, TEM, DLS, and XRD techniques. The intrinsic anion–π interactions between 1 and the anionic amphiphiles were confirmed by crystal diffraction, HRMS analysis, and DFT calculations. Furthermore, the controlled disassembly of the vesicles was promoted by competing anions, such as NO₃^?, Cl^?, and Br^?, or by changing the pH value of the medium.     

Orbital Effect‐Induced Anomalous Anion–π Interactions between Electron‐Rich Aromatic Hydrocarbons and Fluoride

Anion–π interactions generally exist between an anion and an electron‐deficient π‐ring because of the electron‐accepting character of the ring. In this paper, we report orbital effect‐induced anomalous binding between electron‐rich π systems and F^? through anion–π interactions calculated at the MP2/6‐31+G(d,p) and ωB97X‐D/6‐31+G(d,p) levels of theory. We find that anion–π interactions between F^? and electron‐rich π rings increase markedly with increasing number of π electrons and size of the π rings. This is contrary to intuition because anion–π interactions would be expected to gradually decrease because of gradually increasing Coulombic repulsion between the negative charge of the anions and gradually increasing number of π electrons of the aromatic surfaces. Energy decomposition analysis showed that the key to this anomalous effect is the more effective delocalization of negative charge to the unoccupied π* orbitals of larger π rings, which is termed an “orbital effect”.     

Unusual Attractive Au–π Interactions in Small Diacetylene‐Modified Gold Clusters

It is well known that alkynes act as π‐acids in the formation of complexes with metals. We found unprecedented attractive Au–π interactions in diacetylene‐modified [core+exo]‐type [Au₈]⁴⁺ clusters. The 4‐phenyl‐1,3‐butadiynyl‐modified cluster has unusually short Au–C_α distances in the crystal structure, revealing the presence of attractive interactions between the coordinating C≡C moieties and the neighboring bitetrahedral Au₆ core, which is further supported by IR and NMR spectra. Such weak interactions are not found in mono‐acetylene‐modified clusters, which indicates that they are specific for diacetylenic ligands. The attractive Au–π interactions are likely associated with the low energy of the π* orbital in the diacetylenic moieties, into which the valence electrons of the gold core may be back donated. The [Au₈]⁴⁺ clusters show clear red‐shifts of >10 nm with respect to the corresponding mono‐acetylenic clusters in UV/Vis absorption bands, which indicates substantial electronic perturbation effects of the Au–π interactions.     

The Cation–π Interaction in Small‐Molecule Catalysis

Catalysis by small molecules (≤1000 Da, 10^?9 m) that are capable of binding and activating substrates through attractive, noncovalent interactions has emerged as an important approach in organic and organometallic chemistry. While the canonical noncovalent interactions, including hydrogen bonding, ion pairing, and π stacking, have become mainstays of catalyst design, the cation–π interaction has been comparatively underutilized in this context since its discovery in the 1980s. However, like a hydrogen bond, the cation–π interaction exhibits a typical binding affinity of several kcal mol^?1 with substantial directionality. These properties render it attractive as a design element for the development of small‐molecule catalysts, and in recent years, the catalysis community has begun to take advantage of these features, drawing inspiration from pioneering research in molecular recognition and structural biology. This Review surveys the burgeoning application of the cation–π interaction in catalysis.     

Directional Control and Supramolecular Protection Allowing the Chemo‐ and Regioselective Transformation of a Triamine

A Zn^II‐funnel complex based on a calix[6]arene ligand decorated with three tris(imidazolyl) arms at one end of the cone and three NH₂ substituents at the other end, acts as a multipoint recognition host for polyfunctionalized guests. The selectivity is ensured by coordination to Zn^II, CH–π interaction within the calix cone, and H‐bonding at both rims of the cavity. As a result of these multiple interactions, the host can wrap and orient an unsymmetrical triamine guest with a high selectivity. Furthermore, a proton‐monitored switch between the regio‐isomeric adducts allows reversible inversion of the directionality of the system. Thanks to this directional control, the regioselective mono‐carbamoylation of the unsymmetrical triamine guest was successfully achieved on a preparative scale. This case study shows that a funnel‐like receptor can be used as a supramolecular protecting tool allowing a transformation which would be impracticable with conventional covalent chemistry.     

Exclusive π Encapsulation of Light Alkali Metal Cations by a Neutral Molecule

Cation–π interactions are one of the most important classes of noncovalent bonding, and are seen throughout biology, chemistry, and materials science. However, in almost every documented case, these interactions play only a supporting role to much stronger covalent or dative bonds, thus making examples of exclusive cation–π bonding exceedingly rare. In this study, a neutral diboryne molecule is found to encapsulate the light alkali metal cations Li⁺ and Na⁺ in the absence of a net charge, covalent bonds, or lone‐pair donor groups. The resulting encapsulation complexes are, to our knowledge, the first structurally authenticated species in which a neutral molecule binds the light alkali metals exclusively through cation–π interactions.     

Heterometallic FeIII/K Coordination Polymer with a Wide Thermal Hysteretic Spin Transition at Room Temperature

The anionic Fe^III complex exhibiting cooperative spin transition with a wide thermal hysteresis near room temperature, K[Fe(5‐Brthsa)₂] (5‐Brthsa‐H₂=5‐bromosalicylaldehyde thiosemicarbazone), is reported. The hysteresis (Δ=69 K in the first cycle) shows a one‐step transition in heating mode and a two‐step transition in cooling mode. X‐ray structure analysis showed that the coexistence of hydrogen bond and cation–π interactions, as well as alkali metal coordination bonds, to give 2D coordination polymer structure. This result is contrary to previous reports of broad thermal hysteresis induced by coordination bonds of Fe^II spin crossover coordination polymers (with 1D/3D structures), and by strong intermolecular interactions in the molecular packing through π–π stacking or hydrogen‐bond networks. As a consequence, the importance, or the very good suitability of alkali metal‐based coordination bonds and cation–π interactions for communicating cooperative interactions in spin‐crossover (SCO) compounds must be reconsidered.     

Anion Effects on the Formation of Silver(I) Complexes with the Flexible Ligand 4,4′‐Bis(1,2,4‐triazol‐1‐ylmethyl)biphenyl

The reaction of 4,4′‐bis(1,2,4‐triazol‐1‐ylmethyl)biphenyl (btmb) with silver(I) salts of BF₄^–, NO₃^– and N₃^– led to the formation of four new silver(I) coordination polymers {[Ag(btmb)]BF₄}_n ( 1 ), {[Ag₂(btmb)₃](NO₃)₂(H₂O)₅}_n ( 2 ), [Ag₂(btmb)(N₃)₂]_n ( 3 ), and [Ag(btmb)(N₃)]_n ( 4 ). Their coordination number varies from 2 (in 1 ) to 3 (in 2 ), 4 (in 3 ), and 5 (in 4 ). Different from the single chain structure of 1 , complex 2 displays a 1D ladder‐like double chain framework, whereas complex 3 exhibits a 2D layered architecture. Complex 4 has the same anion as complex 3 but shows a different metal‐to‐ligand ratio and a 1D double‐zigzag chain structure. Both 3 and 4 have Ag ··· Ag argentophilic interactions. The ligand btmb adopts both cis or trans configuration in the studied complexes. A trans‐ or cis‐btmb ligand link silver ions with Ag ··· Ag distances of ≈?18 and 13 Å, respectively. BF₄^– and NO₃^– are non‐coordinating anions in 1 and 2 . N₃^– is the bridging anion in 3 (1,3‐bridging fashion) and 4 (1,1‐bridging fashion). These findings suggest that the coordination numbers around the Ag^I ion correlate to the coordination abilities of anions and the btmb to silver ratio. In addition, the influence of anions on thermal stability were also investigated. This work is a good example that nicely supports the less explored field of anion‐dependent structures of complexes with non‐pyridyl ligands.     

Coinage metal complexes of N‐heterocyclic carbene bearing nitrile functionalization: Synthesis and photophysical properties

A new series of N‐heterocyclic carbene (NHC) ligand precursors ( 1 and 2 ) with their [Ag(I)(NHC)₂]PF₆ complexes ( 3 and 4 ) and [ClAu(I)(NHC)] complexes ( 5 and 6 ) are reported. Complexes 5 and 6 were synthesized via transmetalation reaction using either 3 or 4 and AuCl(SMe₂) as reactants, respectively. All the synthesized compounds were fully characterized using elemental analyses and Fourier transform infrared, ¹H NMR and ¹³C NMR spectroscopies. In the crystal structures of 3 , 5 and 6 , the Ag(I) and Au(I) ions are in a linear geometry. The entire structure of 3 is stabilized by significant π–π interactions, while the structures of 5 and 6 are stabilized with the presence of aurophilic interactions between the adjacent Au(I) ions as well as CH–π or π–π interactions. From photoluminescence studies, complexes 5 and 6 show dual‐emission characteristics. The higher‐energy fluorescence originates from ¹XLCT mixed with ¹MLCT, while the lower‐energy phosphorescence is ascribed to ³XLCT and ³MLCT with small contribution of ³ILCT, as evidenced by density functional theory (DFT) and time‐dependent DFT calculations of the modelled molecules.     

A two‐dimensional undulating AgI coordination polymer constructed of Ag—C and Ag—O bonds: poly[[[μ3‐(5,6‐η):κO2:κO2‐(±)‐(1S,2S,3R,4R)‐3‐carboxy‐7‐oxabicyclo[2.2.1]hept‐5‐ene‐2‐carboxylato]silver(I)] monohydrate]

The title coordination polymer, {[Ag(C₈H₇O₅)]·H₂O}_n, is built from Ag⁺ cations and singly protonated dehydronorcantharidin (SP‐DNC) anions, with a distorted trigonal‐planar geometry at the metal centre. The coordination number of Ag^I is three (with one Ag—π bond and two Ag—O bonds, one from each of three different SP‐DNC ligands), if only formal Ag–ligand bonds are considered, but can be regarded as five if longer weak Ag...O interactions are also included. The two‐dimensional corrugated‐sheet coordination polymer forms a non‐interpenetrating framework with (4.8²) topology. Disordered water molecules are sandwiched between the sheets.     

Anion–π Slides for Transmembrane Transport

The recognition and transport of anions is usually accomplished by hydrogen bonding, ion pairing, metal coordination, and anion–dipole interactions. Here, we elaborate on the concept to use anion–π interactions for this purpose. Different to the popular cation–π interactions, applications of the complementary π‐acidic surfaces do not exist. This is understandable because the inversion of the aromatic quadrupole moment to produce π‐acidity is a rare phenomenon. Here, we suggest that π‐acidic aromatics can be linked together to produce an unbendable scaffold with multiple binding sites for anions to move along across a lipid bilayer membrane. The alignment of multiple anion–π sites is needed to introduce a cooperative multi‐ion hopping mechanism. Experimental support for the validity of the concept comes from preliminary results with oligonaphthalenediimide (O‐NDI) rods. Predicted by strongly positive facial quadrupole moments, the cooperativity and chloride selectivity found for anion transport by O‐NDI rods were consistent with the existence of anion–π slides. The proposed mechanism for anion transport is supported by DFT results for model systems, as well as MD simulations of rigid O‐NDI rods. Applicability of anion–π slides to achieve electroneutral photosynthesis is elaborated with the readily colorizable oligoperylenediimide (O‐PDI) rods. To clarify validity, scope and limitations of these concepts, a collaborative research effort will be needed to address by computer modeling and experimental observations the basic questions in simple model systems and to design advanced multifunctional anion–π architectures.     

CF3: An Electron‐Withdrawing Substituent for Aromatic Anion Acceptors? “Side‐On” versus “On‐Top” Binding of Halides

The ability of multiple CF₃‐substituted arenes to act as acceptors for anions is investigated. The results of quantum‐chemical calculations show that a high degree of trifluoromethyl substitution at the aromatic ring results in a positive quadrupole moment. However, depending on the polarizability of the anion and on the substitution at the arene, three different modes of interaction, namely Meisenheimer complex, side‐on hydrogen bonding, or anion–π interaction, can occur. Experimentally, the side‐on as well as a η²‐type π‐complex are observed in the crystal, whereas in solution only side‐on binding is found.