The role of cation-pi interactions in biomolecular association. Design of peptides favoring interactions between cationic and aromatic amino acid side chains.

Cation-pi interactions between amino acid side chains are increasingly being recognized as important structural and functional features of proteins and other biomolecules. Although these interactions have been found in static protein structures, they have not yet been detected in dynamic biomolecular systems. We determined, by (1)H NMR spectroscopic titrations, the energies of cation-pi interactions of the amino acid derivative AcLysOMe (1) with AcPheOEt (2) and with AcTyrOEt (3) in aqueous and three organic solvents. The interaction energy is substantial; it ranges from -2.1 to -3.4 kcal/mol and depends only slightly on the dielectric constant of the solvent. To assess the effects of auxiliary interactions and structural preorganization on formation of cation-pi interactions, we studied these interactions in the association of pentapeptides. Upon binding of the positively-charged peptide AcLysLysLysLysLysNH(2) (5) to the negatively-charged partner AcAspAspXAspAspNH(2) (6), in which X is Leu (6a), Tyr (6b), and Phe (6c), multiple interactions occur. Association of the two pentapeptides is dynamic. Free peptides and their complex are in fast exchange on the NMR time-scale, and 2D (1)H ROESY spectra of the complex of the two pentapeptides do not show intermolecular ROESY peaks. Perturbations of the chemical shifts indicated that the aromatic groups in peptides 6b and 6c were affected by the association with 5. The association constants K(A) for 5 with 6a and with 6b are nearly equal, (4.0 +/- 0.7) x 10(3) and (5.0 +/- 1.0) x 10(3) M(-)(1), respectively, while K(A) for 5 with 6c is larger, (8.3 +/- 1.3) x 10(3) M(-)(1). Molecular-dynamics (MD) simulations of the pentapeptide pairs confirmed that their association is dynamic and showed that cation-pi contacts between the two peptides are stereochemically possible. A transient complex between 5 and 6 with a prominent cation-pi interaction, obtained from MD simulations, was used as a template to design cyclic peptides C(X) featuring persistent cation-pi interactions. The cyclic peptide C(X) had a sequence in which X is Tyr, Phe, and Leu. The first two peptides do, but the third does not, contain the aromatic residue capable of interacting with a cationic Lys residue. This covalent construct offered conformational stability over the noncovalent complexes and allowed thorough studies by 2D NMR spectroscopy. Multiple conformations of the cyclic peptides C(Tyr) and C(Phe) are in slow exchange on the NMR time-scale. In one of these conformations, cation-pi interaction between Lys3 and Tyr9/Phe9 is clearly evident. Multiple NOEs between the side chains of residues 3 and 9 are observed; chemical-shift changes are consistent with the placement of the side chain of Lys3 over the aromatic ring. In contrast, the cyclic peptide C(Leu) showed no evidence for close approach of the side chains of Lys3 and Leu9. The cation-pi interaction persists in both DMSO and aqueous solvents. When the disulfide bond in the cyclic peptide C(Phe) was removed, the cation-pi interaction in the acyclic peptide AC(Phe) remained. To test the reliability of the pK(a) criterion for the existence of cation-pi interactions, we determined residue-specific pK(a) values of all four Lys side chains in all three cyclic peptides C(X). While NOE cross-peaks and perturbations of the chemical shifts clearly show the existence of the cation-pi interaction, pK(a) values of Lys3 in C(Tyr) and in C(Phe) differ only marginally from those values of other lysines in these dynamic peptides. Our experimental results with dynamic peptide systems highlight the role of cation-pi interactions in both intermolecular recognition at the protein-protein interface and intramolecular processes such as protein folding.     

Comparison of C-H...pi and hydrophobic interactions in a beta-hairpin peptide: impact on stability and specificity

We have examined the impact of C-H...pi and hydrophobic interactions in the diagonal position of a beta-hairpin peptide through comparison of the interaction of Phe, Trp, or Cha (cyclohexylalanine) with Lys or Nle (norleucine). NMR studies, including NOESY and chemical shift perturbation studies, of the Lys side chain indicates that Lys interacts in a specific geometry with Phe or Trp through the polarized C epsilon. In contrast, Nle does not interact in a specific manner with the diagonal aromatic residue. Thermal denaturation provides additional support that Lys and Nle interact in fundamentally different manners. Folding of the peptide with a diagonal Trp...Lys interaction was found to be enthalpically driven, whereas the peptide with a diagonal Trp...Nle interaction displayed cold denaturation, as did the control peptide with a diagonal Cha...Nle interaction, indicating different driving forces for interaction of Lys and Nle with Trp. These findings have significant implications for specificity in protein folding and de novo protein design.     

Cation-pi interaction in the polyolefin cyclization cascade uncovered by incorporating unnatural amino acids into the catalytic sites of squalene cyclase

It has been assumed that the pi-electrons of aromatic residues in the catalytic sites of triterpene cyclases stabilize the cationic intermediates formed during the polycyclization cascade of squalene or oxidosqualene, but no definitive experimental evidence has been given. To validate this cation-pi interaction, natural and unnatural aromatic amino acids were site-specifically incorporated into squalene-hopene cyclase (SHC) from Alicyclobacillus acidocaldarius and the kinetic data of the mutants were compared with that of the wild-type SHC. The catalytic sites of Phe365 and Phe605 were substituted with O-methyltyrosine, tyrosine, and tryptophan, which have higher cation-pi binding energies than phenylalanine. These replacements actually increased the SHC activity at low temperature, but decreased the activity at high temperature, as compared with the wild-type SHC. This decreased activity is due to the disorganization of the protein architecture caused by the introduction of the amino acids more bulky than phenylalanine. Then, mono-, di-, and trifluorophenylalanines were incorporated at positions 365 and 605; these amino acids reduce cation-pi binding energies but have van der Waals radii similar to that of phenylalanine. The activities of the SHC variants with fluorophenylalanines were found to be inversely proportional to the number of the fluorine atoms on the aromatic ring and clearly correlated with the cation-pi binding energies of the ring moiety. No serious structural alteration was observed for these variants even at high temperature. These results unambiguously show that the pi-electron density of residues 365 and 605 has a crucial role for the efficient polycyclization reaction by SHC. This is the first report to demonstrate experimentally the involvement of cation-pi interaction in triterpene biosynthesis.     

Simple cation-pi interaction between a phenyl ring and a protonated amine stabilizes an alpha-helix in water

Cation-pi interactions have been proposed to be important contributors to protein structure and function. In particular, these interactions have been suggested to provide significant stability at the solvent-exposed surface of a protein. We have investigated the magnitude of cation-pi interactions between phenylalanine (Phe) and lysine (Lys), ornithine (Orn), and diaminobutanoic acid (Dab) in the context of an alpha-helix and have found that only the Phe...Orn interaction provides significant stability to the helix, stabilizing it by -0.4 kcal/mol. This interaction energy is in the same range as a salt bridge in an alpha-helix, and equivalent to the recently reported Trp...Arg interaction in an alpha-helix, despite the fact that Trp...guanidinium interactions have been proposed to be stronger than Phe...ammonium interactions. These results indicate that even the simplest cation-pi interaction can provide significant stability to protein structure and demonstrate the subtle factors that can influence the observed interaction energies in designed systems.     

Effects of chain length and N-methylation on a cation-pi interaction in a beta-hairpin peptide

The effects of N-methylation and chain length on a cation-pi interaction have been investigated within the context of a beta-hairpin peptide. Significant enhancement of the interaction and structural stabilization of the hairpin have been observed upon Lys methylation. Thermodynamic analysis indicates an increased entropic driving force for folding upon methylation of Lys residues. Comparison of lysine to analogues ornithine (Orn) and diaminobutyric acid (Dab) indicates that lysine provides the strongest cation-pi interaction and also provides the most stable beta-hairpin due to a combination of side chain-side chain interactions and beta-sheet propensities. These studies have significance for the recognition of methylated lysine in histone proteins.     

Cation-pi interaction in model alpha-helical peptides

Cation-pi interactions are increasingly recognized as important in chemistry and biology. Here we investigate the cation-pi interaction by determining its effect on the helicity of model peptides using a combination of CD and NMR spectroscopy. The data show that a single Trp/Arg interaction on the surface of a peptide can make a significant net favorable free energy contribution to helix stability if the two residues are positioned with appropriate spacing and orientation. The solvent-exposed Trp-->Arg (i, i + 4) interaction in helices can contribute -0.4 kcal/mol to the helix stability, while no free energy gain is detected if the two residues have the reversed orientation, Arg-->Trp (i, i + 4). The derived free energy is consistent with other experimental results studied in proteins or model peptides on cation-pi interactions. However in the same system the postulated Phe/Arg (i, i + 4) cation-pi interaction provides no net free energy to helix stability. Thus the Trp-->Arg interaction is stronger than Phe-->Arg. The cation-pi interactions are not sensitive to the screening effect by adding neutral salt as indicated by salt titration. Our results are in qualitative agreement with theoretical calculations emphasizing that cation-pi interactions can contribute significantly to protein stability with the order Trp > Phe. However, our and other experimental values are significantly smaller than estimates from theoretical calculations.     

Stabilizing interactions between aromatic and basic side chains in alpha-helical peptides and proteins. Tyrosine effects on helix circular dichroism

Here we investigate the structures and energetics of interactions between aromatic (Phe or Tyr) and basic (Lys or Arg) amino acids in alpha-helices. Side chain interaction energies are measured using helical peptides, by quantifying their helicities with circular dichroism at 222 nm and interpreting the results with Lifson-Roig-based helix/coil theory. A difficulty in working with Tyr is that the aromatic ring perturbs the CD spectrum, giving an incorrect helicity. We calculated the effect of Tyr on the CD at 222 nm by deriving the intensities of the bands directly from the electronic and magnetic transition dipole moments through the rotational strengths corresponding to each excited state of the polypeptide. This gives an improved value of the helix preference of Tyr (from 0.48 to 0.35) and a correction to the helicity for the peptides containing Tyr. We find that Phe-Lys, Lys-Phe, Phe-Arg, Arg-Phe, and Tyr-Lys are all stabilizing by -0.10 to -0.18 kcal.mol-1 when placed i, i + 4 on the surface of a helix in aqueous solution, despite the great difference in polarity between these residues. Interactions between these side chains have previously been attributed to cation-pi bonds. A survey of protein structures shows that they are in fact predominantly hydrophobic interactions between the CH2 groups of Lys or Arg and the aromatic rings.     

Microcin J25 has a threaded sidechain-to-backbone ring structure and not a head-to-tail cyclized backbone

Microcin J25 is a 21 amino acid bacterial peptide that has potent antibacterial activity against Gram-negative bacteria, resulting from its interaction with RNA polymerase. The peptide was previously proposed to have a head-to-tail cyclized peptide backbone and a tight globular structure (Blond, A., Péduzzi, J., Goulard, C., Chiuchiolo, M. J., Barthélémy, M., Prigent, Y., Salomón, R. A., Farías, R. N., Moreno, F. & Rebuffat, S. Eur. J. Biochem. 1999, 259, 747-755). It exhibits remarkable thermal stability for a peptide of its size lacking disulfide bonds and in part this was previously proposed to derive from its macrocyclic structure. We show here that in fact the peptide does not have a head-to-tail cyclic structure but rather a side chain to backbone cyclization between Glu8 and the N-terminus. This creates an embedded ring that is threaded by the C-terminal tail of the molecule, forming a noose-like feature. The three-dimensional structure deduced from NMR data suggests that slippage of the noose is prevented by two aromatic residues flanking the embedded ring. Unthreading does not occur even when the molecule is enzymatically digested with thermolysin. The new structural interpretation fully accounts for previously reported NMR and biophysical data and is consistent with the remarkable stability of this potent antimicrobial peptide.     

Interaction between PEO-PPO-PEO copolymers and a hexapeptide in aqueous solutions

Interaction between PEO-PPO-PEO copolymers and a hexapeptide, growth hormone releasing peptide-6 (GHRP-6), was investigated by NMR to study the potential use of the copolymers in peptide drug delivery. (1)H NMR and nuclear Overhauser effect spectroscopy (NOESY) measurements determined that PO methyl protons interacted with methyl protons of the Ala moiety, aromatic protons of the Trp moiety, and some of the Phe aromatic protons. The Lys moiety and part of the Phe moiety entered the hydrophilic EO environment via hydrogen bonding. PEO-PPO-PEO copolymers and the peptide formed a complex in 1:1 stoichiometry. Binding constants between copolymers and GHRP-6 were determined, and it was indicated that the copolymers containing more EO and PO units will lead to greater affinity with the peptide. Isothermal titration calorimetry (ITC) measurements confirmed the results of NMR experiments. This study indicates that PEO-PPO-PEO copolymers have great potential in delivering peptide drugs.     

Influence of N-methylation on a cation-pi interaction produces a remarkably stable beta-hairpin peptide

The methylation of lysine in histone tails is a common posttranslational modification that functions in histone-regulated chromatin condensation, with binding of methylated lysine occurring in aromatic pockets on chromodomain proteins. We have synthesized a highly stable 12-residue beta-hairpin peptide that exploits the histone-related cation-pi interaction between a methylated lysine residue and a tryptophan residue. Thermodynamic analysis reveals significant entropic stabilization of the peptide due to methylation of the lysine residue. Chemical denaturation of the peptide demonstrates two-state behavior. In comparison to other reported, highly stable designed beta-hairpins, this peptide is the most thermally stable beta-hairpin reported to date. This study provides insight into the role of Lys methylation in histone proteins and more generally in mediating protein-protein interactions.     

Competition between pi and non-pi cation-binding sites in aromatic amino acids: a theoretical study of alkali metal cation (Li+, Na+, K+)-phenylalanine complexes

To understand the cation-pi interaction in aromatic amino acids and peptides, the binding of M(+) (where M(+) = Li(+), Na(+), and K(+)) to phenylalanine (Phe) is studied at the best level of density functional theory reported so far. The different modes of M(+) binding show the same order of binding affinity (Li(+)>Na(+)>K(+)), in the approximate ratio of 2.2:1.5:1.0. The most stable binding mode is one in which the M(+) is stabilized by a tridentate interaction between the cation and the carbonyl oxygen (O[double bond]C), amino nitrogen (--NH(2)), and aromatic pi ring; the absolute Li(+), Na(+), and K(+) affinities are estimated theoretically to be 275, 201, and 141 kJ mol(-1), respectively. Factors affecting the relative stabilities of various M(+)-Phe binding modes and conformers have been identified, with ion-dipole interaction playing an important role. We found that the trend of pi and non-pi cation bonding distances (Na(+)-pi>Na(+)-N>Na(+)-O and K(+)-pi>K(+)-N>K(+)-O) in our theoretical Na(+)/K(+)-Phe structures are in agreement with the reported X-ray crystal structures of model synthetic receptors (sodium and potassium bound lariat ether complexes), even though the average alkali metal cation-pi distance found in the crystal structures is longer. This difference between the solid and the gas-phase structures can be reconciled by taking the higher coordination number of the cations in the lariat ether complexes into account.     

Sonication‐Induced Coiled Fibrous Architectures of Boc‐L‐Phe‐L‐Lys(Z)‐OMe

An ultra‐short peptide Boc‐L ‐Phe‐L ‐Lys(Z)‐OMe (Z=carbobenzyloxy) was shown to act as a highly efficient and versatile low molecular weight gelator (LMWG) for a variety of aliphatic and aromatic solvents under sonication. Remarkably, this simple dipeptide is not only able to form coiled fibres but also demonstrates self‐healing and thermal chiroptical switching behaviour. The formation of coiled assemblies was found to be influenced by the nature of the solvent and the presence of an additive. By exploiting these properties it was possible to modulate the macroscopic and microscopic properties of the organogels of this ultra‐short peptide, allowing the formation of highly ordered single‐domain networks of helical fibres with dimeric or alternatively fibre‐bundle morphology. The organogels were characterized by using FTIR, SEM, NMR and circular dichroism (CD) spectroscopy. Interestingly, CD experiments showed that the organogels of Boc‐L ‐Phe‐L ‐Lys(Z)‐OMe in aromatic solvents exhibit thermal chiroptical switching. This behaviour was hypothesized to stem from changes in the morphology of the gel accompanied by conformational transformation of the gelling agent. The fact that such a small peptide can demonstrate hierarchical assemblies and the possibility of controlling the self‐association is rather intriguing. The self‐healing ability, chiroptical switching and more importantly the formation of helical assemblies by Boc‐L ‐Phe‐L ‐Lys(Z)‐OMe under sonication, make this dipeptide an interesting example of the self‐assembly ability of ultra‐short peptides.     

Role of Intramolecular Aromatic π–π Interactions in the Self‐Assembly of Di‐l‐Phenylalanine Dipeptide Driven by Intermolecular Interactions: Effect of Alanine Substitution

Although the role of intermolecular aromatic π–π interactions in the self‐assembly of di‐l ‐phenylalanine (l ‐Phe‐l ‐Phe, FF), a peptide that is known for hierarchical structure, is well established, the influence of intramolecular π–π interactions on the morphology of the self‐assembled structure of FF has not been studied. Herein, the role of intramolecular aromatic π–π interactions is investigated for FF and analogous alanine (Ala)‐containing dipeptides, namely, l ‐Phe‐l ‐Ala (FA) and l ‐Ala‐l ‐Phe (AF). The results reveal that these dipeptides not only form self‐assemblies, but also exhibit remarkable differences in structural morphology. The morphological differences between FF and the analogues indicate the importance of intramolecular π–π interactions, and the structural difference between FA and AF demonstrates the crucial role of the nature of intramolecular side‐chain interactions (aromatic–aliphatic or aliphatic–aromatic), in addition to intermolecular interactions, in deciding the final morphology of the self‐assembled structure. The current results emphasise that intramolecular aromatic π–π interaction may not be essential to induce self‐assembly in smaller peptides, and π (aromatic)–alkyl or alkyl–π (aromatic) interactions may be sufficient. This work also illustrates the versatility of aromatic and a combination of aromatic and aliphatic residues in dipeptides in the formation of structurally diverse self‐assembled structures.     

Impact of multiple cation-pi interactions upon calix[4]arene substrate binding and specificity

The cation-pi interaction influence on the conformation and binding of calix[4]arenes to alkali-metal cations has been studied using a dehydroxylated model. The model allows for the separation of cooperative cation-pi and electrostatic forces commonly found in the binding motifs found in calixarene complexes. Starting from the four well-known calix[4]arene conformations, six conformers for this dehydroxylated model (cone, partial cone, flattened cone, chair, 1,2-alternate, and 1,3-alternate) have been characterized by geometry optimization and frequency analysis using the Becke three-parameter exchange functional with the nonlocal correlation functional of Lee, Yang, and Parr and the 6-31G(d) basis set. Without the stabilization provided by the hydroxyl hydrogen bonds in calix[4]arene, neither the cone nor the 1,2-alternate conformation is computed to be a ground-state structure. The partial cone, flattened cone, chair, and 1,3-alternate conformers have been identified as ground-state structures in a vacuum, with the partial cone and the 1,3-alternate as the lowest energy minima in the aromatic model. The C(4)(v)() cone conformation is found to be a transition structure separating the flattened cone (C(2)(v)()) conformers. The energetic and structural preferences of the calix[4]arene model change dramatically when it is bound to Li(+), Na(+), and K(+). The number of pi-faces, the positioning of these pi-faces with respect to the cations, and the nature of the cation were studied as factors in the binding strength. A detailed study of the distances and angles between the aromatic ring centroids and the cations reveals the energetic advantages of multiple weak cation-pi interactions. The geometries are often far from the optimal cation-pi interaction in which the cation approaches in a perpendicular path the aromatic ring center, where the quadrupole moment is strongest. The results reveal that multiple weaker nonoptimal cation-pi interactions contribute significantly to the overall binding strength. This theoretical analysis underscores the importance of neighboring aromatic faces and provides new insight into the significance of cation-pi binding, not only for calix[4]arenes, but also for other supramolecular and biological systems.     

Effect of sequence on peptide geometry in 5-tert-butylprolyl type VI beta-turn mimics

The influence of sequence on turn geometry was examined by incorporating (2S,5R)-5-tert-butylproline (5-(t)BuPro) into a series of dipeptides and tetrapeptides. (2S,5R)-5-tert-Butylproline and proline were respectively introduced at the C-terminal residue of N-acetyl dipeptide N'-methylamides 1 and 2. The conformational analysis of these analogues was performed using NMR and CD spectroscopy as well as X-ray diffraction to examine the factors that control the prolyl amide (in this text, the term "prolyl amide" refers to the tertiary amide composed of the pyrrolidine nitrogen of the prolyl residue and the carbonyl of the N-terminal residue) equilibrium and stabilize type VI beta-turn conformation. The high cis-isomer population with aromatic residues N-terminal to proline was shown to result from a stacking interaction between the partial positive charged prolyl amide nitrogen and the aromatic pi-system as seen in the crystal structure of 1c. The effect of sequence on the prolyl amide equilibrium of 5-(t)BuPro-tetrapeptides (Ac-Xaa-Yaa-5-(t)BuPro-Zaa-XMe, 13 and 14) was studied by varying the amino acids at the Xaa, Yaa, and Zaa positions. High (>80%) cis-isomer populations were obtained with alkyl groups at the Xaa position, an aromatic residue at the Yaa position, and either an alanine or a lysine residue at the Zaa position of the 5-(t)BuPro-tetrapeptide methyl esters in water. Tetrapeptides Ac-Ala-Phe-5-(t)BuPro-Zaa-OMe (Zaa = Ala, Lys), 14d and 14f, with high cis-isomer content adopted type VIa beta-turn conformations as shown by their NMR and CD spectra. Although a pattern of amide proton temperature coefficient values indicative of a hairpin geometry was observed in peptides 14d and 14f, the value magnitudes did not indicate strong hydrogen bonding in water.     

Cation-pi interactions and the gas-phase thermochemistry of the Na(+)/phenylalanine complex

The complex of Na(+) with phenylalanine (Phe) is a prototype for the participation of cation-pi interactions in metal-ion binding to biological molecules. A recent comparison of this complex with the Na(+)/alanine (Na(+)/Ala) counterpart suggested only a small contribution of the phenyl ring interaction to binding, casting doubt on the extent of the cation-pi effect. The present work reexamines this thermochemistry using ligand-exchange equilibrium measurements in the Fourier transform ion cyclotron resonance (FT-ICR) ion trapping mass spectrometer. An increment of 7 +/- 2 kcal mol(-1) was found in the Ala/Phe comparison of binding enthalpies, confirming the importance of cation-pi binding enhancement in the Phe case. Absolute Na(+) binding enthalpies of 38 +/- 2 and 45 +/- 2 kcal mol(-1) were assigned for Ala and Phe, respectively, using pyridine as the thermochemical reference ligand. All of these results were supported by quantum calculations using both density functional and Hartree-Fock/MP2 methods, improved in several respects over previous calculations. Alanine methyl ester (AlaMe) was also observed, and found to have an Na(+) ion affinity larger by 2.3 kcal mol(-1) than Ala. New, lower energy conformations of neutral Phe were discovered in the computations.     

Sequence-specific recognition and cooperative dimerization of N-terminal aromatic peptides in aqueous solution by a synthetic host

This article describes the selective recognition and noncovalent dimerization of N-terminal aromatic peptides in aqueous solution by the synthetic host compound, cucurbit[8]uril (Q8). Q8 is known to bind two aromatic guests simultaneously and, in the presence of methyl viologen, to recognize N-terminal tryptophan over internal and C-terminal sequence isomers. Here, the binding of Q8 to aromatic peptides in the absence of methyl viologen was studied by isothermal titration calorimetry (ITC), (1)H NMR spectroscopy, and X-ray crystallography. The peptides studied were of sequence X-Gly-Gly, Gly-X-Gly, and Gly-Gly-X (X = Trp, Phe, Tyr, and His). Q8 selectively binds and dimerizes Trp-Gly-Gly (1) and Phe-Gly-Gly (4) with high affinity (ternary K = 10(9)-10(11) M(-)(2)); binding constants for the other 10 peptides were too small to be measured by ITC. Both peptides bound in a stepwise manner, and peptide 4 bound with positive cooperativity. Crystal structures of Q8.1 and Q8.4(2) reveal the basis for selective recognition as simultaneous inclusion of the hydrophobic aromatic side chain into the cavity of Q8 and chelation of the proximal N-terminal ammonium group by carbonyl groups of Q8. The peptide sequence selectivity and positively cooperative dimerization reported here are, to the best of our knowledge, unprecedented for synthetic hosts in aqueous solution. Specific peptide recognition and dimerization by synthetic hosts such as Q8 should be important in the study of dimer-mediated biochemical processes and for the separation of peptides and proteins.     

Competition between cation-pi interactions and intermolecular hydrogen bonds in alkali metal ion-phenol clusters. I. Phenol dimer

The competition between ion-molecule and molecule-molecule interactions was investigated in M+(phenol)2 cluster ions for M=Li, Na, K, and Cs. Infrared predissociation spectroscopy in the O-H stretch region was used to characterize the structure of the cluster ions. By adjusting the experimental conditions, it was possible to generate species where argon was additionally bound in order to investigate cold cluster ions. The spectra showed the presence of hydrogen bonding in the colder M+(phenol)2Ar cluster ions but the absence of hydrogen bonding in the warmer M+(phenol)2 species. For the cold species, the IR spectra were compared with minimum-energy ab initio calculations to elucidate the hydrogen-bonded structures. In the dominant hydrogen-bonded configurations observed experimentally, the phenol molecules form hydrogen-bonded dimers and the alkali-metal ions bind to the phenol via a cation-pi interaction with the aromatic ring. Increasing the strength of the cation-pi interaction by decreasing the ion size forces the distance between the phenol O-H groups to increase, thus weakening the intermolecular hydrogen bond. Free-energy differences of different configurations relative to the ground state demonstrate that hydrogen-bonded structures are enthalpically favored, while non-hydrogen-bonded structures are entropically favored and are thus observed in the warm cluster ions.     

Induction of an aromatic six-membered nitrogen ring via cation-pi interaction

Nitrogen clusters have been intensively studied for their potential application as high-energy density materials, but a six-membered nitrogen ring (N6) was not found to be stable and aromatic. To explore the possibility of inducing an aromatic N6 ring via cation-pi interaction, quantum chemistry calculations were performed on the systems of Ca2N6, CaN6, CaN6(2-), N6, and N6(4-) at the B3LYP/6-311+G level. The optimized geometries reveal that the planar structure of the N6 ring is stable only in the Ca2N6 complex. The computed NBO and CHelpG charges demonstrate that the planar N6 moiety in the Ca2N6 complex is almost a 10pi-electron system. The predicted nucleus-independent chemical shift (NICS) values demonstrate that the N6 moiety is aromatic in comparison with the NICS values of benzene. The estimated enthalpy of formation for the Ca2N6 complex is 100.4 kcal/mol for the reaction of 2Ca and 3N2. The binding energy between the Ca2+ cation and the N6(4-) moiety is -1928.8 kcal/mol, with electrostatic interaction serving as the predominant component. When all the calculated results are taken into account, including the planar structure, 10pi-electron system, identical bond length, and negative NICS value of the N6(4-) moiety in the Ca2N6 complex, it is deduced that the alkaline earth metal Ca is capable of inducing an aromatic N6 ring through the cation-pi interaction formed by electron transfer from the Ca atom to the N6 ring.