Substituent effects on aromatic stacking interactions

Synthetic supramolecular zipper complexes have been used to quantify substituent effects on the free energies of aromatic stacking interactions. The conformational properties of the complexes have been characterised using NMR spectroscopy in CDCl(3), and by comparison with the solid state structures of model compounds. The structural similarity of the complexes makes it possible to apply the double mutant cycle method to evaluate the magnitudes of 24 different aromatic stacking interactions. The major trends in the interaction energy can be rationalised using a simple model based on electrostatic interactions between the pi-faces of the two aromatic rings. However, electrostatic interactions between the substituents of one ring and the pi-face of the other make an additional contribution, due to the slight offset in the stacking geometry. This property makes aromatic stacking interactions particularly sensitive to changes in orientation as well as the nature and location of substituents.     

Substituent effects on edge-to-face aromatic interactions

Chemical double mutant cycles have been used to measure the magnitude of edge-to-face aromatic interactions in hydrogen-bonded zipper complexes as a function of substituents on both aromatic rings. The interaction energies vary depending on the combination of substituents from +1.0 kJ mol-1 (repulsive), to -4.9 kJ mol-1 (attractive). The results correlate with the Hammett substituent constants which indicates that electrostatic interactions are responsible for the observed differences in interaction energy. The experiments can be rationalised based on local electrostatic interactions between the protons on the edge ring and the pi-electron density on the face ring as well as global electrostatic interactions between the overall dipoles on the two aromatic groups.     

Substituent effects on the edge-to-face aromatic interactions

The edge-to-face interactions for either axially or facially substituted benzenes are investigated by using ab initio calculations. The predicted maximum energy difference between substituted and unsubstituted systems is approximately 0.7 kcal/mol (approximately 1.2 kcal/mol if substituents are on both axially and facially substituted positions). In the case of axially substituted aromatic systems, the electron density at the para position is an important stabilizing factor, and thus the stabilization/destabilization by substitution is highly correlated to the electrostatic energy. This results in its subsequent correlation with the polarization and charge transfer. Thus, the stabilization/destabilization by substitution is represented by the sum of electrostatic energy and induction energy. On the other hand, the facially substituted aromatic system depends on not only the electron-donating ability responsible for the electrostatic energy but also the dispersion interaction and exchange repulsion. Although the dispersion energy is the most dominating interaction in both axial and facial substitutions, it is almost canceled by the exchange repulsion in the axial substitution, whereas in the facial substitution, together with the exchange repulsion it augments the electrostatic energy. The systems with electron-accepting substituents (NO2, CN, Br, Cl, F) favor the axial substituent conformation, while those with electron-donating substituents (NH2, CH3, OH) favor the facial substituent conformation. The interactions for the T-shape complex systems of an aromatic ring with other counterpart such as H2, H2O, HCl, and HF are also studied.     

Substituent effects on the structures of silver complexes with monoazatrithia-12-crown-4 ethers bearing substituted aromatic rings

New 4'-methoxybenzyl-, 4'-methylbenzyl-, benzyl-, 3',5'-difluorobenzyl-, 3',5'-dichlorobenzyl-, and 4'-nitrobenzyl-armed monoazatrithia-12-crown-4 ethers were prepared by the reductive amination of monoazatrithia-12-crown-4 with the appropriate benzenecarbaldehyde in the presence of NaBH(OAc)3. Cold electrospray ionization mass spectrometry and X-ray crystallography show that silver complexes with armed monoazatrithia-12-crown-4 ethers bearing aromatic side arms with electron-donating groups or electron-withdrawing groups are coordination polymers and trimers, respectively. The structures of the silver complexes were strongly dependent on the strength of the CH...pi interactions, which are controlled by substituent effects on the aromatic side arms.     

Substituent effects on rearrangements in aromatic aldoximes

The effect of substituents on hydrogen and hydroxyl transfer in substituted benzaldoximes reveals interesting differences. A possible explanation in terms of radical electron site and charge site is suggested.     

Substituent effects on the aromatic edge-to-face interaction

Substituent effects on the folding equilibrium of molecular torsion balances are rationalised on the basis of changes in the electrostatic interactions, the exchange repulsion, and the dispersive contributions to the interaction free enthalpy.     

Substituent effects in selenoxide elimination chemistry

2α-(Arylseleno)cholestan-3-ones (3), 2α-(arylseleno)cholest-4-en-3-ones (4), and 4β-(arylseleno)-24-nor-5β-cholan-3-ones (5) were prepared and their stabilities toward oxidative elimination assessed. Simple competitive experiments demonstrate that electron-withdrawing substituents stabilize arylselenides toward oxidation, while electron-donating groups accelerate the oxidation process. In addition, ab initio and density functional calculations on model systems reveal that selenoxides are relatively insensitive to the nature of substituents on selenium toward elimination, suggesting that the oxidation step is rate-determining during oxidative elimination of selenides. Some results for sulfur and tellurium are also presented.     

Cell–cell interactions via non-covalent click chemistry

Metabolic glycoengineering with unnatural sugars became a valuable tool for introducing recognition markers on the cell membranes via bioorthogonal chemistry. By using this strategy, we functionalized the surface of tumor and T cells using complementary artificial markers based on both β-cyclodextrins (β-CDs) and adamantyl trimers, respectively. Once tied on cell surfaces, the artificial markers induced cell–cell adhesion through non-covalent click chemistry. These unnatural interactions between A459 lung tumor cells and Jurkat T cells triggered the activation of natural killer (NK) cells thanks to the increased production of interleukin-2 (IL-2) in the vicinity of cancer cells, leading ultimately to their cytolysis. The ready-to-use surface markers designed in this study can be easily inserted on the membrane of a wide range of cells previously submitted to metabolic glycoengineering, thereby offering a simple way to investigate and manipulate intercellular interactions.

We designed complementary artificial markers that were introduced on the surface of cells previously modified by metabolic glycoengineering. These recognition markers enable unnatural cell–cell adhesion through non-covalent click chemistry.     

Quantitative determination of intermolecular interactions with fluorinated aromatic rings

The chemical double mutant cycle approach has been used to investigate substituent effects on intermolecular interactions between aromatic rings and pentafluorophenyl pi-systems. The complexes have been characterised using 1H and 19F NMR titrations, X-ray crystal structures of model compounds and molecular mechanics calculations. In the molecular zipper system used for these experiments, H-bonds and the geometries of the interacting surfaces favour the approach of the edge of the aromatic ring with the face of the pentafluorophenyl pi-system. The interactions are generally repulsive and this repulsion increases with more electron-withdrawing substituents up to a limit of +2.2 kJ mol(-1), when the complex distorts to minimise the unfavourable interaction. Strongly electron-donating groups cause a change in the geometry of the aromatic interaction and attractive stacking interactions are found (-1.6 kJ mol(-1) for NMe2). These results are generally consistent with an electrostatic model: the polarisation of the pentafluorophenyl ring leads to a partial positive charge located at the centre and this leads to repulsive interactions with the positive charges on the protons on the edge of the aromatic ring; when the aromatic ring has a high pi-electron density there is a large electrostatic driving force in favour of the stacked geometry which places this pi-electron density over the centre of the positive charge on the pentafluorophenyl group.     

Substituent effects in parallel-displaced pi-pi interactions

High-quality quantum-mechanical methods are used to examine how substituents tune pi-pi interactions between monosubstituted benzene dimers in parallel-displaced geometries. The present study focuses on the effect of the substituent across entire potential energy curves. Substituent effects are examined in terms of the fundamental components of the interaction (electrostatics, exchange-repulsion, dispersion and induction) through the use of symmetry-adapted perturbation theory. Both second-order M?ller-Plesset perturbation theory (MP2) with a truncated aug-cc-pVDZ' basis and spin-component-scaled MP2 (SCS-MP2) with the aug-cc-pVTZ basis are found to mimic closely estimates of coupled-cluster with perturbative triples [CCSD(T)] in an aug-cc-pVTZ basis. Substituents can have a significant effect on the electronic structure of the pi cloud of an aromatic ring, leading to marked changes in the pi-pi interaction. Moreover, there can also be significant direct interactions between a substituent on one ring and the pi-cloud of the other ring.     

Ab initio study of substituent effects in the interactions of dimethyl ether with aromatic rings

Ab initio calculations have been used to investigate the interaction energies of dimers of dimethyl ether with benzene, hexafluorobenzene, and several monosubstituted benzenes. The potential energy curves were explored at the MP2/aug-cc-pVDZ level for two basic configurations of the dimers, one in which the oxygen atom of the dimethyl ether was pointed towards the aromatic ring and the other in which the oxygen atom was pointed away from the aromatic ring. Once the optimum intermolecular distances between the dimethyl and the aromatic ring had been determined for each of the dimers in both configurations at the MP2/aug-cc-pVDZ level, single point energy calculations were performed at the MP2/aug-cc-pVTZ level. A CCSD(T) correction term to the energy was determined and this was combined with the MP2/aug-cc-pVTZ energies to estimate the CCSD(T)/aug-cc-pVTZ interaction energies of the dimers. The estimated CCSD(T)/aug-cc-pVTZ interaction energies are predicted to be attractive for all of the dimers in both configurations and dispersion interactions are found to be a large component of the stabilization of the dimers. For the dimers with the dimethyl ether oxygen pointing towards the aromatic ring, the strengths of interaction energies are found to increase as the aromatic ring becomes more electron deficient, while for the dimers with the dimethyl ether oxygen pointing away from the aromatic ring, they increase as the aromatic ring becomes more electron rich. In both cases, the trends can be explained in terms of the electrostatic potentials of the dimethyl ether and the aromatic rings.     

Substituent effects on the bond dissociation enthalpies of aromatic amines

Bond dissociation enthalpy differences, Z-X DeltaBDE = BDE(4-YC(6)H(4)Z-X) - BDE(C(6)H(5)Z-X), for Z = CH(2) and O are largely independent of X and are determined mainly by the stabilization/destabilization effect of Y on the 4-YC(6)H(4)Z(*) radicals. The effects of Y are small (< or =2 kcal/mol for all Y) for Z = CH(2), but they are large for Z = O, where good correlations with sigma(p)(+)(Y) yield rho(+) = 6.5 kcal/mol. For Z = NH, two sets of electrochemically measured N-H DeltaBDEs correlate with sigma(p)(+)(Y), yielding rho(+) = 3.9 and 3.0 kcal/mol. However, in contrast to the situation with phenols, these data indicate that the strengthening effect on N-H BDEs of electron-withdrawing (EW) Y's is greater than the weakening effect of electron-donating (ED) Y's. Attempts to measure N-H DeltaBDEs in anilines using two nonelectrochemical techniques were unsuccessful; therefore, we turned to density functional theory. Calculations on 15 4-YC(6)H(4)NH(2) gave N-H DeltaBDEs correlating with sigma(p)(+) (rho(+) = 4.6 kcal/mol) and indicated that EW and ED Y's had comparable strengthening and weakening effects, respectively, on the N-H bonds. To validate theory by connecting it to experiment, the N-H DeltaBDEs of four 4,4'-disubstituted diphenylamines and five 3,7-disubstituted phenothiazines were both calculated and measured by the radical equilibration EPR technique. For all compounds, theory and experiment agreed to better than 1 kcal/mol. Dissection of N-H DeltaBDEs in 4-substituted anilines and O-H DeltaBDEs in 4-substituted phenols into interaction enthalpies between Y and NH(2)/OH (molecule stabilization/destabilization enthalpy, MSE) and NH*/O* (radical stabilization/destabilization enthalpy, RSE) reveals that for both groups of compounds, ED Y's destabilize the molecule and stabilize the radical, while the opposite holds true for EW Y's. However, in the phenols the effects of substituents on the radical are roughly 3 times as great as those in the molecule, whereas in the anilines the two effects are of comparable magnitudes. These differences arise from the stronger ED character of NH(2) vs OH and the weaker EW character of NH* vs O*. The relatively large contributions to N-H BDEs in anilines arising from interactions in the molecules suggested that N-X DeltaBDEs in 4-YC(6)H(4)NH-X would depend on X, in contrast to the lack of effect of X on O-X and CH(2)-X DeltaBDEs in 4-YC(6)H(4)O-X and 4-YC(6)H(4)CH(2)-X. This suggestion was confirmed for X = CH(3), H, OH, and F, for which the calculated NH-X DeltaBDEs yielded rho(+) = 5.0, 4.6, 4.0, and 3.0 kcal/mol, respectively.     

Substituent effects on aromatic ring: Theoretical studies of molecular geometries of alkylphenols

Molecular mechanics calculations have been carried out for a series of alkylphenols in order to assess the effects of substituents on bond angles. The results are in good agreement with crystallographic data.     

Substituent effects in pi-pi interactions: sandwich and T-shaped configurations

Sandwich and T-shaped configurations of benzene dimer, benzene-phenol, benzene-toluene, benzene-fluorobenzene, and benzene-benzonitrile are studied by coupled-cluster theory to elucidate how substituents tune pi-pi interactions. All substituted sandwich dimers bind more strongly than benzene dimer, whereas the T-shaped configurations bind more or less favorably depending on the substituent. Symmetry-adapted perturbation theory (SAPT) indicates that electrostatic, dispersion, induction, and exchange-repulsion contributions are all significant to the overall binding energies, and all but induction are important in determining relative energies. Models of pi-pi interactions based solely on electrostatics, such as the Hunter-Sanders rules, do not seem capable of explaining the energetic ordering of the dimers considered.     

From molecular chemistry to supramolecular chemistry to superdupermolecular chemistry. Controlling covalent bond formation through non-covalent and magnetic interactions

The reactions of carbon centered radical pairs often involve diffusion controlled combination and/or disproportionation reactions which are non-selective. A triplet geminate pair of radicals is produced by the photolysis of suitable ketones. The reactions of such geminate pairs can be controlled though the application of supramolecular concepts which emphasize non-covalent interaction to "steer" the geminate pair toward a selected pathway. In addition, "superdupermolecular" concepts, which emphasize the control of radical pair reactions through the orientation of electron spins, can be employed to further control the course of geminate pair reactions. Examples of control of a range of the selectivity of geminate radical combinations, which form strong covalent bonds, through supramolecular and superdupermolecular effects will be presented for the photolysis of ketones adsorbed in the supercages of zeolites.     

Substituent effects on the stability of extended benzylic carbocations: a computational study of conjugation

A set of design rules for the prediction of relative stabilities of methoxy substituted naphthyl methyl carbocations are presented based on a series of DFT calculations. The peri-effect, over-crowding, substitutions on the ring carrying the CH(2)(+) group and substitution on the opposite ring are the principal factors that influence the stability of the carbocations. All of these factors have to be taken simultaneously into account. The most pronounced destabilization occurs when the methyl part of the methoxy substituent lies out of the plane of the aromatic core because this causes the resonance stabilization of the carbocation to become hindered. The performance of the DFT-calculations was assessed on the results of a G3(MP2)//B3LYP calculation-a method that is known to predict energies to within chemical accuracy. These values were found to compare well with those obtained at the B3LYP/6-31G(d) level. Thus, a computationally inexpensive method such as the B3LYP/6-31G(d) might prove to be a powerful tool in the design of future complex extended aromatic systems.     

Chemical double-mutant cycles: dissecting non-covalent interactions

Thermodynamic double-mutant cycles and triple-mutant boxes are widely employed for the experimental quantification of non-covalent interactions and cooperative effects in proteins. This review describes the application of these powerful methodologies to the study of non-covalent interactions in synthetic systems.