The S N2 identity exchange reactions of the fluoride ion with benzyl fluoride and 10 para-substituted derivatives (RC6H 4CH 2F, R = CH3, OH, OCH 3, NH2, F, Cl, CCH, CN, COF, and NO2) have been investigated by both rigorous ab initio methods and carefully calibrated density functional theory. Groundbreaking focal-point computations were executed for the C6H5CH 2F + F (-) and C 6H 5CH2Cl + Cl (-) SN2 reactions at the highest possible levels of electronic structure theory, employing complete basis set (CBS) extrapolations of aug-cc-pV XZ (X = 2-5) Hartree-Fock and MP2 energies, and including higher-order electron correlation via CCSD/aug-cc-pVQZ and CCSD(T)/aug-cc-pVTZ coupled cluster wave functions. Strong linear dependences are found between the computed electrostatic potential at the reaction-center carbon atom and the effective SN2 activation energies within the series of para-substituted benzyl fluorides. An activation strain energy decomposition indicates that the SN2 reactivity of these benzylic compounds is governed by the intrinsic electrostatic interaction between the reacting fragments. The delocalization of nucleophilic charge into the aromatic ring in the SN2 transition states is quite limited and should not be considered the origin of benzylic acceleration of SN2 reactions. Our rigorous focal-point computations validate the benzylic effect by establishing SN2 barriers for (F (-), Cl (-)) identity exchange in (C6H5CH2F, C6H 5CH2Cl) that are lower than those of (CH3F, CH3Cl) by (3.8, 1.6) kcal mol (-1), in order.
The performance of four frequently employed population analysis methods is assessed by comparisons with experimentally derived properties of monosubstituted benzene derivatives. The analysis is based on the expected dependence between site reactivities and electron densities at the respective ring carbon atoms. The correspondence between charges obtained from Mulliken, NPA, Hirshfeld, and QTAIM approaches and the σ0 m and σ0 p aromatic substituent constants is examined. The series of molecules investigated includes benzene and 18 monosubstituted derivatives. The atomic charges are derived using the B3LYP, ωB97X-D density functional, and MP2 MO methods combined with the 6-311++G(3df,2pd) basis set. A quantitative correspondence between Hirshfeld charges and σ0 constants is established. Application of Møller–Plesset second-order perturbation theory (MP2) wave functions appears to be essential in obtaining a more realistic electron density distribution. NPA and QTAIM charges provide in most cases a satisfactory description of the substituent effects. The net transfer of charges between substituents and the aromatic ring is assessed.
Gallium has been employed (in the form of soluble salts) to fight various forms of cancer, infectious, and inflammatory diseases. The rationale behind this lies in the ability of Ga(3+) cation to mimic closely in appearance the native ferric ion, Fe(3+), thus interfering with the biological processes requiring ferric cofactors. However, Ga(3+) ion cannot participate in redox reactions and, when substituting for the "native" Fe(3+) ion in the enzyme active site, renders it inactive. Although a significant body of information on the Ga(3+)-Fe(3+) competition in biological systems has been accumulated, the intimate mechanism of the process is still not well understood and several questions remain: What are the basic physical principles governing the competition between the two trivalent cations in proteins? What type of metal centers are the most likely targets for gallium therapy? To what extent are the Fe(3+)-binding sites in the key enzyme ribonucleotide reductase vulnerable to Ga(3+) substitution? Here, we address these questions by studying the competition between Ga(3+) and Fe(3+) ions in model metal binding sites of various compositions and charge states. The results obtained are in line with available experimental data and shed light on the intimate mechanism of the Ga(3+)/Fe(3+) selectivity in various model metal binding sites and biological systems such as serum transferrin and ribonucleotide reductase.
A detailed analysis of the molecular electrostatic potential (MEP) at selected positions in molecular space was performed for a series of substituted benzene derivatives. We show that appropriately selected MEP values can quantitatively reflect the regiospecific effects of substituents on the aromatic ring. Theoretically evaluated electrostatic potentials in close proximity to the ring carbon atoms reflect well both through-space and resonance effects and excellent correlation is established between the MEP values and substituent constants. The best descriptor of the local properties at different ring positions is the electrostatic potential at nuclei (EPN).
IR spectroscopic experiments and theoretical DFT computations reveal the effects of aromatic substituents on π-hydrogen bonding between monosubstituted phenol derivatives and benzene. Simultaneous formation of two π-hydrogen bonds (red-shifting O-H···π and blue-shifting ortho-C-H···π) contribute to the stability of these complexes. The interaction of the acidic phenol O-H proton-donating group with the benzene π-system dominates the complex formation. The experimental shifts of O-H stretching frequencies for the different phenol complexes vary in the range 45-74 cm(-1). Strong effects on hydrogen-bonding energies and frequency shifts of electron-withdrawing aromatic substituents and very weak influence of electron-donating groups have been established. Experimental quantities and theoretical parameters are employed in rationalizing the properties of these complexes. The acidities of the proton-donating phenols describe quantitatively the hydrogen-bonding process. The results obtained provide clear evidence that, when the structural variations are in the proton-donating species, the substituent effects on π-hydrogen bonding follow classic mechanisms, comprising both resonance and direct through-space influences. The performance of three alternative DFT functionals (B3LYP, B97-D, and PBE0 combined with the 6-311++G(2df,2p) basis set) in predicting the O-H frequency shifts upon complexation is examined. For comparison, O-H frequency shifts for several complexes were also determined at MP2/6-31++G(d,p).
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