Substituent Parameters Research Articles

Nuclear Magnetic Shielding of Monoboranes: Calculation and Assessment of 11B NMR Chemical Shifts in Planar BX3 and in Tetrahedral [BX4]- Systems.

11B NMR chemical shifts of tricoordinated BX3 and tetracoordinated BX4- compounds (X = H, CH3, F, Cl, Br, I, OH, SH, NH2, and CH═CH2) were computed, and the shielding tensors were explored not only within the nonrelativistic GIAO approach but also by application of both relativistic ZORA computations including spin-orbit coupling as well as scalar nonrelativistic ZORA computations (BP86 level of density functional theory). The contributions of the spin-orbit coupling to the overall shieldings are decisive for X = Br and I in both series. No relationship was found between the 2p orbital occupancies or 1/ΔE (difference between LUMO and suitably occupied MO that can be coupled with LUMO) with the shielding tensors (or their principal values) in the BX3 series. However, a multidimensional statistical approach known as factor analysis (frequently used in chemometrics) revealed that three factors account for 92% of the cumulative proportion of total variance. The main components of the first factor are occupancies in the 2px and 2py orbitals and 1/ΔE; the second factor is mainly the occupancy in the 2pz orbital and the inductive substituent parameters by Taft. Finally, the third factor consists exclusively (98.4%) of the electrostatic potential (Vmax), which is directly related to the so-called π-hole magnitudes.

Energetics of Saddling versus Ruffling in Metalloporphyrins: Unusual Ruffled Dodecasubstituted Porphyrins

Presented herein is a first major density functional theory (BP86/D3/STO-TZ2P) survey of the energetics of saddling versus ruffling for a wide range of dodecasubstituted metalloporphyrins with M = Ni, Cu, Zn, Pd, and Pt. For the majority of X8TPP (i.e., β-octasubstituted-meso-tetraphenylporphyrin), the calculations indicated a clear preference for the saddled conformation, consistent with a large body of experimental data. The preference for the saddled conformation relative to the ruffled conformation was found to vary from about ∼0.3–0.4 eV for Me8TPP derivatives up to 1 eV for I8TPP and (CF3)8TPP derivatives. For X = Ph, that is, dodecaphenylporphyrins, the saddled and the ruffled conformation are almost equienergetic, with even a slight preference for the ruffled conformation in some cases. This finding provides a satisfactory explanation for the X-ray crystallographic observation of both saddled and ruffled conformations for dodecaphenylporphyrin complexes as well as for spectroscopic evidence for conformational mobility of these complexes in solution. The calculations also indicate near-equienergetic saddled and ruffled conformations for meso-tetraacetylenyltetrabenzoporphyrins, again consonant with key crystallographic findings. By and large, both the energetics and nonplanar distortions of the metalloporphyrin derivatives correlated well with the Charton and Sterimol B1 steric parameters of the peripheral substituents.

A detailed experimental and computational study of monocarbohydrazones

The substituent and solvent effect on intramolecular charge transfer (ICT) of twelve monocarbohydrazones (mCHs) were studied using experimental and theoretical methodology. The effects of specific and non-specific solvent–solute interactions on the UV–Vis absorption maxima shifts were evaluated using linear free energy relationships (LFERs) principles, i.e. using the Kamlet-Taft and Catalán models. Linear free energy relationships in the form of single substituent parameter equation (SSP) was used to analyze substituent effect on UV–Vis, NMR and pKa change. According to crystallographic data and quantum chemical calculations, the trans (E) form was found to be more stable. A photochromism of compounds with 2-hydroxyphenyl and 2-pyridylimino groups substituted at imine carbon atom results in E/Z isomerization due to creation of intermolecular hydrogen bond in E and Z form, respectively. Multiple stage mass spectrometry (MS-MSn) analysis was applied to define main fragmentation pathways. Furthermore, the experimental findings were interpreted with the aid of ab initio MP2/6–311G(d,p) and time-dependent density functional (TD-DFT) methods. TD-DFT calculations were performed to quantify the efficiency of intramolecular charge transfer (ICT) with the aid of the charge-transfer distance (DCT) and the amount of transferred charge (QCT) calculation. It was found that both substituents and solvents influence electron density shift i.e. extent of conjugation, and affect ICT character in the course of excitation.

Novel Co(II) phthalocyanines of extended periphery and their water-soluble derivatives. Synthesis, spectral properties and catalytic activity

Novel complexes of cobalt and copper with substituted phthalocyanines were synthesized and characterized. Their water-soluble derivatives were obtained by sulfonation under mild conditions and structurally proved. Aggregation equilibrium in water mediums was shown and influence of geometrical and electron parameters of macroheterocycle peripheral substituents on these processes was established. Catalytic activity upon liquid-phase oxidation of N,N-diethylcarbamodithiolate to thiuram E was studied. Kinetic parameters of substrate oxidation in presence of cobalt phthalocyanines were considered.

Effect of Substituents on the Bond Strength of Air-Stable Dicyanomethyl Radical Thermochromes.

A series of substituted aryl dicyanomethyl radicals were synthesized, and the bonding thermodynamic parameters for self-dimerization were determined from van't Hoff plots obtained from variable-temperature electron paramagnetic resonance and ultraviolet-visible spectroscopy. At low temperatures, the radicals dimerize, but the colored, air-stable free radicals return upon heating. Heating and cooling cycles (5-95 °C) can be repeated without radical degradation and with striking thermochromic behavior. We find a linear free energy relationship between the Hammett para substituent parameter and the dimerization equilibrium constant, with para electron-donating substituents leading to a weaker bond and electron-withdrawing substituents leading to stronger bonds, following a captodative effect. Density functional theory investigations [B98D/6-31+G(d,p)] reveal that the dimers prefer a slip-stacked geometry and feature elongated bonds.

Olefinic vs aromatic way of substituent effects: The case of 3- and 4-substituted cyclohexa-1,3-dienamine derivatives

Quantum chemical modeling was used to confront substituent effects in olefinic systems with an analogous situation in benzene. The B3LYP/6-311++G(d,p) method was applied to examine electron-donating properties of the amino group in a series of 3- (meta-like) and 4- (para-like) X-substituted cyclohexa-1,3-dienamines (X = NMe2, NH2, OH, OMe, Me, H, F, Cl, CF3, CN, CHO, COMe, CONH2, COOH, NO2, NO). As in the case of substituted anilines (PCCP, 2016, 18, 11711), the substituent properties were described by σ, charge of the substituent active region(X), and substituent effect stabilization energy descriptors; the amino group was characterized by structural and electronic parameters, whereas a transmitting moiety—by aromaticity index harmonic oscillator model of aromaticity. All applied substituent properties parameters were found to be mutually interrelated, with much better correlations for the para-derivatives than the meta-derivatives. Electron-donating ability of the amino group is stronger affected (circa 1.4 times) by substituent acting from position 4 in cyclohexa-1,3-dienamines than in aniline derivatives. It was also numerically confirmed that the reverse substituent effect acting to para-position is stronger (circa 1.14 times) in olefinic systems than in aromatic ones. Moreover, for 1-4 interactions, an increase of the electron-attracting power of the substituent increases π-electron delocalization in the olefinic series, whereas decreases it in the aromatic ones.

Development of Novel Hydrophobic Pharmacophores Based on Three-dimensional Molecular Architectures and Elements Chemistry.

Hydrophobic interaction, as well as polar interactions such as hydrogen bonding and electrostatic interaction, plays an essential role in the interaction between biologically active compounds and their target molecules. Therefore, the application of novel hydrophobic structures other than simple hydrocarbons or aromatic rings is expected to be useful in the development of biologically active compounds with distinctive chemical and pharmacological properties. In this study, we developed various bioactive compounds bearing a boron cluster, silicon-containing or germanium-containing functionalities as novel hydrophobic structures. Regarding the boron cluster-based compounds, we developed highly potent nonsteroidal androgen receptor (AR) antagonists, progesterone receptor (PR) antagonists, and non-secosteroidal vitamin D receptor (VDR) agonists. Regarding the Group 14 elements, we systematically determined hydrophobicity parameters of various trialylmethyl, trialkylsilyl and trialkylgermyl substituents, and revealed that silicon and germanium containing compounds exhibited higher hydrophobicity than the corresponding carbon analogues, with a difference in log P value of approximately 0.6, independent of the alkyl species. We also revealed that sila- and germa-substitution of carbon could enhance their biological activity. Furthermore, we demonstrated that silyl substructures could function as mimetics of cis-diatomic substructures. These results are expected to expand the chemical space of hydrophobic pharmacophores and thus contribute to the development of novel and distinctive drug candidates.

Solvent and substituent effect on intramolecular charge transfer in 5-arylidene-3-substituted-2,4-thiazolidinediones: Experimental and theoretical study

The substituent and solvent effect on intramolecular charge transfer (ICT) in 5-arylidene-3-methyl-2,4-thiazolidinediones (series 1) and 5-arylidene-3-phenyl-2,4-thiazolidinediones (series 2) was studied by using experimental and theoretical methodology. The effect of specific and non-specific solvent–solute interactions on the UV–vis absorption maxima shifts was evaluated by using the Kamlet-Taft and Catalán solvent parameter sets. Linear free energy relationships (LFERs) have been applied to the UV–vis and 13C NMR data by using SSP (single substituent parameter) and DSP (dual substituent parameters). Comparative LFER analysis of 10 styrenic series was performed in order to distinguish contribution of structural and electronic substituent effect on extent of π-polarization in a side chain (vinyl) group. Furthermore, the experimental findings were interpreted with the aid of ab initio MP2 and time-dependent density functional (TD-DFT) methods. TD-DFT calculations are performed to quantify the efficiency of intramolecular charge transfer (ICT) allowing us to define the charge-transfer distance (DCT), amount of transferred charge (QCT), and difference of dipole moments between the ground and excited states (μCT). It was found that both substituents and solvents influence electron density shift, i.e. extent of conjugation, and affect intramolecular charge transfer character in the course of excitation.

Color in Bridge-Substituted Cyanines

Theories of color in cyanine dyes have evolved around the idea of a "resonance" of structures with distinct bonding and charge localization. Understanding the emergence of resonance models from the underlying many-electron problem remains a central issue for these systems. Here, the issue is addressed using a maximum-entropy approach to valence-bond representations of state-averaged complete-active space self-consistent field models. The approach allows calculation of energies and couplings of high-energy valence-bond structures that mediate superexchange couplings and chemical bonding. A series of valence-bond Hamiltonians for a series of bridge-substituted derivatives of Michler's hydrol blue (a monomethine cyanine) is presented. The Hamiltonians are approximated with a simple linear model parametrized by the Brown-Okamoto σp+ parameter of the bridge substituent. A quantitative lower bound on σp+, beyond which a resonant cyanine-like ground state will not exist, is presented. The large effective coupling in two-state resonance models emerges from superexchange associated with either covalent bonding or charge-carrier delocalization, with the former contribution significantly the stronger. The results provide ab initio justification for empirical diabatic-state models of methine optical response. They are of general interest for understanding the optoelectronic response in cyanines.

Controlling the Conformational Energy of a Phenyl Group by Tuning the Strength of a Nonclassical CH···O Hydrogen Bond: The Case of 5-Phenyl-1,3-dioxane.

Anancomeric 5-phenyl-1,3-dioxanes provide a unique opportunity to study factors that control conformation. Whereas one might expect an axial phenyl group at C(5) of 1,3-dioxane to adopt a conformation similar to that in axial phenylcyclohexane, a series of studies including X-ray crystallography, NOE measurements, and DFT calculations demonstrate that the phenyl prefers to lie over the dioxane ring in order to position an ortho-hydrogen to participate in a stabilizing, nonclassical CH···O hydrogen bond with a ring oxygen of the dioxane. Acid-catalyzed equilibration of a series of anancomeric 2-tert-butyl-5-aryl-1,3-dioxane isomers demonstrates that remote substituents on the phenyl ring affect the conformational energy of a 5-aryl-1,3-dioxane: electron-withdrawing substituents decrease the conformational energy of the aryl group, while electron-donating substituents increase the conformational energy of the group. This effect is correlated in a very linear way to Hammett substituent parameters. In short, the strength of the CH···O hydrogen bond may be tuned in a predictable way in response to the electron-withdrawing or electron-donating ability of substituents positioned remotely on the aryl ring. This effect may be profound: a 3,5-bis-CF3 phenyl group at C(5) in 1,3-dioxane displays a pronounced preference for the axial orientation. The results are relevant to broader conformational issues involving heterocyclic systems bearing aryl substituents.

Monofunctionalized Cobaltocenium Compounds by Dediazoniation Reactions of Cobaltoceniumdiazonium Bis(hexafluorophosphate)

Monofunctionalized cobaltocenium salts are obtained for the first time from cobaltoceniumdiazonium bis(hexafluorophosphate) with various nucleophiles via Sandmeyer-type and related reactions. For successful conversions, reaction conditions are quite critical: either standard solution chemistry in nitromethane or solvent-free ball milling proved necessary, depending on the type of reactant. By this synthetic approach valuable synthons such as iodocobaltocenium and azidocobaltocenium salts are accessible that open up new vistas in cobaltocenium chemistry. Spectroscopic characterization by NMR, IR, HRMS, and single-crystal structure analysis as well as the results of electrochemical studies are reported. Derivatives with two reversible reductions show the expected relation of the half-wave potentials with the Hammett substituent parameter σp of the respective substituent with a slightly larger slope for the first reduction. The carboxylic acid (reductive deprotonation of the −COOH functionality), the iodo (p...

Solvatochromism of Thiouracil Azo Dyes

A series of sixteen synthesized thiouracil azo dyes was obtained by condensation of arylazo acetoacetic esters with thiourea. Purified products were characterized by UV–Vis, FT–IR, 1H and 13C NMR spectroscopy. The UV–Vis absorption spectra of all synthesized compounds were recorded in nineteen solvents of different properties. The study and analysis of the spectral data of azo dyes generally indicate that the tautomeric equilibrium is shifted to the hydrazone tautomeric form in the solid state. Linear solvation energy relationships describe solvent influence on solvatochromism of the hydrazone form with the use of the Catalan model. Linear free energy relationships were applied in the form of single substituent parameter model to analyze substituent electronic effects on the spectral behavior of the compounds by Hammett’s equation. The correlations obtained with aid of theoretical calculations give insight into the influence of molecular conformation on the transmission of substituent effects, as well as different solvent–solute interactions.

A LFER Kinetic Study of The Reaction of 5‐Substituted Orotic Acids with Diazodiphenylmethane

ABSTRACTLinear free energy relationships (LFER) were applied to the kinetic data for the reaction of 5‐substituted orotic acids, series 1, with diazodiphenylmethane (DDM) in N,N–dimethylformamide and compared with results obtained for 2‐substituted benzoic acids, series 2. The correlation analysis of the kinetic data with σ substituent parameters was carried out using SSP (single substituent parameter) methods. From the sign and value of proportinality constant ρ, lower sensitivity to the substituent effect was obtained in series 1, 0.876, than in the series 2, 1.877. Evaluation of substituent “ortho‐effect” was performed using the Charton model, which includes the steric substituent parameter, and Fujita and Nishioka's model, which describes the total ortho‐effect as contribution of ordinary polar effect, the ortho‐steric and ortho‐polar effects. Results of correlations, obtained by using the Charton model, showed highest contribution of the polar effect, 0.861 vs. 2.101, whereas the steric effect is of lowest significance, 0.117 vs. 0.055, for series 1 and 2, respectively. Also, a low negative value of coefficient with the steric effect, –0.08, obtained from the Fujita–Nishioka model indicated low steric effect, influencing a decrease of the reaction rate in series 1. The structural and substituent effects were also studied by using the density functional theory method, and together with kinetic data, it gave a better insight into the influence of the effect of both geometry and substituent on the π−electron density shift induced reactivity of investigated acids.

Dysphonia Severity Index in Typically Developing Indian Children

Dysphonia is a variation in an individual's quality, pitch, or loudness from the voice characteristics typical of a speaker of similar age, gender, cultural background, and geographic location. Dysphonia Severity Index (DSI) is a recognized assessment tool based on a weighted combination of maximum phonation time, highest frequency, lowest intensity, and jitter (%) of an individual. Although dysphonia in adults is accurately evaluated using DSI, standard reference values for school-age children have not been studied. This study aims to document the DSI scores in typically developing children (8-12 years). A total of 42 typically developing children (8-12 years) without complaint of voice problem on the day of testing participated in the study. DSI was computed by substituting the raw scores of substituent parameters: maximum phonation time, highest frequency, lowest intensity, and jitter% using various modules of CSL 4500 software. The average DSI values obtained in children were 2.9 (1.23) and 3.8 (1.29) for males and females, respectively. DSI values are found to be significantly higher (P = 0.027) for females than those for males in Indian children. This could be attributed to the anatomical and behavioral differences among females and males. Further, pubertal changes set in earlier for females approximating an adult-like physiology, thereby leading to higher DSI values in them. The mean DSI value obtained for male and female Indian children can be used as a preliminary reference data against which the DSI values of school-age children with dysphonia can be compared.

Receptor binding profiles and quantitative structure-affinity relationships of some 5-substituted-N,N-diallyltryptamines.

N,N-Diallyltryptamine (DALT) and 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) are two tryptamines synthesized and tested by Alexander Shulgin. In self-experiments, 5-MeO-DALT was reported to be psychoactive in the 12-20mg range, while the unsubstituted compound DALT had few discernible effects in the 42-80 mg range. Recently, 5-MeO-DALT has been used in nonmedical settings for its psychoactive effects, but these effects have been poorly characterized and little is known of its pharmacological properties. We extended the work of Shulgin by synthesizing additional 5-substituted-DALTs. We then compared them to DALT and 5-MeO-DALT for their binding affinities at 45 cloned receptors and transporter proteins. Based on in vitro binding affinity, we identified 27 potential receptor targets for the 5-substituted-DALT compounds. Five of the DALT compounds had affinity in the 10-80 nM range for serotonin 5-HT1A and 5-HT2B receptors, while the affinity of DALT itself at 5-HT1A receptors was slightly lower at 100 nM. Among the 5-HT2 subtypes, the weakest affinity was at 5-HT2A receptors, spanning 250-730 nM. Five of the DALT compounds had affinity in the 50-400 nM range for serotonin 5-HT1D, 5-HT6, and 5-HT7 receptors; again, it was the unsubstituted DALT that had the weakest affinity at all three subtypes. The test drugs had even weaker affinity for 5-HT1B, 5-HT1E, and 5-HT5A subtypes and little or no affinity for the 5-HT3 subtype. These compounds also had generally nanomolar affinities for adrenergic α2A, α2B, and α2C receptors, sigma receptors σ1 and σ2, histamine H1 receptors, and norepinephrine and serotonin uptake transporters. They also bound to other targets in the nanomolar-to-low micromolar range. Based on these binding results, it is likely that multiple serotonin receptors, as well as several nonserotonergic sites are important for the psychoactive effects of DALT drugs. To learn whether any quantitative structure-affinity relationships existed, we evaluated correlations among physicochemical properties of the congeneric 5-substituted-DALT compounds. The descriptors included electronic (σp), hydrophobic (π), and steric (CMR) parameters. The binding affinity at 5-HT1A, 5-HT1D, 5-HT7, and κ opioid receptors was positively correlated with the steric volume parameter CMR. At α2A, α2B, and α2C receptors, and at the histamine H1 receptor, binding affinity was correlated with the Hammett substituent parameter σp; higher affinity was associated with larger σp values. At the σ2 receptor, higher affinity was correlated with increasing π. These correlations should aid in the development of more potent and selective drugs within this family of compounds.

Solvatochromism and azo–hydrazo tautomerism of novel arylazo pyridone dyes: Experimental and quantum chemical study

The state of the tautomeric equilibria of eleven arylazo pyridone dyes was evaluated from UV–Vis absorption spectra with the aid of the quantum mechanical modeling. NMR analysis and theoretical calculations, by using PCM/ωB97X-D/6-311G(d,p) method, confirmed that prepared compounds exist mainly in Hydrazo form. Internal hydrogen bonding in Hydrazo tautomer, analyzed by AIM topological analysis and total electron density at the bond critical point (BCP), confirmed a presence of strong hydrogen bond which contributes to higher stability of Hydrazo form. Linear solvation energy relationships (LSERs) rationalized solvent influence on solvatochromism of all compounds in Hydrazo form and KT by using Kamlet–Taft model. Linear free energy relationships (LFERs) were applied to the substituent-induced NMR chemical shifts (SCS) using SSP (single substituent parameter) and DSP (dual substituent parameter) model. Density plots over the highest occupied (HOMO) and lowest unoccupied molecular orbitals (LUMO) energy surface provide information on the charge transfer during excitation. The molecular electrostatic potential (MEP) surface map was plotted over the optimized geometry of the molecules in order to visualize electron density distribution and explain origin of solvent/solute interactions.

N-(substituted phenyl)-2-chloroacetamides: LSER and LFER study

The UV absorption spectra of twelve N-(substituted phenyl)-2-chloroacetamides were recorded in eighteen solvents. The effect of specific and non-specific solvent–solute interactions on the absorption maxima shifts was evaluated by using the Kamlet–Taft solvent parameter set, i.e. applying linear solvation energy relationships (LSER) principles. Optimized geometries and experimental results were interpreted by using DFT (B3LYP/6-311+G(d,p) method) and time-dependent density functional (TD-DFT) method. Overall electron density in both ground and excited state was obtained by the use of Quantum Theory of Atoms in Molecules, i.e. Bader’s analysis. It was found that both solvent and substituents cause appropriate change of the extent of conjugation in the molecules that further affect their intra-molecular charge transfer (ICT) character. Linear free energy relationships (LFERs) were applied to the substituent-induced NMR chemical shifts (SCS) using single substituent parameter (SSP) and dual substituent parameter (DSP) model. Transmission mode of the electronic effects of substituent was discussed according to the results of theoretical calculations and results of LFER correlations. Comparative analysis of presented results with the ones published for structurally similar series of amide which contained cyano group, instead chlorine, provides additional information on the impact of present group to the properties of investigated compound.

Conformational stability of 5-substituted orotic acid derivatives analyzed by measuring 13C NMR chemical shifts and applying linear free energy relationships

Conformational stability of various 5-substituted orotic acid derivatives was studied by applying linear free energy relationships (LFER) to the 13CNMR chemical shifts. The correlation analysis for the substituent-induced chemical shifts (SCS) with inductive (σI), and various resonance (σR) parameters were carried out through Single Substituent Parameter (SSP) and Dual Substituent Parameter (DSP) methods, and multiple regression analysis. Good Hammett correlations for all carbons were obtained, while electrophilic substituent constants better fitted for C2 carbon with electron-donor substituents. Conformational analysis of various derivatives using RB3LYP/6-311++G (3df,3dp) DFT method, together with 13CNMR data suggests that most of the substituted orotic acid derivatives exist in planar conformation, except nitro and alkyl substituted derivatives. Internal rotation of carboxylic group showed significant impact on the extent of conjugative interaction making syn conformation more stable in all the derivatives studied. Further, of all 5-substituted orotic acid derivatives, diketo form proved to be the most stable form compared to zwitterionic and enol tautomeric forms. Optimized geometries and transmission effects of particular substituent through well-defined π-resonance units suggest that these units behave as isolated as well as conjugated fragments, depending on the type of substituent.

A Successful Attempt to Obtain the Linear Dependence Between One-Photon and Two-Photon Spectral Properties and Hammett Parameters of Various Aromatic Substituents in New π-Extended Asymmetric Organic Chromophores.

A series of new asymmetric chromophores containing aromatic substituents and possessing the excellent π-extension in space were prepared through multi-steps routes. One-photon and two-photon spectral properties of these new chromophores could be tuned by these substituents finely and simultaneously. The linear correlation of the wave numbers of the one-photon absorption and emission maxima to Hammett parameters of these substituents was presented. Near infrared two-photon absorption emission integrated areas of the target chromophores were correlated linearly to Hammett constants of these substituted groups.

Electronic Properties of Chlorine, Methyl, and Chloromethyl as Substituents to the Ethylene Group--Viewed from the Core of Carbon.

"Substituent effects" is an important and useful concept in organic chemistry. Although there are many approaches to parametrizing the electronic and steric effects of substituents, the physical basis for the parameters is often unclear. The purpose of the present work is to explore the properties of chemical shifts in carbon 1s energies as a well-defined basis for characterizing substituents to an ethylene C═C moiety. To this end, high-resolution carbon 1s photoelectron spectra of six chloro-substituted ethenes and seven chloro-substituted propenes have been measured in the gas phase. Site-specific adiabatic ionization energies have been determined from the spectra using theoretical ab initio calculations to predict the vibrational structures. For two molecules, 3-chloropropene and 2,3-dichloropropene, the spectral analyses give quantitative results for the conformer populations. The observed shifts have been analyzed in terms of initial-state (potential) and relaxation effects, and charge relaxation has also been analyzed by means of natural resonance theory. On the basis of core-level spectroscopy and models, chlorine, methyl, and chloromethyl have been characterized in terms of their effect on the carbon to which they are attached (α site) as well as the neighboring sp(2) carbon (β site). The derived spectroscopic substituent parameters are characterized by both inductive (electronegativity) effects and the ability of each substituent to engage in electron delocalization via the π system. Moreover, the adopted approach is extended to include substituent-substituent interaction parameters.