Polar Substituent Effects Research Articles

Rationalizing IR intensities in terms of electronic parameters

► CO stretching band intensities for a series of p -substituted acetanilides are computed. ► Intensities are rationalized in terms of electronic parameters. ► q NBO , q Hirsh and EPN are examined. ► The established correlation A C O ′ / q C NBO can be applied for predicting IR intensities. The electronic effect of polar substituents on the CO stretching band intensity in a series of thirteen p -substituted acetanilides is studied by applying ab initio MP2 computations and density functional theory at the B3LYP and M06-2X level combined with two basis sets 6-31+G(d,p) and 6-311+G(2d,2p). It is shown that calculations at the theoretical levels employed provide a valuable approach in studying the factors determining the IR band intensities in the studied series of compounds. An excellent linear dependence between the CO stretching band intensity and the atomic NBO charges on the carbonyl carbon is established. It is concluded that the variations of the electronic indices upon substitution can be used for quantitative characterization of the IR band intensities in the studied series of acetanilides.

Significant enhancement in radical-scavenging activity of curcuminoids conferred by acetoxy substituent at the central methylene carbon

For a compound to be a radical-trapping antioxidant, the antioxidant-derived radical must be sufficiently inert to molecular oxygen as this would generate harmful chain-propagating peroxyl radicals. Curcumin has a unique structure with phenolic hydroxyl group as well as β-diketone moiety in the same molecule, both of which are able to donate electrons to free radicals. However, due to the reactivity toward molecular oxygen, the carbon-centered radical derived from β-diketone moiety do not serve as radical-trapping antioxidants. In this study, we reasoned that stabilization of the carbon-centered radical through substitution with an electron-withdrawing group would enhance the radical-scavenging antioxidative activity of the resulting curcuminoids. Thus, various substituents (methyl, allyl, methoxy, xanthate, and acetoxy) covering broad spectrum of the polar substituent effect were introduced to the central methylene position of both phenolic and non-phenolic curcuminoids. With the free phenolic hydroxyl groups present, the methylene-substituent did not exert significant effect on the antioxidant activity of the curcuminoids (EC 50 = 23.2–30.3 μM) with the exception of the acetoxy-substituted derivative (EC 50 = 8.7 μM) which showed more potent activity than curcumin (EC 50 = 22.6 μM). When substituted to the non-phenolic curcumin scaffold, however, the methylene-substituent enhanced antioxidant activity of the otherwise inactive curcuminoids in the increasing order of methyl < allyl < methoxy < xanthate ≪ acetoxy, which is well correlated with the polar inductive effects of the substituents.

Linear free energy relationships applied to the reactivity and the 13C NMR chemical shifts in 4-[[(substituted phenyl)imino]methyl]benzoic acids

Abstract Linear free energy relationships (LFER) were applied to the kinetic data and 13 C NMR chemical shifts in 4-[[(substituted phenyl)imino]methyl]benzoic acids. The correlation analysis for the kinetic data and substituent-induced chemical shifts (SCS) with σ using single substituent parameter (SSP), as well as inductive ( σ I ) and various resonance ( σ R ) parameters using dual-substituent parameter (DSP), were carried out. The presented calculations account satisfactorily for the polar and resonance substituent effects having similar contributions at all carbons studied. Negative ρ values were found for several correlations (reverse substituent effect). Exceptionally good Hammett correlation of 13 C NMR chemical shifts of azomethine carbon with electrophilic substituent constants σ + indicates a significant resonance interaction in the aniline part of molecules. The conformations of investigated compounds have been studied by the use of DFT method, and together with 13 C NMR chemical shifts and kinetic data, give a better insight into the influence of such a structure on the transmission of electronic substituent effects. New σ constants for substituted phenyliminomethyl group have been calculated.

A DFT-GIAO and DFT-NBO study of polar substituent effects on NMR 17 O chemical shifts in some rigid polycyclic alkanes

17O NMR shieldings of 3-substituted(X)bicyclo[1.1.1]pentan-1-ols (1, Y = OH), 4-substituted(X)bicyclo[2.2.2]octan-1-ols (2, Y = OH), 4-substituted(X)-bicyclo[2.2.1]heptan-1-ols (3, Y = OH), 4-substituted(X)-cuban-1-ols (4, Y = OH) and exo- and endo- 6-substituted(X)exo-bicyclo[2.2.1]heptan-2-ols (5 and 6, Y = OH, respectively), as well as their conjugate bases (1–6, Y = O−), for a set of substituents (X = H, NO2, CN, NC, CF3, COOH, F, Cl, OH, NH2, CH3, SiMe3, Li, O−, and NH) covering a wide range of electronic substituent effects were calculated using the DFT-GIAO theoretical model at the B3LYP/6-311 + G(2d, p) level of theory. By means of natural bond orbital (NBO) analysis various molecular parameters were obtained from the optimized geometries. Linear regression analysis was employed to explore the relationship between the calculated 17O SCS and polar field and group electronegativity substituent constants (σF and σχ, respectively) and also the NBO derived molecular parameters (oxygen natural charge, Qn, occupation numbers of the oxygen lone pairs, no, and occupancy of the CO antibonding orbital, σ*CO(occup)). In the case of the alcohols (1–6, Y = OH) the 17O SCS appear to be governed predominantly by the σχ effect of the substituent. Furthermore, the key determining NBO parameters appear to be no and σ*CO(occup). Unlike the alcohols, the calculated 17O SCS of the conjugate bases (1–6, Y = O−), except for system 1, do not respond systematically to the electronic effects of the substituents. An analysis of the SCS of 1(Y = O−) raises a significant conundrum with respect to their origin. Copyright © 2010 John Wiley & Sons, Ltd.

Calculated polar substituent effects on the stability of 4-substituted(X) - cub-1-yl and -bicyclo[2.2.2]oct-1-yl cations: a DFT study

The effects of substituents on the stability of 4-substituted(X) cub-1-yl cations (2), as well as the benchmark 4-substituted(X) bicyclo[2.2.2]oct-1-yl cation systems (7), for a set of substituents (X = H, NO2, CN, NC, CF3, COOH , F, Cl, HO, NH2, CH3, SiH3, Si(CH3)3, Li, O−, and NH) covering a wide range of electronic substituent effects were calculated using the DFT theoretical model at the B3LYP/6-311 + G(2d,p) level of theory. Linear regression analysis was employed to explore the relationship between the calculated relative hydride affinities (ΔE, kcal/mol) of the appropriate isodesmic reactions for 2/7 and polar field/group electronegativity substituent constants (σF and σχ, respectively). The analysis reveals that the ΔE values of both systems are best described by a combination of both substituent constants. This highlights the distinction between through-space and through-bond electronic influences characterized by σF and σχ, respectively. Copyright © 2010 John Wiley & Sons, Ltd.

ChemInform Abstract: Transmission of Polar Substituent Effects in the Adamantane Ring System as Monitored by 19F NMR: Hyperconjugation as a Stereoinductive Factor.

A limited series of (E)- and (Z)-5-substituted adamant-2-yl fluorides 8 and 9, respectively, has been synthesized and characterized, and the 19 F chemical shifts have been measured in several solvents. A wide range of 19 F substituent chemical shifts (SCS, ppm) are obtained for the former system (ca. 9.1 (c-C 6 H 12 ), 9.6 (CDCl 3 ), and 11.8 (HFIP)) compared to the latter (ca. 0.6 (c-C 6 H 12 ), 0.7 (CDCl 3 ), and 2.3 (HFIP)). Factorization of the 19 F SCS into polar field (ρ F σ F ) and residual contributions ( 19 F SCS-ρ F σ F ) reveals the predominance of the latter solvent-independent component for the E fluorides (8). Comparison of 8 with a similar dissection of the 19 F SCS of 4-substituted bicyclo[2.2.]oct-1-fluorides 2 strongly suggests that the origin of the large residual contributions for 8 is «through-three-bond] electron delocalization or double hyperconjugation. The importance of this long-range electronic mechanism as a factor governing π-facial diastereoselection in 2,5-disubstituted adamantanes is discussed

Structure–activity relationships in 1,4-benzodioxan-related compounds. 10. Novel α 1-adrenoreceptor antagonists related to openphendioxan: Synthesis, biological evaluation, and α 1d computational study

A series of novel openphendioxan analogues were synthesized and tested at α 1-adrenoreceptor (AR) subtypes by binding and functional assays. The α 1d-AR binding profile was also examined by means of 2D, 3D-QSAR together with docking studies. Multiple regression analysis suggested the relevance of adequate number of heteroatoms in the whole molecule and of passive membrane diffusion to enhance α 1d-AR affinity. Docking simulations against a computational structural model of the biological target further proved this evidence and furnished support for chemiometric analysis, where polar, electrostatic, hydrophobic and shape effects of the ortho substituents in the phenoxy terminal, most likely governing ligand binding, helped the depiction of pharmacophore hypothesis for the examined ligands data set.

ChemInform Abstract: Use of Competition Kinetics with Fast Reactions of Grignard Reagents.

Competition kinetics are useful for estimation of the reactivities of Grignard reagents if the reaction rates do not differ widely and if exact rates are not needed. If the rate of mixing is slower than the rate of reaction, the ratios between the rates of fast and slow reagents are found to be too small. This is concluded from experiments in which results obtained by competition kinetics are compared with results obtained directly by flow stream procedures. A clearer picture of the reactivity ratios is obtained when the highly reactive reagent is highly diluted with its competitor. A fast reagent may account for almost all the product even when present as only 1 part in 100 parts of the competing agent. In this way allylmagnesium bromide is estimated to react with acetone, benzophenone, benzaldehyde, and diethylacetaldehyde ca. 1.5 x 10(5) times faster than does butylmagnesium bromide. The rates found for the four substrates do not differ significantly, and it seems possible that there is a ceiling over the rate of reaction of this reagent, for example, caused by diffusion control. This may explain that competition kinetics using allylmagnesium bromide have failed to show kinetic isotope effects or effects of polar substituents with isotopically or otherwise substituted benzophenones. A recently reported alpha-deuterium secondary kinetic isotope effect for the reaction of benzaldehyde with allylmagnesium bromide was observed at -78 degrees C, but was absent at room temperature. It is suggested that the reaction of benzophenone and benzaldehyde with allylmagnesium bromide has a radical-concerted mechanism since no radical-type products are produced and since no color from an intermediate ketyl is observed even at -78 degrees C.

Effect of the remote polar substituents on the pi-facial selectivity of carbonyl ene reaction: A computational study

Effect of remote polar substituents on the pi-diastereofacial selectivity of Lewis acid catalyzed carbonyl ene reaction has been investigated. Quantum chemical investigations using B3LYP/6-31G∗ level of theory on various substrates where the carbonyl group resides in an isosteric environment revealed that electrostatic effect plays a crucial role in determining the relative energies of the corresponding transition structures (TS) of the carbonyl ene reaction. This fact is nicely reflected in the product diastereoselectivities of various model carbonyl ene reactions.

Impact of ligands on CO2 adsorption in metal-organic frameworks: First principles study of the interaction of CO2 with functionalized benzenes. II. Effect of polar and acidic substituents

Intermolecular interactions between the CO(2) molecule and a range of functionalized aromatic molecules have been investigated using density functional theory. The work is directed toward the design of linker molecules which could form part of new metal-organic framework materials with enhanced affinity for CO(2) adsorption at low pressure. Here, the focus was on the effect of introducing polar side groups, and therefore functionalized benzenes containing -NO(2), -NH(2), -OH, -SO(3)H, and -COOH substituents were considered. The strongest types of intermolecular interactions were found to be: (i) between lone pair donating atoms (N,O) of the side groups and the C of CO(2) (enhancement in binding energy of up to 8 kJ mol(-1) compared to benzene); and (ii) hydrogen bond interactions between acidic protons (of COOH and SO(3)H groups) and CO(2) oxygen (enhancement of 3-4 kJ mol(-1)). Both of these types of interaction have the effect of polarizing the CO(2) molecule. Weaker types of binding include hydrogen-bond-like interactions with aromatic H and pi-quadrupole interactions. The strongest binding is found when more than one interaction occurs simultaneously, as in C(6)H(5)SO(3)H and C(6)H(5)COOH, where simultaneous lone pair donation and H-bonding result in binding energy enhancements of 10 and 11 kJ mol(-1), respectively.

Influence of solvent on the ortho substituent effect in the alkaline hydrolysis of phenyl esters of substituted benzoic acids

AbstractThe second‐order rate constants k (dm3 mol−1 s−1) for the alkaline hydrolysis of phenyl esters of meta‐, para‐ and ortho‐substituted benzoic acids in aqueous 5.3 M NaClO4 and 1.0 M Bu4NBr were measured by UV/Vis spectrophotometry at 25 °C. The variations in the ortho inductive, ortho resonance, as well as meta and para polar effects with solvent parameters were studied using data for the alkaline hydrolysis of phenyl esters of substituted benzoic acids in various media. The dependence of the ortho substituent effect on solvent can be precisely described with the following equation: Δlog kortho = log kortho − log kH = 0.059 + 2.19σI + 0.304σ°R + 2.79E − 0.016ΔEσI − 0.085ΔEσ°R, where ΔE is the solvent electrophilicity, ΔE = ES − EH2O, characterizing the hydrogen‐bond donating power of the solvent. The increase in the meta and para polar substituent effects with decrease in the solvent hydrogen‐bond donor capacity (electrophilicity) was approximately to the same extent (−0.068ΔEσ°m,p) as the resonance term for the ortho substituents. The steric term of ortho substituents was independent of the solvent parameters. The variations in the ortho inductive, ortho resonance, as well as meta and para polar substituent effects with the solvent electrophilicity were to the same extent as in phenyl benzoates containing the substituents in the phenyl part. The substituent effects in the alkaline hydrolysis of ethyl benzoates appeared to vary with the solvent electrophilicity nearly to the same extent as in the alkaline hydrolysis of substituted phenyl esters of benzoic acids. Copyright © 2009 John Wiley &amp; Sons, Ltd.

Supramolecular Liquid Crystals Induced by Hydrogen-Bonding Interactions Between Non-Mesomorphic Compounds. I. 4-(4′-Pyridylazophenyl)-4″-Substituted Benzoates and 4-Substituted Benzoic Acids

Equimolar binary mixtures of the title compounds were prepared to investigate the effect of different polar substituents, either on the pyridine-based derivatives or on the acid component, on the extent and stability of the supramolecular liquid crystal phases induced by intermolecular hydrogen bonding. None of the pyridine-based derivative or the acid complement is mesomorphic, but the hydrogen-bonded complexes are. The mixtures prepared were characterized for their mesophase behavior by differential scanning calorimetry, DSC, and polarized light microscopy, PLM. Five azo pyridine-based derivatives (I a–e), with molecular formula X-C6H4COOC6H4-N=N-C5H4N, were prepared that differ from each other by the substituent X. The latter varies between CH3O, CH3, H, Br, and NO2. Six 4-substitutedbenzoic acids (Y-C6H4COOH, II a-f) were used; the substituent Y varies between CH3O, CH3, H, Br, CN, and NO2. Nematic mesophase is induced in most of the binary mixtures investigated.

Transmission of polar substituent effects across the cubane ring system: 19F substituent chemical shifts (SCS) of 4‐substituted (X) cub‐1‐yl fluorides revisited

Abstract19F NMR shieldings of 4‐substituted (X) cub‐1‐yl fluorides (4) for a set of substituents (XH, NO2, CN, NC, CF3, COOH, F, Cl, HO, NH2, CH3, Si(CH3)3, Li, O− and NH) covering a wide range of electronic substituent effects were calculated using the DFT‐GIAO theoretical model. The level of theory, B3LYP/6‐311+G(2d,p), provided 19F substituent chemical shifts (SCS) in good agreement with experimental values where known. By means of NBO analysis, various molecular parameters were obtained from the optimized geometries. Linear regression analysis was employed to explore the relationship between the calculated 19F SCS and polar field, resonance and group electronegativity substituent constants (σF, σR and σx, respectively) and also the NBO derived molecular parameters (fluorine natural charges (Qn), electron occupancies on fluorine of lone pairs (nF) and occupation number of the CF antibonding orbital (σCF*)). The key determining parameters appear to be nF and σCF*(occup). Both factors are a function of the electrostatic field influence of the substituent (σF effect) but are counteractive in their influence on the shifts. No evidence for a significant resonance effect influence on the shifts could be identified. Copyright © 2009 John Wiley &amp; Sons, Ltd.

Azomesogens with polar chloro, nitro and phenolic –OH substituents†

Two new mesogenic homologous series containing chloro, nitro and phenolic hydroxy groups were synthesised and their molecular structures characterised by a combination of element analysis and standard spectroscopic methods. The mesomorphic behaviour of the compounds of both series was investigated by polarising optical microscopy and, in some cases, differential scanning calorimetry. All the compounds of both the series exhibit an enantiotropic nematic mesophase. In series I higher members also exhibit an enantiotropic smectic A (SmA) mesophase, whereas in series II the enantiotropic SmA mesophase commences somewhat earlier for the middle members. The mesomorphic properties of both series are compared with each other and also with the properties of other structurally related series to evaluate the effects of different polar substituents on mesomorphism. †. This paper was presented at the International Conference on Liquid Crystals (ICLC‐2006) held at Department of Physics, University of Mumbai, Santacruz (E), Vidyanagari, Mumbai during 5–8 December 2006.

Linear free energy relationships of the 1H and 13C NMR chemical shifts in 3-cyano-4-(substituted phenyl)-6-phenyl-2(1 H)pyridones

Linear free energy relationships (LFER) were applied to the 1H and 13C NMR chemical shifts in 3-cyano-4-(substituted phenyl)-6-phenyl-2(1 H)pyridones. The correlation analysis for the substituent-induced chemical shifts (SCS) with inductive ( σ I), and various resonance ( σ R) parameters were carried out using SSP (single substituent parameter), DSP (dual substituent parameter), and DSP-NLR (dual substituent parameter non-linear resonance) methods, as well as by multiple regression analysis. The presented calculation accounts satisfactorily for the polar and resonance substituent effects operating at pyridone carbon atoms. Negative ρ values were found for several correlations (reverse substituent effect). The conformations of investigated compounds have been studied by the use of semi-empirical MO-PM6 method and B3LYP density functional (DFT) hybrid methods. The twist of the plane of 4-substituted phenyl ring ( θ 1) is determined by electronic substituent effects, while the angles θ 2 are almost constant.

Nature of transmission of polar substituent effects in γ-disposed bicyclo[2.2.1]heptane (norbornane) and adamantane ring systems as monitored by 19F NMR: A DFT- GIAO and – NBO analysis

Nature of transmission of polar substituent effects in γ-disposed bicyclo[2.2.1]heptane (norbornane) and adamantane ring systems as monitored by 19F NMR: A DFT- GIAO and – NBO analysis

Polar substituent effect of the ester group on conformational equilibria of O-mono-substituted cyclohexanes —the para-substituent effect in cyclohexyl benzoates

Together with the nonsubstituted reference compound, para-methoxy- and para-nitro cyclohexyl benzoates have been synthesized and their conformational equilibria studied by low temperature NMR spectroscopy and theoretical DFT calculations. The free energy differences Δ G° between axial and equatorial conformers were examined with respect to polar substituent influences on the conformational equilibrium of O-mono-substituted cyclohexane.

Supramolecular Hydrogen-Bonded Liquid Crystals Formed from 4-(4′-Pyridylazophenyl)-4″–Substituted Benzoates and 4-Alkoxybenzoic Acids

Phase diagrams of the binary mixtures of the title compounds were constructed to investigate the effect of different polar substituents, on the pyridine-based derivatives, as well as the alkoxy-chain length, on the acids, on the extent and stability of the supramolecular liquid crystal phases induced by intermolecular hydrogen bonding. None of the newly prepared pyridine-based derivatives is mesomorphic, but the hydrogen-bonded complexes are. The mixtures prepared were characterized for their mesophase behavior by differential scanning calorimetry (DSC) and polarized light microscopy (PLM). Five pyridine-based derivatives (I a-e), with molecular formula X-C6H4COOC6H4-N=N-C5H4N, were prepared that differ from each other by the substituent X. The latter varies between CH3O, CH3, H, Br, and NO2. Four 4-alkoxybenzoic acids (CnH2n+1OC6H4COOH, II 10–II 18) were used; the number of carbons (n) of their alkoxy groups varies between 10, 12, 14, and 18. Smectic C mesophase is induced in most of the binary mixtures investigated.

Steric effects of polar substituents evaluated in terms of energy by means of isodesmic reactions

Steric effects of various polar and some charged groups were estimated on sterically crowded cyclopropane cis-1,2-bis derivatives 2 or 3, in which the variable substituent is in the proximity of a t-butyl group or of a methyl group. The steric energy was evaluated with reference to the pertinent mono derivatives, that is as reaction energy of an isodesmic reaction, in which the crowded compound is formally synthesized from simple derivatives. Energies were calculated within the framework of the density functional theory at level B3LYP/6-311+G(d,p)//B3LYP/6-311+G(d,p) for 11 dipolar and 5 charged substituents. Interaction of charged substituents is not only steric (destabilizing) but also inductive (stabilizing). The steric effects evaluated in this way differ distinctly from the standard steric constants derived purely from the van der Waals radii of the substituents.

Variation of the temperature‐dependent substituent effects with solvent in alkaline hydrolysis of substituted phenyl and alkyl benzoates and phenyl tosylates

AbstractThe second‐order rate constants k for the alkaline hydrolysis of eight substituted alkyl benzoates have been measured spectrophotometrically in aqueous 5.3 M NaClO4 and 0.5 M n‐Bu4NBr at various temperatures. Variation of the substituent effect with temperature in alkaline hydrolysis of ortho‐, meta‐, and para‐substituted phenyl benzoates, phenyl tosylates, and alkyl benzoates in various solvents (water, aqueous 0.5 M Bu4NBr, 80% (v/v) DMSO, 2.25 M Bu4NBr, and 5.3 M NaClO4) was studied. The susceptibility to temperature variation of the meta and para polar substituent effect, the ortho inductive effect, and the alkyl polar effect for various media showed good correlation with the solvent electrophilicity, ES, which characterizes the hydrogen‐bond donating power of the solvent. The variation of the temperature‐dependent ortho inductive effect with solvent hydrogen‐bond donor capacity (electrophilicity) was found to be nearly twice smaller than that for meta and para polar effect. The temperature‐dependent alkyl polar substituent effect was found to vary with ES nearly by the same extent as the polar effect of meta and para substituents. The dependences of the ρ values (altogether 109 values of ρ) on the (1/T) term for various media were found to cross nearly at the same isosolvent temperature (1/βisosolv ≈ 2 × 10−3) for meta‐, para‐, ortho‐, and alkyl‐substituted esters. At T = βisosolv the difference (ρ)S − (ρ)Water becomes zero for all polar substituent effects in all media considered and the additional inductive effect from the ortho position (compared with para derivatives) disappears for all solvents studied. Copyright © 2007 John Wiley &amp; Sons, Ltd.