Electrostatic CH-π Interactions Can Override Fluorine Gauche Effects To Exert Conformational Control.

Fluorine gauche effects are conformational properties of 2-fluoroethanes often applied in modern molecular designs. However, the physical origins of fluorine gauche effects are not well understood, with the consensus favoring the established hyperconjugation theory over an emerging electrostatic model. Using a series of model systems, we show that a shift to fluorine gauche effects can be influenced by intramolecular CH⋅⋅⋅π aromatic interactions, a through-space event. Modulating the π-ring (forming the aromatic interaction) with substituent groups resulted in a linear Hammett relationship, thus indicating that the CH⋅⋅⋅π interaction has electrostatic features. For instance, attaching a nitro group (an electron-withdrawing substituent) to the π-ring weakened the CH⋅⋅⋅π interaction and led to a gauche preference, whereas an anti conformer is preferred with amine as substituent. The experimental results performed by using proton NMR spectroscopy are corroborated by gas-phase DFT calculations and solid-state X-ray crystallography.

Rationalizing hydrogen bond solvation with Kamlet-Taft LSER and molecular torsion balances.

The strength of a weak intramolecular hydrogen bond was quantified using molecular torsion balances and found to vary between -0.99 kcal mol-1 and +1.00 kcal mol-1 due to solvation. Analyzing the results using Kamlet-Taft's Linear Solvation Energy Relationship enabled partitioning of the hydrogen-bond strength into physically meaningful solvent parameters through a linear equation: ΔGH-Bond = -1.37 - 0.14α + 2.10ß + 0.74(π* - 0.38δ) kcal mol-1 (R2 = 0.99, n = 14), where α and ß represent the solvent hydrogen-bond acceptor and donor parameters, respectively, and π* associates with the solvent nonspecific polarity/dipolarity parameter. Based on the coefficient of each solvent parameter (derived by linear regression), the ß electrostatic term emerged as the dominant contributor to solvent effects on hydrogen bonding. This finding aligns with the natural attributes of hydrogen bonds as electrostatic interactions, but the contributions from the nonspecific interactions of the solvent (e.g., dispersion) are also important. Hydrogen bond solvation affects molecular properties and functions, and this study provides a predictive tool to harness the efficiency of hydrogen bonds.

In Vivo Sex-Dependent Effects of Perinatal Pb2+ Exposure on Pilocarpine-Induced Seizure Susceptibility and Taurine Neuropharmacology.

Lead (Pb2+) is a developmental neurotoxicant that disrupts the GABA-shift and subsequently causes alterations in the brain's excitation-to-inhibition (E/I) balance. This finding suggests that neurodevelopmental Pb2+ exposures may increase the risk of brain excitability and/or seizure susceptibility. Prior studies have suggested that neurodevelopmental Pb2+ exposures may cause excitotoxicity of cholinergic neurons, but little to no research has further investigated these potential relationships. The present study sought to evaluate the potential for perinatal neurodevelopmental Pb2+ exposures of 150 ppm and 1000 ppm on pilocarpine-induced seizures through the M1 receptor. The study also evaluated the potential for sex- and treatment-dependent differences in brain excitability. The study revealed that Control females have elevated cholinergic brain excitability and decreased GABAergic inhibition in response to pilocarpine-induced seizures. At low Pb2+ exposures, males exhibited more cholinergic brain excitability, whereas at higher Pb2+ exposures, females exhibited more cholinergic brain excitability. Further, taurine was able to provide neuroprotection against pilocarpine-induced seizures in males, whereas females did not reveal such observations. Thus, the present study adds new insights into the potential for cholinergic seizure susceptibility as a function of sex and the dosage ofneurodevelopmental Pb2+ exposure and how taurine may provide selective pharmacodynamics to treat or recover cholinergic system aberrations induced by neurotoxicants.

Taurine-Derived Compounds Produce Anxiolytic Effects in Rats Following Developmental Lead Exposure.

Lead (Pb2+) is a developmental neurotoxicant that disrupts the GABA-shift and subsequently causes alterations in the brain's excitation-to-inhibition (E/I) balance. Taurine is a well-established neuroprotective and inhibitory compound for regulating brain excitability. Since mechanistically taurine can facilitate neuronal inhibition through the GABA-AR, the present study examined the anxiolytic potential of taurine derivatives. Treatment groups consisted of the following developmental Pb2+-exposures: Control (0 ppm) and Perinatal (150 ppm or 1,000 ppm lead acetate in the drinking water). Rats were scheduled for behavioral tests between postnatal days (PND) 36-45 with random drug assignments to either saline, taurine, or taurine-derived compound (TD-101, TD-102, or TD-103) to assess the rats' responsivity to each drug in mitigating the developmental Pb2+-exposure and anxiety-like behaviors through the GABAergic system. Long-Evans hooded rats were assessed using an open field (OF) test for preliminary locomotor assessment. Twenty-four hours later, the same rats were exposed to the elevated plus maze (EPM) and were given an i.p. injection of 43 mg/Kg of the saline, taurine, or TD drugs 15 min prior to testing. Each rat was tested using the triple-blind random assignment method for each drug condition. The OF data revealed that Control female rats had increased locomotor activity over Control male rats, and the Pb2+-exposed males and females had increased locomotor activity when compared to the Control male and female rats. However, in the EPM, the Control female rats exhibited more anxiety-like behaviors over Control male rats, and the Pb2+-exposed male and female rats showed selective responsivity to TD drugs when compared to taurine. For Pb2+-exposed males, TD-101 showed consistent recovery of anxiety-like behaviors similar to that of taurine regardless of Pb2+ dose, whereas in Pb2+-exposed females TD-101 and TD-103 showed greater anxiolytic responses in the EPM. The results from the present psychopharmacological study suggests that taurine and its derivatives are interesting drug candidates to explore sex-specific mechanisms and actions of taurine and the associated GABAergic receptor properties by which these compounds alleviate anxiety as a potential behavioral pharmacotherapy for neurodevelopmental Pb2+ exposure.

Determining the Ionization Constants of Organic Acids Using Fluorine Gauche Effects.

Using NMR spectroscopy, the conformational studies of two fluoroethylsulfonamides (N-(2-fluoroethyl)-p-tolylsulfonamide (1) and N-(2-fluoroethyl)trifluoromethanesulfonamide (2)) revealed that fluorine gauche effects are a function of ionization. While acids 1 and 2 exhibited gauche effects (with gauche populations of 87% and 92% in DMSO-d6, respectively), their anions, on the other hand, preferred the anti conformer (with gauche populations of 35% and 55%, respectively). The ability of these compounds to undergo conformational changes as a function of ionization enabled their application as molecular probes (standards) for determining the acidity (pKa) of organic compounds in DMSO, which was achieved with the aid of the equation Krel = [(3JAH - 3Jobs)/(3Jobs - 3JA)]2, where Krel is the ratio of ionization constants of two acids (standard and test acids), 3JAH and 3JA are the proton-fluorine vicinal coupling constants of the standard acid and its anion, respectively, and 3Jobs represents the proton-fluorine vicinal coupling constant observed at the midpoint of an acid-base equilibrium. As a means of demonstrating its utility, this equation accurately calculated the ionization constants (Ka) of several organic compounds in DMSO. Taking advantage of fluorine's unique gauche effect as a strategy for molecular design has the potential to open a new frontier in structural chemistry.

Assessing the Anxiolytic Properties of Taurine-Derived Compounds in Rats Following Developmental Lead Exposure: A Neurodevelopmental and Behavioral Pharmacological Pilot Study.

Lead (Pb2+) is a developmental neurotoxicant that causes alterations in the brain's excitation-to-inhibition (E/I) balance. By increasing chloride concentration through GABA-ARs, taurine serves as an effective inhibitory compound for maintaining appropriate levels of brain excitability. Considering this pharmacological mechanism of taurine facilitated inhibition through the GABA-AR, the present pilot study sought to explore the anxiolytic potential of taurine derivatives. Treatment groups consisted of the following developmental Pb2+-exposures: Control (0 ppm) and Perinatal (150 ppm or 1000 ppm lead acetate in the drinking water). Rats were scheduled for behavioral tests between postnatal days (PND) 36-45 with random assignments to either solutions of Saline, Taurine, or Taurine Derived compounds (i.e., TD-101, TD-102, or TD-103) to assess the rats' responsiveness to each drug in mitigating the developmental Pb2+-exposure through the GABAergic system. Long Evans Hooded rats were assessed using an Open Field (OF) test for preliminary locomotor assessment. Approximately 24-h after the OF, the same rats were exposed to the Elevated Plus Maze (EPM) and were given an i.p. injection of 43 mg/Kg of the Saline, Taurine, or TD drugs 15-min prior to testing. Each rat was tested using the random assignment method for each pharmacological condition, which was conducted using a triple-blind procedure. The OF data revealed that locomotor activity was unaffected by Pb2+-exposure with no gender differences observed. However, Pb2+-exposure induced an anxiogenic response in the EPM, which interestingly, was ameliorated in a gender-specific manner in response to taurine and TD drugs. Female rats exhibited more anxiogenic behavior than the male rats; and as such, exhibited a greater degree of anxiety that were recovered in response to Taurine and its derivatives as a drug therapy. The results from the present psychopharmacological pilot study suggests that Taurine and its derivatives could provide useful data for further exploring the pharmacological mechanisms and actions of Taurine and the associated GABAergic receptor properties by which these compounds alleviate anxiety as a potential behavioral pharmacotherapy for treating anxiety and other associated mood disorders.

Solvent Modulation of Aromatic Substituent Effects in Molecular Balances Controlled by CH-π Interactions.

CH-π aromatic interactions are ubiquitous in nature and are capable of regulating important chemical and biochemical processes. Solvation and aromatic substituent effects are known to perturb the CH-π aromatic interactions. However, the nature by which the two factors influence one another is relatively unexplored. Here we demonstrate experimentally that there is a quantitative correlation between substituent effects in CH-π interactions and the hydrogen-bond acceptor constants of the solvating molecule. The CH-π interaction energies were measured by the conformational study of a series of aryl-substituted molecular balances in which the conformational preferences depended on the relative strengths of the methyl and aryl CH-π interactions in the folded and unfolded states, respectively. Due to the favorable methyl-aromatic interactions, the balances were found to exist predominantly in the folded state. The observed substituent effect in the conformational preferences of the balances was controlled by the explicit solvation/desolvation of the aryl proton. The interpretation of the conformational free energy as a function of substituents and solvation using Hunter's solvation model revealed that a linear relationship exists between the sensitivity of aromatic substituent effects (i.e., the ρ values derived from Hammett plots) and the hydrogen-bond acceptor propensity (ßs) of the solvent molecule: ρ = 0.06ßs - 0.04.

Cationic CHπ interactions as a function of solvation.

The energy (ΔG) of a cationic CHπ interaction was measured experimentally through the conformational studies of new molecular torsion balances using proton NMR spectroscopy. Each of the molecular balance adopted folded and unfolded conformations for which the ratio of the conformational equilibrium (i.e., folded/unfolded ratio) provided a quantitative measure of the ΔG as a function of solvation. An excellent linear solvation energy relationship between the ΔG values and the Hunter's solvent hydrogen-bond parameters (αs and ßs) revealed that electrostatic interaction is the physical origin of the observed conformational preferences in solution.

Conformational preferences of N,N-dimethylsuccinamate as a function of alkali and alkaline earth metal salts: experimental studies in DMSO and water as determined by 1H NMR spectroscopy.

The fraction of gauche conformers of N,N-dimethylsuccinamic acid (1) and its Li(+), Na(+), K(+), Mg(2+), Ca(2+), and N(Bu)4(+) salts were estimated in DMSO and D2O solution by comparing the experimental vicinal proton-proton couplings determined by (1)H NMR spectroscopy with those calculated using the Haasnoot, de Leeuw, and Altona (HLA) equation. In DMSO, the gauche preferences were found to increase with decreasing Ahrens ionic radius of the metal counterion. The same trend was not seen in D2O, where the gauche fraction for all of the metallic salts were estimated to be approximately statistical or less. This highlights the importance of metal chelation on the conformation of organic molecules in polar aprotic media, which has implications for protein folding.

Quantifying macrocyclization-induced strain utilizing N-phenylimides as conformational reporters.

Incorporating an N-phenylimide unit into macrocycles enabled measurements of macrocyclization strains by comparing the N-phenylimide's conformational changes to similar units attached to a linear-chain control. Systems of larger macrocycles displayed negligible macrocyclization strain, while smaller macrocycles demonstrated proportionate effects, emphasizing the use of N-phenylimides as conformational reporters of macrocyclization strain.

Conformational preferences of cis-1,3-cyclopentanedicarboxylic acid and its salts by 1H NMR spectroscopy: energetics of intramolecular hydrogen bonds in DMSO.

The conformational populations of cis-1,3-cyclopentanedicarboxylic acid (1) and its mono- and dianion were established in DMSO solution by comparing the vicinal proton­proton coupling constants (3J(HH)) obtained in solution to their theoretical counterparts. Geometries used for 3J(HH) theoretical estimation (using Karplus-type equations) were obtained from optimized structures at the B3LYP/6-31G(2d,2p) level. The diacid (1) adopted many conformations, whereas the ionized species (1A mono- and 1B dianion) assumed single conformations. A downfield chemical shift of 19.45 ppm (Δδ(H) = 7.43 ppm) observed at −60 °C was indicative of intramolecular hydrogen bonding in 1A, which was later corroborated by determining the ratio of the first (K1) to the second (K2) ionization constants. K1/K2 in DMSO (1.3 × 10(7)) was significantly larger than the value in water (2 × 10). In addition, K1/K(E) = 200 (where K(E) is the acidity constant of the monomethylester of 1) was greater than the intramolecular hydrogen bonding threshold value of 2. The calculated intramolecular hydrogen bond strength of 1A was ~3.1 kcal mol(­1), which is ~2.7 kcal mol(­1) more stable than the values for cis-1,3-cyclohexanedicarboxylic acid (2A). Thus, the relative energies of intramolecular hydrogen bonding in the monoanions 1A and 2A suggests that 1,3-diaxial conformers are more favored for cyclopentane than for cyclohexane rings.

Substituent effects on energetics of peptide-carboxylate hydrogen bonds as studied by 1H NMR spectroscopy: implications for enzyme catalysis.

Substituent effects in N-H···O hydrogen bonds were estimated by comparing the acidities of two series of model compounds: N-benzoylanthranilic acids (A) and 4-benzoylamidobenzoic acids (B). Intramolecular N-H···O hydrogen bonds were found to be present in the A series of compounds, while B acids were used as control models. The respective pK(a) values for A and B acids were determined experimentally in DMSO solution using proton NMR spectroscopy. With X = H, the pK(a) for A and B acids were observed to be 7.6 and 11.6, respectively, a difference of 4.0 units (ΔpK(a)). However, with X = p-NO2, the ΔpK(a) value between A and B acids increased to 4.7 units: the pK(a) values for A and B acids were determined as 6.7 and 11.4, respectively. The ΔpK(a) values between A and B acids as a function of the X substituents were studied in 10 other examples. The effects of X substituents in A acids could be predicted on the basis of the observed linear Hammett correlations, and the sensitivity of each substituent effect was found to be comparable to those observed for the ionization of substituted benzoic acids (ρ = 1.04 for A acids, and ρ = 1.00 for benzoic acids).

Quantification of CH···π interactions: implications on how substituent effects influence aromatic interactions.

Attractive interactions between a substituted benzene ring and an α-substituted acetate group were determined experimentally by using the triptycene model system. The attractive interaction correlates well with the Hammett constants σ(m) (R(2)=0.90), but correlates much better with the acidity of the α-protons (R(2)=0.98).

Relative substituent position on the strength of pi-pi stacking interactions.

It was observed that the relative position of the arene substituents have a profound influence on the strength of pi-pi stacking in the 9-benzyl substituted triptycene system. A new series of model compounds (3a-i) capable of revealing quantitatively pi-pi stacking interactions was studied. This series of compounds (3a-i) has an ortho substituted methyl group in one of the two interacting arenes and the syn/anti ratios were determined and compared to a series previously studied compounds (4a-i) that have a para methyl group on the corresponding arene. A greater than 50% increase in the strength of pi-pi stacking interactions was observed with the methyl group in the ortho position comparing to that in the para position. No difference in pi-pi stacking interactions was observed when the other aromatic ring was a pentafluorobenzoate group.

Quantitative model for rationalizing solvent effect in noncovalent CH-Aryl interactions.

The strength of CH-aryl interactions (ΔG) in 14 solvents was determined via the conformational analysis of a molecular torsion balance. The molecular balance adopted folded and unfolded conformers in which the ratio of the conformers in solution provided a quantitative measure of ΔG as a function of solvation. While a single empirical solvent parameter based on solvent polarity failed to explain solvent effect in the molecular balance, it is shown that these ΔG values can be correlated through a multiparameter linear solvation energy relationship (LSER) using the equation introduced by Kamlet and Taft. The resulting LSER equation [ΔG = -0.24 + 0.23α - 0.68ß - 0.1π* + 0.09δ]-expresses ΔG as a function of Kamlet-Taft solvent parameters-revealed that specific solvent effects (α and ß) are mainly responsible for "tipping" the molecular balance in favour of one conformer over the other, where α represents a solvents' hydrogen-bond acidity and ß represents a solvents' hydrogen-bond basicity. Furthermore, using extrapolated data (α and ß) and the known π* value for the gas phase, the LSER equation predicted ΔG in the gas phase to be -0.31 kcal mol-1, which agrees with -0.35 kcal mol-1 estimated from DFT-D calculations.

Conformational equilibria of N,N-dimethylsuccinamic acid and its lithium salt as a function of solvent.

The conformational preferences of N,N-dimethylsuccinamic acid and its Li(+) salt were estimated by comparing the respective experimental NMR vicinal proton-proton coupling constants to semiempirical coupling constants for each staggered conformer as derived by the Haasnoot-De Leeuw-Altona method. The strong gauche preferences for the Li(+) salts clearly depended more on the solvents' hydrogen-bond donating strength (α) than on their hydrogen-bond accepting (ß) counterpart, where α and ß are the corresponding Kamlet-Taft parameters.