Resonance Enhancement via Imidazole Substitution Predicts New Cation Receptors

Design and development of cation receptors represent a fascinating area of research, particularly in dealing with chemical and biological applications that require fine-tuning of cation−π interactions. The electronic nature of a substituent is largely responsible for tuning the strength of cation−π interaction, and recent studies have shown that substituent resonance effect contributes significantly to such interactions. Using substituent resonance effect as a key electronic factor, we have proposed new cation−π receptors (<b><b>1···</b>M⁺−4···M⁺</b>; M⁺ = Li⁺, Na⁺, K⁺, NH₄⁺, and NMe₄⁺). B3LYP/6-311+G­(d,p) density functional theory (DFT) calculations show that by using a strategy of resonance donation from six nitrogen atoms via three substituted imidazole subunits, more than 4-fold increase in cation−π interaction energy (<i>E</i>_M⁺) can be achieved for a single phenyl ring compared to benzene. The <i>E</i>_M⁺ (M⁺ = NH₄⁺, NMe₄⁺) of <b>4</b>···M⁺, wherein M⁺ interacts with only one phenyl ring, is significantly higher than <i>E</i>_M⁺ of a known cation host with several aromatic rings (abstract figure). Our hypothesis on resonance enhancement of cation−π interaction is verified using several π-systems (<b>5</b>–<b>10</b>) containing a lone pair bearing six nitrogens and observed that a nitrogen lone pair attached to a double bond is more effective for donation than the lone pair that is directly attached to the benzenoid ring. Further, a convenient strategy to design electron rich π-systems is provided on the basis of topographical analysis of molecular electrostatic potential

Accurate Prediction of Cation−π Interaction Energy Using Substituent Effects

Substituent effects on cation−π interactions have been quantified using a variety of Φ–X···M⁺ complexes where Φ, X, and M⁺ are the π-system, substituent, and cation, respectively. The cation−π interaction energy, <i>E</i>_M⁺, showed a strong linear correlation with the molecular electrostatic potential (MESP) based measure of the substituent effect, Δ<i>V</i>_min (the difference between the MESP minimum (<i>V</i>_min) on the π-region of a substituted system and the corresponding unsubstituted system). This linear relationship is <i>E</i>_M⁺ = <i>C</i>_M⁺(Δ<i>V</i>_min) + <i>E</i>_M⁺′ where <i>C</i>_M⁺ is the reaction constant and <i>E</i>_M⁺′ is the cation−π interaction energy of the unsubstituted complex. This relationship is similar to the Hammett equation and its first term yields the substituent contribution of the cation−π interaction energy. Further, a linear correlation between <i>C</i>_M⁺ and <i>E</i>_M⁺′ has been established, which facilitates the prediction of <i>C</i>_M⁺ for unknown cations. Thus, a prediction of <i>E</i>_M⁺ for any Φ–X···M⁺ complex is achieved by knowing the values of <i>E</i>_M⁺′ and Δ<i>V</i>_min. The generality of the equation is tested for a variety of cations (Li⁺, Na⁺, K⁺, Mg⁺, BeCl⁺, MgCl⁺, CaCl⁺, TiCl₃⁺, CrCl₂⁺, NiCl⁺, Cu⁺, ZnCl⁺, NH₄⁺, CH₃NH₃⁺, N­(CH₃)₄⁺, C­(NH₂)₃⁺), substituents (N­(CH₃)₂, NH₂, OCH₃, CH₃, OH, H, SCH₃, SH, CCH, F, Cl, COOH, CHO, CF₃, CN, NO₂), and a large number of π-systems. The tested systems also include multiple substituted π-systems, viz. ethylene, acetylene, hexa-1,3,5-triene, benzene, naphthalene, indole, pyrrole, phenylalanine, tryptophan, tyrosine, azulene, pyrene, [6]-cyclacene, and corannulene and found that <i>E</i>_M⁺ follows the additivity of substituent effects. Further, the substituent effects on cationic sandwich complexes of the type C₆H₆···M⁺···C₆H₅X have been assessed and found that <i>E</i>_M⁺ can be predicted with 97.7% accuracy using the values of <i>E</i>_M⁺′ and Δ<i>V</i>_min. All the Φ–X···M⁺ systems showed good agreement between the calculated and predicted <i>E</i>_M⁺ values, suggesting that the Δ<i>V</i>_min approach to substituent effect is accurate and useful for predicting the interactive behavior of substituted π-systems with cations

Appraisal of through-bond and through-space substituent effects via molecular electrostatic potential topography

Through-bond (TB) and through-space (TS) substituent effects in substituted alkyl, alkenyl, and alkynyl arenes are quantified separately using molecular electrostatic potential (MESP) topographical analysis. The deepest MESP point over the aromatic ring (V<SUB>min</SUB>) is considered as a probe for monitoring these effects for a variety of substituents. In the case of substituted alkyl chains, the TS effect (79.6%) clearly dominates the TB effect, whereas in the unsaturated analogues the TB effect (~55%) overrides the TS effect

Correlation and Prediction of Redox Potentials of Hydrogen Evolution Mononuclear Cobalt Catalysts via Molecular Electrostatic Potential: A DFT Study

Reduction potentials (<i>E</i>⁰) of six mononuclear cobalt catalysts (<b>1</b>–<b>6</b>) for hydrogen evolution reaction and electron donating/withdrawing effect of nine X-substituents on their macrocyclic ligand are reported at solvation effect-included B3P86/6-311+G** level of density functional theory. The electrostatic potential at the Co nucleus (<i>V</i>_Co) is found to be a powerful descriptor of the electronic effect experienced by Co from the ligand environment. The <i>V</i>_Co values vary substantially with respect to the nature of macrocycle, type of apical ligands, nature of substituent and oxidation state of the metal center. Most importantly, <i>V</i>_Co values of both the oxidized and reduced states of all the six complexes show strong linear correlation with <i>E</i>⁰. The correlation plots between <i>V</i>_Co and <i>E</i>⁰ provide an easy-to-interpret graphical interpretation and quantification of the effect of ligand environment on the reduction potential. Further, on the basis of a correlation between the relative <i>V</i>_Co and relative <i>E</i>⁰ values of a catalyst with respect to the CF₃-substituted reference system, the <i>E</i>⁰ of any X-substituted <b>1</b>–<b>6</b> complexes is predicted

Uncovering the Most Kinetically Influential Reaction Pathway Driving the Generation of HCN from Oxyma/DIC Adduct:A Theoretical Study

The combination of ethyl (hydroxyimino)cyanoacetate (Oxyma) and diisopropylcarbodiimide (DIC) has demonstrated superior performance in amino acid activation for peptide synthesis. However, it was recently reported that Oxyma and DIC could react to generate undesired hydrogen cyanide (HCN) at 20 °C, raising safety concerns for the practical use of this activation strategy. To help minimize the risks, there is a need for a comprehensive investigation of the mechanism and kinetics of the generation of HCN. Here we show the results of the first systematic computational study of the underpinning mechanism, including comparisons with experimental data. Two pathways for the decomposition of the Oxyma/DIC adduct are derived to account for the generation of HCN and its accompanying cyclic product. These two mechanisms differ in the electrophilic carbon atom attacked by the nucleophilic sp2-nitrogen in the cyclization step and in the cyclic product generated. On the basis of computed “observed” activation energies, ΔGobs⧧, the mechanism that proceeds via the attack of the sp2-nitrogen at the oxime carbon is identified as the most kinetically favorable one, a conclusion that is supported by closer agreement between predicted and experimental 13C NMR data. These results can provide a theoretical basis to develop a design strategy for suppressing HCN generation when using Oxyma/DIC for amino acid activation.</p

Computer-aided solvent design for suppressing HCN generation in amino acid activation

A highly toxic compound, hydrogen cyanide (HCN), was discovered to result from the reaction between Ethyl cyano (hydroxyimino) acetate (Oxyma) and diisopropylcarbodiimide (DIC), a popular reagent combination for amino acid activation. The reaction solvent has been found to influence the amount of HCN produced so that judicious solvent choice offers a route to suppressing HCN formation. Given the safety implications and the time-demanding nature of experimental solvent selection, we employ a methodology of quantum mechanical computer-aided molecular design (QM-CAMD) to design a new reaction solvent in order to minimize the amount of HCN formed. In this work, we improve on the original QM-CAMD approach with an enhanced surrogate model to predict the reaction rate constant from several solvent properties. A set of solvents is selected for model regression using model-based design of experiments (MBDoE), where the determinant of the information matrix of the design, known as D-criterion, is maximized. The use of a model-based approach is especially beneficial here as it links the large discrete space of solvent molecules to the reduced space of solvent properties. The resulting surrogate model exhibits an improved adjusted coefficient of determination and leads to more accurate predicted rate constants than the model generated without using MBDoE. The proposed DoE-QM-CAMD algorithm reaches convergence in one iteration. In the future, the main reaction of amino acid activation will be considered to design a solvent that maintains the rate of the main reaction while minimizing HCN generation.</p

Conformational Sampling over Transition-Metal-Catalyzed Reaction Pathways: Toward Revealing Atroposelectivity

The Py-Conformational-Sampling (PyCoSa) technique is introduced as a systematic computational means to sample the configurational space of transition-metal-catalyzed stereoselective reactions. When applied to atroposelective Suzuki–Miyaura coupling to create axially chiral biaryl products, the results show a range of mechanistic possibilities that include multiple low-energy channels through which C–C bonds can be formed

Conformational Sampling over Transition-Metal-Catalyzed Reaction Pathways: Toward Revealing Atroposelectivity

The Py-Conformational-Sampling (PyCoSa) technique is introduced as a systematic computational means to sample the configurational space of transition-metal-catalyzed stereoselective reactions. When applied to atroposelective Suzuki–Miyaura coupling to create axially chiral biaryl products, the results show a range of mechanistic possibilities that include multiple low-energy channels through which C–C bonds can be formed

Nickel-Catalyzed Double Carboxylation of Alkynes Employing Carbon Dioxide

The nickel-catalyzed double carboxylation of internal alkynes employing carbon dioxide (CO₂) has been developed. The reactions proceed under CO₂ (1 atm) at room temperature in the presence of a nickel catalyst, Zn powder as a reducing reagent, and MgBr₂ as an indispensable additive. Various internal alkynes could be converted to the corresponding maleic anhydrides in good to high yields. DFT calculations disclosed the indispensable role of MgBr₂ in the second CO₂ insertion