Methyl Cation Affinities Research Articles

Chemical reactivity and regioselectivity investigation for the formation of 3,5-disubstituted isoxazole via cycloaddition [2 + 3] and antitrypanosomal activity prediction

The antitrypanosomal activity of 3,5-disubstituted isoxazole has been investigated through molecular docking, revealing its binding to Plasmodium falciparum through seven hydrogen interactions demonstrating high affinity, supported by Molecular Dynamics Simulations. Followed by the Quantum Theory of Atoms in Molecules (AIM) studies, confirming the strength of hydrogen bonds and an acceptable ADMET profile has been found. The chemical reactivity of the cycloaddition [3 + 2] has been explored using Density Functional Theory (DFT). Results revealed a reverse electron demand, which was confirmed by global reactivity indices. Electron displacement was investigated based on Fukui functions, Methyl Cation Affinity (MCA), Methyl Anion Affinity (MAA), and Molecular Electrostatic Potential (MEP). The regioselectivity of the reaction was explored in the gas phase first and in dichloromethane secondarily to assess their impact on the reaction using the Integral Equation Formalism Polarizable Continuum (IEFPCM) model. Finally, additional bioactive compounds with 3,5-disubstituted isoxazole properties have been found using screening methods.

Pushing the Upper Limit of Nucleophilicity Scales by Mesoionic N-Heterocyclic Olefins.

A series of mesoionic, 1,2,3-triazole-derived N-heterocyclic olefins (mNHOs), which have an extraordinarily electron-rich exocyclic CC-double bond, was synthesized and spectroscopically characterized, in selected cases by X-ray crystallography. The kinetics of their reactions with arylidene malonates, ArCH=C(CO2 Et)2 , which gave zwitterionic adducts, were investigated photometrically in THF at 20 °C. The resulting second-order rate constants k2 (20 °C) correlate linearly with the reported electrophilicity parameters E of the arylidene malonates (reference electrophiles), thus providing the nucleophile-specific N and sN parameters of the mNHOs according to the correlation lg k2 (20 °C)=sN (N+E). With 21<N<32, the mNHOs are much stronger nucleophiles than conventional NHOs. Some mNHOs even excel the reactivity of mono- and diacceptor-substituted carbanions. It is exemplarily shown that the reactivity parameters thus obtained allow to calculate the rate constants for mNHO reactions with further Michael acceptors and predict the scope of reactions with other electrophilic reaction partners including carbon dioxide, which gives zwitterionic mNHO-carboxylates. The nucleophilicity parameters N correlate linearly with a linear combination of the quantum-chemically calculated methyl cation affinities and buried volumes of mNHOs, which offers a valuable tool to tailor the reactivities of strong carbon nucleophiles.

Mesoionische N‐Heterocyclische Olefine verschieben die obere Grenze der Nucleophilie‐Skala

AbstractMesoionische, 1,2,3‐Triazol‐abgeleitete N‐heterocyclische Olefine (mNHOs) mit außerordentlich elektronenreicher, exocyclischer CC–Doppelbindung wurden synthetisiert und spektroskopisch charakterisiert, z. T. durch Röntgenstrukturanalyse. Die Kinetik der mNHO‐Reaktionen mit Arylidenmalonaten (ArCH=C(CO2Et)2) zu zwitterionischen Addukten wurde photometrisch in THF bei 20 °C verfolgt. Die resultierenden Geschwindigkeitskonstanten 2. Ordnung k2(20 °C) korrelieren linear mit zuvor bestimmten Elektrophilieparametern E der Arylidenmalonate (Referenzelektrophile) und liefern gemäß der Beziehung lg k2(20 °C)=sN(N+E) die nucleophilspezifischen N‐ und sN‐Parameter der mNHOs. Die mNHOs sind mit 21&lt;N&lt;32 viel stärkere Nucleophile als herkömmliche NHOs. Einige mNHOs übertreffen sogar die Reaktivität von mono‐ und diakzeptor‐substituierten Carbanionen. Es wird an Beispielen gezeigt, dass es die so bestimmten Reaktivitätsparameter ermöglichen, die Geschwindigkeitskonstanten für mNHO‐Reaktionen mit weiteren Michael‐Akzeptoren zu berechnen. Auch die Reaktionen mit anderen elektrophilen Reaktionspartnern, inklusive Kohlenstoffdioxid, das zwitterionische mNHO‐Carboxylate bildet, lassen sich vorhersagen. Die Nucleophilie‐Parameter N korrelieren linear mit einer Linearkombination der quantenchemisch berechneten Methylkation‐Affinitäten und %Vbur („buried volumes“) der mNHOs, was ein wertvolles Werkzeug liefert, um Reaktivitäten starker Kohlenstoff‐Nucleophile maßzuschneidern.

Quantum Mechanics and Machine Learning Synergies: Graph Attention Neural Networks to Predict Chemical Reactivity

There is a lack of scalable quantitative measures of reactivity that cover the full range of functional groups in organic chemistry, ranging from highly unreactive C-C bonds to highly reactive naked ions. Measuring reactivity experimentally is costly and time-consuming, and no single method has sufficient dynamic range to cover the astronomical size of chemical reactivity space. In previous quantum chemistry studies, we have introduced Methyl Cation Affinities (MCA*) and Methyl Anion Affinities (MAA*), using a solvation model, as quantitative measures of reactivity for organic functional groups over the broadest range. Although MCA* and MAA* offer good estimates of reactivity parameters, their calculation through Density Functional Theory (DFT) simulations is time-consuming. To circumvent this problem, we first use DFT to calculate MCA* and MAA* for more than 2,400 organic molecules thereby establishing a large data set of chemical reactivity scores. We then design deep learning methods to predict the reactivity of molecular structures and train them using this curated data set in combination with different representations of molecular structures. Using 10-fold cross-validation, we show that graph attention neural networks applied to a relational model of molecular structures produce the most accurate estimates of reactivity, achieving over 91% test accuracy for predicting the MCA* ± 3.0 or MAA* ± 3.0, over 50 orders of magnitude. Finally, we demonstrate the application of these reactivity scores to two tasks: (1) chemical reaction prediction and (2) combinatorial generation of reaction mechanisms. The curated data sets of MCA* and MAA* scores is available through the ChemDB chemoinformatics web portal at cdb.ics.uci.edu under Chemical Reactivities data sets.

Methyl Cation Affinities of Canonical Organic Functional Groups.

Methyl cation affinities are calculated for the canonical nucleophilic functional groups in organic chemistry. These methyl cation affinities, calculated with a solvation model (MCA*), give an emprical correlation with the NsN term from the Mayr equation under aprotic conditions when they are scaled to the Mayr reference cation (4-MeOC6H4)2CH+ (Mayr E = 0). Highly reactive anionic nucleophiles were found to give a separate correlation, while some ylides and phosphorus compounds were determined to give a poor correlation. MCA*s are estimated for a broad range of simple molecules representing the canonical functional groups in organic chemistry. On the basis of a linear correlation, we estimate the range of nucleophilicities of organic functional groups, ranging from a C-C bond to a hypothetical tert-butyl carbanion, toward the reference electrophile to be about 50 orders of magnitude.

Efficient Syntheses of New Super Lewis Basic Tris(dialkylamino)-Substituted Terpyridines and Comparison of Their Methyl Cation Affinities.

Syntheses of very electron-rich dialkylamino-substituted 2,2':6',2''-terpyridines (TPYs) were adapted to moderate scale preparation without tedious purification of intermediates. The key 4'-bromo-6,6''-dimethyl-2,2':6',2''-terpyridine-4,4''-diyl bisnonaflate is now available in gram quantities. Its nucleophilic aromatic substitution with dimethylamine provided mixtures of 4'-bromo-substituted 4,4''-bis(dimethylamino)-TPY and the tris(dimethylamino)-TPY. The bromo compound was used in a Buchwald-Hartwig amination to provide the tris(dimethylamino)-TPY in excellent yield. The 4'-bromo substituent was reductively removed to furnish the bis(dimethylamino)-TPY. The same sequence of reactions with pyrrolidine as nucleophile leads to the hitherto unknown pyrrolidino-TPYs. Calculations at the MP2(FC)/6-31+G(2d,p)//B98/6-31G(d) level predict very high methyl cation affinities for compounds of this type, with the 4,4',4''-tri(pyrrolidin-1-yl)-TPY being the most Lewis basic TPY synthesized to date. The efficiently prepared electron-rich TPYs should be excellent ligands for many applications.

Nucleophilicities and Lewis Basicities of Sterically Hindered Pyridines

The structures of the covalent Lewis adducts and/or frustrated Lewis pairs derived from 2- and 2,6-substituted pyridines with diaryl (Ar2CH+) and with the more bulky triaryl (Ar3C+) carbenium ions were analyzed by UV-vis and NMR spectroscopy. Thermodynamics (equilibrium constants) and kinetics (rate constants) of the associations of the carbon-centered Lewis acids Ar2CH+ with a series of sterically hindered pyridines were investigated and used for the determination of the Lewis basicities and nucleophilicities, on the basis of the Mayr electrophilicity/nucleophilicity and Lewis acidity/basicity linear free energy relationships. In addition, methyl and benzhydryl cation affinities were computed to elucidate the respective steric and electronic contributions of the substituents to the nitrogen atom Lewis basicity. The influence of the size of the reference carbenium ion on the magnitude of the repulsion induced by the pyridine substituents (Me, tBu in 2- or 2,6-positions) was also analyzed. Cumulated steric repulsion was found to decrease the reactivity of the nitrogen atom by up to 10 orders of magnitude.

Effect of the Number of Methyl Groups on the Cation Affinity of Oxygen, Nitrogen, and Phosphorus Sites of Lewis Bases.

The effect of number of CH3 groups (n) on the cation (H+, Li+, Na+, Al+, CH3+) affinity, polarizability, and dipole moment of 14 simple molecules was investigated. Linear correlations were observed between the polarizabilities and the number of methyl groups. The variations of the cation affinities and dipole moments with the number of methyl groups (n) were not linear, and a quadratic function was proposed for obtaining a good fit of the experimental data. Also, because the proton affinities (PA), lithium cation affinities (LCA), sodium cation affinities (SCA), aluminum cation affinity (AlCA), and methyl cation affinity (MCA) varied quadratically with polarizabilities (α), a formula of the form [cation affinities] = a + bα + cα2 was proposed. After correction of the PAs, LCAs, SCAs, AlCA, and MCA for the dipole/charge interaction (Eμ), linear relationships were observed between the corrected cation affinities and n or α. The contribution of Eμ to PA and MCA was small (less than 20%), and its contribution to LCA and SCA was large (>50%). The electrostatic contribution to AlCA was considerable (20-50%); however, it was smaller than the electrostatic contribution to LCA and SCA.

Alkali Metal Cation versus Proton and Methyl Cation Affinities: Structure and Bonding Mechanism.

We have analyzed the structure and bonding of gas‐phase Cl−X and [HCl−X]+ complexes for X+= H+, CH3 +, Li+, and Na+, using relativistic density functional theory (DFT). We wish to establish a quantitative trend in affinities of the anionic and neutral Lewis bases Cl− and HCl for the various cations. The Cl−X bond becomes longer and weaker along X+ = H+, CH3 +, Li+, and Na+. Our main purpose is to understand the heterolytic bonding mechanism behind the intrinsic (i.e., in the absence of solvent) alkali metal cation affinities (AMCA) and how this compares with and differs from those of the proton affinity (PA) and methyl cation affinity (MCA). Our analyses are based on Kohn–Sham molecular orbital (KS‐MO) theory in combination with a quantitative energy decomposition analysis (EDA) that pinpoints the importance of the different features in the bonding mechanism. Orbital overlap appears to play an important role in determining the trend in cation affinities.

Unprecedented strong Lewis bases--synthesis and methyl cation affinities of dimethylamino-substituted terpyridines.

A versatile method for the synthesis of functionalized 2,2':6',2''-terpyridines by assembly of the terminal pyridine rings is presented. The cyclization precursors-bis-β-ketoenamides-are prepared from 4-substituted 2,6-pyridinedicarboxylic acids and acetylacetone or its corresponding enamino ketone. Treatment with trimethylsilyl trifluoromethanesulfonate induces a twofold intramolecular condensation providing an efficient access to 4,4''-di- and 4,4',4''-trifunctionalized 6,6''-dimethyl-2,2':6',2''-terpyridines. Using this method, hitherto unknown 4,4''-bis(dimethylamino)- and 4,4',4''-tris(dimethylamino)terpyridines have been prepared that show remarkably high calculated Lewis basicities.

Nucleofugality in oxygen and nitrogen derived pseudohalides in Menshutkin reactions: the importance of the intrinsic barrier.

In order to study the nucleofugality of polyatomic anionic leaving groups derived from oxygen and nitrogen, a contingent of 19 methylating agents consisting of amines or alcohols activated with carbonyl or sulfonyl substituents has been examined via ab initio calculations. We have calculated gas phase activation energies for alkylation of ammonia, and methyl cation affinities. We find that polyatomic anionic leaving groups derived from nitrogen will have higher activation energies for Menshutkin (SN2) alkylation even when they have similar methyl cation affinities. This inherent deficit in the nucleofugality of nitrogen-derived leaving groups appears to be a result of the way bond cleavage is synchronized with bond formation to the incoming ammonia nucleophile. The nitrogen leaving groups showed greater dissociation from the methyl fragment than oxygen leaving groups relative to the length of the forming carbon-nitrogen bond. Additionally the second sulfonyl group present in a sulfonimide appears to be less effective at activating nitrogen due to a preference for tetrahedral geometries at the departing nitrogen in the transition states involving leaving sulfonamide groups. Optimal delocalization of electron density is therefore frustrated due to the geometry of the leaving group.

Computational study of proton and methyl cation affinities of imidazole-based highly energetic ionic liquids

The present study deals with the evaluation of gas phase proton and methyl cation affinities for alkyl- and nitrosubstituted imidazoles using DFT (B3LYP)/6-31 + G(d) and MP2 methods in the Gaussian 03 software package. The extent of charge delocalization of these cations is correlated with proton affinity. The study reveals that weakly electron-donating alkyl groups at position 1 of the imidazole enhance its proton affinity, which also increases with increasing alkyl chain length. This is expected to result in an increased tendency to form salts. In contrast, the presence of strongly electron-withdrawing nitro groups lowers proton affinity, which decreases as the number of nitro groups on the ring increases. The same trend is observed for the methyl cation affinity, but to a lower degree. These trends in the proton and methyl cation affinities were analyzed to study the effects of these substituents on the basicity of the energetic imidazole moieties and their tendency to form salts. This, in turn, should aid searches for better highly energetic ionic liquids. In addition, calculations performed on different isomers of mono and dinitroimidazoles show that 5-nitro-1H-imidazole and 2,4-dinitro-1H-imidazole are more stable than the other isomers. Amongst the many nitro derivatives of imidazoles considered in the present study, cations resulting from these two would be the best choice for creating highly energetic ionic liquids when coupled with appropriate energetic anions.

Methyl Cation Affinities of Neutral and Anionic Maingroup-Element Hydrides: Trends Across the Periodic Table and Correlation with Proton Affinities

We have computed the methyl cation affinities in the gas phase of archetypal anionic and neutral bases across the periodic table using ZORA-relativistic density functional theory (DFT) at BP86/QZ4P//BP86/TZ2P. The main purpose of this work is to provide the methyl cation affinities (and corresponding entropies) at 298 K of all anionic (XH(n-1)(-)) and neutral bases (XH(n)) constituted by maingroup-element hydrides of groups 14-17 and the noble gases (i.e., group 18) along the periods 2-6. The cation affinity of the bases decreases from H(+) to CH(3)(+). To understand this trend, we have carried out quantitative bond energy decomposition analyses (EDA). Quantitative correlations are established between the MCA and PA values.

Structures, energetics, and dynamics of gas phase ions studied by FTICR and HPMS

Both Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) and high-pressure mass spectrometry (HPMS) are very powerful tools in the field of gas phase ion chemistry. Many experimental method developments based on FTICR-MS and HPMS are summarized, including the coupling of a high-pressure external ion source to a FTICR mass spectrometer, blackbody infrared radiative dissociation (BIRD), coupling laser desorption ionization with HPMS, infrared multiple photon dissociation (IRMPD), radiative association and bimolecular routes to gas phase cluster ion formation. An abundance of thermochemical data, such as proton affinities, gas phase acidities, methyl cation affinities and metal cation affinities, have been obtained. Some of these data are the basis of the standard data listed in the NIST thermochemical databases. Ion-molecule interactions, energetics, reactivities, and structures of molecules have been extensively investigated using the methods developed based on HPMS and FTICR mass spectrometric techniques.

Estimating the Stereoinductive Potential of Cinchona Alkaloids with a Prochiral Probe Approach

Cinchona alkaloids occupy a privileged status due to their optimal possession of two desirable properties, namely catalytic efficiency and stereoselectivity. This paper proposes a new quantitative measure, the energy difference between the adducts formed by re and si face attack to Mosher's cation (DeltaMOSCA(re-si)) as a measure of stereoinductive potential, by taking the example of cinchona alkaloids. Other descriptors such as methyl cation affinities and the one based on continuous symmetry measures are also estimated and correlated with DeltaMOSCA(re-si) values.

Methyl Cation Affinities of Organocatalysts

Methyl Cation Affinities of Organocatalysts

Methyl Cation Affinities of Commonly Used Organocatalysts

Methyl cation affinities (MCAs) and proton affinities (PAs) of a variety of N- and P-based organocatalysts have been calculated at the MP2(FC)/6-31+G(2d,p)//B98/6-31G(d) level of theory. Correlations between MCA and PA values have been used to identify factors leading to the potentially poor predictive value of PA data for organocatalytic activity. One of the relevant factors concerns steric effects between organocatalysts and the reactant electrophiles, which are not well-modeled by reaction with a proton. A second important factor concerns systematic differences in bond strengths between second- and third-row elements. This latter point makes MCA values much better descriptors of the catalytic activity of phosphanes than PA or pKa data.

Assessment of theoretical methods for the calculation of methyl cation affinities

The methyl cation affinity (MCA; 298 K) of a variety of neutral and anionic bases has been examined computationally with a wide variety of theoretical methods. These include high-level composite procedures such as W1, G3, G3B3, and G2, conventional ab initio methods such as CCSD(T) and MP2, as well as a selection of density functional theory (DFT) methods. Experimental results for a variety of small model systems are well reproduced with practically all these methods, and the performance of DFT based methods are far superior in comparison to their MP2 analogs for these small models. For larger model, systems including motifs frequently encountered in organocatalysts, the performance deteriorates somewhat for DFT methods, while it improves significantly for MP2, rendering the former methods unreliable for common organic bases. Thus, MP2 calculations performed in combination with basis sets such as 6-31+G(2d, p) or larger, appear to offer a practical and reliable approach to compute MCAs of organic bases.

Prediction of the Formation and Stabilities of Energetic Salts and Ionic Liquids Based on ab Initio Electronic Structure Calculations

A computational approach to predict the thermodynamics for forming a variety of imidazolium-based salts and ionic liquids from typical starting materials is described. The gas-phase proton and methyl cation acidities of several protonating and methylating agents, as well as the proton and methyl cation affinities of many important methyl-, nitro-, and cyano-substituted imidazoles, have been calculated reliably by using the computationally feasible DFT (B3LYP) and MP2 (extrapolated to the complete basis set limit) methods. These accurately calculated proton and methyl cation affinities of neutrals and anions are used in conjunction with an empirical approach based on molecular volumes to estimate the lattice enthalpies and entropies of ionic liquids, organic solids, and organic liquids. These quantities were used to construct a thermodynamic cycle for salt formation to reliably predict the ability to synthesize a variety of salts including ones with potentially high energetic densities. An adjustment of the gas phase thermodynamic cycle to account for solid- and liquid-phase chemistries provides the best overall assessment of salt formation and stability. This has been applied to imidazoles (the cation to be formed) with alkyl, nitro, and cyano substituents. The proton and methyl cation donors studied were as follows: HCl, HBr, HI, (HO)2SO2, HSO3CF3 (TfOH), and HSO3(C6H4)CH3 (TsOH); CH3Cl, CH3Br, CH3I, (CH3O)2SO2, CH3SO3CF3 (TfOCH3), and CH3SO3(C6H4)CH3 (TsOCH3). As substitution of the cation with electron-withdrawing groups increases, the triflate reagents appear to be the best overall choice as protonating and methylating agents. Even stronger alkylating agents should be considered to enhance the chances of synthetic success. When using the enthalpies of reaction for the gas-phase reactants (eq 6) to form a salt, a cutoff value of -13 kcal mol(-1) or lower (more negative) should be used as the minimum value for predicting whether a salt can be synthesized.

Methyl Cation Affinities of Rare Gases and Nitrogen and the Heat of Formation of Diazomethane

The methyl cation affinities of the rare gases have been calculated at 0 and 298 K by using coupled cluster theory including noniterative, quasiperturbative triple excitations with the new correlation-consistent basis sets for Xe up through aug-cc-pV5Z in some cases. To achieve near chemical accuracy (+/-1 kcal/mol) in the thermodynamic properties, we add to the estimated complete basis set valence binding energies, based on frozen core coupled cluster theory energies, two corrections: (1) a core/valence correction and (2) a scalar relativistic correction. Vibrational zero-point energies were computed at the coupled cluster level of theory at the CCSD(T)/aug-cc-pVDZ level. The calculated rare gas methyl cation affinities (MCA in kcal/mol) at 298 K are the following: MCA(He) = 1.7, MCA(Ne) = 2.5, MCA(Ar) = 16.9, MCA(Kr) = 25.5, and MCA(Xe) = 36.6. Because of the importance of the MCA(N(2)) in the experimental measurements of the MCA scale, we calculated a number of quantities associated with CH(3)N(2)(+) and CH(2)N(2). The calculated values for diazomethane at 298 K are: DeltaH(f)(CH(2)N(2)) = 65.3 kcal/mol, PA(CH(2)N(2)) = 211.9 kcal/mol, and MCA(N(2)) = 43.2 kcal/mol.