Ambident Nucleophilic Substitution: Understanding Non-HSAB Behavior through Activation Strain and Conceptual DFT Analyses

The ability to understand and predict ambident reactivity is key to the rational design of organic syntheses. An approach to understand trends in ambident reactivity is the hard and soft acids and bases (HSAB) principle. The recent controversy over the general validity of this principle prompted us to investigate the competing gas-phase S_N2 reaction channels of archetypal ambident nucleophiles CN⁻, OCN⁻, and SCN⁻ with CH₃Cl (S_N2@C) and SiH₃Cl (S_N2@Si), using DFT calculations. Our combined analyses highlight the inability of the HSAB principle to correctly predict the reactivity trends of these simple, model reactions. Instead, we have successfully traced reactivity trends to the canonical orbital-interaction mechanism and the resulting nucleophile–substrate interaction energy. The HOMO–LUMO orbital interactions set the trend in both S_N2@C and S_N2@Si reactions. We provide simple rules for predicting the ambident reactivity of nucleophiles based on our Kohn–Sham molecular orbital analysis.     

Reaction of the ambident electrophile dimethyl carbonate with the ambident nucleophile phenylhydrazine

To explore the ambident electrophilic reactivity of dimethyl carbonate (DMC), reactions with the ambident nucleophile phenylhydrazine were investigated. When a Br?nsted base was used, selective carboxymethylation occurred at N-1, after that several other compounds were produced selectively utilizing various conditions. Formation of these compounds was explained by using the Hard-Soft Acid-Base (HSAB) theory. Catalysis by some metal salts altered the reactivity of phenylhydrazine, which effected selective carboxymethylation at N-2 of phenylhydrazine instead.     

Elucidating the hard/soft acid/base principle: a perspective based on half-reactions

A comprehensive analysis is presented for the acid-base double-exchange reaction as well as the associated acid-displacement and base-displacement "half-reactions" with the goal of elucidating the meaning of the hard/soft acid/base (HSAB) principle and the conditions for its validity. When electron-transfer effects are important and other effects are negligible, the HSAB principle is driven by the surpassing stability of the soft acid/soft base product. When electrostatic effects dominate the reactivity, the HSAB principle is driven by the surpassing stability of the hard acid/hard base product. Because electron-transfer effects favor soft/soft interactions, while electrostatic effects favor hard/hard interactions, acid-base exchange reactions may be used to determine whether a reagent's reactivity is dominated by electron-transfer or by electrostatic effects. Because electron-transfer and electrostatic considerations separately favor the HSAB principle whenever the electronic chemical potentials of the acids and bases involved in the reaction are similar, our analysis provides strong support for the HSAB principle. The electronic chemical potential measures the intrinsic strength of acids and bases.     

Diels-Alder反应中的次级轨道效应

利用概念密度泛函理论下的局域软度和广义局域软度,结合局域硬软酸碱(HSAB)原理,研究环戊二烯与CH2=CHCOCnH2n+1之间的Diels-Alder反应的立体选择性,其中活性因子均是由ABEEMσπ模型获得.与以往不同的是,除了将主要参与反应的4个原子作为反应中心之外,还将产生次级轨道效应(SOI)的2个原子也作为参与反应的一部分.得到的结果表明,所有反应的立体选择性均与实验结果取得了很好的一致性,由此提出了一种定量快速处理包含次级轨道效应的Diels-Alder反应的立体选择性的方法.     

Arylazide cycloaddition to methyl propiolate: DFT-based quantitative prediction of regioselectivity

Several 1(4-substituted)phenyl-4- or 5-methoxycarbonyl-1,2,3-triazoles have been synthesized by 1,3-dipolar cycloaddition of the corresponding arylazides to methyl propiolate in carbon tetrachloride. The regioselectivity of these reactions cannot be rationalized on the basis of the electronic demands of the reactants or frontier molecular-orbital theory. Therefore, we applied to this problem a quantitative formulation of the HSAB principle to this problem developed within density functional theory. Global and local reactivity indices were computed at B3LYP/6-311+G(d,p) level both in vacuo and in carbon tetrachloride (by the COSMO approach). The direction of charge transfer upon reactive encounter has been determined and the computed regioselectivity has been shown to be in good agreement with the experimental results. The relationship between computed and experimental data and how it is affected by the solvent have been discussed.     

Insight into the hard-soft acid-base properties of differently substituted phenylhydrazines in reactions with dimethyl carbonate

Following the preliminary studies on the reactivity of the ambident nucleophile phenylhydrazine with dimethyl carbonate, investigations involving para-substituted phenylhydrazines were carried out in order to probe differences in the reactivity within this class of nucleophile. Phenylhydrazines substituted by electron withdrawing or donating substituents showed an increase in reactivity of the phenylhydrazine toward dimethyl carbonate. Under the basic conditions used, all phenylhydrazines displayed hard nucleophilicity, signifying that para-substitution on the phenyl ring has little effect on the hard-soft behavior of this class of nucleophile. This conclusion fits well within the results previously obtained using other para-substituted nucleophiles, i.e., phenols.     

Asymmetric transformations involving 1,2-dicarbonyl compounds as pronucleophiles

This article concentrates on the versatile nucleophilic reactivity of 1,2-dicarbonyl compounds in various asymmetric transformations. Although underexploited in comparison to their 1,3-dicarbonyl homologues, the presence of adjacent multiple reactive centres allows the selection of specific activation modes for enhancing the reactivity of these important ambident pronucleophiles. They can be involved in selective formation of C-C, C-O or C-N bonds leading to various optically active targets in the acyclic and cyclic series including three- to seven-membered ring systems. Recent contributions in the field of biochemical, organometallic and organic catalytic transformations as well as some relevant stoichiometric approaches are discussed from synthetic and mechanistic point of views highlighting some important stereochemical issues.     

Lithiated anions derived from (alkenyl)pentamethyl phosphoric triamides: an accurate study of the carbanion formation mechanism

The mechanism of the formation of lithiated carbanions derived from (alkenyl) pentamethyl phosphoric triamides has been elucidated. Whereas a few initial ambident allylphosphoramide anion was formed with n-BuLi, both reversible α-reprotonation and not reversible γ-reprotonation simultaneously occurred as a result of the reaction between the ambident carbanion formed and the starting enephosphoramide. A such autocatalytic process led partially to the transposed allylphosphoramide isomer. In the case of α-phenyl substituent the transposed phosphoramide was not a difficulty because it was further γ-deprotonated in situ with the n-BuLi still present, provided finally the expected ambident anion. With α-methyl and α-propyl substituent the transposed enephosphoramide formed in the autocatalytic process was not γ-deprotonated and consequently was prejudicial to the preparation of the target ambident carbanion. In these last cases, adapted experimental conditions avoided the autocatalytic process and allowed the preparation of the corresponding anions.     

α-Oxo-γ-Butyrolactam, N-Containing Pronucleophile in Organocatalytic One-Pot Assembly of Butyrolactam-Fused Indoloquinolizidines

The ambident reactivity of α-oxo-γ-butyrolactam has been explored in an organocatalytic one-pot Michael/Pictet-Spengler sequence. The synthetically interesting and medicinally important pentacyclic butyrolactam-fused indoloquinolizidines can be efficiently constructed in a highly stereocontrolled manner. Importantly, the chemistry described herein provides a general catalytic method for the enantioselective synthesis of butyrolactam-incorporated chemical entities.     

The Reactivity of Ambident Nucleophiles: Marcus Theory or Hard and Soft Acids and Bases Principle?

The model reactions CH₃X + (NH—CH=O)M ➔ CH₃—NH—NH═O or NH═CH—O—CH₃ + MX (M = none, Li, Na, K, Ag, Cu; X = F, Cl, Br) are investigated to demonstrate the feasibility of Marcus theory and the hard and soft acids and bases (HSAB) principle in predicting the reactivity of ambident nucleophiles. The delocalization indices (DI) are defined in the framework of the quantum theory of atoms in molecules (QT-AIM), and are used as the scale of softness in the HSAB principle. To react with the ambident nucleophile NH═CH—O⁻, the carbocation H₃C⁺ from CH₃X (F, Cl, Br) is actually a borderline acid according to the DI values of the forming C…N and C…O bonds in the transition states (between 0.25 and 0.49), while the counter ions are divided into three groups according to the DI values of weak interactions involving M (M…X, M…N, and M…O): group I (M = none, and Me₄N) basically show zero DI values; group II species (M = Li, Na, and K) have noticeable DI values but the magnitudes are usually less than 0.15; and group III species (M = Ag and Cu(I)) have significant DI values (0.30–0.61). On a relative basis, H₃C⁺ is a soft acid with respect to group I and group II counter ions, and a hard acid with respect to group III counter ions. Therefore, N-regioselectivity is found in the presence of group I and group II counter ions (M = Me₄N, Li, Na, K), while O-regioselectivity is observed in the presence of the group III counter ions (M = Ag, and Cu(I)). The hardness of atoms, groups, and molecules is also calculated with new functions that depend on ionization potential (I) and electron affinity (A) and use the atomic charges obtained from localization indices (LI), so that the regioselectivity is explained by the atomic hardness of reactive nitrogen atoms in the transition states according to the maximum hardness principle (MHP). The exact Marcus equation is derived from the simple harmonic potential energy parabola, so that the concepts of activation free energy, intrinsic activation barrier, and reaction energy are completely connected. The required intrinsic activation barriers can be either estimated from ab initio calculations on reactant, transition state, and product of the model reactions, or calculated from identity reactions. The counter ions stabilize the reactant through bridging N- and O-site of reactant of identity reactions, so that the intrinsic barriers for the salts are higher than those for free ambident anions, which is explained by the increased reorganization parameter Δr. The proper application of Marcus theory should quantitatively consider all three terms of Marcus equation, and reliably represent the results with potential energy parabolas for reactants and all products. For the model reactions, both Marcus theory and HSAB principle/MHP principle predict the N-regioselectivity when M = none, Me₄N, Li, Na, K, and the O-regioselectivity when M = Ag and Cu(I). © 2019 Wiley Periodicals, Inc.     

Reaction potential map analysis of chemical reactivity—III

Reaction potential maps (RPM) have been introduced as a new tool for the study of molecular reactivity. The equipotential energy maps, which are created on given planes around a molecule, define reaction contours towards specific counter-reagent models and are evaluated by perturbation theory. Since the calculated interaction energy involves electrostatic, polarization, exchange, and charge transfer energies, the RPM's can be used to predict site selectivity in a variety of chemical reactions. We found that the calculated RPM's of the SCN^– anion explained well the experimental observations that it reacts at the S atom with soft electrophiles and at the N atom with hard electrophiles. The difference in reactivity between SCN^– and OCN^– was clearly shown by the RPM's of these anions. The ambident nucleophilic nature of the NO ₂ ^– and the CH₂CHO^– anions was also well represented by their RPM's.     

Bistrimethylsilylpropargylic ether: a versatile ambident synthon to access substituted allenyne ethers and alpha-substituted bispropargylic alcohols

The reactivity of 1,5-bis(trimethylsilyl)propargylic ethers 3 toward bases and electrophiles was investigated. Bispropargylic ethers 4, substituted allenyne ethers 6-8, and alpha-substituted bispropargylic ethers 9 were prepared in good yields, respectively, by protodesilylation, isomerization, or metalation/alkylation of bispropargylic protected alcohol 3. The ambident behavior of metalated synthon 3 was discussed and rationalized. Removal of the protecting groups of 9 easily afforded useful alpha-substituted bispropargylic alcohol.     

Studies on organophosphorous compounds: IX. C-Phosphorylation of compounds bearing an active methylene group

The behaviour of carbanions of para-substituted benzylcyanides and ambident enolates toward phosphorylation has been examined. In the former case the C-phosphorylation proceeded smoothly, while the ambident enolate ions derived either from β-diketones or from β-ketoesters gave exclusively regiospecific O-phosphorylation products on reaction with diethyl phosphoryl chloride. The experimental results are well supported by reaction selectivity in terms of E_qo/E_C.OC/ based on EHMO calculation.     

Nickel 0-catalyzed cross-coupling of alkyl arenesulfonates with aryl Grignard reagents

The nickel-catalyzed cross-coupling reactions of neopentyl arenesulfonates with arylmagnesium bromides, involving nucleophilic aromatic substitution of alkyloxysulfonyl groups by aryl nucleophiles, take place in high yields. Optimal efficiencies are obtained by adding 3 + 2 equiv of the Grignard reagent to a mixture of dppfNiCl(2) and the sulfonate in refluxing THF. Neopentyl arenesulfonates are useful sources of the electrophilic aryl groups in these transition metal-catalyzed cross-coupling reactions. Aryl sulfonates are inappropriate due to their ambident reactivity under the reaction conditions. This new cross-coupling reaction can be used for the creative elimination of alkyloxysulfonyl groups from aromatic compounds and for the preparation of unsymmetric terphenyls and oligophenyls.     

Reactivity of the 4d transition metals toward N hydrogenation and NH dissociation: a DFT-based HSAB analysis

The density functional theory (DFT) based hard-soft acid-base (HSAB) reactivity indices, including the electrophilicity index, have been successfully applied to many areas of molecular chemistry. In this work we test the applicability of such an approach to fundamental surface chemistry. We have considered, as prototypical surface reactions, both the hydrogenation of atomic nitrogen and the dissociative adsorption of the NH molecular radical. By use of a DFT methodology, the minimum energy reaction pathways, and corresponding reaction barriers, of the above reactions over Zr(001), Nb(110), Mo(110), Tc(001), Ru(001), Rh(111), and Pd(111) have been determined. By consideration of the chemical potential and chemical hardness of the surface metal atoms, and the principle of electronegativity equalization, it is found that the charge transferred to the NH radical during the process of dissociative adsorption correlates very well with that determined by Mulliken population analysis. Furthermore, it is found that the stability of the NH/surface transition state complex relates directly to this charge transfer and that the trend in transition state stability predicted by a HSAB treatment correlates very strongly with that determined by DFT calculations. With regards to N hydrogenation, we find that during the course of the reaction, H loses cohesion to the surface, as it must migrate from a 3-fold hollow site to either a bridge or top site, to react with N. Partial density of states (PDOS) and Mulliken population analysis reveal that this loss of bonding is accompanied by charge transfer from H to the surface metal atoms. Moreover, by simple modeling, we show that the reaction barriers are directly proportional to this mandatory charge transfer. Indeed, it is found that the reaction barriers correlate very well with the electrophilicity index of the metal atoms.     

硬软酸碱理论在材料研究中的应用 I: 二元β-W结构化合物超导性的研究

本文从键性的角度出发, 应用硬软酸碱原理, 研究了具有β-W结构二元化合物的超导性能, 用硬软酸碱理论的HS标度, 获得一个化合物预期的超导转变温度值的规则。ΔHS规则可以用作寻找新超导材料的指引。     

Relative antioxidant efficiency of a large series of carotenoids in terms of one electron transfer reactions

The relative antioxidant efficiency, expressed as electron donating capability, of a large series of carotenoids has been studied using density functional theory. Their reactivity toward nine different radicals has been modeled as well as the electron transfer between pairs of carotenoids, one of which is present as a radical cation. The influence of the solvent polarity has also been studied. Torulene was found to be the most easily oxidized carotenoid, followed by lycopene. This higher reactivity is proposed in the present work for the first time, and the potential implications of such a finding are discussed. Since torulene has not been previously studied, compared to other carotenoids in terms of oxidation potentials, further experimental studies are suggested in order to confirm or reject this prediction. Ionization potential seems to be a magnitude calculable at low computational cost that correctly predicts the relative ease of oxidation in a series of carotenoids. The nuclear reorganization energy associated with electron-transfer reactions has been calculated in a very simple but apparently efficient way that allows computation of free energy barriers and relative rate constants in good agreement with the experimental values. In addition, an additive correction is proposed to include the effect of increasing the size of basis sets on the energies of Car(n) --> Car(n-1)(*+) processes. The general agreement between different calculated magnitudes and the corresponding available experimental data supports the predictions from this work.     

Computational advances in organic chemistry: Molecular structure and reactivity. Edited by C. Ögretir and I. G. Csizmadia,NATO ASI Series C,Vol, 330.

We here report an AM 1 study for the reaction of different types of radicals with the acetone enolate ion 1 and other ambident nucleophiles. The theoretical reactivity order determined is phenyl > methyl > tert-butyl ? bicyclo-[2.2.1]hept-1-yl. The activation energy for the coupling of aliphatic radicals is ascribed mainly to nonbonded interactions. Considering possible solvent effects, we propose the same order of reactivity in solution. The coupling reaction of phenyl radical with 1 is an exothermic process with nonactivation energy in the gas phase. Any energy barrier in solution is here ascribed to desolvation of the anion. The regiochemistry of the coupling of radicals with ambident nucleophiles such as 1 , phenoxide, or phenylamide anions is also explained on a theoretical basis. © 1992 John Wiley & Sons, Inc.