Nucleophilicities of Para‐Substituted Phenoxide Ions in Water and Correlation Analysis

Second‐order rate constants for the reactions of 2‐aryl‐4,6‐dinitrobenzotriazole 1‐oxides 1a‐d with some 4‐X‐substituted phenoxide ions 2a‐d (X = OCH₃, H, Cl, and CN) have been measured in aqueous solution at 20°C. The pK_a values for the σ‐complexation processes of a series of benzotriazole 1a‐d measured in water have been used to determine their electrophilicity parameters E according to the correlation E = –3.20 – 0.662 pK_a (F. Terrier, S. Lakhdar, T. Boubaker, and R. Goumont, J Org Chem, 2005 , 70, 6242–6253). For these reactions, plots of log k versus the electrophilicity parameters E of the benzotriazoles 1a‐d were linear, allowing to derive the nucleophilicity parameters N and s for phenoxide ions as defined by the Mayr equation log k₁ (20°C) = s (E + N) (H. Mayr, M. Patz. Angew Chem, Int Ed Engl 1994 , 33, 938–957). The N values are found to cover a range of nucleophilicity from 6.85 to 10.22, going from 4‐cyanophenoxide 2d for the least reactive ion to 4‐methoxyphenoxide 2a for the most reactive nucleophile. Good linear correlations were found between the nucleophilicity parameters N of phenoxide ions 2a‐d and the pK_a values of their conjugate acids (N = –3.05 + 1.25 pK_a) and the constants of the substituents X (N = 9.21 – 2.51).     

Mechanism and Linear Free Energy Relationships in Michael‐Type Addition of 4‐Substituted Anilines to Activated Olefin in Acetonitrile

Kinetic studies for the Michael‐type reactions of ethyl‐3‐(4′‐N,N‐dimethylaminophenyl)‐2‐(nonafluorobutane)sulfonylpro‐penoate 1 with 4‐X‐substituted anilines 2a–e (X = OCH₃, CH₃, H, F, and Cl) have been investigated in acetonitrile at 20°C. A quadratic dependence of the pseudo–first‐order rate constants (k_obsd) versus [ 2a–e ] has been observed and has been interpreted in terms of a dimer nucleophile mechanism. The finding of a relatively large negative ρ value (?3.09) for the Hammett plot suggests that the intermediate ( I^± ) is highly zwitterionic in nature. A linear correlation (r² = 0.9989) between the Hammett's substituent constants σ and nucleophilicity parameters N of 4‐X‐substituted anilines in acetonitrile has been observed. The electrophilicity parameters E of the olefin 1 is evaluated, using the correlations σ versus N and log k versus σ and compared with the electrophilicities of analogously Michael acceptors.     

Nucleophilic Substitution Reactions of 2‐Methoxy‐3‐X‐5‐nitrothiophenes: Effect of Substituents and Structure–Reactivity Correlations

A kinetic study is reported for reactions of 2‐methoxy‐3‐X‐5‐nitrothiophenes 1a–d (X = SO₂CH₃, CO₂CH₃, CONH₂, H) with piperidine in different solvents at 20°C. It is shown that the reactions take place through a S_NAr mechanism with the initial nucleophilic addition step being rate limiting. The satisfactory Hammett correlations (log k₁ vs. σ) obtained in the present system confirms that a 3‐X substituent exerts an effect on the 2‐position of the same type as that exerted from the 5‐position. The second‐order rate constants associated with these reactions are employed to determine the electrophilicity parameters E of the thiophenes 1a–d according to the relationship log k (20°C) = s(E + N) (Angew. Chem., Int. Ed. Engl. 1994, 33, 938–957). The E values of 1a–d are found to cover a range from ?21.33 to ?17.18, going from 1d , the least reactive, to 1a , the most reactive thiophene. Interestingly, a linear correlation (r² = 0.9910) between the electrophilicity parameters E determined in this work and the Hammett's σ constants values has been observed and discussed. On the other hand, we have found that the reported rate constants of some thiophenes 1 complexation by the methoxide ion in methanol are 3.5–73.5 times higher than predicted by Mayr's approach.     

Kinetics and quantification of the electrophilic reactivities of substituted thiophenes and structure‐reactivity relationships

Second‐order rate constants (k₁) have been measured spectrophotometrically for reactions of 2‐methoxy‐3‐X‐5‐nitrothiophene 1a‐c (X = NO₂, CN, and COCH₃) with secondary cyclic amines (pyrrolidine 2a , piperidine 2b , and morpholine 2 c ) in CH₃CN and 91:9 (v/v) CH₃OH/CH₃CN at 20°C. The experimental data show that the rate constants (k₁) values exhibit good correlation with the parameters of nucphilicity (N) of the amines 2a‐c and are consistent with the Mayr's relationship log k (20°C) = s(E + N). We have shown that the electrophilicity parameters E derived for 1a–c and those reported previously for the thiophenes 1d‐g (X = SO₂CH₃, CO₂CH₃, CONH₂, and H) are linearly related to the pK_a values for their gem‐dimethoxy complexes in methanol. Using this correlation, we successfully evaluated the electrophilicity E values of 12 structurally diverse electrophiles in methanol for the first time. In addition, a satisfactory linear correlation (r² = 0.9726) between the experimental (log k_exp) and the calculated (log k_calcd) values for the σ‐complexation reactions of these 12 electrophiles with methoxide ion in methanol has been observed and discussed.     

Electrophilic Reactivities of Azodicarboxylates

The kinetics of the reactions of the azodicarboxylates 1 with the enamines 2 have been studied in CH₃CN at 20 °C. The reactions follow a second‐order rate law and can be described by the linear free energy relationship log k₂(20 °C)=s(N+E) (E=electrophilicity parameter, N=nucleophilicity parameter, and s=nucleophile‐specific slope parameter). With E parameters from ?12.2 to ?8.9, the electrophilic reactivities of 1 turned out to be comparable to those of α,β‐unsaturated iminium ions, amino‐substituted benzhydrylium ions, and ordinary Michael acceptors. While the E parameters of the azodicarboxylates 1 determined in this work also hold for their reactions with triarylphosphines, they cannot be used for estimating rate constants for their reactions with amines. Comparison of experimental and calculated rate constants for cycloadditions and ene reactions of azodicarboxylates provides information on the concertedness of these reactions.     

Nucleophilicity of Glutathione: A Link to Michael Acceptor Reactivities

Deprotonated glutathione is among the most potent biological nucleophiles and plays an important physiological role in cellular detoxification by forming covalent conjugates with Michael acceptors. The electrophilicity E of various Michael acceptors was characterized recently according to the Patz–Mayr relation lg k₂=s_N(N+E). We now determined the nucleophilic reactivity (N, s_N) of glutathione (GSH) in aqueous solution at 20 °C to connect published GSH reactivities (k_GSH) with Mayr's electrophilicity scale (E). In this way, electrophilicities E of more than 70 Michael acceptors could be estimated, which can now be used to systematically predict novel reactions with the multitude of nucleophiles whose nucleophilicity parameters N/s_N are known.     

A Nucleophilicity Scale for the Reactivity of Diazaphospholenium Hydrides: Structural Insights and Synthetic Applications

Nucleophilicity parameters (N, s_N) of a group of representative diazaphospholenium hydrides were derived by kinetic investigations of their hydride transfer to a series of reference electrophiles with known electrophilicity (E) values, using the Mayr equation log k₂=s_N(N+E). The N scale covers over ten N units, ranging from the most reactive hydride donor (N=25.5) to the least of the scale (N=13.5). This discloses the highest N value ever quantified in terms of Mayr's nucleophilicity scales reported for neutral transition‐metal‐free hydride donors and implies an exceptional reactivity of this reagent. Even the least reactive hydride donor of this series is still a better hydride donor than those of many other nucleophiles such as the C?H, B?H, Si?H and transition‐metal M?H hydride donors. Structure–reactivity analysis reveals that the outstanding hydricity of 2‐H‐1,3,2‐diazaphospholene benefits from the unsaturated skeleton.     

Predicting Absolute Rate Constants for Huisgen Reactions of Unsaturated Iminium Ions with Diazoalkanes

The kinetics and stereochemistry of the reactions of iminium ions derived from cinnamaldehydes and MacMillan's imidazolidinones with diphenyldiazomethane and aryldiazomethanes were investigated experimentally and with DFT calculations. The reactions of diphenyldiazomethane with iminium ions derived from MacMillan's second‐generation catalysts gave 3‐aryl‐2,2‐diphenylcyclopropanecarbaldehydes with yields >90 % and enantiomeric ratios of ≥90:10. Predominantly 2:1 products were obtained from the corresponding reactions with monoaryldiazomethanes. The measured rate constants are in good agreement with the rate constants derived from the one‐center nucleophilicity parameters N and s_N of diazomethanes and the one‐center electrophilicity parameters E of iminium ions as well as with quantum chemically calculated activation energies.     

Kinetic Studies on Nucleophilic Addition Reactions of 4‐X‐substituted Anilines to N1‐methyl‐4‐nitro‐2,1,3 benzothiadiazolium terafluoroborate in Acetonitrile: Reaction Mechanism and Mayr's Approach

The kinetics of the coupling of N1‐methyl‐4‐nitro‐2,1,3 benzothiadiazolium tetrafluoroborate 1 with a series of 4‐X‐substituted anilines 2a–f (X = OH, OMe, Me, H, Cl, and CN) have been investigated in acetonitrile at 20°C. The second‐order rate constants result in a nonlinear Brönsted‐type plot. The Hammett plot is also nonlinear, whereas the Yukawa–Tsuno plot exhibits an excellent linear correlation with ρ = –1.62 and r = 1.44. The large Brönsted (β_nuc = 1.24) and Hammett (ρ = –5.16) values suggest that the reactions proceed trough a single electron transfer mechanism. The finding of satisfactory correlation between the log k₁ of the reactions and the oxidation potentials (E°) of anilines 2a–d supports this mechanism. On the other hand, electrophilicity parameter E of benzothiadiazolium cation 1 as defined by the correlation log k_20°C = s(E + N) has been determined and compared with the electrophilic reactivities of a large variety of electrophiles.     

Hydrocarbation of CC Bonds: Quantification of the Nucleophilic Reactivity of Ynamides

Donor‐substituted diarylcarbenium ions Ar₂CH⁺ react with ynamides to give 1‐amido‐substituted allyl cations (α,β‐unsaturated iminium ions). Kinetic studies show that these adducts, which correspond to the addition of a C? H bond across the C?C bond, are formed stepwise with initial formation of keteniminium ions and subsequent 1,3‐hydride shifts. The linear correlations between the second‐order rate constants (lg k₂, 20 °C) with the electrophilicity parameters E of the diarylcarbenium ions allow us to include ynamides in our comprehensive nucleophilicity scale and thus predict potential electrophilic reaction partners.     

Electrophilic reactivities of 7-L-4-nitrobenzofurazans in σ-complexation processes: Kinetic studies and structure–reactivity relationships

The second-order rate constants (k) for reaction of 7-chloro-4-nitrobenzofurazan 1 and 7-methoxy-4-nitrobenzofurazan 2 with a series of nitroalkyl anions and several of para-substituted phenoxide anions in aqueous solution at 20 °C have been reported. On the basis of the linear novel approach recently designed by Mayr and coworkers, the electrophilicity parameters E at the C-5 position of the two nitrobenzofurazans 1 and 2 have been quantified and ranked on the comprehensive electrophilicity scale. Mayr's approach was found to correctly predict the rate constants for the addition of phenoxide anions at the C-5 position of 1 and 2 witting a factor of <2. Analysis of the kinetic measurements using Brønsted's model shows that β_nuc values remain remarkably constant for changes in the nature of the substituent and that the σ-complexation process is associated with high Marcus intrinsic barriers. In addition, satisfactory correlations between the log k_exp (k_exp values measured in this work for reactions of benzofurazans 1 and 2 with a series of phenoxide anions in aqueous solution at 20 °C) and log k_calcd (k_calcd values calculated from equation 1 using the electrophilicity parameters E of benzofurazans 1 and 2 and the previously published nucleophilicity parameters N and s_N of the phenoxide anions) with a slope very close to unity have been obtained and discussed.     

First‐Principles Prediction of Nucleophilicity Parameters for π Nucleophiles: Implications for Mechanistic Origin of Mayr’s Equation

Quantitative nucleophilicity scales are fundamental to organic chemistry and are usually constructed on the basis of Mayr’s equation [log k=s(N+E)] by using benzhydrylium ions as reference electrophiles. Here an ab initio protocol was developed for the first time to predict the nucleophilicity parameters N of various π nucleophiles in CH₂Cl₂ through transition‐state calculations. The optimized theoretical model (BH&HLYP/6‐311++G(3df,2p)//B3LYP/6‐311+G(d,p)/PCM/UAHF) could predict the N values of structurally unrelated π nucleophiles within a precision of ca. 1.14 units and therefore may find applications for the prediction of nucleophilicity of compounds that are not readily amenable to experimental characterization. The success in predicting N parameters from first principles also allowed us to analyze in depth the electrostatic, steric, and solvation energies involved in electrophile–nucleophile reactions. We found that solvation does not play an important role in the validity of Mayr’s equation. On the other hand, the correlations of the E, N, and log k values with the energies of the frontier molecular orbitals indicated that electrostatic/charge‐transfer interactions play vital roles in Mayr’s equation. Surprising correlations observed between the electrophile–nucleophile C? C distances in the transition state, the activation energy barriers, and the E and N parameters indicate the importance of steric interactions in Mayr’s equation. A method is then proposed to separate the attraction and repulsion energies in the nucleophile–electrophile interaction. It was found that the attraction energy correlated with N+E, whereas the repulsion energy correlated to the s parameter.     

SNAr reactions of substituted pyridines with secondary amines in aqueous solution: Kinetic and reactivity indices in density functional theory

A kinetic study is reported for the reactions of 2-methoxy-3-nitropyridine 1a and 2-methoxy-5-nitropyridine 1b with three secondary amines 2a–c (morpholine, piperidine, and pyrrolidine) in aqueous solution at 20°C. The Brønsted-type plots are linear with β_nuc = 0.52 and 0.55 for pyridines 1a and 1b , respectively, indicating that the reaction proceeds through a S_NAr mechanism in which the first step is the rate-determining step. Additional theoretical calculations using the DFT/B3LYP method confirm that the C-2 carbon being the most electrophilic center for the both pyridines 1a and 1b . The second-order rate constants have been used to evaluate the electrophilicity parameters E of 1a and 1b according to the linear free energy relationship log k (20°C) = s_N (N + E). The E parameters thus derived are compared with the electrophilic reactivities of a large variety of anisoles. The validity of these E values has been satisfactorily verified by comparison of calculated and experimental second-order rate constants for the reactions of pyridines 1a and 1b with anion of ethyl benzylacetate.     

Electrophilicities of Bissulfonyl Ethylenes

Kinetics of the reactions of bissulfonyl ethylenes with various carbanions, a sulfur ylide, and siloxyalkenes have been investigated photometrically at 20 °C. The second‐order rate constants have been combined with the known nucleophile‐ specific parameters N and s_N for the nucleophiles to calculate the empirical electrophilicity parameters E of bissulfonyl ethylenes according to the linear free energy relationship log k(20 °C)=s_N(N+E). Structure‐reactivity relationships are discussed, and it is shown that the electrophilicity parameters E derived in this work can be employed to define the synthetic potential of bissulfonyl ethylenes as Michael acceptors.     

SN2’ versus SN2 Reactivity: Control of Regioselectivity in Conversions of Baylis–Hillman Adducts

TiCl₄‐induced Baylis–Hillman reactions of α,β‐unsaturated carbonyl compounds with aldehydes yield the (Z)‐2‐(chloromethyl)vinyl carbonyl compounds 5 , which react with 1,4‐diazabicyclo[2.2.2]octane (DABCO), quinuclidine, and pyridines to give the allylammonium ions 6 . Their combination with less than one equivalent of the potassium salts of stabilized carbanions (e.g. malonate) yields methylene derivatives 8 under kinetically controlled conditions (S_N2’ reactions). When more than one equivalent of the carbanions is used, a second S_N2’ reaction converts 8 into their thermodynamically more stable allyl isomers 9 . The second‐order rate constants for the reactions of 6 with carbanions have been determined photometrically in DMSO. With these rate constants and the previously reported nucleophile‐specific parameters N and s for the stabilized carbanions, the correlation log k (20 °C)=s(N + E) allowed us to calculate the electrophilicity parameters E for the allylammonium ions 6 (?19<E <?18). The kinetic data indicate the S_N2’ reactions to proceed via an addition–elimination mechanism with a rate‐determining addition step.     

Ethenesulfonyl Fluoride: The Most Perfect Michael Acceptor Ever Found?

The kinetics of the reactions of ethenesulfonyl fluoride (ESF) with sulfonium and pyridinium ylides were measured photometrically to determine the electrophilicity parameter of ESF according to the correlation lg k_{20 °C}=s_N(N+E). With E=?12.09, ESF is among the strongest Michael acceptors in our comprehensive electrophilicity scale, which explains its excellent performance in reactions with many nucleophiles. Its predicted usability as a reagent in electrophilic aromatic substitutions with electron‐rich arenes was confirmed by uncatalyzed reactions with alkyl‐substituted pyrroles.     

Ambident electrophilicity of 4-nitrobenzochalcogenadiazoles: Kinetic studies and structure-reactivity relationships

The kinetics of the reactions of 4-nitrobenzofurazane 1a , 4-nitrobenzothiadiazole 1b , and 4-nitrobenzoselenadiazole 1c with a series of 4-Y-substituted phenoxide anions 2a-e (Y = OMe, Me, H, Cl, and CN) in aqueous solution at 20°C were investigated photometrically. The derived second-order rate constants (k₂) have been combined with the nucleophilicity parameters values of these series of anions 2a-e to determine the electrophilicity parameters E of electrophiles 1a-c according to the linear free-energy relationship (log k₂)/s versus N. General reactivity of these electrophiles 1a-c is found to be fairly similar with E values ranging in −10.77 ± 0.61 < E < −7.53 ± 0.29. The comparison with structurally related neutral electron-deficient heteroaromatic and aromatic compounds revealed that 1a - c are more reactive than 1,3,5-trinitrobenzene, as benchmark aromatic electrophile used in nucleophilic addition or substitution processes. The rate constants for the reactions of 4-nitrobenzochalcogenadiazoles 1a-c with some other nucleophiles were measured and found to agree with those calculated from Mayr's equation. Finally, analysis of the rate data in terms of the Brønsted approach reveals that 1a-c exhibits especially low intrinsic reactivity in σ-adducts 3 forming reactions.     

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(CO₂Et)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 s_N parameters of the mNHOs according to the correlation lg k₂(20 °C)=s_N(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.     

Azo‐Coupling Reactions of Para‐X‐Benzenediazonium Cations with 3‐Ethoxythiophene in Acetonitrile

Kinetic studies for the azo‐coupling reactions of 3‐ethoxythiophene 1 with a series of 4‐X‐substituted diazonium cations 2a‐e (X = OCH₃, CH₃, H, Cl, and NO₂) have been investigated in acetonitrile at 20°C. The second‐order rate constants have been employed to determine the nucleophilicity parameters N and s of the thiophene 1 according the Mayr equation. Thus, the nucleophile‐specific parameters N and s of thiophene 1 have been derived and compared with the reactivities of other C‐nucleophiles in acetonitrile (pyrroles, furan, indoles, etc.). The Yukawa–Tsuno plot resulted in an excellent correlation (R² = 0.9980) with an r value of 0.89, suggesting that the nonlinear Hammett plot observed in the present work is due to resonance demand of the π–electron donor substituent of on the –N₂⁺ moiety. Importantly, using the concept of global electrophilicity (ω) proposed by Parr, we successfully predict the electrophilicity parameters E of seven substituted diazonium cations whose experimental data are available.     

The ambident electrophilic behavior of 5‐nitro‐3‐X‐thiophenes in σ‐complexation processes

Kinetics of the reactions of 3,5‐dinitrothiophene 1 and 3‐cyano‐5‐nitrothiophene 2 with a series of parasubstituted phenoxide anions 3a–c have been investigated in aqueous solution at 20°C. Two unsubstituted electrophilic centers (C(2) and C(4)) of the two thiophenes have been identified. The Fukui functions correctly predict the C(2) and C(4) atoms as the most electrophilic centers of these electron‐deficient thiophenes 1 and 2 . Analysis of the experimental data in terms of Brønsted relationships reveals that the reaction mechanism likely involves a single‐electron transfer (SET) process. The excellent correlations upon plotting the rate constants versus the oxidation potentials E^o values is an additional evidence that reactions between thiophenes and phenoxide anions are proceeding through an initial electron transfer. It is of particular interest to note that the systems studied in this paper provide a rare example of a SET mechanism in σ‐complexation reactions. According to the free energy relationship log k = s(N + E) (Angew. Chem., Int. Ed. Engl., 1994, 33, 938–957), the electrophilicity parameters E of the C‐4 and C‐2 positions of the thiophenes have been determined and compared with the reactivities of other ambident electrophiles. On the other hand, the second‐order rate constants for the reactions of these thiophenes with the hydroxide ion has been measured in water and 50% water–50% acetonitrile and found to agree with those calculated theoretically using Mayr's equation from the E values determined in this work and from the previously published N and s parameters of OH⁻.