Nucleophilic reactivities of indoles

The kinetics of the coupling of indole (1a), N-methylindole (1b), 5-methoxyindole (1c), and 5-cyanoindole (1d) with a set of reference benzhydryl cations have been investigated in acetonitrile and/or dichloromethane. The second-order rate constants for the reactions correlate linearly with the electrophilicity parameter E of the benzhydryl cations. This allows the determination of the reactivity parameters, N and s, characterizing the nucleophilicity of 1a-d according to the linear free enthalpy relationship log k(20 degrees C) = s(N + E) (Acc. Chem. Res. 2003, 36, 66). The nucleophilicity parameters thus defined describe nicely the reactions of 1a-d with 4,6-dinitrobenzofuroxan (2), a neutral superelectrophilic heteroaromatic whose electrophilicity (E) has been recently determined. On this ground, the kinetics of the coupling of 2 with a large variety of indole structures have been studied in acetonitrile, leading to a ranking of this family of pi-excessive carbon nucleophiles over a large domain of the nucleophilicity scale N. Importantly, two linear and parallel correlations are obtained on plotting the measured N values versus the pK(a)(H(2)O) values for protonation at C-3 of 5-X-substituted indoles and 5-X-substituted 2-methylindoles, respectively. This splitting reveals that the presence of the 2-methyl group causes steric hindrance to the approach of 2 from the adjacent C-3 position of an indole structure. The N vs pK(a)(H(2)O) correlation for 5-X-substituted indoles is used for a rapid determination of the C-3 basicity of indoles whose acidity constants cannot be measured through equilibrium studies in strongly acidic aqueous media.     

Electrophilicity of 5-benzylidene-1,3-dimethylbarbituric and -thiobarbituric acids

The kinetics of reactions of acceptor-stabilized carbanions 2a-m with benzylidenebarbituric and -thiobarbituric acids 1a-e has been determined in a dimethyl sulfoxide solution at 20 degrees C. Second-order rate constants were employed to determine the electrophilicity parameters E of the benzylidenebarbituric and -thiobarbituric acids 1a-e according to the correlation equation log k(20 degrees C) = s(N + E). With E parameters in the range of -10.4 to -13.9, the electrophilicities of 1a-e are comparable to those of analogously substituted benzylidenemalononitriles.     

Quantification of the electrophilic reactivities of aldehydes, imines, and enones

The rates of the epoxidation reactions of aldehydes, of the aziridination reactions of aldimines, and of the cyclopropanation reactions of α,β-unsaturated ketones with aryl-stabilized dimethylsulfonium ylides have been determined photometrically in dimethyl sulfoxide (DMSO). All of these sulfur ylide-mediated cyclization reactions as well as the addition reactions of stabilized carbanions to N-tosyl-activated aldimines have been shown to follow a second-order rate law, where the rate constants reflect the (initial) CC bond formation between nucleophile and electrophile. The derived second-order rate constants (log k(2)) have been combined with the known nucleophilicity parameters (N, s(N)) of the aryl-stabilized sulfur ylides 4a,b and of the acceptor-substituted carbanions 4c-h to calculate the electrophilicity parameters E of aromatic and aliphatic aldehydes (1a-i), N-acceptor-substituted aromatic aldimines (2a-e), and α,β-unsaturated ketones (3a-f) according to the linear free-energy relationship log k(2) = s(N)(N + E) as defined in J. Am. Chem. Soc.2001, 123, 9500-9512. The data reported in this work provide the first quantitative comparison of the electrophilic reactivities of aldehydes, imines, and simple Michael acceptors in DMSO with carbocations and cationic metal-π complexes within our comprehensive electrophilicity scale.     

Determination of the electrophilicity parameters of diethyl benzylidenemalonates in dimethyl sulfoxide: reference electrophiles for characterizing strong nucleophiles

The second-order rate constants of the reactions of nine substituted diethyl benzylidenemalonates 1 a-i with the carbanions 2 a-e have been determined spectrophotometrically in dimethyl sulfoxide (DMSO). Product studies show that the nucleophiles attack regioselectively at the electrophilic C==C double bond of the Michael acceptors to form the carbanionic adducts 4. The correlation log k(20 degrees C)=s(N+E) allows the determination of the electrophilicity parameters E for the electrophiles 1 a-i from the rate constants determined in this work and the previously published N and s parameters for the nucleophiles 2 a-e. The electrophilicities E for compounds 1 a-i cover a range of six units (-17.7>E>-23.8) and correlate excellently with Hammett's substituent constants sigma(p). The title compounds are roughly ten orders of magnitude less reactive than analogously substituted benzylidene Meldrum's acids, their cyclic analogues. Due to their low reactivities, compounds 1 a-i are suitable reference electrophiles for determining the reactivities of highly reactive nucleophiles, such as carbanions with 16相似文献   

Scope and limitations of cyclopropanations with sulfur ylides

The rates of the reactions of the stabilized and semistabilized sulfur ylides 1a-g with benzhydrylium ions (2a-e) and Michael acceptors (2f-v) have been determined by UV-vis spectroscopy in DMSO at 20 °C. The second-order rate constants (log k(2)) of these reactions correlate linearly with the electrophilicity parameters E of the electrophiles 2 as required by the correlation log k(2) = s(N + E), which allowed us to calculate the nucleophile-specific parameters N and s for the sulfur ylides 1a-g. The rate constants for the cyclopropanation reactions of sulfur ylides with Michael acceptors lie on the same correlation line as the rate constants for the reactions of sulfur ylides with carbocations. This observation is in line with a stepwise mechanism for the cyclopropanation reactions in which the first step, nucleophilic attack of the sulfur ylides at the Michael acceptors, is rate determining. As the few known pK(aH) values for sulfur ylides correlate poorly with their nucleophilic reactivities, the data reported in this work provide the first quantitative approach to sulfur ylide reactivity.     

Ranking the reactivity of superelectrophilic heteroaromatics on the electrophilicity scale

The kinetics of the reactions of a series of reference carbon nucleophiles, consisting of N-methylpyrrole A, indole B, N-methylindole C, and enamines D-G, with 10 electron-deficient aromatic and heteroaromatic substrates (1-10), resulting in the formation of stable anionic sigma-adducts, have been investigated in acetonitrile at 20 degrees C. It is shown that the second-order rate constants k(1) pertaining to the carbon-carbon coupling step of these processes fit nicely the three-parameter equation log k (20 degrees C) = s(N + E), allowing the determination of the electrophilicity parameters E of 1-10 and therefore the ranking of these neutral electron-deficient compounds on the comprehensive electrophilicity scale defined for cationic electrophiles by Mayr et al. (Mayr, H.; Kempf, B,; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66). The E values of 1-10 are found to cover a range from -13 to -5, going from 1,3,5-trinitrobenzene 1, the least reactive molecule, to 4,6-dinitrotetrazolo[1,5-a]pyridine 8, 4-nitro-6-trifluoromethanesulfonylbenzofuroxan 3, and 4,6-dinitrobenzofuroxan 2, the three most reactive heterocycles. Of major interest is that the E value of 2 is essentially the same as that for 4-nitrobenzenediazonium cation (E = -5.1), approaching that of the tropylium cation family (E approximately -3 to -6) as well as a number of metal-coordinated carbenium ions. Such a ranking holds promise for expanding the range of coupling reactions which can be envisioned with such strongly electron-deficient neutral heteroaromatics as nitrobenzofuroxans and related compounds. Arguments are also given which exclude the possibility for the reactions studied to proceed via an electron-transfer mechanism.     

Electrophilicities of trans-β-nitrostyrenes

The kinetics of the reactions of the trans-β-nitrostyrenes 1a-f with the acceptor-substituted carbanions 2a-h have been determined in dimethyl sulfoxide solution at 20 °C. The resulting second-order rate constants were employed to determine the electrophile-specific reactivity parameters E of the trans-β-nitrostyrenes according to the correlation equation log k(2)(20 °C) = s(N)(N + E). The E parameters range from -12 to -15 on our empirical electrophilicity scale (www.cup.lmu.de/oc/mayr/DBintro.html). The second-order rate constants for the reactions of trans-β-nitrostyrenes with some enamines were measured and found to agree with those calculated from the electrophilicity parameters E determined in this work and the previously published N and s(N) parameters for enamines.     

Reference scales for the characterization of cationic electrophiles and neutral nucleophiles

Twenty-three diarylcarbenium ions and 38 pi-systems (arenes, alkenes, allyl silanes and stannanes, silyl enol ethers, silyl ketene acetals, and enamines) have been defined as basis sets for establishing general reactivity scales for electrophiles and nucleophiles. The rate constants of 209 combinations of these benzhydrylium ions and pi-nucleophiles, 85 of which are first presented in this article, have been subjected to a correlation analysis to determine the electrophilicity parameters E and the nucleophilicity parameters N and s as defined by the equation log k(20 degrees C) = s(N + E) (Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938-957). Though the reactivity scales thus obtained cover more than 16 orders of magnitude, the individual rate constants are reproduced with a standard deviation of a factor of 1.19 (Table 1). It is shown that the reactivity parameters thus derived from the reactions of diarylcarbenium ions with pi-nucleophiles (Figure 3) are also suitable for characterizing the nucleophilic reactivities of alkynes, metal-pi-complexes, and hydride donors (Table 2) and for characterizing the electrophilic reactivities of heterosubstituted and metal-coordinated carbenium ions (Table 3). The reactivity parameters in Figure 3 are, therefore, recommended for the characterization of any new electrophiles and nucleophiles in the reactivity range covered. The linear correlation between the electrophilicity parameters E of benzhydryl cations and the corresponding substituent constants sigma(+) provides Hammett sigma(+) constants for 10 substituents from -1.19 to -2.11, i.e., in a range with only very few previous entries.     

Electrophilicity parameters of 5-benzylidene-2,2-dimethyl[1,3]dioxane-4,6-diones (benzylidene Meldrum's acids)

Kinetics of the reactions of four benzylidene Meldrum's acids 1 with acceptor-substituted carbanions 2 were studied photometrically in DMSO at 20 degrees C. The reactions follow second-order kinetics, and the second-order rate constants were found to follow the correlation log k2 (20 degrees C) = s(N + E) (eq 1), which was used to calculate the electrophilicity parameters E for compounds 1. Hammett correlations are given, which allow one to assign electrophilicity parameters for various beta,beta-acceptor substituted styrenes and thus to predict a large number of absolute rate constants for a manifold of Michael additions. The reactions of primary and secondary amines are approximately 2 orders of magnitude faster than predicted by the correlation (1), supporting transition states which are stabilized by hydrogen bridges from NH to the carbonyl groups of the benzylidene Meldrum's acids.     

Electrophilicities of symmetrically substituted 1,3-diarylallyl cations

Kinetics of the reactions of nine symmetrically substituted 1,3-diarylallyl cations with different nucleophiles were studied photometrically in dichloromethane, acetonitrile, and DMSO solutions. The second-order rate constants k(2) were found to follow the correlation log k(2) = s(N)(N + E). The electrophilicity parameters E of the title cations were derived, using the known values of s(N) and N of the nucleophilic reaction partners, and compared with the electrophilicities of analogously substituted benzhydrylium ions. Good linear correlations were found between the electrophilicities E and the quantum chemically calculated gas-phase methyl anion affinities of the allyl cations and the σ(+) constants of the substituents X.     

Kinetic Studies on SNAr Reactions of Substituted Benzofurazan Derivatives: Quantification of the Electrophilic Reactivities and Effect of Amine Nature on Reaction Mechanism

Kinetics of the nucleophilic aromatic substitution reactions of 7‐L‐4‐nitrobenzofurazans 1 ( 1a : L = Cl and 1b : L = OCH₃) and secondary cyclic amines (morpholine, piperidine, and pyrolidine) 2a–c have been measured in acetonitrile solution at 20°C. The derived values of second‐order rate constants (k ₁) have been employed to determine the electrophilicity parameters E for both benzofurazans 1a and 1b according to the linear free enthalpy relationship: log k (20°C) = s_N(E + N ) (Eq. 1 ). The second‐order rate constants for reactions of benzofurazans 1 with a series of 4‐X‐substituted anilines 3a–d (X = OH, OCH₃, CH₃, and H) have also been measured in MeCN and found to agree within a factor of 0.14–50 with those calculated by Eq. 1 from the electrophilicity parameters E measured in this work and the known nucleophile‐specific parameters N and s _N of anilines 3 . On the other hand, the reactions of these benzofurazans 1 with anilines 3 exhibit linear Brønsted‐type plots with β_nuc = 1.27 for 1a and 1.01 for 1b , which are considerably greater than those (0.57 for 1a and 0.62 for 1b ) obtained with the secondary cyclic amines 2 . These high values of β_nuc have been interpreted in terms of a single electron transfer mechanism. Secondary evidence for the validity of this mechanism is provided by the agreement between the rate constants, k ₁, for substitution of benzofurazans 1 by the anilines 3 and their oxidation potentials E °.     

Characterization of the nucleophilic reactivities of thiocarboxylate, dithiocarbonate and dithiocarbamate anions

The kinetics of the reactions of thiocarboxylate and thiocarbonate anions with benzhydrylium ions have been determined in acetonitrile solution using laser-flash photolytic techniques. The second-order rate constants (k) correlate linearly with the electrophilicity parameters E of the benzhydrylium ions, as required by the correlation log k (20 °C) = s(N)(N + E) (J. Am. Chem. Soc., 2001, 123, 9500-9512), allowing us to calculate the nucleophile-specific parameters N and s(N) for these anions. With these parameters, a direct comparison of the reactivities of thiocarboxylate, dithiocarbonate and dithiocarbamate anions with other nucleophiles becomes possible.     

Free Energy Relationships for Reactions of Substituted Benzhydrylium Ions: From Enthalpy over Entropy to Diffusion Control

Second-order rate constants k(2) for the reactions of various donor- and acceptor-substituted benzhydrylium ions Ar(2)CH(+) with π-nucleophiles in CH(2)Cl(2) were determined by laser flash irradiation of benzhydryl triarylphosphonium salts Ar(2)CH-PAr(3)(+)X(-) in the presence of a large excess of the nucleophiles. This method allowed us to investigate fast reactions up to the diffusional limit including reactions of highly reactive benzhydrylium ions with m-fluoro and p-(trifluoromethyl) substituents. The rate constants determined in this work and relevant literature data were jointly subjected to a correlation analysis to derive the electrophilicity parameters E for acceptor-substituted benzhydrylium ions, as defined by the linear free energy relationship log?k(2)(20 °C) = s(N)(N + E). The new correlation analysis also leads to the N and s(N) parameters of 18 π-nucleophiles, which have only vaguely been characterized previously. The correlations of log?k(2) versus E are linear well beyond the range where the activation enthalpies ΔH(?) of the reactions are extrapolated to reach the value of ΔH(?) = 0, showing that the change from enthalpy control to entropy control does not cause a bend in the linear free energy relationship, a novel manifestation of the compensation effect. A flattening of the correlation lines only occurs for k(2) > 10(8) M(-1) s(-1) when the diffusion limit is approached.     

Nucleophilicities of primary and secondary amines in water

The kinetics of the reactions of 26 primary and secondary amines with benzhydrylium ions in water were investigated photometrically. Because the parallel reactions of the benzhydrylium ions with hydroxide and water are much slower, the second-order rate constants for the reactions of amines with benzhydrylium ions could be determined reliably. Reactivities of anilines were also studied in acetonitrile solution. Plots of log k2,N for these reactions vs the electrophilicity parameters E of the benzhydrylium ions were linear, which allowed us to derive the nucleophilicity parameters N and s for amines as defined by the equation log k(20 degrees C)=s(E+N). Because the slope parameters for the different amines are closely similar; the relative nucleophilicities are almost independent of the electrophiles and can be expressed by the nucleophilicity parameters N. The correlation between nucleophilicity N and pKaH values is poor, and it is found that secondary alkyl amines and anilines are considerably more nucleophilic, while ammonia is much less nucleophilic than expected on the basis of their pKaH values.     

Nucleophilic reactivities of the anions of nucleobases and their subunits

The kinetics of the reactions of different heterocyclic anions derived from imidazoles, purines, pyrimidines, and related compounds with benzhydrylium ions and structurally related quinone methides have been studied in DMSO and water. The second-order rate constants (log k(2)) correlated linearly with the electrophilicity parameters E of the electrophiles according to the correlation log k(2) = s(N)(N+E) (H. Mayr, M. Patz, Angew. Chem. 1994, 106, 990-1010; Angew. Chem. Int. Ed. Engl. 1994, 33, 938-957) allowing us to determine the nucleophilicity parameters N and s(N) for these anions. In DMSO, the reactivities of these heterocyclic anions vary by more than six orders of magnitude and are comparable to carbanions, amide and imide anions, or amines. The azole anions are generally four to five orders of magnitude more reactive than their conjugate acids.     

Counterion effects in iminium-activated electrophilic aromatic substitutions of pyrroles

Electrophilic substitution of pyrroles by α,β-unsaturated iminium ions is slow in acetonitrile when only weakly basic counterions are present. When the reactions are carried out in the presence of KCF(3)CO(2), fast deprotonation of the intermediate σ-adducts occurs, and the rate constant for the rate-determining CC bond-forming step can be predicted from the electrophilicity parameter E of the iminium ion and the N and s parameters of the pyrroles.     

Reactions of carbocations with unsaturated hydrocarbons: electrophilic alkylation or hydride abstraction?

Benzhydryl cations were used as reference electrophiles to determine the hydride donor reactivities of unsaturated hydrocarbons. The kinetics of the reactions were followed by UV-vis spectroscopy and conductivity measurements, and it was found that the second-order rate constants for the hydride transfer processes were almost independent of the solvents or counterions employed. The rate constants correlate linearly with the previously published empirical electrophilicity parameters E of the benzhydrylium ions. Therefore, the linear free energy relationship log k(20 degrees C) = s(E + N) could be employed to characterize the hydride reactivities of the hydrocarbons by the nucleophilicity parameters N and s. The similarity of the slopes s for hydride donors and pi-nucleophiles allows a direct comparison of the reactivities of these different functional groups based on their nucleophilicity parameters N. Since nucleophilicity parameters of -5 < N < 0 have been found for a large variety of allylic and bisallylic hydride donors, a rule of thumb is derived that hydride transfer processes may compete with carbon-carbon bond-forming reactions when carbocations are combined with olefins of pi-nucleophilicity N < 0.     

Electrophilicity parameters for benzylidenemalononitriles

Kinetics of the reactions of stabilized carbanions (derived from nitroethane, diethyl malonate, ethyl cyanoacetate, ethyl acetoacetate, acetyl acetone) with benzylidenemalononitriles have been determined in dimethyl sulfoxide solution at 20 degrees C. The second-order rate constants are employed to determine the electrophilicity parameters E of the benzylidenemalononitriles according to the correlation equation log k (20 degrees C) = s(E + N). Comparison with literature data shows that this equation allows the semiquantitative prediction of the reactivities of benzylidenemalononitriles toward a wide variety of nucleophiles, including carbanions, enamines, amines, water, and hydroxide.     

Nucleophilicity parameters of enamides and their implications for organocatalytic transformations

The kinetics of the reactions of eleven substituted enamides with benzhydrylium ions (diarylcarbenium ions) were determined in acetonitrile solution. The second-order rate constants follow the correlation log k(2) (20 °C)=s(N)(E+N), which allowed us to derive reactivity parameters N and s(N). With 4.6相似文献   

Reactions of nitroheteroarenes with carbanions: bridging aromatic, heteroaromatic, and vinylic electrophilicity

The relative rate constants for the vicarious nucleophilic substitution (VNS) of the anion of chloromethyl phenyl sulfone (1-) with a variety of nitroheteroarenes, for example, nitropyridines, nitropyrroles, nitroimidazoles, 2-nitrothiophene, and 4-nitropyrazole, have been determined by competition experiments. It was shown that nitropyridines are approximately four orders of magnitude more reactive than nitrobenzene. Among the five-membered heterocycles 2-nitrothiophene is the most active followed by nitroimidazoles and 4-nitropyrazole. Nitropyrroles are the least electrophilic nitroheteroarenes with reactivities comparable to nitrobenzene. Quantum chemically calculated methyl anion affinities (B3LYP/6-311G(d,p)//B3LYP/6-31G(d)) of the nitroarenes correlated only moderately with the partial relative rate constants. The correlation of these activities with the LUMO energies of nitroarenes is even worse. By measuring the second-order rate constants of the addition of 1- to nitroarenes and to diethyl arylidenemalonates 10, it was possible to link the electrophilic reactivities of nitroheteroarenes with the comprehensive electrophilicity scale based on the linear-free-energy-relationship log k(20 degrees C)=s(N+E).