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.     

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.     

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.     

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.     

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.     

Nucleophilic aromatic substitution by [<Superscript>18</Superscript>F]fluoride at substituted 2-nitropyridines

For the radiofluorination of benzenes and benzene derivatives, the electrophilic reaction with [¹⁸F]F₂ is a very common route. Yet, aromatic nucleophilic substitution (S_NAr) by n.c.a [¹⁸F]fluoride, which can be produced efficiently in high amounts, has been considered to be very desirable. However, to facilitate ¹⁸F-labelling via S_NAr at an electron rich aromatic system, an appropriate leaving group must be present together with an auxiliary group in ortho or para position to the leaving group. An interesting alternative for the auxiliary group is the heteroatom of a heteroaromatic system, for which pyridine is a leading example. Dolci et al. (J Label Compd Radiopharm 42:975–985, 1999) have evaluated the scope of the nucleophilic aromatic fluorination of 2-substituted pyridine rings using the activated K [¹⁸F]F-K₂₂₂ complex. As methyl and methoxy groups are known to enhance the electron density of an aromatic system by the +I and the +M effect, respectively, S_NAr is unlikely to occur. Until now, the effect of these substituents has not been studied towards the ¹⁸F-radiofluorination of substituted 2-nitropyridines by use of [¹⁸F]fluoride. Therefore, we have investigated the effect of methoxy and methyl groups in 2-nitropyridines. The results showed that 3-methoxy-2-nitropyridine and 3-methyl-2-nitropyridine can efficiently be substituted by [¹⁸F]fluoride with high RCY’s (70–89%) in short reaction times (1–30 min) at a reaction temperature of 140 °C. Moreover, 3-methoxy-6-methyl-2-[¹⁸F]fluoropyridine was obtained from the corresponding nitro-precursor in a high yield of 81 ± 1% after 30 min at 140 °C. In case of 2-nitropyridines data indicates the effect of methyl and methoxy groups on S_NAr to be of minor importance.     

Quantification of the Electrophilicities of Diazoalkanes: Kinetics and Mechanism of Azo Couplings with Enamines and Sulfonium Ylides

Kinetics and mechanism of the reactions of methyl diazoacetate, dimethyl diazomalonate, 4-nitrophenyldiazomethane, and diphenyldiazomethane with sulfonium ylides and enamines were investigated by UV-Vis and NMR spectroscopy. Ordinary alkenes undergo 1,3-dipolar cycloadditions with these diazo compounds. In contrast, sulfonium ylides and enamines attack at the terminal nitrogen of the diazo alkanes to give zwitterions, which undergo various subsequent reactions. As only one new bond is formed in the rate-determining step of these reactions, the correlation lg k₂(20 °C)=s_N(N+E) could be used to determine the one-bond electrophilicities E of the diazo compounds from the measured second-order rate constants and the known reactivity indices N and s_N of the sulfonium ylides and enamines. The resulting electrophilicity parameters (−21<E<−18), which are 11–14 orders of magnitude smaller than that of the benzenediazonium ion, are used to define the scope of one-bond nucleophiles which may react with these diazoalkanes.     

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).     

Structure-reactivity relationships on Michael additions of secondary cyclic amines with 3-cyanomethylidene-2-oxindoline derivatives

A kinetic study of the nucleophilic addition reactions of 3-cyanomethylidene-2-oxindoline derivatives with cyclic amines (namely: piperidine, morpholine and pyrrolidine) in MeCN solution at 20 °C is reported. The second-order rate constants showed of this process fit nicely the Brönsted equation log k₁ = β_nuc pK_a + C, allowing the determination of the β_nuc parameter in the range of 0.63 < β_nuc < 0.77 that indicates that the degree of formation of N–C bond in the transition state is more half complete. Moreover, the analysis of the kinetic measurements based on a good linear log k (20 °C) = s_N (E + N) free enthalpy relationship are used to assess the electrophilic reactivity in term of E parameter of these series of 2-oxindoline derivatives Michael acceptors. Of major interest is that the estimated E values were established to cover a domain of reactivity of ~3 units of E, ranging from −17.5 for 2-(5-chloro-2-oxindolin-3-ylidene)malononitrile (the most reactive electrophile) to −20.3 for ethyl 2-(5-chloro-1-methyl-2-oxindolin-3-ylidene)-2-cyanoacetate (the least reactive electrophile). The theoretical reactivity indices ω based on the conceptual Density Functional Theory (DFT) explains correctly the experimental electrophilicity E ordering founded in terms of experimental scales.     

Nucleophilicities and carbon basicities of pyridines

Rate and equilibrium constants for the reactions of pyridines with donor‐substituted benzhydrylium ions have been determined spectrophotometrically. The correlation equation log k(20 °C)=s(N+E), in which s and N are nucleophile‐specific parameters and E is an electrophile‐specific parameter, has been used to determine the nucleophilicity parameters of various pyridines in CH₂Cl₂ and aqueous solution and to compare them with N of other nucleophiles. It is found that the nucleophilic organocatalyst 4‐(dimethylamino)pyridine (DMAP) and tertiary phosphanes have comparable nucleophilicities and carbon basicities despite widely differing Brønsted basicities. For that reason, these reactivity parameters are suggested as guidelines for the development of novel organocatalysts. The Marcus equation is employed for the determination of the intrinsic barriers of these reactions.     

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.     

Kinetic study of nucleophilic reactivity of heterocyclic amines with 4,6-dinitrobenzofuroxan in acetonitrile

The reaction kinetics of 4,6-dinitrobenzofuroxan with five heterocyclic amines was investigated spectrophotometrically (UV–Vis) in acetonitrile at 20 °C. It was observed that the rate constants of these reactions increased as follows: 2-aminopyrimidine > 2-aminothiazole > 2-aminobenzothiazole > 5-amino-3,4-dimethylisoxazole > 2-amino-5-trifluoromethyl-1,3,4-thiadiazole. Further, second-order rate constants (k₁) pertaining to the C–N and C–C bond forming step of these complexation processes fit to the three parameter equation log k (20 °C) = s_N (N + E), allowing the determination of the nucleophilicity parameters (N) of the five heterocyclic amines. The heterocyclic amines were subsequently ranked on the comprehensive nucleophilicity scale defined by Mayr et al. (2003), providing a direct comparison of n-, π-, and σ-nucleophiles.     

Dual Nucleophilic Substitution Reactions of O,O‐Diethyl 2,4‐dinitrophenyl Phosphate and Thionophosphate Triesters

The reactions of the title compounds with phenoxides, secondary alicyclic (SA) amines, and pyridines, in 44 wt% ethanol–water, at 25°C and an ionic strength of 0.2 M, were subjected to kinetic and product studies. From analytical techniques (HPLC and NMR), two pathways were detected (nucleophilic attack at the phosphoryl center and at the C‐1 aromatic carbon) for the reactions of all the nucleophiles with the phosphate ( 2 ) and for the pyridinolysis of the thionophosphate ( 1 ). Only aromatic nucleophilic substitution was found for the reactions of 1 with phenoxides and SA amines. For the dual reactions, the nucleophilic rate constants (k_N) were separated in two terms: $k_{\rm N}^{\rm P}$ and $k_{\rm N}^{{\rm Ar}}$, which are the rate constants for the corresponding electrophilic centers. The absence of a break in the Brønsted‐type plots for the attack at P is consistent with concerted mechanisms. The Brønsted slopes, β_Ar 0.32–0.71, for the attack at the aromatic C‐1, are in agreement with stepwise mechanisms where formation of a Meisenheimer complex is the rate‐determining step. © 2013 Wiley Periodicals, Inc. Int J Chem Kinet 45: 202–211, 2013     

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.     

Inherent Reactivity of Spiro-Activated Electrophilic Cyclopropanes

The kinetics of the ring-opening reactions of thiophenolates with geminal bis(acceptor)-substituted cyclopropanes in DMSO at 20 °C was monitored by photometric methods. The determined second-order rate constants of the S_N2 reactions followed linear relationships with Mayr nucleophilicity parameters (N/s_N) and Brønsted basicities (pK_aH) of the thiophenolates as well as with Hammett substituent parameters (σ) for groups attached to the thiophenolates. Phenyl-substituted cyclopropanes reacted by up to a factor of 15 faster than their unsubstituted analogues, in accord with the known activating effect of adjacent π-systems in S_N2 reactions. Variation of the electronic properties of substituents at the phenyl groups of the cyclopropanes gave rise to parabolic Hammett relationships. Thus, the inherent S_N2 reactivity of electrophilic cyclopropanes is activated by electron-rich π-systems because of the more advanced C1−C2 bond polarization in the transition state. On the other hand, electron-poor π-systems also lower the energetic barriers for the attack of anionic nucleophiles owing to attractive electrostatic interactions.     

Electrophilic Reactivities of 1,2‐Diaza‐1,3‐dienes

The kinetics of the reactions of 1,2‐diaza‐1,3‐dienes 1 with acceptor‐substituted carbanions 2 have been studied at 20 °C. The reactions follow a second‐order rate law, and can be described by the linear free energy relationship log k(20 °C)=s(N+E) [Eq. (1)]. With Equation (1) and the known nucleophile‐specific parameters N and s for the carbanions, the electrophilicity parameters E of the 1,2‐diaza‐1,3‐dienes 1 were determined. With E parameters in the range of ?13.3 to ?15.4, the electrophilic reactivities of 1 a–d are comparable to those of benzylidenemalononitriles, 2‐benzylideneindan‐1,3‐diones, and benzylidenebarbituric acids. The experimental second‐order rate constants for the reactions of 1 a – d with amines 3 and triarylphosphines 4 agreed with those calculated from E, N, and s, indicating the applicability of the linear free energy relationship [Eq. (1)] for predicting potential nucleophilic reaction partners of 1,2‐diaza‐1,3‐dienes 1 . Enamines 5 react up to 10² to 10³ times faster with compounds 1 than predicted by Equation (1), indicating a change of mechanism, which becomes obvious in the reactions of 1 with enol ethers.     

Quantification of Ion‐Pairing Effects on the Nucleophilic Reactivities of Benzoyl‐ and Phenyl‐Substituted Carbanions in Dimethylsulfoxide

Second‐order rate constants for the reactions of acceptor‐substituted phenacyl (PhCO?CH^??Acc) and benzyl anions (Ph?CH^??Acc) with diarylcarbenium ions and quinone methides (reference electrophiles) have been determined in dimethylsulfoxide (DMSO) solution at 20 °C. By studying the kinetics in the presence of variable concentrations of potassium, sodium and lithium salts (up to 10^?2 mol L^?1), the influence of ion‐pairing on the reaction rates was examined. As the concentration of K⁺ did not have any influence on the rate constants at carbanion concentrations in the range of 10^?4–10^?3 mol L^?1, the acquired rate constants could be assigned to the reactivities of the free carbanions. The counter ion effects increase, however, in the series K⁺<Na⁺<Li⁺, and the sensitivity of the carbanion reactivities toward variation of the counter ion strongly depends on the structure of the carbanions. The reactivity parameters N and s_N of the free carbanions were derived from the linear plots of log k₂ against the electrophilicity parameters E of the reference electrophiles, according to the linear‐free energy relationship log k₂(20 °C)=s_N(N+E). These reactivity parameters can be used to predict absolute rate constants for the reactions of these carbanions with other electrophiles of known E parameters.     

Nucleophilic reactivities of Schiff base derivatives of amino acids

Treatment of α-imino esters derived from glycine esters and benzophenone or benzaldehydes with potassium tert butoxide in DMSO gave persistent solutions of carbanions at 20?°C. The kinetics of their reactions with quinone methides and benzylidene malonates (reference electrophiles) have been followed photometrically under pseudo-first order conditions. The reactions followed second-order rate laws. Since addition of 18-crown-6 ether did not affect the reaction rates, the measured rate constants correspond to the reactions of the non-paired carbanions. Plots of the second-order rate constants against the electrophilicity parameters E of the electrophiles are linear, which allowed us to derive the nucleophile-specific parameters N and s_N, according to the linear Gibbs energy relationship lg k₂(20?°C)?=?s_N(N + E). The Ph₂C?=?N- and PhCH?=?N- groups act as very weak electron acceptors with the consequence that Ph₂C?=?N-CH^–-CO₂R and PhCH?=?N-CH^–-CO₂R have a similar nucleophilicity as Ph-CH^–-CO₂Et, the anion of ethyl phenylacetate.     

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.