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Reactivity of diethyl benzylidenemalonates with secondary cyclic amine dimers in acetonitrile: Structure-reactivity relationships and mechanism

We report on a kinetic study for the nucleophilic addition reactions of diethyl 4-X-substituted benzylidenemalonates 1a-c (X = N(CH3)2, OCH3 and CH3) with N-nucleophiles, such as morpholine 2a, piperidine 2b and pyrrolidine 2c by UV–vis spectroscopy in acetonitrile solution at 20 °C. The Hammett plots demonstrate much better linear correlations with σp+ constants than with σp constants. These results are best interpreted in terms of ground state stabilization through resonance interactions between the electron-donating substituent and the CO2Et group. The effect of amine basicity on the reaction rate was examined quantitatively, leading to linear correlations with high βnuc values in the 0.82–0.93 range. The origin of the abnormally high βnuc values was interpreted in terms of dimer mechanism. Finally, with the help of our new proposed linear free energy relationship log k1K (20 °C) = sN (E + N) + log K, the stability of the dimer amines (K) have been evaluated from the measured apparent second-order rate constant (k1K) and the previously reported E, N and sN parameters of the employed electrophiles 1a-c and nucleophiles 2a-c. Additionally, a complementary theoretical study utilizing Density Functional Theory (DFT) with the B3LYP/6-311g(d,p) method was conducted in acetonitrile. An attempt is made to establish the correlation between equilibrium constant and stabilization energy the studied systems.

Electrophilicity, mechanism and structure–reactivity relationships of cyclic secondary amines addition to 2-methoxy-3,5-dinitropyridine

The second-order rate constants (k) for the nucleophilic aromatic substitution reactions of 2‑methoxy-3,5-dinitropyridine 1 with secondary cyclic amines 2a-c in acetonitrile solution at 20 °C are reported. The logarithms of these rate constants are particularly significant as possible measures of the electrophilicity parameters E for 2‑methoxy-3,5-dinitropyridine 1 according to the linear free energy relationship log k (20 °C) = sN(N + E). Additional kinetic data for reactions of 2-methoxy-3,5-dinitropyridine 1 with a series of nitroalkyl anions in DMSO solution are also measured and found to agree with those calculated by Mayr's approach from the known two solvent-dependent parameters N and sN of nitroalkyl anions and the electrophilicity parameter E measured in this work. A Single Electron Transfer (SET) mechanism is proposed for the SNAr reactions, on the basis of the linear Brönsted plot with the βnuc value of 0.94. The validity of this mechanism is confirmed by the agreement between the rate constants, k, and the oxidation potentials E° of these series of secondary cyclic amines. Also, reactivity descriptors such as the electronic chemical potential (μ), and the chemical hardness (η) for a series of pyridine derivatives were calculated by Density Functional Theory (DFT), and it is shown that the global electrophilicity index (ω = μ2/2η) is significantly correlated with the electrophilicity parameters E.

Dynamics of the dimethyl sulfide exchange of (1,3‐diphenylallyl)dimethylsulfonium ions

The dynamics of the allylic rearrangement of the (1,3-diphenylallyl)dimethylsulfonium ion in CD2Cl2, which proceeds via intermediate 1,3-diphenylallyl cations, has been investigated by variable temperature 1H NMR spectroscopy. At low temperature, the three allylic protons give rise to an AMX system, and the two diastereotopic S-methyl groups resonate at different frequencies. At higher temperature, an AX2 system for the allylic protons and a single signal for the S-methyl groups are observed. The resulting exchange rate constant of (364 ± 2) s–1 at 25°C, which corresponds to the rate of the heterolytic cleavage of the C–S bond, was used to explore the range of validity of the linear free energy relationship log khet(25°C) = sf (Nf + Ef), which describes the rates of heterolytic cleavages by the electrofugality parameter Ef and the solvent-dependent nucleofuge-specific parameters Nf and sf. The observed rate constant corroborates a previous conclusion that two different sets of Nf and sf parameters may exist for the same nucleofuge. Knowledge of whether the reverse bond-forming reaction occurs under activation or under diffusion control is crucial for the choice of the appropriate set of nucleofugality parameters.

Lewis Acidic Boranes, Lewis Bases, and Equilibrium Constants: A Reliable Scaffold for a Quantitative Lewis Acidity/Basicity Scale.

A quantitative Lewis acidity/basicity scale toward boron‐centered Lewis acids has been developed based on a set of 90 experimental equilibrium constants for the reactions of triarylboranes with various O‐, N‐, S‐, and P‐centered Lewis bases in dichloromethane at 20 °C. Analysis with the linear free energy relationship log K B=LA B+LB B allows equilibrium constants, K B, to be calculated for any type of borane/Lewis base combination through the sum of two descriptors, one for Lewis acidity (LA B) and one for Lewis basicity (LB B). The resulting Lewis acidity/basicity scale is independent of fixed reference acids/bases and valid for various types of trivalent boron‐centered Lewis acids. It is demonstrated that the newly developed Lewis acidity/basicity scale is easily extendable through linear relationships with quantum‐chemically calculated or common physical–organic descriptors and known thermodynamic data (ΔH BF3 ). Furthermore, this experimental platform can be utilized for the rational development of borane‐catalyzed reactions.

Relationships between experimental and theoretical scales of electrophilicity of 7-L-4-nitrobenzofurazans

Kinetics of the reactions of 7-Imidazolium-4-nitrobenzofurazan 1a and 7-phenoxy-4-nitrobenzofurazan 1b with secondary amines 2a-c were studied spectrophotometrically in acetonitrile at 20 °C. 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 + E). The theoretical electrophilic reactivity of the 7-phenoxy-4-nitrobenzofurazan 1a and 7-Imidazolium-4-nitrobenzofurazan 1b and two other nitrobenzofurazans 1c (L = OCH3) and 1d (L = Cl) have been studied by Density Functional Theory (DFT/B3LYP: Becke, 3-parameter, Lee- Yang-Parr) and the 6–311g(d,p) basis set implemented in Gaussian 09W Software. The derived electronic chemical potential (μ) and the corresponding chemical hardness (η) parameters have been used to calculate the global electrophilicity index (ω) of these series of electrophiles defined by the relationship ω = μ2/η. A good correlation between the calculated ω values and their experimentally observed electrophilic reactivities (i.e., Mayr’s electrophilicities E) is found and discussed.

Electrophilicities of 4‐Nitrobenzochalcogenadiazoles

AbstractThrough the linear free energy relationship log k=sN (N + E), the electrophilicity parameters E of 4‐nitrobenzochalcogenadiazoles 1 a and 1 b have been determined, at 20 °C, by kinetic investigations of their electrophilic addition reactions to a series of nitroalkyl anions 2 a‐c in aqueous solution. The derived E‐parameters of electrophiles 1 a (E=‐12.80) and 1 b (E=‐11.46) have been integrated into the electrophilicity scale established by Mayr. Interestingly the less activated compound (1 a) has an E value which is practically the same as that of the 1,3,5‐trinitrobenzene (E=‐13.19), the common reference aromatic electrophile. Mayr's approach was found to predict the rate constants for σ‐complexation reactions of our electrophiles 1 a and 1 b with aniline and 4‐chloroaniline in acetonitrile with a factor of 10−36. Good linear correlation (r2=0.9979) between the electrophilicity parameters E of 4,6‐dinitrobenzochalcogenadiazoles 3 a‐c and E values of their analogously 4‐nitrobenzochalcogenadiazoles 1 a‐c has been found and analysed. Furthermore, effect of basicity of nitronate anions 2 a‐c on their nucleophilic reactivity has also been examined quantitatively on the basis of kinetic data. Imbalance effect is suggested to be responsible for the finding of an inequality between the Brønsted αelec and βnuc values.

Electrophilic Reactivities of Vinyl p-Quinone Methides.

The electrophilic reactivity of a series of 8-arylated vinyl p-quinone methides (pVQMs) was determined by analyzing the kinetics of their reactions with carbanions in DMSO at 20 °C according to the linear free energy relationship log k = sN(N + E). The electrophilicity parameters E for pVQMs were used to successfully predict Michael-additions with structurally diverse C-, N-, S-, and H-nucleophiles.

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

AbstractA 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 βnuc = 0.52 and 0.55 for pyridines 1a and 1b, respectively, indicating that the reaction proceeds through a SNAr 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) = sN (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.

Exploration of the Synthetic Potential of Electrophilic Trifluoromethylthiolating and Difluoromethylthiolating Reagents.

The electrophilicity parameters (E) of some trifluoromethylthiolating and difluoromethylthiolating reagents were determined by following the kinetics of their reactions with a series of enamines and carbanions with known nucleophilicity parameters (N, sN ), using the linear free-energy relationship log k2 =sN (N+E). The electrophilic reactivities of these reagents cover a range of 17 orders of magnitude, with Shen and Lu's reagent 1 a being the most reactive and Billard's reagent 1 h being the least reactive electrophile. While the observed electrophilic reactivities (E) of the amido-derived trifluoromethylthiolating reagents correlate well with the calculated Gibbs energies for heterolytic cleavage of the X-SCF3 bonds (Tt+ DA), the cumol-derived reagents 1 f and 1 g are more reactive than expected from the thermodynamics of the O-S cleavage. The E parameters of the tri/difluoromethylthiolating reagents derived in this work provide an ordering principle for their use in synthesis.

Kinetics of Electrophilic Fluorinations of Enamines and Carbanions: Comparison of the Fluorinating Power of N-F Reagents.

Kinetics of the reactions of enamines and carbanions with commonly used fluorinating reagents, N-fluorobenzenesulfonimide (NFSI), N-fluoropyridinium salts, Selectfluor, and an N-fluorinated cinchona alkaloid, have been investigated in acetonitrile. The reactions follow second-order kinetics, and from the measured rate constants one can derive that the fluorinations proceed via direct attack of the nucleophiles at fluorine, not by SET processes. Correlations of the fluorination rates with the p KaH values of the nucleofugal leaving groups and the calculated fluorine plus detachment energies are discussed. The rate constants for the reactions with deoxybenzoin-derived enamines follow the linear free energy relationship log k2(20 °C) = sN( N + E) which allows the empirical electrophilicity parameters E for these fluorinating agents to be derived from the measured rate constants and the tabulated N and sN parameters for the nucleophiles. Though the deviations of the measured rate constants from those calculated by this relationship are larger than for reactions of Csp2-centered electrophiles with nucleophiles, it is shown that the electrophilicity parameters E reported in this work are able to rationalize known fluorination reactions and are, therefore, recommended as guide for designing new electrophilic fluorinations.

Kinetics and Mechanism of Oxirane Formation by Darzens Condensation of Ketones: Quantification of the Electrophilicities of Ketones

The kinetics of epoxide formation by Darzens condensation of aliphatic ketones 1 with arylsulfonyl-substituted chloromethyl anions 2 (ArSO2CHCl-) have been determined photometrically in DMSO solution at 20 °C. The reactions proceed via nucleophilic attack of the carbanions at the carbonyl group to give intermediate halohydrin anions 4, which subsequently cyclize with formation of the oxiranes 3. Protonation of the reaction mixture obtained in THF solution at low temperature allowed the intermediates to be trapped and the corresponding halohydrins 4-H to be isolated. Crossover experiments, i.e., deprotonation of the halohydrins 4-H in the presence of a trapping reagent for the regenerated arylsulfonyl-substituted chloromethyl anions 2, provided the relative rates of backward ( k-CC) and ring closure ( krc) reactions of the intermediates. Combination of the kinetic data ( k2exptl) with the splitting ratio ( k-CC/ krc) gave the second-order rate constants kCC for the attack of the carbanions 2 at the ketones 1. These kCC values and the previously reported reactivity parameters N and sN for the arylsulfonyl-substituted chloromethyl anions 2 allowed us to use the linear free energy relationship log k2(20 °C) = sN( N + E) for deriving the electrophilicity parameters E of the ketones 1 and thus predict potential nucleophilic reaction partners. Density functional theory calculations of the intrinsic reaction pathways showed that the reactions of the ketones 1 with the chloromethyl anions 2 yield two rotational isomers of the intermediate halohydrin anions 4, only one of which can cyclize while the other undergoes retroaddition because the barrier for rotation is higher than that for reversal to the reactants 1 and 2. The electrophilicity parameters E correlate moderately with the lowest unoccupied molecular orbital energies of the carbonyl groups, very poorly with Parr's electrophilicity indices, and best with the methyl anion affinities calculated for DMSO solution.

Nucleophilicity Parameters of Arylsulfonyl-Substituted Halomethyl Anions.

The rates of the reactions of the arylsulfonyl-substituted carbanions carrying α-chloro and α-bromo substituents (1a-e) with quinone methides 2a-g and benzylidenemalonates 2h and 2i in DMSO were determined photometrically at 20 °C. The reactions were performed under pseudo-first-order conditions, and the second-order rate constants were obtained as the slopes of the plots of the pseudo-first-order rate constants versus the concentrations of the reactants used in excess. The second-order rate constants correlate linearly with the parameters E of the reference electrophiles according to the linear free energy relationship log k2(20 °C) = sN(N + E), which allowed us to derive the nucleophile-specific parameters N and sN of carbanions 1a-e. The resulting nucleophilicity parameters N (23 < N < 29) reveal the title compounds to be among the most reactive nucleophiles so far integrated on our comprehensive nucleophilicity scale.

Nucleophilicity Parameters of Stabilized Iodonium Ylides for Characterizing Their Synthetic Potential.

Kinetics and mechanisms of the reactions of the β-dicarbonyl-substituted iodonium ylides 1(a-d) with several π-conjugated carbenium and iminium ions have been investigated. All reactions proceed with rate-determining attack of the electrophile at the nucleophilic carbon center of the ylides to give iodonium ions, which rapidly expel iodobenzene and undergo different subsequent reactions. The second-order rate constants k2 for the reactions of the iodonium ylides with benzhydrylium ions correlate linearly with the electrophilicity parameters E of the benzhydrylium ions and thus follow the linear free energy relationship log k(20 °C) = sN(N + E) (eq 1), where electrophiles are characterized by one parameter (E), while nucleophiles are characterized by two parameters: the nucleophilicity N and the susceptibility sN. The nucleophilicity parameters 4 < N < 8 for iodonium ylides 1(a-d) derived from these correlations show that substituting hydrogen for Ph-I(+) at the carbanionic center of Meldrum's acid or dimedone, respectively, reduces the nucleophilicity by approximately 10 orders of magnitude. The iodonium ylides 1(a-d) thus have nucleophilicities similar to those of pyrroles, indoles, and silylated enol ethers and, therefore, should be suitable substrates in iminium-activated reactions. Good agreement of the measured rate constant for the cyclopropanation of the imidazolidinone-derived iminium ion 10a with the iodonium ylide 1a with the rate constant calculated by eq 1 suggests a stepwise mechanism in which the initial nucleophilic attack of the iodonium ylide at the iminium ion is rate-determining. The reaction of cinnamaldehyde with iodonium ylide 1a catalyzed by (5S)-5-benzyl-2,2,3-trimethyl-imidazolidin-4-one (11a, MacMillan's first-generation catalyst) gives the corresponding cyclopropane with an enantiomeric ratio of 70/30 and, thus, provides proof of principle that iodonium ylides are suitable substrates for iminium-activated cyclopropanations.

Benzhydrylium and tritylium ions: complementary probes for examining ambident nucleophiles

Abstract The linear free energy relationship log k = sN(N + E) (eq. 1), in which E is an electrophilicity, N is a nucleophilicity, and s N is a nucleophile-dependent sensitivity parameter, is a reliable tool for predicting rate constants of bimolecular electrophile-nucleophile combinations. Nucleophilicity scales that are based on eq. (1) rely on a set of structurally similar benzhydrylium ions (Ar2CH+) as reference electrophiles. As steric effects are not explicitely considered, eq. (1) cannot unrestrictedly be employed for reactions of bulky substrates. Since, on the other hand, the reactions of tritylium ions (Ar3C+) with hydride donors, alcohols, and amines were found to follow eq. (1), tritylium ions turned out to be complementary tools for probing organic reactivity. Kinetics of the reactions of Ar3C+ with π-nucleophiles (olefins), n-nucleophiles (amines, alcohols, water), hydride donors and ambident nucleophiles, such as the anions of 5-substituted Meldrum’s acids, are discussed to analyze the applicability of tritylium ions as reference electrophiles.

Quantification of the ambident electrophilicities of halogen-substituted quinones.

Kinetics and mechanisms of the reactions of p-quinone, 2,5-dichloro-p-quinone, 2,3,4,5-tetrachloro-p-quinone (chloranil), 2,3,4,5-tetrafluoro-p-quinone (fluoranil), and 3,4,5,6-tetrachloro-o-quinone with π-nucleophiles (siloxyalkenes, enamines) and amines have been investigated. Products arising from nucleophilic attack at all conceivable sites, that is, at C and O of the carbonyl groups (pathways a, b) as well as at halogenated and nonhalogenated conjugate positions (pathways c, d), were observed. The partial rate constants for the C-attack pathways (a, c, d), which are derived from the photometrically determined second-order rate constants and the product ratios followed the linear free energy relationship log k (20 °C) = sN(E + N) ( Mayr , H.; J. Am. Chem. Soc. 2001 , 123 , 9500 - 9512 ). It was, therefore, possible to calculate the electrophilicity parameters E of the different positions of the quinones from log k (20 °C) and the N and sN parameters of the nucleophilic reaction partners, which have previously been derived from their reactions with benzhydrylium ions. Almost all rate constants for the C-attack pathways (a, c, d) were considerably larger than those calculated for the corresponding SET processes, indicating the operation of polar mechanisms. SET mechanisms may only account for the formation of the products formed via O-attack. With the E parameters determined in this work, it is now possible to predict rate constants for the reactions of these quinones with a large variety of nucleophiles and, thus, envisage unprecedented reactions of quinones.

Structures and Reactivities of Iminium Ions Derived from Substituted Cinnamaldehydes and Various Chiral Imidazolidin‐4‐ones

AbstractA series of α,β‐unsaturated iminium ions derived from substituted cinnamaldehydes and C2‐ and C5‐substituted chiral imidazolidin‐4‐ones were isolated and characterized in solution and in the solid state. The kinetics of the reactions of the iminium ions with silyl ketene acetals were determined in dichloromethane at 20 °C. The resulting second‐order rate constants were used to estimate the electrophilicity E of the iminium ions according to the linear free energy relationship log k2(20 °C)=sN(N+E). The kinetics for the reactions of two of the iminium ions with tributylphosphine were studied by laser flash spectroscopy and their second‐order rate constants were found to agree within a factor of 2.2 with those calculated by using the linear free energy relationship above.

Electrophilicities of 1,2‐Disubstituted Ethylenes

AbstractThe kinetics of the reactions of maleic anhydride, N‐methylmaleimide, fumaronitrile, diethyl fumarate, and diethyl maleate with pyridinium and sulfonium ylides were studied in DMSO at 20 °C. All of the reactions were found to follow a second‐order rate law, and can be described by the linear free energy relationship log k2 (20 °C) = sN(N + E), where N and sN are solvent‐dependent nucleophile‐specific parameters, and E is an electrophile‐specific parameter. The electrophilicity parameters E of the investigated acceptor‐substituted alkenes were derived from the linear correlations of (log k2)/sN vs. N, and range from –19.8 to –11.1.

Nucleophilicity Parameters of Pyridinium Ylides and Their Use in Mechanistic Analyses

Kinetics of the reactions of pyridinium, isoquinolinium, and quinolinium ylides with diarylcarbenium ions, quinone methides, and arylidene malonates (reference electrophiles) have been studied in dimethylsulfoxide solution by UV-vis spectroscopy. The second-order rate constants (log k2) were found to correlate linearly with the electrophilicities E of the reference electrophiles, as required by the linear free-energy relationship log k(20°C) = sN(N + E) (J. Am. Chem. Soc. 2001, 123, 9500), which allowed us to derive the nucleophile-specific parameters N and sN for these ylides. Pyridinium substitution is found to have a similar effect on the reactivity of carbanionic reaction centers as alkoxycarbonyl substitution. Agreement between the rate constants measured for the 1,3-dipolar cycloadditions of pyridinium, isoquinolinium, and quinolinium ylides with acceptor substituted dipolarophiles (arylidenemalononitrile and substituted chalcone) and those calculated from E, N, and sN shows that the above correlation can also be employed for predicting absolute rate constants of stepwise or highly unsymmetrical concerted cycloadditions. Deviations between calculated and experimental rate constants by a factor of 10(6) were demonstrated to indicate a change of reaction mechanism.

Nucleophilic Reactivities of Schiff Bases

Abstract The nucleophile-specific parameters N and sN, as defined by the linear free energy relationship log k = sN(N+E) (J. Am. Chem. Soc. 2001, 123, 9500 - 9512), were determined for five imines 1a-e by studying the kinetics of their reactions with benzhydrylium ions in dichloromethane solution at 20 °C. These parameters allowed us to include representative Schiff bases into our comprehensive nucleophilicity scale and compare their reactivities with those of other N-nucleophiles

ChemInform Abstract: A Quantitative Approach to Nucleophilic Organocatalysis

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