Meisenheimer Adduct Research Articles

A one-pot tandem synthesis of various 1,2-disubstituted benzimidazoles

A facile method to synthesize various 1,2-disubstituted benzimidazoles is developed. It is suggested that formation of a Meisenheimer adduct between the substrate, amine, and solvent aids the N-arylation process. The generality of the protocol is demonstrated by the efficient reactions involving numerous substituents ranging from electron-withdrawing groups to electron-donating groups.

ChemInform Abstract: Direct Methoxylation of Nitroarenes and Nitroazaarenes with Alkaline Methoxides via Nucleophilic Displacement of an Aromatic Hydrogen Atom.

Treatment of 1,3-dinitrobenzene and 5-substituted derivatives with excess potassium or sodium methoxide in 1,3-dimethylimidazolidin-2-one (DMI) at room temperature results in the displacement of an aromatic hydrogen at the 4-position by methoxide, affording 2,4-dinitroanisole and its 6-substituted derivatives, respectively, in low to moderate yield. In contrast, an equimolar reaction under similar conditions leads to the replacement of the nitro group in preference to the ring hydrogen. The reaction does not take place with lithium methoxide as a base. Mono- and dinitronaphthalenes and nitroquinolines undergo similar displacement of a hydrogen atom at the position ortho or para to the nitro group, giving the corresponding methoxy derivatives in moderate yield. A slow addition of the nitro compound to a large excess of potassium methoxide under an oxygen atmosphere has been found to enhance the conversion and improve the product yield. On the basis of the product distribution as well as the kinetic isotope effect kH/kD = 2.1, direct displacement of a ring hydrogen atom by methoxide ion has been interpreted in terms of the rate-determining release of an ipso-hydrogen atom as a proton from the initially formed Meisenheimer adduct.

Di‐ and Trifluorobenzenes in Reactions with Me2EM (E = P, N; M = SiMe3, SnMe3, Li) Reagents: Evidence for a Concerted Mechanism of Aromatic Nucleophilic Substitution

AbstractDimethyl(trimethylsilyl)phosphane (Me3SiPMe2) has been successfully used for the substitution of fluorine variously in 1,3‐ (1) or 1,2‐difluorobenzene (2) or in 1,3,5‐ (3) or 1,2,3‐trifluorobenzene (4) by the Me2P group at 150–190 °C either in benzene solution or without solvent to give 1‐(dimethylphosphanyl)‐3‐fluorobenzene (5) from 1, 1‐(dimethylphosphanyl)‐2‐fluorobenzene (6) from 2, 1‐(dimethylphosphanyl)‐3,5‐difluorobenzene (7) from 3 or a 1:1 mixture of 1‐(dimethylphosphanyl)‐2,3‐difluorobenzene (8) and 1‐(dimethylphosphanyl)‐2,6‐difluorobenzene (9) from 4. The substrate selectivities and regioselectivities exhibited by 4 with Me3SiPMe2 and in competitive reactions between 1 and 2 or 3 and 4 with Me2PSiMe3, Me2PSnMe3 or Me2PLi indicate relative fluorine substituent rate factors fo‐F > fm‐F, whereas for reactions that proceed through a two‐step SNAr mechanism the opposite sequence is typical. High‐level quantum‐chemical DFT and MP2 calculations predict that the gas‐phase reactions should each proceed by a concerted mechanism with a single transition state. These predictions are in good agreement with the experimental observations, especially because the structural features of the Meisenheimer adduct are unfavourable for the SNAr mechanism. This proposal is consistent with the observation of the opposite sequence (fm‐F > fo‐F) for the reactions between the same substrates and MeONa in DMSO/CH3OH solvent mixtures. The novel phosphanes were characterized by spectroscopic (NMR) and spectrometric (MS) investigation, preparation of the thiophosphanes ArFPSMe2 10–12, their spectroscopic data and, in the case of 12, by its X‐ray structure. The phosphanes 5–9 were treated with bis(benzonitrile)dichloropalladium(II) to afford the corresponding bis(phosphane)palladium dichloride complexes 17–21 and 23 in isolated yields of up to 95 %.

Formation of Stable Meisenheimer Adduct Ion Pairs in Apolar Solvents: Implications for Stereoselective Reactions

[reaction: see text] A detailed study concerning the formation of Meisenheimer adducts in biphasic solvent systems is described. The process relies on utilizing a significantly lipophilic quaternary ammonium salt to transfer a nucleophile (e.g., hydroxide ion) between an aqueous and organic layer containing the electron-deficient aromatic substrate. Provided that the organic layer is sufficiently apolar, the resultant Meisenheimer adduct is considerably stable, likely the result of a strong ion-pairing interaction between the large polarizable anionic complex and the diffusively charged tetraalkylammonium cation. Using the diethylamide of 3,5-dinitrobenzoic acid as a model compound, the influence of ion-pairing reagents and solvents on adduct formation was investigated. Dramatically increased equilibrium formation of the Meisenheimer adduct is observed in the biphasic medium (e.g., benzene/2 M NaOH) relative to the same adduct generated in single-phase systems. Spectroscopic studies on this adduct are consistent with those conducted in single-phase polar or dipolar aprotic solvents. The methodology is extended to performing highly enantioselective biphasic kinetic resolutions of several racemic electron-deficient amides.

Direct methoxylation of nitroarenes and nitroazaarenes with alkaline methoxides via nucleophilic displacement of an aromatic hydrogen atom

Treatment of 1,3-dinitrobenzene and 5-substituted derivatives with excess potassium or sodium methoxide in 1,3-dimethylimidazolidin-2-one (DMI) at room temperature results in the displacement of an aromatic hydrogen at the 4-position by methoxide, affording 2,4-dinitroanisole and its 6-substituted derivatives, respectively, in low to moderate yield. In contrast, an equimolar reaction under similar conditions leads to the replacement of the nitro group in preference to the ring hydrogen. The reaction does not take place with lithium methoxide as a base. Mono- and dinitronaphthalenes and nitroquinolines undergo similar displacement of a hydrogen atom at the position ortho or para to the nitro group, giving the corresponding methoxy derivatives in moderate yield. A slow addition of the nitro compound to a large excess of potassium methoxide under an oxygen atmosphere has been found to enhance the conversion and improve the product yield. On the basis of the product distribution as well as the kinetic isotope effect kH/kD = 2.1, direct displacement of a ring hydrogen atom by methoxide ion has been interpreted in terms of the rate-determining release of an ipso-hydrogen atom as a proton from the initially formed Meisenheimer adduct.

Aromatic nucleophilic substitution of hydrogen: mechanism of reaction of 6-nitroquinoline with cyanide ions, with and without participation of methyl cyanoacetate

The mechanism of nucleophilic substitution of hydrogen (SNArH) in 6-nitroquinoline 1 by action of cyanide ion in the presence or in the absence of methyl cyanoacetate in dimethyl sulfoxide has been studied by means of 1H NMR. The main reaction products and some side products have been identified and their time–concentration dependences have been determined. An experiment with 13C enriched potassium cyanide proved that the cyano group replaces hydrogen at the 5-position of the starting compound 1. The two main products obtained from the reaction mixture of 6-nitroquinoline 1 and potassium cyanide are 6-hydroxyquinoline-5-carbonitrile 11 and 6,6′-azoquinoline-5,5′-dicarbonitrile 13. On the basis of the data obtained, a mechanism has been suggested for aromatic nucleophilic substitution of hydrogen by cyanide ion in 6-nitroquinoline 1 involving a Meisenheimer adduct of 6-nitroquinoline 1 with cyanide ion and 6-nitrosoquinoline-5-carbonitrile 14 as unstable intermediates.

Kinetics and Mechanism of Reaction of 2,4-Dinitrobenzaldehyde with Hydroxide Ion

The reaction of 2,4-dinitrobenzaldehyde with hydroxide ion in water is first order in the substrate. The reaction order in hydroxide ion varies from one to two at lower and higher OH- concentrations, respectively. The reaction mechanism has been suggested, the pKa value of reaction product 2-nitro-4-nitrosophenol and the equilibrium constant of formation of the Meisenheimer adduct from 2-nitro-4-nitrosophenoxide and hydroxide ion have been determined.

Nucleophilic aromatic substitution (S NAr): Evidence of an electron transfer process in the reaction between acyclic alkyl amines and both aromatic and heteroaromatic halides.

A wide literature exists on S NAr reactions of aromatic and heteroaromatic halides with or without activating nitro groups. Most likely the first event is not the formation of a Meisenheimer adduct but an Electron Transfer process leading to radical intermediates. Here it is reported the first experimental evidence, by EPR spectroscopy, of the detection of the radical species involved in such a type reaction.

Equilibrium constants for the formation of sulphite addition compounds of aromatic aldehydes

The equilibrium concentration of the sulphite Meisenheimer adduct of 1,3,5-trinitrobenzene, formed from potassium sulphite/18-crown-6 and trinitrobenzene, in dimethyl sulphoxide solution, is reduced in the presence of an aromatic aldehyde, with an accompanying decrease in the absorbance of the solution due to the intensely coloured Meisenheimer adduct. Equilibrium constants have accordingly been determined for the formation of the sulphite Meisenheimer adduct of trinitrobenzene and for the formation of a series of substituted benzaldehyde sulphite dianions in dimethyl sulphoxide solution.

Formation of spiro adduct from N-methyl-N-(2,4,6-trinitrophenyl)glycine anion

The intramolecular nucleophilic addition of N-methyl-N-(2,4,6-trinitrophenyl)glycine anion in methanol-dimethyl sulfoxide mixtures produces spiro[(3-methyl-5-oxazolidinone)-2,1'-(2',4',6'-trinitrobenzenide)]. The spiro adduct has been identified by means of 1H and 13C NMR spectroscopy. This is the first case when the formation of a Meisenheimer adduct with carboxylate ion is observed. Logarithm of the equilibrium constant of adduct formation increases linearly with the mole fraction of dimethyl sulfoxide in its mixture with methanol.

Decomposition of hexachloroacetone in dimethyl sulphoxide solution: a source of trichloromethanide anions

Hexachloroacetone (HCA) decomposes in dimethyl sulphoxide solution at room temperature. In the presence of an excess of 1,3,5-trinitrobenzene (TNB) the progress of the reaction can be monitored by the appearance of the visible absorption characteristic of the formation of the trichloromethyl Meisenheimer adduct of TNB in nearly quantitative yield (2 mol of adduct per mol of HCA). The reaction is slower than the decomposition of trichloroacetic acid under the same conditions, the difference being attributable to a large negative entropy of activation. The reaction rate is markedly increased by the addition of water and slightly depressed by addition of acid. The kinetics are consistent with a ratelimiting breakdown of the gem-diol hydrate of HCA into trichloroacetic acid and trichloromethanide anions, followed by the more rapid decomposition of trichloroacetic acid.

Addition of cyanide ions to aromatic aldehydes: a competition method for the determination of equilibrium constants of nucleophilic addition reactions

The equilibrium concentration of the cyanide Meisenheimer adduct of 1,3,5-trinitrobenzene, formed from potassium cyanide–18-crown-6 and trinitrobenzene, in DMSO solution, is reduced in the presence of an aromatic aldehyde, with an accompanying decrease in the absorbance of the solution due to the intensely coloured Meisenheimer adduct. Equilibrium constants have accordingly been determined for the formation of the cyanide Meisenheimer adduct of trinitrobenzene and for the formation of members of a series of substituted benzaldehyde cyanohydrin anions in dimethyl sulphoxide solution.

The reaction of trihalogenomethyl anions with carbonyl compounds: competitive reactivity comparisons and applications to the synthesis of α-trihalogenomethyl alcohols

Trihalogenomethyl anions, generated by decarboxylation of trichloro- and tribromo-acetic acid in dimethyl sulphoxide solution, react with added aldehydes. In the presence of 1,3,5-trinitrobenzene, the reaction with aldehydes competes with the formation of the coloured Meisenheimer adduct. The reduction in absorbance from the value in the absence of aldehyde has been used to measure the reactivity of trihalogenomethyl anions towards a series of aldehydes relative to their reactivity towards trinitrobenzene. For 4-substituted benzaldehydes, the reactivities obey a linear ρσ– relationship. The most reactive aldehyde used is only two times less reactive towards CCl3– or CBr3– than hydrogen ions, and it is concluded that, in dimethyl sulphoxide solutions, the reaction between trichloromethyl anions and hydrogen ions is not encounter-controlled. The reactions with aldehydes have been used to prepare several new compounds of the formula RCH(OY)CX3 where R = aryl or pyridyl, X = Br or Cl, and Y = H or COCH3.

The decarboxylation of trichloroacetic acid and the reactions of the trichloromethyl anion with 1,3,5-trinitrobenzene and with hydrogen ions: kinetic measurements in dimethyl sulphoxide solution

Rate measurements are reported for the formation of a Meisenheimer adduct in solutions of 1,3,5-trinitrobenzene and trichloroacetic acid or sodium trichloroacetate at very low concentrations (<10–4M). Study of the rate constants and final absorbances of the solutions shows that the rate-limiting step is in all cases the unusually rapid unimolecular breakdown of the trichloroacetate anion (Ea83 kJ mol–1; ΔS‡ 11 J mol–1 K–1). The rate constants of the reactions of the trichloromethyl anion thus formed with trinitrobenzene or hydrogen ions are nearly equal. From the effect of added hydrochloric acid on the reaction rate a value of the hiterto unreported dissociation constant of trichloroacetic in DMSO (2.9 × 10–4 mol l–1) has been deduced. Approximate deuterium isotope effects are derived for the dissociation constant and for some of the rate constants. Preliminary measurements show that the analogous breakdown of tribromoacetic acid in DMSO is a considerably faster reaction.

Hydride transfer from cyclohexadienyl anions: the reaction between the hydride Meisenheimer adduct of 2,4-dinitroaniline and 1,3,5-trinitrobenzene

The hydride Meisenheimer adduct of 2,4-dinitroaniline transfers hydride to 1,3,5-trinitrobenzene to form its corresponding hydride Meisenheimer adduct. The reaction is practically irreversible. In dilute solution in dimethyl sulphoxide it exhibits second-order kinetics and the observation of several sharp isosbestic points shows that it occurs without formation of any detectable intermediate species.

Mechanism of the conversion of a nitrobenzene into a 4-nitrosophenol in 15·8Mpotassium hydroxide

Quantitative conversion of 2-nitrobenzoate ion into 2-nitroso-5-hydroxybenzoate ion occurs in 15·8 M potassium hydroxide; kinetic and spectral studies are consistent with a mechanism which involves rate-limiting formation of a Meisenheimer adduct with hydroxide ion followed by proton abstraction.

Meisenheimer adduct formation between 2,4-dinitrophenetole and ethanolic alkali ethoxide solutions: the course of the acidity function J E and thermodynamic solvent isotope effects

Spectrophotometric measurements of the equilibrium constant (Kapp) for formation of a Meisenheimer adduct from 2,4-dinitroanisole and ethanolic sodium and potassium ethoxide have been used to define an acidity function JE for alkoxide solutions in ethanol (analogous to the functions JM for methanol). Sodium and potassium ethoxide behave identically up to a concentration of ca. 0.3 mol dm–3; above this value solutions of sodium ethoxide are slightly less basic. The dependence of Kapp on base concentration is interpreted in terms of ion-pairing effects. The formation of a 1 : 2 adduct becomes significant at high base concentrations, and appears to involve cation-specific ion-pairing effects. The limiting value of log Kapp at low concentrations is -3.1. In EtOD solutions of the same alkoxide concentration, the equilibrium constant is greater than that in EtOH solutions by a factor of 2.5. This result and measurements in mixtures of EtOH and EtOD are consistent with the formulation of the ethoxide ion as an entity containing three hydrogen-bonded solvent molecules, and a deuterium fractionation factor of ca. 0.72–0.73 for the hydrogen-bonded positions.

Substitution Reactions of Nitrothiophens. II. The Anomalous Reaction of 4-Nitro-2-thenylidene Diacetate with the 2-Nitropropan-2-ide Ion

The reaction of 4-nitro-2-thenylidene diacetate with 2-nitropropan-2-ide ion gives rise to 4-nitro-2-thenaldehyde (6), which is converted into its Meisenheimer adduct (13), together with small amounts of 2-(2'-methylprop-1'-enyl)-4-nitrothiophen (a), 5-(1'-methyl-1'-nitroethyl)-2-(2-methylprop-1''-enyl)-4-nitrothiophen (9) and 2-methyl-1-[5'-(1''-methyl-1''-nitroethyl)-4'-nitro-2'-thienyl]-2-nitro- propyl acetate (10). Mechanistic routes relating the adduct (13), whose 1H and 13C N.M.R. data are presented, and the two other proposed intermediates, 5-(1'-methyl-1'-nitroethyl)-4-nitro-2-thenalde- hyde (11) and 2-methyl-2-nitro-1-(4'-nitro-2'-thienyl)propyl acetate (12), are discussed.