Potassium hydroxide (KOH) in dimethyl sulfoxide (DMSO) forms a superbasic medium that allows one to access cross-coupling products from reactions between aryl halides with various sulfur-, oxygen- and nitrogen-based nucleophiles under transition metal-free conditions.

Dimethyl Sulfoxide/Potassium Hydroxide: A Superbase for the Transition Metal‐Free Preparation of Cross‐Coupling Products

Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones.

3.02 – Imidazoles

A kinetic study is reported for nucleophilic substitution reactions of 2,4-dinitro-1-fluorobenzene (DNFB) with a series of secondary amines in MeCN and H2O at 25.0 degrees C. The reaction in MeCN results in an upward curvature in the plot of k(obsd) vs [amine], indicating that the reaction proceeds through a rate-limiting proton transfer (RLPT) mechanism. On the contrary, the corresponding plot for the reaction in H2O is linear, implying that general base catalysis is absent. The ratios of the microscopic rate constants for the reactions in MeCN are consistent with the proposed mechanism, e.g., the facts that k2/k(-1) 10(2) suggest that formation of a Meisenheimer complex occurs before the rate-limiting step and the deprotonation by a second amine molecule becomes dominant when [amine] > 0.01 M, respectively. The Bronsted-type plots for k1k2/k(-1) and k1k3/k(-1) are linear with betanuc values of 0.82 and 0.84, respectively, which supports the proposed mechanism. The Bronsted-type plot for the reactions in H2O is also linear with betanuc = 0.52 which has been interpreted to indicate that the reaction proceeds through rate-limiting formation of a Meisenheimer complex. DNFB is more reactive toward secondary amines in MeCN than in H2O. The enhanced basicity of amines as well as the increased stability of the intermediate whose charges are delocalized through resonance are responsible for the enhanced reactivity in the aprotic solvent.

Choice of Solvent (MeCN vs H2O) Decides Rate-Limiting Step in SNAr Aminolysis of 1-Fluoro-2,4-dinitrobenzene with Secondary Amines: Importance of Brønsted-Type Analysis in Acetonitrile

The rates of aromatic nucleophilic substitution reactions in liquid ammonia are much faster than those in protic solvents indicating that liquid ammonia behaves like a typical dipolar aprotic solvent in its solvent effects on organic reactions. Nitrofluorobenzenes (NFBs) readily undergo solvolysis in liquid ammonia and 2-nitrofluorobenzene is about 30 times more reactive than the 4-substituted isomer. Oxygen nucleophiles, such as alkoxide and phenoxide ions, readily displace fluorine of 4-NFB in liquid ammonia to give the corresponding substitution product with little or no competing solvolysis product. Using the pK(a) of the substituted phenols in liquid ammonia, the Bronsted β(nuc) for the reaction of 4-NFB with para-substituted phenoxides is 0.91, indicative of the removal of most of the negative charge on the oxygen anion and complete bond formation in the transition state and therefore suggests that the decomposition of the Meisenheimer σ-intermediate is rate limiting. The aminolysis of 4-NFB occurs without general base catalysis by the amine and the second-order rate constants generate a Bronsted β(nuc) of 0.36 using either the pK(a) of aminium ion in acetonitrile or in water, which is also interpreted in terms of rate limiting breakdown of the Meisenheimer σ-intermediate. Nitrobenzene and diazene are formed as unusual products from the reaction between sodium azide and 4-NFB, which may be due to the initially formed 4-nitroazidobenzene decomposing to give a nitrene intermediate, which may then give diazene or be trapped by ammonia to give the unstable hydrazine which then yields nitrobenzene.

The kinetics and mechanisms of aromatic nucleophilic substitution reactions in liquid ammonia.

Mechanisms of aromatic nucleophilic substitution reactions by amines in solvents of low relative permittivity

The reactions of 2,6-dinitrophenyl phenyl ether and of 6-methyl-2,4-dinitrophenyl phenyl ether with piperidine, morpholine, butylamine and benzylamine are base catalysed in both dimethyl sulfoxide and acetonitrile. The reaction of 2-phenoxy-3,5-dinitropyridine with aniline is base catalysed in acetonitrile, but not in dimethyl sulfoxide, and its reactions with piperidine, morpholine, butylamine and benzylamine in acetonitrile are also base catalysed. The results are discussed in terms of the prevailing theories of aromatic nucleophilic substitution reactions. Increase in activation of the substrate increases the k2/k–1 and k3/k–1 ratios. For ortho substituents, steric/steroelectronic effects in the transition state reduce both k–1, the rate constant for the decomposition of the zwitterionic intermediate to reactants, and k2 and k3, the rate constants for its decomposition to products. When the substrate has two ortho groups the different behaviour of primary and secondary amines found with substrates containing only one ortho-nitro group is not observed.

The effect of ortho substituents on the mechanism of aromatic nucleophilic substitution reactions in dipolar aprotic solvents

For base-catalysed aromatic nucleophilic substitution reactions in benzene, catalysis by added base is observed irrespective of whether the catalyst is a stronger or a weaker base than the nucleophile. In acetonitrile, catalysis is only observed if the catalyst has either approximately the same strength or is a stronger base than the nucleophile. These observations are shown to indicate a difference in the mechanism of catalysis in the two solvents.

Base catalysis of aromatic nucleophilic substitution reactions in aprotic and dipolar aprotic solvents

The reactions of 2-trifluoromethyl- and 2-cyano-4-nitrofluoro-benzenes with piperidine, n-butylamine and benzylamine in acetonitrile are not base catalysed, but the reactions with morpholine are catalysed. In benzene, the reactions of the 2-cyano-substrate with all four nucleophiles are catalysed. In acetonitrile, the reaction of 2-cyano-4-nitrophenyl phenyl ether with piperidine is base catalysed, whereas that of n-butylamine is not. In benzene, the reactions of this substrate with both nucleophiles are catalysed. The reasons why the reactions of secondary amines in aromatic nucleophilic substitution reactions are more prone to base catalysis than the corresponding reactions with primary amines of the same basicity are discussed.

The origins of the dichotomy of amine effects in aromatic nucleophilic substitution reactions

The kinetics of the reactions of 1-chloro- and 1-fluoro-2,4-dinitrobenzene with morpholine have been studied in dimethyl sulphoxide, dimethylformamide, and nitromethane. The results confirm that the decomposition of the intermediate to products by the uncatalysed path takes place by a unimolecular mechanism. The kinetics of the reactions of 2,4-dinitroanisole with n-butylamine and piperidine in dipolar aprotic solvents have been determined. They show that when primary amines are the nucleophiles, reaction by the uncatalysed path does not occur by the unimolecular mechanism, but by the specific base-general acid (SB–GA) route. The reactions in dimethyl sulphoxide give another example of secondary amines reacting by a base catalysis mechanism whereas the corresponding reaction of a primary amine of the same basicity is not base-catalysed.In a search for electrophilic catalysis the effects of lithium, trialkylammonium, and tetraalkylammonium ions on the reactions of piperdine with 2,4-dinitroanisole and of morpholine with 2,4-dinitrophenyl phenyl ether in dimethyl sulphoxide were investigated. No catalysis was found and a tentative reason is given. When aniline reacts with 2,4,6-trinitrophenyl methyl ether in dimethyl sulphoxide, 82% of the reaction occurs at the methyl carbon atom, and when the substrate is 2,4,6-trinitrophenyl phenyl ether the reaction is not base-catalysed. The first two observations of the change from base-catalysed to uncatalysed aromatic nucleophilic substitution reactions brought about by a change from protic to dipolar aprotic solvent are recorded.

Mechanism of the uncatalysed path of aromatic nucleophilic substitution in dipolar aprotic solvents when primary and secodary amines are the nucleophiles; a search for electrophilic catalysis of these reactions

Jack Hirst

Papers

Mechanisms of aromatic nucleophilic substitution reactions by amines in solvents of low relative permittivity

The effect of ortho substituents on the mechanism of aromatic nucleophilic substitution reactions in dipolar aprotic solvents

Base catalysis of aromatic nucleophilic substitution reactions in aprotic and dipolar aprotic solvents

The origins of the dichotomy of amine effects in aromatic nucleophilic substitution reactions

Mechanism of the uncatalysed path of aromatic nucleophilic substitution in dipolar aprotic solvents when primary and secodary amines are the nucleophiles; a search for electrophilic catalysis of these reactions