The Kinetics and Mechanisms of Aromatic Nucleophilic Substitution Reactions in Liquid Ammonia

Abstract

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 Brønsted 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 Brønsted 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.

Enhancing Peptide Ligand Binding to Vascular Endothelial Growth Factor by Covalent Bond Formation

“…22 Due to the electron withdrawing and resonance properties of –NO 2 groups in the 2- and 4-positions of the benzene ring of 1,5-difluoro-2,4-dinitrobenzene (DFDNB), in addition to the activating effect of the 5-fluorine on the 1-fluorine, 23-25 DFDNB appears to be a very reactive cross-linker. The symmetric nature of DFDNB may give the impression that the reactivity of both fluorine leaving groups is equal.…”

A Greatly Under-Appreciated Fundamental Principle of Physical Organic Chemistry

“…Very recently some common organic reactions have begun to be studied in liquid ammonia as a solvent, rather than in water [79,80]. It is going to be very interesting to compare the mechanisms of the same reaction in the two different solvents.…”

Nucleophilic Aromatic Substitution

“…8 A kinetic study of the reaction of the aromatic triflone (6) with substituted anilines in methanol shows that nucleophilic attack is rate limiting. Fluoronitrobenzenes readily undergo solvolysis to give nitroanilines, while reaction with oxygen and sulfur nucleophiles gives the corresponding substitution products with little competing solvolysis product.…”

“…There has also been a theoretical study by DFT showing the favourable effects of hydrogen bonding on substitutions including reactions of 2,4-difluoronitrobenzene with amines, shown in (8), and an intramolecular Smiles rearrangement of an aryl imidate. 15 An intramolecular aminodehalogenation reaction has been used in the formation of benzimidazol-2-ones from N-phenyl ureas; reaction occurs in dimethylsulfoxide (DMSO) in the presence of base.…”