Michael R. Crampton

σ-Adduct formation and oxidative substitution in the reactions of 4-nitrobenzofurazan and some derivatives with hydroxide ions in water

The reactions of hydroxide ions with 4-nitrobenzofurazan, 1a, 4-nitrobenzofuroxan, 1b, and with three 4-nitro-7-substituted benzofurazans have been examined using 1H NMR and UV-visible spectroscopies. In each case initial reaction is at the 5-position to give an anionic sigma-adduct. Kinetic and equilibrium results are reported. NMR spectra show that in the case of 1a oxidation of the anionic adduct yields 4-nitro-5-hydroxybenzofurazan. In the case of 1b rearrangement of the 5-hydroxy adduct to the thermodynamically more stable 7-hydroxy adduct, possibly by a Boulton-Katritzky mechanism, precedes oxidation. When the 7-substituent in the 4-nitrobenzofurazan is Cl, OMe or OPh the eventual product is 7-hydroxy-4-nitrobenzofurazan produced by nucleophilic displacement of the substituent.

Kinetic and equilibrium studies of σ-adduct formation and nucleophilic substitution in the reactions of 2-phenoxy-3,5-dinitropyridine and 2-ethoxy-3,5-dinitropyridine with aliphatic amines in dipolar aprotic solvents

The reactions of aliphatic amines with 2-phenoxy-3,5-dinitropyridine, 4, and 2-ethoxy-3,5-dinitropyridine, 5, in DMSO result in the rapid reversible formation of anionic sigma-adducts at the 6-position. Kinetic studies show that proton transfer from the initially formed zwitterions to base may be rate-limiting. Slower reactions result, except in the case of 5 and piperidine, in displacement of the 2-substitutent via intermediates which have lower thermodynamic stabilities than their 6-isomers. Base catalysis of the substitution process is attributed in the case of 4 to rate-limiting proton transfer from zwitterionic intermediates, but in 5 to acid catalysis of ethoxide departure (SB-GA mechanism). X-Ray crystallography of 5 shows a planar non-strained structure although the structure of 2-piperidino-3,5-dinitropyridine, 10c, shows distortion resulting from steric interactions of the 2- and 3-substituents. Kinetic and equilibrium results are compared with those for related reactions of the more sterically strained 2,4,6-trinitrobenzene derivatives. Results for the reactions of 4 and 5 with pyrrolidine in three dipolar aprotic solvents are compared. Values of equilibrium constants for sigma-adduct formation decrease in the order DMSO > DMF >> Acetonitrile, while values of rate constants for proton transfer are in the reverse order.

Dissociation kinetics of DNA-anthracycline and DNA-anthraquinone complexes determined by stopped-flow spectrophotometry

The first order rate constants for the dissociation of daunorubicin, doxorubicin, and 1-; 1,4-; 1,5-; and 1,8-; N,N-diethylaminoethylamino-substituted anthraquinones from calf thymus DNA were determined using stopped-flow spectrophotometry. Sodium dodecyl sulphate was used to disrupt the equilibrium. In all cases there was an increase in the rate constant with temperature. The dissociation rate constants at 20 degrees, 25 degrees and 37 degrees, were in the order 1-; much greater than 1,8-; greater than 1,4-; greater than daunorubicin and doxorubicin greater than 1,5-disubstituted anthraquinone. The 1,5-disubstituted anthraquinone (VII) thus shows the slowest rate of dissociation from DNA; the DNA complex dissociating more slowly than the DNA complexes of the anthracyclines, daunorubicin and doxorubicin. The result is consistent with the data from computer graphics modelling studies [39] which show that DNA-breathing (transient base pair unstacking) has to occur to allow the docking of the 1,5-disubstituted anthraquinone (VII) into the receptor site. Hence once the 1,5-disubstituted anthraquinone molecule has intercalated into DNA, DNA-breathing is required before dissociation can take place. This is not necessary with the other compounds (though the 1,4-disubstituted anthraquinone (V) can bind in this manner as well). So the very slow dissociation of the DNA/1,5-disubstituted anthraquinone complex relative to that of the DNA complexes of the other compounds examined here, supports the proposed mode of binding [39].

The stabilities of Meisenheimer complexes. Part 34. Kinetic studies of σ-adduct formation and nucleophilic substitution in the reactions of 2,4,6-trinitrophenetole with aliphatic amines in dimethyl sulphoxide

The reaction of 2,4,6-trinitrophenetole with aliphatic amines in dimethyl sulphoxide results in the formation of anionic σ-adducts via zwitterionic intermediates. Rapid attack at the 3-position is followed by attack at the ethoxy-substituted 1-position. The 1-adducts formed by reaction with n-butylamine and benzylamine undergo acid-catalysed expulsion of ethoxide to yield N-substituted picramides; that formed by reaction with piperidine is relatively stable. Rate and equilibrium data for these reactions have been determined and compared with data for reactions of related compounds. Increased steric crowding at the reaction centre caused by a change from primary amines to piperidine results in reductions in the rate of proton transfer from zwitterionic intermediates to amine catalyst and in the rate of leaving-group expulsion.

ACIDITIES OF SOME SUBSTITUTED AMMONIUM IONS IN DIMETHYL SULFOXIDE

pK a Values in DMSO are reported for ammonium ions derived from amines which have previously been widely used as nucleophiles in nucleophilic aromatic substitution reactions; values are also given for four polynitrodiphenylamines used as indicators.

The acid–base behaviour of hexamine and its N-acetyl derivatives

The protonation equilibria and decomposition reactions in aqueous hydrochloric acid of hexamine and its acylated derivatives (2), (3), and (4) have been examined by u.v. and 1H n.m.r. spectroscopy. pKa Values at 25 °C are: hexamine 4.89, 3,7-diacetyl-1,3,5,7-tetra-azabicyclo[3.3.3.1]nonane (DAPT) 0.7, 1,3,5,7-tetra-acetyl-1,3,5,7-tetra-azacyclo-octane (TAT)-2.5, and 1,3,5-triacelyl-1,3,5-triaza cyclohexane (TRAT)–2.3. Rates of decomposition of the protonated substrates decrease in the order DAPT > TAT > hexamine.Reaction of hexamine with picryl acetate may involve nucleophilic catalysis via the N-acetylhexaminium cation (6).

The stabilities of Meisenheimer complexes. Part 33. Kinetic studies of the formation of isomeric σ-adducts from 2,4,6-trinitrobenzyl chloride and aliphatic amines in dimethyl sulphoxide

Kinetic and equilibrium data are reported for the reversible colour-forming reactions of 2,4,6-trinitro-benzyl chloride with some aliphatic amines in dimethyl sulphoxide and are compared with data for reactions of 1,3,5-trinitrobenzene. With n-butylamine and benzylamine three processes are observable : attack at the 3-position, attack at the 1-position, and transfer of a side-chain proton. For piperidine and pyrrolidine only two-of these are observable, attack at the 1-position being disfavoured for steric reasons. The formation of anionic σ-adducts occurs via zwitterionic intermediates and it is shown that the proton-transfer step may be kinetically significant. Reductions of rate constants for proton-transfer below the values expected for diffusion-controlled reaction are attributed to steric effects which are increased when reaction involves secondary amines and when the CH2Cl group is at the reaction site. Specific effects of chloride ions are noted and are attributed to their interaction with substituted ammonium ions.

The nitration of arenes in perfluorocarbon solvents

Perfluorocarbons have been used effectively as solvents and bulking agents in the reactions of toluene, benzene, phenol, benzyl chloride and chlorobenzene with nitric acid or dinitrogen pentoxide to yield highly nitrated products. Reactions are carried out in a single stage, at lower temperatures, and producing smaller amounts of waste acid than in traditional processes.

Kinetic and equilibrium studies of the ambident reactivity of aniline, and some derivatives, towards 4,6-dinitrobenzofuroxan†‡

The reactions of aniline and its derivatives at the 7-position of 4,6-dinitrobenzofuroxan (DNBF) may result in rapid reaction via the nitrogen centre to give anionic σ-adducts. Equilibrium constants for these reactions in DMSO are reported and correlate with pKa values of the corresponding anilinium ions. Slower reactions are observed involving electrophilic substitution by DNBF at ring-carbon atoms of the aniline derivatives; rate constants are reported. These reactions produce zwitterionic carbon-bonded σ-adducts which, in the presence of excess aniline, are in rapid equilibrium with deprotonated forms. Equilibrium constants for this acid–base process have been measured and indicate that the negatively charged DNBF moiety is electron withdrawing relative to hydrogen.

The Strecker reaction: kinetic and equilibrium studies of cyanide addition to iminium ions.

Kinetics studies are reported of the reactions of benzylidene benzylamine 4a, and of benzylidene allylamine 4b, with cyanide in aqueous buffers to give the corresponding [small alpha]-aminonitriles. The results allow the calculation of values of rate and equilibrium constants for reaction of the iminium ions formed from 4a and 4b with cyanide ions. These values are compared with those, obtained from the hydrolysis reactions, for reaction of the iminium ions with hydroxide ions and with water. Comparison with some other iminium ions reveals that those formed from 4a and 4b are relatively unreactive due to the possibilities of charge delocalisation.