Donald R. Marshall

2,3-Dihydro-1,4-diazepines

Publisher Summary This chapter discusses 2,3-dihydro-1,4-diazepines. The first diazepine to be prepared, namely the 5,7-dimethyl derivative, is obtained by condensation of acetylacetone with ethylenediamine, and the reaction between β-dicarbonyl compounds and 1,2-diamines has remained the commonest method for the preparation of these compounds. Dihydrodiazepines are extremely stable compounds over a very wide range of pH and their hydrolysis may be ignored at high alkalinity. Bisoxoenamines, on the other hand, are readily hydrolyzed and at all but moderately alkaline pH the hydrolysis equilibrium is such that this condensation is effectively suppressed, leaving formation of the dihydrodiazepine to proceed without competition. At moderately alkaline pH, however, the bisoxoenamine is stable and furthermore precipitates from solution. Thus, its formation competes successfully with the alternative reaction and it is the predominant product. At higher temperatures the yields of bisoxoenamine drop sharply even at the most favored pH values. Almost identical results are found in reactions of other alicyclic or aliphatic diamines with acetyl-acetone.

Diazepines—XXII : 13C NMR spectra of 2,3-dihydro-1,4-diazepinium salts☆

Abstract The 13 C NMR spectra of a number of 2,3-dihdyro-1,4-diazepinium salts, like 1 H NMR spectra, confirm shape, and charge distribution for these compounds. The ring has a half-chair shape which is inverting rapidly at room temperature. The atoms in the conjugated portion of the ring show alternating polarity, and phenyl groups attached to these positions act, respectively, as electron-donors or electron-acceptors. A methyl substituent in the saturated portion of the ring shows equal preference for quasi-equatorial and quasi-axial conformations. Some comparisons are drawn between present results and similar results obtained with related benzene derivatives.

Elimination and addition reactions. Part 33. Formation and behaviour of carbanions derived from sulphones and nitriles bearing β-′onium substituents

Kinetics of elimination reactions of β-arylsulphonylethyl- and β-cyanoethyl-ammonium and -sulphonium salts have been measured in ethanolic triethylamine buffers. The reactions show buffer saturation kinetics; at low buffer base concentrations ionisation to form the intermediate carbanion is rate-determining, but at higher buffer base concentrations the intermediate carbanion is formed in a rapidly established pre-equilibrium step and the observed rate constant does not change with increasing base concentration at constant buffer ratio.The rate data separately yield the ionisation rates of the substrates studied, together with the ratio (k2: k–1) of the rate constants for loss of the ′onium leaving group from the carbanion and its reprotonation.Formation of a carbanion from a sulphone is very sensitive to steric and polar effects; ionisation of nitriles is less sensitive in both respects, particularly the former.The elimination-reprotonation ratio (k2: k–1) depends upon the activating group, but for a given activating group and type of leaving group it is insensitive to the structure of the leaving group. It is also insensitive to substitution at either Cα or Cβ.Comparisons are drawn with unactivated elimination reactions of ′onium salts, and the Hammett ρ value has been obtained for expulsion of the leaving group in the 2-phenylethylammonium series.

Diazepines. Part 25. Preparation and properties of 6-aryl-2,3-dihydro-1,4-diazepinium salts. Electronic interaction between the rings and steric inhibition thereof

A variety of 6-aryldihydrodiazepinium salts (including also 6-biphenyl-4-yl, 6-α-naphthyl, and 6-N-pyridyl) has been prepared, mostly by reactions of 1,2-diamines with 3-aryl-1,5-diazapentadienium salts. The electron-rich dihydrodiazepinium cation activates the 6-aryl substituent towards electrophilic attack, and halogenation and nitration take place at the p-position. Substituents vicinal to the ring junction in either the six- or seven-membered rings inhibit this reactivity, presumably by preventing coplanarity of the two rings; the 13C n.m.r. spectra of these vicinally substituted compounds also show the lowered electronic interactions between the rings. NN′-Diphenyl and NN′-dibenzyl substituents also inhibit electrophilic substitution in the 6-phenyl ring. Solution in deuteriosulphuric acid generates a stable radical species. Nucleophiles (monoamines, diamines, sodium hydroxide) attack the 5-and 7-positions of the diazepine ring. The 13C n.m.r. and mass spectra of these compounds are discussed.

Elimination and addition reactions. Part 32. Discrimination between concerted and stepwise processes in activated elimination reactions

In 1,2-elimination reactions activated by phenylsulphonyl, cyano, and benzoyl groups with leaving groups SO2Ph, SPh, and OPh, comparison of ionisation rates with elimination rates confirms that the (E1cB)R mechanism operates in the sulphonyl and cyano activation series but in the benzoyl series the mechanism for all leaving groups is (E1cB)I. This difference in behaviour is discussed.For all three activation series, comparison of elimination rates with predicted ionisation rates suggests assignments of (E1cB)I mechanism when the leaving group is Cl, OAc, OTs, or OMes but E2 mechanisms when it is I and possibly Br.In all the cases studied, α- and β-phenyl substituents in chloro-, bromo-, and mesyloxy-sulphones affect elimination rates in a manner paralleled by the effect of these substituents on ionisation rates. The results strengthen assignments of (E1cB)1 mechanisms where these have been made.The results are compared with those obtained in other systems in relation to current views on the relationship between stepwise and concerted processes.

Diazepines. Part IV. Dihydrodiazepinium salts from the condensation reaction between NN′-disubstituted ethylenediamines and β-dicarbonyl compounds

β-Diketones as well as β-dialdehydes react with 1,2-dianilinoethane to form 2,3-dihydro-1,4-diphenyl-1,4-diazepinium salts. Other NN′-disubstituted ethylenediamines react similarly. The NN′-dihydrodiphenyl-diazepinium salts are stable in acid but not in alkali. Substitution of the diazepinium cation by bromine has been effected.

Elimination and addition reactions. Part 30. Leaving group abilities in alkene-forming eliminations activated by sulphonyl groups

Rates of elimination of the group Z from a series of β-substituted sulphones, PhSO2·CH2·CH2Z, in ethanolic sodium ethoxide at 25 °C have been measured. For each substrate, the mechanism of the reaction has been shown to be the reversible carbanion mechanism [(E1cB)R] by determination of the primary kinetic deuterium isotope effect or by demonstration that deuterium-hydrogen exchange at Cβ is very much faster than elimination.The kobs, values obtained for these substrates encompass the equilibrium constant for carbanion formation and the rate constant for ejection of the leaving group. The effect of the leaving group on the equilibrium constant, assessed from a Taft plot for sulphone detritiation, has been taken into account where possible in comparison of leaving group abilities.All positively charged leaving groups depart very easily. Among neutral leaving groups the following order of familiar groups is found PhSe > PhO > PhS > PhSO2 > PhSO > NMeTs > NMeAc > CN. The range of reactivity values spans ca. 1016. Carbon-linked leaving groups such as cyano are exceptionally poor.No simple correlation is obtained between leaving group order and pKa of ZH, the dissociation energy of the C–Z bond, the inverse nucleophilicity of Z:, or the polar effect of Z as measured by values of σI(CH2Z) or the 13C chemical shift of Cα–Z.Comparisons are drawn between the present data and earlier, usually qualititative, observations on elimination reactions.

Diazepines. Part XVI. Nuclear magnetic resonance spectra of 2,3-di-hydro-1H-1,4-diazepinium salts

The n.m.r. spectra of a number of 2,3-dihydro-1H-1,4-diazepinium perchlorates are discussed. They indicate that the dihydrodizepinium cation has a half-chair shape which inverts rapidly at room temperature, but inversion is slow at lower temperatures. Variable temperature kinetic studies of the inversion show that it is facilitated by the presence of larger groups at the 6-position, but is independent of the electronic nature of these substituents. There appears to be complete delocalisation in the unsaturated portion of the molecule, and the 6-position has a greater electron density than the 5(7)-positions.

Diazepines. Part V. 2,3-Dihydro-1H-1,4-diazepines

When equimolar mixtures of β-diketones and aliphatic 1,2-diamines are heated in acetic acid 2,3-dihydro-1H-1,4-diazepine derivatives are formed. If, however, 2 : 1 mixtures of these reactants are kept at room temperature, either in alcohols or without solvent, open-chain condensation products result. Glycinamide reacts with acetyl-acetone to give an azomethine rather than a diazepine. Perhydro-1,4-diazepine could not be dehydrogenated to a dihydrodiazepine. The 2,3-dihydro-1H-1,4-diazepinium cation is very stable, as evinced by the pK values of the diazepine and by its relative stability to permanganate oxidation.

Diazepines, Part 28. Crystal and molecular structures of some dihydrodiazepinium salts and correlation with their reactivity and spectra

The crystal and molecular structures of 6-bromo-5-methyl-7-phenyl-, 6-bromo-5,7-diphenyl- and 6-bromo-1,4-dimethyl-dihydrodiazepinium perchlorates have been determined. Some features of these structures, and of other recently determined structures of dihydrodiazepinium salts are discussed and compared with other properties, particularly the reactivity of 6-halogenodihydrodiazepinium salts towards nucleophiles, and the spectra and structure of 5,7-diphenyl derivatives.