Nucleophilic substitutions high-pressure

H. Aromatic Nucleophilic Substitution with Amines under High Pressure... 

The reaction rate is primarily determined by the enthalpy of activation (A// ), which is usually the case in square planar nucleophilic substitution reactions. Of greater importance, so far as a dissociative versus an associative mechanism is concerned, are the entropies and volumes of activation, AS and AY, respectively. Note that the values are negative for both the fct and the steps. The observed decrease in entropy is what we would expect for a mechanism in which two particles come together to give an activated complex. The volume of activation is determined by doing the reaction under high pressure ... 

There has been a review of die effects of high pressure on the substitution reactions of amines witii haloaromatic compounds, including polyhalobenzenes.17 Nucleophilic substiditions by amines often proceed readily hi dimethyl sulfoxide (DMSO). The pKa values, hi DMSO, have been reported for some ammonium ions derived from amines widely used as nucleophiles in 5nAt reactions.18 Correlations have been established19 between die oxidation potentials and the basicities of some arylamhie and diarylamine anions and die rate constants for dieir reactions with aiyl halides in DMSO. 

Additional evidence for the occurrence of gas-phase intermolecular and intramolecular nucleophilic substitution was obtained in an investigation on the reactivity of mono- and dichlorophenols within the high-pressure mass spectrometer source under conditions of argon-enhanced negative ion mass spectrometry282. It was shown that the reactant anions involved in these processes are derived exclusively from the chlorophenols and not from possible impurities such as residual oxygen, water, etc. Thus, for example, the formation of an abundant [2M - H - Cl]" adduct was attributed to an intermolecular nucleophilic Cl displacement by an [M - H]" chlorophenoxide ion282. 

In Chapter 43 we also gave the structure of timolol, a thia diazole-based [3-blocker drug for reduction of high blood pressure. This compound has an aromatic 1,2,5-thiadiazole ring system and a saturated morpholine as well as an aliphatic side chain. Its synthesis relies on ring formation by rather a curious method followed by selective nucleophilic substitution, rather in the style of the last synthesis. The aromatic ring is made by the action of S2CI2 on cyanamide . 

Chlorobenzene, commercially produced by the Raschig process (see p. 108), is resistant to nucleophilic substitution under normal conditions, but in the Dow process, treatment with sodium hydroxide at 300 °C under high pressure is effective. Phenol may also be prepared from chlorobenzene by reaction with steam at 450 °C over a catalyst. 

The concept of electron-rich P(f catalysts is based on the analogy between nucleophilic aromatic substitution (eq. (12a)) and Pd° insertion (cf. eq. (12b)) [42 c, d]. It had previously been applied in the carbonylation of aryl chlorides [38 a, b]. Related work by Milstein [42] and Basset [43] should be consulted. High-pressure conditions seem to enhance the aryl chloride reactivity, too [44]. Meanwhile, various other methods have been developed for the selective activation of aryl chlorides with defined Pd complexes as well as in situ systems (cf. Section 3.1.6.4). 

The first part of this chapter deals with the effects of high pressure on cycloaddition reactions, particularly the Diels-Alder reaction, which is the most important cycloaddition reaction. The second part will illustrate applications of pressure to nucleophilic substitutions, condensations and other reactions (miscellaneous reactions), such as Mannich, Heck, ene, SeAr, Wittig, Horner-Wadsworth Emmons and multicomponent Strecker reactions. 

Aminolysis of epoxides is also promoted by high pressure or silica gel catalysis. For example, 2V-(p-hydroxyalkyl)glycine esters have been prepared in high yields by nucleophilic substitution at 1.0 GPa or under silica gel catalysed conditions of various epoxides with a stoichiometric amount of tert- butyl glycinate. 

Under thermal activation conditions, ester 161 reacts with benzylamine to give a mixture of a-amino-p,y-unsaturated ester 164 and amide 165, but under 1.1 GPa pressure ester 161 gives the spiro-aziridines 162 and 163 in high yield and good diastereoselectivity. These are part of an attractive class of compounds that are formed by hetero-Michael addition of amine onto the unsaturated ester 161, followed by intramolecular nucleophilic substitution of the bromine atom (Scheme 7.41). ... 

Michael additions are rather sensitive to steric hindrance hence, an addition of a nucleophile to yS-disubstituted a, S-unsaturated esters is nearly impossible. On the other hand, the application of high pressure alleviates this limitation and even allows the formation of two adjacent quaternary centers. The reaction of methyl tert-butylcyclohexylidenebromoacetate (107) with benzylamine in refluxing methanol as described by Duhamel et al. gave a mixture of the ester 108a and the amide 108b (Scheme 8.26) [57]. At room temperature another reaction channel is opened which leads to the aziridines 109 and 110. In this reaction, a Michael addition first takes place and this is followed by an intramolecular nucleophilic substitution. At atmospheric pressure, however, a reaction time of 60 days was necessary to obtain an 82 % yield. In contrast, at 1.1 GPa the addition took less than 4 days and the diastereomeric ratio rose from 1 1.7 at ambient pressure to 1 10 at 1.1 GPa in favor of 110. 

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