Hydrochloric acid nucleophilic substitution reactions

The prominent role of alkyl halides in formation of carbon-carbon bonds by nucleophilic substitution was evident in Chapter 1. The most common precursors for alkyl halides are the corresponding alcohols, and a variety of procedures have been developed for this transformation. The choice of an appropriate reagent is usually dictated by the sensitivity of the alcohol and any other functional groups present in the molecule. Unsubstituted primary alcohols can be converted to bromides with hot concentrated hydrobromic acid.4 Alkyl chlorides can be prepared by reaction of primary alcohols with hydrochloric acid-zinc chloride.5 These reactions proceed by an SN2 mechanism, and elimination and rearrangements are not a problem for primary alcohols. Reactions with tertiary alcohols proceed by an SN1 mechanism so these reactions are preparatively useful only when the carbocation intermediate is unlikely to give rise to rearranged product.6 Because of the harsh conditions, these procedures are only applicable to very acid-stable molecules. 

In the presence of proton and/or Lewis acid and strong nucleophiles bicyclo[3.2.0]heptan-6-ones are converted to 3-substituted cycloheptanones (Table 15). Bicyclo[3.2.0]heptan-6-ones rearrange to give 3-iodocycloheptanones on treatment with iodotrimethylsilane. Zinc(II) iodide or mercury(II) halides as catalysts enhance the rate and the selectivity of the reaction.31 If a second, enolizable carbonyl group is present, an intramolecular alkylation may follow the ring enlargement under these reaction conditions.32 Consecutive treatment with tributyltin hydride/ 2,2 -azobisisobutyronitrile affords reduced, iodo-free cycloheptanones, whilst treatment with l,8-diazabicyclo[5.4.0]undecene yields cycloheptenones.33 Similarly, benzenethiol adds to the central bond of bicyclo[3.2.0]heptan-6-ones in the presence of zinc(II) chloride and hydrochloric acid under anhydrous conditions to form 3-(phenylsulfanyl)cycloheptanones.34... 

Reactive acid derivatives (i.e. acid chlorides and acid anhydrides) get hydrolysed by water to give the constituent carboxylic acids (Following fig.). The reaction is an example of nucleophilic substitution where water acts as the nucleophile. Hydrochloric acid is a by-product from the hydrolysis of an acid chloride, so pyridine is generally added to the reaction mixture to mop it up (Fig.J). 

If the activated aromatic compound reacts with a mixture of formalin, concentrated hydrochloric acid, and ZnCl2, the result is a so-called chloromethylation (Figure 5.29). The stable reaction product is a primary benzyl chloride. This reaction is initiated by an electrophilic substitution by protonated formaldehyde it is terminated by an SN1 reaction in which a chloride ion acts as the nucleophile. 

Nucleophilic aromatic substitution of the fluorine substituents by benzene-dithiolate sulfur atoms (step a), reduction of the nitro compound (step b), diazotization, reaction with KSaCOEt, alkaline hydrolysis, and acidification gave tpS4 H2 (step c). It could be purified via the [Ni(tpS4)]2 complex (Fig. 1), which is readily hydrolyzed with dilute hydrochloric acid to give pure tpS4 H2. 

Nucleophilic substitution of the diazo group is practically the only method for the production of nitro derivatives of tetrazole [392, 436 143], 5-Nitrotetrazole itself was isolated and identified in the form of metallic salts [436-440, 442, 443], The mechanism of substitution of the diazo group by a nitro group in heterocyclic compounds has not been studied specially. As already mentioned, in many cases the reaction takes place as catalytic nucleophilic substitution and does not require the use of a catalyst (copper salts) [392,444], The results from investigation of the kinetics of the substitution of the diazonium group by the nitro group in compounds of the benzene series make it possible to suppose that the diazonitrite is formed intermediately and quickly reacts with a second nitrite anion [392,444], Some difference between the kinetics of the reaction of 3-diazonium-5-carboxy-l,2,4-triazole and 3-diazonium-5-methoxycarbonyl-l,2,4-triazole with sodium nitrite in hydrochloric acid and the analogous process in the benzene series is probably due to prototropic... 

Sometimes a cathodic substitution reaction takes place during the reduction of ortho-substituted nitrobenzenes thus the reduction of 2-nitrophenoxyacetic acid (21) in 2 N hydrochloric acid (50% ethanol) yielded 5-chloro-2H-l,4-benzoxazin-3(4H)-one (22), Y = C1) rather than the expected cyclic hydroxamic acids02 in the presence of another nucleophile Y (e.g., thiocyanate) ring substitution with this reagent occurs. 

The hydrolysis rates of 1,3-dioxolanes are decreased by substitution of four methyl groups at the positions 4 and 5. 2,4,4,5,5-Pentamethyl-l,3-dioxolane reacts 6.5 times more slowly than 2-methy 1-1,3-dioxolane [161]. The AS value is decreased by 9 eu. A Hammett p value of—2.0 has been found for the substituent effect on the hydrolysis of 2-phenyl-4,4,5,5-tetramethyl-l,3-dioxolane in dilute aqueous hydrochloric acid [167]. The data obey the simple Hammett equation, and it is not necessary to apply o+ values. For the reaction of the unsubstituted 2-phenyl-4,4,5,5-tetramethyl compound, the solvent isotope effect is kH/kD = 0.42, and AS is —14.2 eu. General catalysis by formic acid has been observed in the hydrolysis of the p-methoxy compound. However, the rate is not significantly increased by addition of strong nucleophiles. 

The degree of substitution is determined by reaction temperature [7]. The first substituent is introduced in an exothermic reaction at 0°C, the second at 40-45°C and complete substitution required temperatures of 80-100°C. Tertiary amines were employed as base in order to remove hydrochloric acid liberated during the reaction. More satisfactory results (i.e., reaction time and yield) were obtained by employing a two-fold mole increase of amine-nucleophile, thereby obtaining products 7 to 12 as clear, viscous and distillable liquids in yields greater than 90 %. 

In the reactions of 6 with N- and C-nucleophiles in ethanol at room temperature and an equimolar amount of hydrochloric acid, the dimethylamino group was substituted to give 7 and 8 in 61-80% yields, respectively. Since 6 is soluble in water with hydrochloric acid, the reactions can also be carried out in water with essentially the same yields, as the corresponding reactions in ethanol, with simple isolation of the products (Scheme 3). 

In 1910 Robert Pschorr and Gerhard Hoppe reported the synthesis of indole via the reaction of o-nitrophenylace-tonitrile with tin foil and concentrated hydrochloric acid to give initially o-aminophenylacetonitrile. Subsequent treatment with sodium in boiling ethanol afforded indole (Scheme 1, equation 1) [1], The starting o-nitrophenylace-tonitrile was synthesized from o-nitrophenylacetic acid in a few steps. Although this simple synthesis of indole is first attributed to Pschorr and Hoppe, it was Makosza who greatly extended it by means of his vicarious nucleophilic substitution (VNS) of hydrogen as an efficient route to the prerequisite o-nitrophenylacetonitriles, as presented in Chapter 43. 

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