Alkyl halides, hydrolysis

Alkyl and aryl halides are susceptible to hydrolysis leading to a hydroxyl plus the resulting halo acid (Fig. 88). For alkyl halides, the hydrolysis can occur via SN1 (cationic intermediate, associated with a racemization if the center is asymmetric), SN2 (direct nucleophilic attack with inversion of configuration) or by other mechanisms, but a detailed mechanistic discussion is beyond the scope of this chapter. 

The susceptibility of alkyl halides to hydrolysis is a function of the halide (generally, I > Br > Cl > F). In contrast, the rates of aryl halide hydrolysis are generally F > Cl > Br > I. The reversal of the order of rates is because aryl halides hydrolyze via an addition-elimination reaction (March, (129)). The nucleophilic addition step, which is typically the ratedetermining step, is facilitated by the strongly electronegative fluorine. 

After lithiation (LDA), reaction with alkyl halide and hydrolysis, derivatives of a-alkyl acetic acid are obtained with high yield and optical purity of 70-85%86,87. In a mechanistic investigation that involved 13C-NMR studies of lithium derivatives of 45,... 

Alcohols may be prepared by the nucleophilic substitution of alkyl halides, the hydrolysis of esters, the reduction of carbonyl... 

Arylboronic acids.Aryl halides, alkyl borates, and magnesium in THF react under ultrasonication. Hydrolysis of the reaction mixtures provides arylboronic acids. 

The most important method of preparing primary aliphatic amines is that due to Gabriel, in which the undesirable formation of secondary and tertiary amines is excluded.443 It consists of treatment of potassium phthalimide with an alkyl halide and hydrolysis of the A-alkylphthalimide formed. 

White phosphorus reacts with Grignard reagents and organolithium compounds, generating phosphides which give phosphines on hydrolysis phenyl-lithium yields up to 40% of phenylphosphine in this way.361 Alkylation by alkyl halides before hydrolysis leads to unsymmetrical tertiary phosphines.215... 

A-Alkylation Reactions. The 9-BBN complexes of diamines such as 1,8-diaminonaphthalene and 2-aminobenzylamine serve as substrates for selective iV-alkylation. N-chelated borane complexes undergo regioselective mono-(V-alkylation with an alkyl halide under basic conditions without further alkylation. Hydrolysis of the corresponding intermediate provides the mono-iV-alkyl-ated product in excellent yields (eq 53). In this case, the 9-BBN chelation of the diamine both protects the aromatic amine and activates the benzylic amine. 

Treat this 8-ketoester with one equivalent of sodium ethoxide to form an anion followed by alkylation of the anion with one equivalent of an allyl halide. Subsequent hydrolysis of the ester in aqueous base followed by acidification and thermal decarboxylation gives the desired product. 

Problem 28.5 The enolate derived from diethyl acetamidomalonate is treated with each of the following alkyl halides. After hydrolysis and decarboxylation, what amino acid is formed (a) CH3I (b) (CHj aCHCHaCI (c) CH3CH2CH(CH3)Br ... 

The a-carbanion undergoes an Sn2 reaction with the alkyl halide, a Hydrolysis and decarboxylation forms the methyl ketone. 

Anilides and a-Naphthalides. The Grignard reagents prepared from alkyl halides react with phenyl isocyanate (CgHjN=C=0) or with a-uaphthy l isocyanate (C,oH, N=C=0) to yield addition products that are converted by hydrolysis into anihdes and a-naphthalides respectively RX + Mg —> RMgX... 

If only the monocarboxybc acid is required, the ester after hydrolysis with potash may be strongly acidified with sulphuric acid and the mixture heated under reflux the mineral acid promotes decarboxylation at a temperature just above 100°. The net result is the replacement of the halogen atom of the alkyl halide by —CH COOH thus in the above example ... 

The Lewis base that acts as the nucleophile often is but need not always be an anion Neutral Lewis bases can also serve as nucleophiles Common examples of substitutions involving neutral nucleophiles include solvolysis reactions Solvolysis reactions are substitutions m which the nucleophile is the solvent m which the reaction is carried out 8olvolysis m water (hydrolysis) converts an alkyl halide to an alcohol... 

Primary and secondary alkyl halides may be converted to the next higher carboxylic acid by a two step synthetic sequence involving the preparation and hydrolysis of nitriles Nitnles also known as alkyl cyanides are prepared by nucleophilic substitution... 

Section 19 12 Nitnles which can be prepared from primary and secondary alkyl halides by nucleophilic substitution with cyanide ion can be converted to car boxyhc acids by hydrolysis... 

The anion of a p keto ester may be alkylated at carbon with an alkyl halide and the product of this reaction subjected to ester hydrolysis and decarboxylation to give a ketone... 

---