Reactions of Acyl Halides Acyl Halides Hydrides Hydride Reduction Lithium aluminum hydride LiAlH4 reduces acyl halides to primary alcohols acyl halides with react with a weaker reducing agent to yield an aldehyde We can convert an acyl chloride into an aldehyde by hydride reduction In this transformation we face a selectivity problem lithium aluminum hydride LiAlH4 and sodium borohydride reduce acyl halides to alcohols To prevent such overreduction we must modify LiAlH4 by letting it first react with three molecules of 2 methyl 2 propanol tert butyl alcohol This treatment neutralizes three of the reactive hydride atoms leaving one behind that is nucleophilic enough to attack an acyl chloride by not the resulting aldehyde Example Reactions of Carboxylic Acid Anhydrides Carboxylic Acid Anhydrides Water Hydrolysis occurs quickly even in moist air with no acid or base catalyst Reagents must be protected from moisture In every addition elimination reaction except hydrolysis the carboxylic acid side product is usually undesired and is removed by work up with aqueous base Reactions of Carboxylic Acid Anhydrides Carboxylic Acid Anhydrides Alcohols MECHANISM Cyclic anhydrides undergo similar nucleophilic addition elimination reactions that lead to ring opening Reactions of Carboxylic Acid Anhydrides Carboxylic Acid Anhydrides Amines MECHANISM Reactions of Esters Esters Water Ester Hydrolysis Acid Catalysis Base Catalysis Saponification Esters undergo nucleophilic substitution reactions by means of addition elimination pathways though with reduced activity relative to halides and anhydrides Thus catalysis by acid or base becomes a frequent necessity The mechanism of this transformation via acid catalysis is the reverse of esterification As in esterification the acid serves two purposes 1 It protonates the carbonyl oxygen to make the ester more reactive toward nucleophilic attack 2 It protonates the alkoxy oxygen in the tetrahedral intermediate to make it a better leaving group MECHANISM Strong bases also promote ester hydrolysis through an addition elimination mechanism The base converts the poor nucleophile water into the negatively charged and more highly nucleophilic hydroxide ion Ester hydrolysis is frequently achieved by using hydroxide itself in at least stoichiometric amounts as the base Example MECHANISM Reactions of Esters Esters Alcohols Transesterification Esters react with alcohols in an acid or base catalyzed transformation called transesterification this allows for the direct conversion of one ester into another without proceeding through the free acid Like esterification transesterification is reversible To reverse the equilibrium a large excess of the alcohol is usually employed sometimes in the form of solvent The mechanisms of transesterification by acid and base are analogous to the mechanisms of the corresponding hydrolyses to the carboxylic acids Acid catalyzed transesterification begins with protonation of the carbonyl oxygen followed by nucleophilic attack of the alcohol on the carbonyl carbon In contrast under basic conditions the alcohol is first deprotonated and the resulting alkoxide ion then adds to the ester carbonyl group Lactones are opened to hydroxyl esters by transesterification Butyrolactone Conversion of a Lactone into an Open Chain Ester 3 Bromopropyl 4 hydroxybutanoate 3 Bromopropanol Reactions of Esters Esters Amines Amines which are more nucleophilic than alcohols readily transform esters into amides No catalyst is needed but heating is required MECHANISM Reactions of Esters Esters Organometallic Reagents Methyl Formate Organometallic Reagents Esters can be converted into alcohols by using two equivalents of grignard or organolithium reagents after protonation ordinary esters are transformed into tertiary alcohols whereas formate esters furnish secondary alcohols Examples The reactions begins with addition of the organometallic reagent to the carbonyl function in the usual manner to give the magnesium salt of a hemiacetal At room temperature rapid elimination results in the formation of an intermediate ketone or aldehyde from formates The resulting carbonyl then immediately adds a second equivalent of organometallic reagent Subsequent acidic aqueous work up leads to the observed alcohol MECHANISM Reactions of Esters Esters Hydrides Alcohols Aldehydes Lithium aluminum hydride reduces esters to primary alcohols 0 5 equivalent of the hydride is required because only two hydrogens are needed per ester function A milder reducing agent allows the reaction to be stopped at the aldehyde oxidation stage such a reagent is diisobutylaluminum hydride when used in low temperatures in toluene Examples Reactions of Esters Enolates Reactions of Amides Amides Water Acidic Conditions Basic Conditions Prolonged heating in 6 M HCl or 40 aqueous NaOH is required Base hydrolysis requires loss of a very poor leaving group The reaction proceeds as in ester hydrolysis because the tetrahedral intermediate is high in energy compared to the resonance stabilized substrate and product molecules The equilibrium is driven forward through very rapid protonation of the strongly basic leaving group by the carboxylic acid that is liberated in the elimination step The overall process therefore furnishes the carboxylate salt which is protonated during subsequent aqueous work up to produce the acid MECHANISM Base Catalyzed Acid hydrolysis liberates the amine in the form of an ammonium salt MECHANISM Acid Catalyzed Examples Reactions of Amides Amides Hydrides Amines Aldehydes Lithium aluminum hydride reduces amides to amines 1 amides reduce to 1 amines 2 amides reduce to 2 amines 3 amides reduce to 3 amines DIBAL reduces amides to aldehydes Examples The mechanism of amide reduction by LiAlH4 to produce an amine begins with hydride addition which gives a tetrahedral intermediate Elimination of an aluminum alkoxide leads to an iminium ion Addition of a second hydride gives the final amine product MECHANISM Amide Reduction by LiAlH4 to an Amide Reactions of Amides Enolates Reactions of Amides Amidates and Their Halogenation The Hofmann Rearrangement Amidates Hofmann Rearrangement In amides hydrogens on both the carbon and nitrogen atoms next to the carbonyl group are acidic Removal of the NH hydrogen which has a pKa of about 22 with base leads to an amidate ion The CH proton is less acidic with a pKa of about 30 therefore deprotonation of the carbon leading to an amide enolate is more