"Characteristic Reactions of Carboxylic Acid Derivatives"
Characteristic Reactions of Carboxylic Acid Derivatives • Undergo substitution reactions (called nucleophilic acyl substitution): • The nucleophile attacks the acyl carbon to form a tetrahedral intermediate. • The leaving group (Y) is lost and the C=O is reformed. • The nucleophile can be neutral or negatively charged. • Nucleophiles: organometallics (Grignard, organolithium, Gilman), hydride, water, alcohol, amine • The reaction rate depends on the leaving group ability of Y group. • Leaving group ability (based on base strength): O Br, Cl > O C R > OR > NR 2 best leaving group poor leaving group (weakest base) (strongest base) most reactive least reactive derivative derivative • Hydrogen and alkyl groups (aldehydes and ketones) do not act as leaving groups. Why? • Hydrides (H) and carbanions (C) are very strong bases and are too reactive to act as leaving groups. • Interconversion of acyl groups is possible: see Figure 21.2 • A more reactive acyl group can be converted to a less reactive group. O O O O R1 C Cl + O C R2 R1 C O C R2 + Cl stronger base weaker base equilibrium to products • A less reactive acyl group can not be converted to a more reactive group. O O O O R 1 C O C R 2 + Cl R1 C Cl + O C R2 weaker base stronger base equilibrium to reactants Reactions 1. Reactions of Acid Chlorides and Anhydrides • Both compounds react similarly: both have good leaving groups (that are weak bases). a. Reaction with alcohols and water • No catalyst (acid or base) needed • Synthesis of esters (from alcohols) and carboxylic acids (from water) O O CH3 C Cl + H2 O CH3 C OH + HCl (as gas) O O O O CH3 C O C CH3 + H2 O CH3 C OH + HO C CH3 Y group O O O O CH3 C O C CH3 + CH3 OH CH3 C OCH3 + HO C CH3 Mechanism: same for both acid chlorides and anhydrides • Involves an initial attack of C=O carbon by H 2O or ROH • When using acid chlorides, an amine base (pyridine, triethylamine) is added to neutralize HCl by-product b. Reaction with amines: synthesis of amides from NH 3, 1o or 2o amines • For acid halides, excess amine (2 equivalents) is needed for the reaction: the second equivalent will neutralize the acid by-product (which may otherwise react with the amide). O O C Cl + H N CH2 CH3 C N CH2 CH3 + HCl CH2 CH3 CH2 CH3 o 2 amine H (use in excess) H N CH2 CH3 Cl CH2CH3 O O C Cl + H N CH2CH3 C N CH2CH3 CH 2CH3 CH2CH 3 CH3 CH3 N,N-diethyl-m-toluamide (DEET) active ingredient in Off O O O O NH 2 + CH 3 C O C CH3 N C CH3 + HO C CH3 H • Only one equivalent of amine needed for anhydride reaction: acetic acid is a weak acid and not very reactive with amides. Mechanistic overview: similar to hydrolysis mechanism • Amine nitrogen attacks the C=O carbon to form tetrahedral intermediate. • The leaving group leaves, then deprotonates the ammonium intermediate.