Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution

Carboxylic Acid Derivatives:Nucleophilic Acyl Substitution

NOMENCLATURE

ACYL GROUPS ACID HALIDES IUPAC an acyl group -oyl Common “oh-wheel” -yl ethanoyl acetyl “eel” butanoyl chloride ethanoyl chloride benzoyl chloride butyryl chloride acetyl chloride

SALTS OF ACIDS metal -oate “oh-ate” sodium pentanoate potassium benzoate potassium benzenecarboxylate

ESTERS alkyl group ethyl pentanoate -oate methyl 2-methylpropanoate methyl isobutyrate

ESTERS isopropyl benzenecarboxylate isopropyl benzoate tert-butyl phenylethanoate

ESTERS methyl cyclohexanecarboxylate

Esters as Flavoring Substances

an acyl group ACYL FUNCTIONAL GROUP INTERCONVERSIONS

SOME ACYL COMPOUNDS ACID DERIVATIVES carboxylic acid acid chloride primary secondary tertiary amides ester anhydride These compounds differ from aldehydes and ketones in that they have a leaving group: -OH -Cl -OR -NH2 -O(C=O)R

COMPARISON OF CARBONYL COMPOUNDS The typical reaction of an aldehyde or ketone is addition, or an addition followed by loss of water. enamine -H2O imine acetal :Nu-R hemiacetal Acid derivatives (acyl compounds) undergo substitution reactions. + :X a leaving group displacement :Nu-R

Nucleophilic Acyl Substitution SIMPLIFIED VIEW - addition of nucleophile - elimination of leaving group - carbonyl group forms again most aren’t this simple, proton transfers are usually required

+I +R -I REACTIVITY OF CARBONYL COMPOUNDS most reactive least reactive special case ( acidic H ) .. .. OH- .. no catalyst required acid catalyst required with weak nucleophiles only acid catalyst required (base may be used for hydrolysis) acid required (in the conjugate base C=O is deactivated) Not acid derivatives; different chemistry.

REACTIVITY IS ALSO REFLECTED IN THE STABILITY OF THE LEAVING GROUP (not considering acid catalysis) MOST REACTIVE - Cl - - O-R’ - NH2 STRONGEST BASE

PREPARATION OF ACID CHLORIDES

QUICK REVIEW Preparation of an Acid Chloride benzene or “neat” thionyl chloride ( a liquid ) The same reagent that converts alcohols to halides R-O-H R-Cl

CHLORIDES, BROMIDES AND IODIDES In SN2 reactions you learned the rate sequence R-I > R-Br > R-Cl and that iodides are better substrates than chlorides. This is true. Based on this knowledge ….. many students assume that if acid chlorides are good, the acid bromides and iodides must be better. However …… acid bromides and iodides are difficult to prepare, and the iodides are quite unstable ….. you should use the chlorides. They are easily prepared from the acid by: R-COOH + SOCl2

REACTIONS THAT DO NOT REQUIRE CATALYSIS ACID CHLORIDES ACID ANHYDRIDES

REACTIONS OF ACID CHLORIDES NO CATALYST REQUIRED Hydrolysis Acid Ester - + Amide 2 equivalents

.. - : : Cl .. .. - : : Cl .. ACID CHLORIDES d- .. .. - : : : d+ .. .. : : + .. .. .. .. very reactive no catalyst needed .. water or alcohol .. .. : : .. .. .. + .. .. + ..

Preparations of an Acid Anhydride best method NaOH P2O5 heat The acid chloride and the acid may be reacted directly to form the anhydride, but the reaction usually gives a better yield if the carboxylate salt is used (shown above). 2 This method works best with small MW liquid acids or diacids that can make a cyclic anhydride. + HCl

Formation of Cyclic Anhydrides heat + Geometry is important in forming cyclic anhydrides. phthalic acid phthalic anhydride Linear anhydrides are usually not made by this method. heat + maleic acid maleic anhydride cis trans fumaric acid no reaction heat

ACID ANHYDRIDES ARE ALMOST AS REACTIVE AS ACID CHLORIDES NO CATALYST REQUIRED 2 equivalents Hydrolysis + H-OH + Acid + R’-OH + Ester .. .. - + R2NH2 Amide 2 equivalents

EVERYTHING CAN BE MADE FROM THE ACID (CHLORIDE) RMgX + CO2 NaOH H2O SOCl2 Na+ R’OH “ACID DERIVATIVES” NH3 NR’2H …. or the anhydride

REACTIONS THAT REQUIRE ACID CATALYSIS

H H O H H O H Acid-Catalyzed Nucleophilic Acyl Substitution SIMPLIFIED .. + : ..

Functional Group Interconversions Conversions that proceed via the acid chloride or anhydride. These Reactions Do Not Require Catalyst

Functional Group Interconversions R’OH H2O NH3 NR’2H NH3 NR’2H R’OH H2O These New Interconversions Are Also Possible

Reactions That Do Not Go Via the Acid Chloride or Anhydride R’OH These pathways require acid catalysis, although in the hydrolysis reactions (H2O) basic catalysis (NaOH) may also be used. The basic product is: H2O R’’OH NH3 NR’2H NH3 NR’2H - + R’OH H2O Na instead of the acid. Reactions Requiring Acid Catalysis ….. typically H2SO4

Fischer Esterification EQUILIBRIUM The equilibrium position is usually about 50/50 unless shifted by using an excess of a reactant or removing water. ECONOMICS: use an excess of the cheaper starting reactant.

Fischer Esterification MECHANISM H2SO4 + 2 ROH 2 ROH2+ + SO42- + .. .. .. .. + : : 2 + H+ .. .. + RCOOH .. slow .. + .. .. .. .. 1 excess : .. : .. .. + : : .. .. .. .. + H2O + .. lost

Transesterification mechanism is similar to the Fischer Esterification EXAMPLE heat excess

Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution