Chapter 20 Carboxylic Acid Derivatives. Nucleophilic Acyl Substitution

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1 ucleophilic Acyl Substitution hapter 20 arboxylic Acid Derivatives ucleophilic Acyl Substitution Y (1) need to have Y as a u Y u u + Y (2) could not happen with aldehydes or ketones as : and : are poor leaving groups l ' ' 2 carboxylic acid chloride carboxylic acid carboxylic acid anhydride carboxylic ester carboxamide Y = l ' 2 We saw this before: 3 1) LiAl 4, Et 2 2) 2 LiAl 4 2 LiAl

2 elative eactivity of arboxylic Acid Derivatives (1) the more positive (electrophilic) the carbonyl carbon, the more reactive (attractive) to an incoming nucleophile δ ' δ > δ > δ δ > δ + l ' 2 (a) l is very electronegative and l is a good leaving group -- carbonyl carbon is very electrophilic (b) carboxylate anions ( 2 ) are also good leaving groups (c) is less electronegative and 2 are less good as leaving groups so amides are the least reactive of the carboxylic acid derivatives l carboxylic acid chloride carboxylic acid anhydride ' carboxylic ester ' 2 carboxamide (d) (e) reactions at carboxylic acid derivatives can also have steric effects

3 Y u Y u sp 2 sp3 Y < < < Y Y Y reactivity substituents attached to carbonyl carbon can sterically affect the approach (attack) of the nucleophile eactivity at carbonyl carbon of carboxylic acid derivative: (1) if carbonyl carbon is positive (electrophilic) enough and nucleophile is strong enough, then Y u Y u u + Y (2) if the nucleophile is weak, then -- i.e. make the carbonyl carbon more positive (electrophilic) Y E + E Y u E u Y etc. E + = E Y

4 eactions of arboxylic Acids: into (1) ester, (2) acid chloride or (3) anhydride (1) onversion of 2 into arboxylic Acid Ester ( 2 ) (a) Acidic esterification: l (i) acidic esterification is an (can drive equilibrium in either direction depending on conditions chosen) (ii) can use many different kinds of alcohols ( 3, 3 2,...)

5 (iii) evidence for mechanism? * + 3 l * * = 18 isotope X alkyl acyl bond bond (b) Williamson Ester Synthesis 18 label experiment is evidence for cleavage in mechanism Base 3 I 3 + I -- (c) Diazomethane ( 2 2 ) Esterification diazomethane + (i) great way to make methyl esters (ii) cleaves the - alkyl bond: 2 2 3

6 (2) onversion of 2 into arboxylic Acid hloride: very useful l l l (i) Pl 3 and oxalyl chloride will also make acid chlorides (ii) PBr 3 can make acid bromides (()-Br) (iii) oxalyl chloride: a very gently reaction (less acid generated): l l pyridine l (iv) Sl 2 and l (=)-(=) l convert X into a good leaving group δ S 2 + l S l δ + l S l l S l l + l

7 (3) onversion of 2 into arboxylic Acid Anhydrides ((=) (=)) P P + 2 2/3 1/3P 2 3 P 4 5 not generally so useful as one uses up 2 moles of 2 eactions of arboxylic Acid alides ((=) X with X = l or Br) (1) onversion of (=) l into arboxylic Acids ( 2 ) l 2 + l 2 2 l (i) (ii) usually one adds a (or pyridine) to absorb the -l

8 (2) onversion of (=) l into arboxylic Acid Esters ( 2 ) '- l ' l pyridine (i) least sterically hindered alcohol reacts faster (ii) need to add a base (pyridine) to absorb the -l generated in the reaction 3 3 l 3 3 (3) onversion of (=) l into arboxamides ((=) 2 ) 3 l 2 + -l 3 4 l l ( 3 ) 2 2 l (i) 3 : amines do not make amides (need to be able to lose a - proton) (ii) one can use pyridine to absorb the l produced (if your amine is valuable)

9 (4) eduction of (=) l (a) onversion of (=) l into Alcohols 1) LiAl 4, TF 2) l 2 Al 2 l Al + l LiAl 4 rapidly reduces the aldehyde that is generated as an intermediate (b) onversion of (=) l into Aldehydes - need less powerful : source (lithium tri-tert-butoxyaluminum hydride) l 1) LiAl( t Bu) 3 2) 2 -- LiAl(( 3 ) 3 ) in Et 2 or TF is a less nucleophilic : source -- will only react with very reactive carbonyl compounds (like acid chlorides) but not with aldehydes

10 (5) eaction of (=) l with Grignard eagents 1) '-MgBr, Et 2 l 2) 2 ' ' ' MgBr 2 l ' ' ketone ' MgBr ' ' + l (i) Grignard addition yields ketone which then reacts with -MgBr again l 1) 2 eq. 3 2 MgBr 2) 2 (ii) if one is careful, one can add only 1 equivalent of MgBr to get a ketone, but cuprate reaction is better (6) eaction of (=) l with rganocuprates 1) ' 2 uli, 78 l 2) 2 ' l 1) ( 3 ) 2 uli 2) 2 3 l 1) ( 2 =) 2 uli 2) 2 2

11 eactions of Anhydrides (Ac--Ac, Ac 2 ) ) LiAl 4 2) 2 3 Ac 2 is often used as a protecting group for a hydroxyl group Ac Ac Ac 2 pyridine + ortho 3

12 eactions of Esters (1) onversion of 2 into arboxylic Acids ( 2 ) (a) Basic onditions: ' 1) a 2) ' 3 + workup ' + ' + ' equilibrium driven to carboxylate anion Evidence for acyl bond cleavage in above mechanism? 3 2 * 2 3 1) a, 2 2) * = 18 isotope * 2 3

13 (b) Acidic onditions: can also hydrolyze an ester under acidic conditions ' +, ' + ' ' ' ' + ' ' (i) same steps as esterification of an acid (see before) (ii) one can drive equilibrium in either direction (2) onversion of 2 into arboxamides ((=) 2 ) ' 3 Et ' better yields are obtained from reactions with acid chlorides (so this method is not used often) l + -l 2 4 l 3

14 (3) eduction of Esters ( 2 ) (a) LiAl 4 reduction 1) LiAl 4, TF 2) ' 2 Al 2 ' Al + ' the initially formed aldehyde is rapidly reduced by the LiAl 4 reagent (b) To get aldehyde, then use a less reactive hydride source such as DIBA [ 2 Al- bond is less hydriditic (due to the electron donating ability of the alkyl groups attached to aluminum) ) DIBA, toluene, 78 2) 3 + Al DIBA = ( 3 ) ( 3 ) 2 diisobutyl aluminum hydride DIBA reaction stops at aldehyde as DIBA cannot reduce an aldehyde

15 (4) eaction of 2 with Grignard reagents 2 equivalents 1) "-MgBr, Et 2 ' 2) 2 " " 3 1) 2 eq. 2) (5) yclic Esters: Lactones (a) Basic onditions 1) a, 2 2) workup (i) cyclic esters react just like acyclic esters but the leaving group remains with the acid derivative

16 (b) LiAl 4 reduction 1) LiAl 4, Et 2 2) 3 + 1) DIBA, toluene, 78 2) 2 (c) Grignard reaction 3 3 1) 2 eq. 3 MgBr 2) 2 eactions of Amides: amides are less reactive than other acid derivatives and used in the important scaffolding for proteins

17 (1) onversion of (=) 2 into carboxylic acid 2 : hydrolysis (a) Acidic ydrolysis: conditions are more severe (heat) than for esters steps heat (b) Basic ydrolysis 1) 2) workup

18 (2) eduction of amides 2 1) LiAl 4 2 2) 2 amine 2 Al Al 3 2 Li Al 3 imine Al Li + -Al 3 Why? is a better leaving group than 2 (pk a ( 3 ) ~ 33; pk a ( 2 ) ~16) 2 1) LiAl 4 2) 2 2 (3) yclic Amides: Lactams 3 3 1) LiAl 4 2) Preparation of itriles (- ) (1) displacement (S 2 rxn) 2 Br a Et 2 typical limitations of an S 2 reaction

19 (2) Dehydration (loss of 2 ) from Amide Sl 2, benzene + S l 2 80 (i) Sl 2, P 2 5, P(=)l 3, and Ac 2 work as dehydrating agents 2 l S l S l + S l + S l (ii) very general as one can easily make amides eactions of itriles ( ) δ + δ (i) is electropositive and electrophilic, so nucleophiles attack carbon of nitrile (ii) is electronegative and nucleophilic and basic, so electrophiles attack nitrogen of nitrile

20 (1) ydrolysis of itriles ( ) (a) Acidic ydrolysis many steps 3 + (b) Basic ydrolysis 1) a, 2 2) many steps

21 (2) ydride eduction of itrile (a) LiAl 4 eduction 1) LiAl 4 2) 2 1) LiAl 4 2) ) LiAl 4 2) 2 2 ow? δ + δ 1) LiAl 4 2) workup Al Al 3 Al 2

22 (b) Selective eduction δ + δ 1) DIBA 2) 2 Al( 2 ( 3 ) 2 ) 2 2 Al' 2 2 imine recall that imine and water are at equilibrium with aldehydes, but that the carbonyl group is favored at equilibrium (3) Grignard Addition to itrile δ + δ 1) '-MgBr 2) 2 ' ' MgBr 2 ' MgBr 2 MgBr ' imine 1) 2) 2 (i) just like DIBA reduction, but a ketone is produced (ii) an alternative to Friedel-rafts acylation

23 Thiol Esters: (=) S S' S' as leaving group (pk a (S) ~ 10) (i) very important in biological systems (ii) acetyl coenzyme A is a common acetylating agent in biological systems (iii) thiol esters are intermediate in reactivity between anhydrides and oxygen esters