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100 Chapter 21. Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions General Mechanism: Carboxylic Acid Deri

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100 Chapter 21. Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions General Mechanism: Carboxylic Acid Deri Chapter 21. Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions General mechanism: O leaving O O acyl C O group R Y group + Y: C C C R Y R Nu R Nu :Nu Y tetrahedral intermediate Carboxylic acid derivatives: Increasing reactivity O O O O O O C C C C C C R OH R N R OR' R O R' R Cl carboxylic acid acid amide ester acid anhydride chloride parent O O O C C P Chapter 21.8 function group R SR' R O O O please read thioester acyl phosphate 197 21.1 Naming Carboxylic Acid Derivatives: (Please read) Acid Chlorides: Derived from the carboxylic acid name by replacing the -ic acid ending with -yl choride or replacing the -carboxylic acid ending with -carbonyl chloride O O O C C Cl C Cl H3C Cl acetyl chloride benzoyl chloride Cyclohexancarbonyl chloride (from acetic acid) (from benzoic acid) (from cyclohexane carboxylic acid) Acid Anhydrides: Name symmetrical anhydrides as the carboxylic acid except the word acid is replaced with anhydride O O O O C C O C C H3C O CH3 acetic anhydride benzoic anhydride 198 100 Amides: Primary amides (RCONH2) are named as the carboxylic acid except the -ic acid ending is replaced with -amide or the -carboxylic acid ending is replaced with -carboxamide. O O O C C NH C 2 NH2 H3C NH2 acetamide benzamide Cyclohexancarboxamide (from acetic acid) (from benzoic acid) (from cyclohexane carboxylic acid) Substituted amides are named by first identifying the substituent(s) with an N- in front of it, then naming the parent amide O O O C CH2CH3 C CH CH C CH3 N 2 3 H3C N N H CH 3 CH2CH3 N-methylacetamide N-ethyl-N-methylbenzamide N,N-diethylcyclohexancarboxamide 199 Esters: Esters are named by first identify the group on the carboxylate oxygen, then identifying the carboxylic acids and replacing the -oic acid with -ate. O O O C CH3 C O C H3C OCH2CH3 OC(CH3)3 ethyl acetate methyl benzoate tert-butylcyclohexancarboxylate 21.2 Nucleophilic acyl substitution reactions O Y = a leaving group O O + Y: -OH, -OR’, -NR , -Cl, C C C 2 R Y R 2- Nu R Nu -O2CR’, -SR’,-OPO3 :Nu Y tetrahedral intermediate 200 101 Relative reactivity of carboxylic acid derivatives: The mechanism of nucleophilic acyl substitution involves two critical steps that can influence the rate of the overall reaction: 1) the initial addition to the carbonyl groups, and 2) the elimination of the leaving group. The nature of the acyl group: The rate of addition to the carbonyl carbon is slower as the steric demands of the R group increase. Branching at the α-carbon has the largest effect. Increasing reactivity O O O O R C < R C < R C H C C Y C Y C Y < C Y R R R H H H H H Recall from Chapter 4: -CH3 ΔG°= 7.6 KJ/mol -CH2CH3 8.0 R -CH(CH ) 9.2 Keq 3 2 R H -C(CH3)3 > 18 -CH2C(CH3)3 8.4 H 201 -C6H5 12.6 Nature of the leaving group (Y): In general, the reactivity of acyl derivatives correlate with leaving group ability. Increasing reactivity O O O O O C C C C < C R N < R OR' < R O R' R Cl amide ester acid anhydride acid chloride What makes a good leaving group? R’2N-H R’O-H R’CO2-H Cl-H pKa: 30-40 16-18 4-5 -7 The reactivity of the acyl derivative inversely correlates with their resonance electron-donating ability Resonance effect of the Y atom reduces the O O electrophilicity of the carbonyl carbon. C C R NH2 R NH2 Partial double bond character of the C-N bond makes it harder to break. 202 102 All acyl derivatives are prepared directly from the carboxylic acid Less reactive acyl derivative (amides and esters) are more readily prepared from more reactive acyl derivatives (acid chlorides and anhydrides) acid chloride acid anhydride ester amide y t acid anhydride i v i t c a carboxylic e r acid ester amide g n i s a e r ester c n I amide amide 203 Nucleophilic acyl substitution reactions O hydrolysis C Y= -Cl, -O2CR', -OR', -NR'2 R OH H2O carboxylic acid O aminolysis C Y= -OH, -Cl, -O2CR', -OR' R NR' R'2NH 2 amide O O C alcoholysis R Y C Y= -OH, -Cl, -O2CR' R OR' Carboxylic acid R'OH ester derivative Y= -OH, -Cl, -O CR', O H H 2 reduction Y= -OH, -Cl, -O CR', -OR' -OR', -NR'2 C C 2 H R H R OH H H C Y= -NR2 R NR2 O R'' R'' C C R''-M R R'' R OH R''-M = R''2CuLi R''-M = R''-MgBr, R''-Li Y= -Cl Y= -Cl, -OR' 204 103 21.3 Nucleophilic acyl substitution reactions of carboxylic acids Nucleophilic acyl substitution of carboxylic acids are slow because -OH is a poor leaving group Reactivity is enhanced by converting the -OH into a better leaving groups However, acid chlorides, anhydrides, esters and amides can be prepared directly from carboxylic acids O C R OH carboxylic acid O O O O O C C C C R Cl R O R' R OR' R NR'2 acid chloride acid anhydride ester amide 205 Conversion of carboxylic acids into acid chlorides Reagent: SOCl2 (thionyl chloride) O SOCl2, !" O C C + SO2 + HCl R OH R Cl Recall the conversion of 1° and 2° alcohols to alkyl chlorides Mechanism (p. 780), please read 206 104 Conversion of carboxylic acids into acid anhydrides (please read) Reagent: heat Reaction is best for the preparation of cyclic anhydrides from di-carboxylic acids Conversion of carboxylic acids into esters 1. Reaction of a carboxylate salt with 1° oXXXr 2° alkyl halides Reagents: NaH, R’-X, THF O O O H CH C Br C NaH, THF C 3 2 OH C O O CH2CH3 SN2 Na Note the similarity to the Williamson ether synthesis (Chapter 18.3) 207 Conversion of carboxylic acids into esters 2. Fisher esterification reaction: acid-catalyzed reaction of carboxylic acids with 1° or 2° alcohols to give esters Reagents: ROH (usually solvent), HCl (strong acid) HO H HO H H3CH2C OH C OH C OCH2CH3 C C + H2O HCl O O Mandelic acid Ethyl mandelate Mechanism: (Fig. 21.5, p. 782) 208 105 Conversion of carboxylic acids into amides Not a particularly good reaction for the preparation of amides. Amines are organic bases; the major reaction between a carboxylic acid and an amine is an acid-base reaction (proton transfer) 21.4: Chemistry of Acid Halides Preparation of acid halides (Chapter 21.3) Reaction of a carboxylic acid with thionyl chloride (SOCl2) O SOCl2, !" O C C + SO2 + HCl R OH R Cl 209 Reactions of acid halides Friedel-Crafts acylation (Chapter 16.4): reaction of an acid chloride with a benzene derivative to give an aryl alkyl ketone. O O SOCl O C 2 R C C + HCl R OH R Cl AlCl3 carboxylic acid acid chloride Nucleophilic acyl addition reactions of acid halides 1. hydrolysis O H2O O C C R Cl NaHCO3 R OH acid chloride -or- carboxylic acid NaOH 210 106 2. Alcoholysis: Acid chlorides react with alcohols to give esters. reactivity: 1° alcohols react faster than 2° alcohols, which react faster than 3° alcohols O pyridine O Cl OH + C + C N R Cl R O H acid chloride ester 3. Aminolysis: Reaction of acid chlorides with ammonia, 1° or 2° amines gives amides. O O + H2NR2 Cl C + HNR2 C R Cl R NR2 amine acid chloride (two equiv) ester 211 4. Reduction: Acid chlorides are reduced to primary alcohols with lithium aluminium hydride (LiAlH4) 5. Reaction of acid chlorides with organometallic reagents: Reacts with two equivalents of a Grignard reagent to give a 3° alcohols (recall reaction with esters) a) THF O + OH b) H3O + MgXCl + H C MgX C CH C 3 R 3 R Cl CH3 Grignard reagent acid chloride 3° alcohol (two equiv.) 212 107 Reaction of acid halides with diorganocopper reagents a) ether O + O b) H3O C + (H3C)2 CuLi C R Cl R CH3 diorganocopper acid chloride ketone reagent Mechanism (page 787), not typical, specific to diorganocopper reagents. please look it over if you like Diorganocopper reagent can be alkyl, aryl or vinyl O a) 4 Li(0) H C O H H H b) CuI H3CH2CH2C Cl H C C C 2 C C H CH CH C C H C Cu Li 3 2 2 H Br H H 2 Fill in the reagents: O O OH O O OCH2CH3 OCH2CH3 OCH2CH3 O O O OH Cl CH2CH3 Ch. 21.6 213 21.5 Chemistry of acid anhydrides Preparation of acid anhydrides O Na O O O O O + NaCl C + C C C C C R Cl O R' R O R' R O R' Cl acid chloride sodium acid anhydride carboxylate Reactions of acid anhydrides Acid anhydrides are slightly less reactive reactive that acid chlorides; however, the overall reactions are nearly identical and they can often be used interchangeably. They do not react with diorganocopper reagents to give ketone 214 108 21.6 Chemistry of esters Preparation of esters Na 1. O O O NaH, THF H3C I Limited to 1° alkyl halides C C C R OH R O R O CH and tosylates SN2 3 2. O O H3CH2C-OH Limited to simple 1° and 2° C R OH C alcohols (used as solvent) HCl R O CH2CH3 H3C CH 3.
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