Chapter 21. Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions

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1 hapter 21. arboxylic Acid Derivatives and ucleophilic Acyl Substitution eactions acyl group Y leaving group arboxylic acid derivatives: carboxylic acid Y :u General mechanism: ' u u + Y: Y tetrahedral intermediate Increasing reactivity ' acid anhydride parent function group P hapter 21.8 S' please read thio acyl phosphate 197 l acid chloride 21.1 aming arboxylic Acid Derivatives: (Please read) Acid hlorides: Derived from the carboxylic acid name by replacing the -ic acid ending with -yl choride or replacing the -carboxylic acid ending with -carbonyl chloride 3 l l l acetyl chloride (from acetic acid) benzoyl chloride (from benzoic acid) yclohexancarbonyl chloride (from cyclohexane carboxylic acid) Acid Anhydrides: ame symmetrical anhydrides as the carboxylic acid except the word acid is replaced with anhydride 3 3 acetic anhydride benzoic anhydride

2 Amides: Primary s ( 2 ) are named as the carboxylic acid except the -ic acid ending is replaced with - or the -carboxylic acid ending is replaced with -carbox acet (from acetic acid) benz (from benzoic acid) yclohexancarbox (from cyclohexane carboxylic acid) Substituted s are named by first identifying the substituent(s) with an - in front of it, then naming the parent methylacet -ethyl--methylbenz,-diethylcyclohexancarbox 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 ( 3 ) 3 ethyl acetate methyl benzoate tert-butylcyclohexancarboxylate 21.2 ucleophilic acyl substitution reactions Y :u u u Y + Y: Y = a leaving group -, -, - 2, -l, - 2, -S,-P 3 2- tetrahedral intermediate

3 elative 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 group increase. Branching at the α-carbon has the largest effect. Y Increasing reactivity < < Y < Y Y ecall from hapter 4: K eq - 3 ΔG = 7.6 KJ/mol ( 3 ) ( 3 ) 3 > 18-2 ( 3 ) ature of the leaving group (Y): In general, the reactivity of acyl derivatives correlate with leaving group ability. Increasing reactivity < ' < ' < l acid anhydride What makes a good leaving group? l- pk a : The reactivity of the acyl derivative inversely correlates with their resonance electron-donating ability 2 2 esonance effect of the Y atom reduces the electrophilicity of the carbonyl carbon. Partial double bond character of the - bond makes it harder to break

4 All acyl derivatives are prepared directly from the carboxylic acid Less reactive acyl derivative (s and s) are more readily prepared from more reactive acyl derivatives (s and anhydrides) acid anhydride carboxylic acid acid anhydride Increasing reactivity 203 ucleophilic acyl substitution reactions hydrolysis Y= -l, - 2 ', -', -' 2 2 carboxylic acid aminolysis ' 2 ' 2 Y= -, -l, - 2 ', -' Y arboxylic acid derivative alcoholysis ' ' Y= -, -l, - 2 ' Y= -, -l, - 2 ', -', -' 2 reduction 2 Y= -, -l, - 2 ', -' Y= - 2 ''-M '' ''-M = '' 2 uli Y= -l '' '' ''-M = ''-MgBr, ''-Li Y= -l, -'

5 21.3 ucleophilic acyl substitution reactions of carboxylic acids ucleophilic acyl substitution of carboxylic acids are slow because - is a poor leaving group eactivity is enhanced by converting the - into a better leaving groups owever, s, anhydrides, s and s can be prepared directly from carboxylic acids carboxylic acid l ' acid anhydride ' ' onversion of carboxylic acids into s eagent: Sl 2 (thionyl chloride) Sl 2,!" l + S 2 + l ecall the conversion of 1 and 2 alcohols to alkyl chlorides Mechanism (p. 780), please read

6 onversion of carboxylic acids into acid anhydrides (please read) eagent: heat eaction is best for the preparation of cyclic anhydrides from di-carboxylic acids onversion of carboxylic acids into s 1. eaction of a carboxylate salt with 1 or XXX 2 alkyl halides eagents: a, -X, TF a, TF a 3 2 Br S ote the similarity to the Williamson ether synthesis (hapter 18.3) 207 onversion of carboxylic acids into s 2. Fisher ification reaction: acid-catalyzed reaction of carboxylic acids with 1 or 2 alcohols to give s eagents: (usually solvent), l (strong acid) 3 2 l Mandelic acid Mechanism: (Fig. 21.5, p. 782) 2 3 Ethyl mandelate

7 onversion of carboxylic acids into s ot a particularly good reaction for the preparation of s. Amines are organic bases; the major reaction between a carboxylic acid and an amine is an acid-base reaction (proton transfer) 21.4: hemistry of Acid alides Preparation of acid halides (hapter 21.3) eaction of a carboxylic acid with thionyl chloride (Sl 2 ) Sl 2,!" l + S 2 + l 209 eactions of acid halides Friedel-rafts acylation (hapter 16.4): reaction of an acid chloride with a benzene derivative to give an aryl alkyl ketone. Sl 2 carboxylic acid l All 3 + l ucleophilic acyl addition reactions of acid halides 1. hydrolysis l 2 a 3 -or- a carboxylic acid

8 2. Alcoholysis: Acid chlorides react with alcohols to give s. reactivity: 1 alcohols react faster than 2 alcohols, which react faster than 3 alcohols + l pyridine + l 3. Aminolysis: eaction of s with ammonia, 1 or 2 amines gives s. + 2 l amine (two equiv) l eduction: Acid chlorides are reduced to primary alcohols with lithium aluminium hydride (LiAl 4 ) 5. eaction of s with organometallic reagents: eacts with two equivalents of a Grignard reagent to give a 3 alcohols (recall reaction with s) l + 3 MgX Grignard reagent (two equiv.) a) TF b) alcohol + MgXl

9 eaction of acid halides with diorganocopper reagents l + ( 3 ) 2 uli diorganocopper reagent a) ether b) ketone Mechanism (page 787), not typical, specific to diorganocopper reagents. please look it over if you like Diorganocopper reagent can be alkyl, aryl or vinyl 2 Br a) 4 Li(0) b) ui Fill in the reagents: 2 u Li l h l hemistry of acid anhydrides Preparation of acid anhydrides l a + ' l sodium carboxylate ' ' acid anhydride + al eactions of acid anhydrides Acid anhydrides are slightly less reactive reactive that s; however, the overall reactions are nearly identical and they can often be used interchangeably. They do not react with diorganocopper reagents to give ketone

10 21.6 hemistry of s Preparation of s a, TF a 3 I S l Limited to 1 alkyl halides and tosylates Limited to simple 1 and 2 alcohols (used as solvent) 3. Sl 2 l 3 3 pyridine 3 3 Very general method, 1, 2 and 3 alcohols usually work fine eactions of s ' 2 (a, 2 or 3 + ) ' 2 MgX - carboxylic acid ' 2 - '' '' 3 alcohol aldehyde 1 alcohol 215 ydrolysis of s: s can be hydrolyzed to the carboxylic acids with aqueous hydroxide (saponification) or aqueous acid. Mechanism of the base-promoted hydrolysis (Figure 21.9) 3 a) a, 2 b) 3 + carboxylic acid

11 Acid-catalyzed hydrolysis of s (Figure 21.10, p. 793) (reverse of the Fischer ification) carboxylic acid 217 Aminolysis: onversion of s to s 3 eduction of s LiAl 4 reduces s to primary alcohols 3 LiAl 4 LiAl 4 3 fast

12 eduction of s Diisobutylaluminium hydride (DIBA) can reduce an to aldehyde ibu 3 DIBA Al ibu Esters do not react with ab 4 or B 3 eaction of s with Grignard reagents: Esters will react with two equivalents of a Grignard reagent to give 3 alcohols 3 _ 2 3 MgX _ ) 2 3 MgBr 2) 3 + _ _ MgBr the The Grignard reagent can be alkyl, vinyl or aryl hemistry of Amides Preparation of s: s are prepared from the reaction of an with ammonia, 1 or 2 amines Sl 2 carboxylic acid 3 2 unsubstitiuted (1 ) l ' 2 ' mono-substitiuted (2 ) ' 2 ' ' di-substitiuted (3 ) eactions of s: Amides bonds are very stable do to resonance between the nitrogen lone pair and the π-bond of the carbonyl

13 ydrolysis- Amides are hydrolyzed to the carboxylic acids and amine with either aqueous acid or aqueous hydroxide. Acid promoted mechanism: Base promoted mechanism 2 a, Proteases: catalyzes the hydrolysis of bonds of peptides 3 2 protease Asp Arg Val Tyr Ile is Pro Phe is Leu Val Ile is Asn angiotensinogen AE inhibitors aspartyl protease renin 2 Asp Arg Val Tyr Ile is Pro Phe is Leu angiotensin I (little biological activity) Zn 2+ protease angiotensin converting enzyme (AE) Asp Arg Val Tyr Ile is Pro Phe angiotensin II (vasoconstriction high blood pressure) Diovan S 2 aptopril

14 eduction of s to primary amines: s can be reduced by LiAl 4 or B 3 (but not ab 4 ) to give primary amines Mechanism: Sl l LiAl Thios and Acyl Phosphates: Biological arboxylic AcidDerivatives (please read) 21.9 Polys and Polys: Step-Growth Polymers (please read) Spectroscopy of arboxylic Acid Derivatives I: typical = stretching frequencies for: carboxylic acid: 1710 cm -1 : 1735 cm -1 : 1690 cm -1 aldehyde: 1730 cm -1 ketone 1715 cm -1 onjugation (= π-bond or an aromatic ring) moves the = absorption to lower energy (right) by ~15 cm aliphatic conjugated aromatic 1735 cm cm cm aliphatic conjugated aromatic 1690 cm cm cm

1 M: Protons on the α-carbon (next to the =) of s and s have a typical chemical shift range of δ 2.0-2.

15 1 M: Protons on the α-carbon (next to the =) of s and s have a typical chemical shift range of δ ppm Proton on the carbon attached to the oxygen atom have a typical chemical shift range of δ ppm δ 4.1 2, q, J= 7.1 δ 2.0 3, s δ 1.2 3, t, J= δ 3.4 2, q, J= 7.0 δ 2.0 3, s δ 1.1 3, t, J= M: very useful for determining the presence and nature of carbonyl groups. The typical chemical shift range for = carbon is δ ppm Aldehydes and ketones: δ ppm arboxylic acids, s and s: δ ppm Dl Dl

11 12 2 1 M δ 7.5 2, m δ 7.7 1, d, J= 15.0 δ 7.

0 δ 1.3 3, t, J= 7.0 I 13 M 130.2 128.8 127.

16 M δ 7.5 2, m δ 7.7 1, d, J= 15.0 δ 7.3 3, m δ 6.4 1, d, J= 15.0 δ 4.2 2, q, J= 7.0 δ 1.3 3, t, J= 7.0 I 13 M Dl 3 TMS

Carboxylic Acid Derivatives and Nitriles

Carboxylic Acid Derivatives and itriles Carboxylic Acid Derivatives: There are really only four things to worry about under this heading; acid chlorides, anhydrides, esters and amides. We ll start with