Chapter 21: Carboxylic Acid Derivatives and Nu Acyl Substitutions

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1 rganic hemistry hapter 21: arboxylic Acid Derivatives and u Acyl Substitutions Lecture utline I. DEFIITI & MELATUE F ABXYLI AID DEIVATIVES A. ABXYLI AID DEIVATIVES The organic compounds that are classified as derivatives are all carbonyl-containing compounds (except for nitriles) that can be converted to a by hydrolysis, i.e., addition of water. This condition requires that the derivative has an electronegative atom bonded to the carbon atom of the carbonyl group. The functional groups that belong to this class of compounds are: Anhydride " X Acyl halide Ester ' ( 2 )n Lactone 2 ' ' 2 Primary Amide Secondary Amide Tertiary Amide ( 2 )n Lactam ' " " ' ( 2 )n ( 2 )n Primary Imide Secondary Imide yclic Imide (Primary) yclic Imide (secondary) itrile 2 Urea 2 B. MELATUE F ABXYLI AID DEIVATIVES (21.1) 1. omenclature of Acyl alides a. Acyl halides are named by replacing the "ic acid" ending of the corresponding with "yl" followed by the halide. It is represented as two words. 2. omenclature of Anhydrides a. Symmetrical anhydrides (both carbonyl groups are the same) are named by replacing the "acid" suffix of the corresponding with "anhydride" b. Unsymmetrical anhydrides are named by removing the "acid" suffix from each of the two acyl groups that make up the anhydride, placing the names in alphabetical order and adding an "anhydride" suffix. c. yclic anhydrides have common names. 3. omenclature of Esters a. Esters have two carbon containing components; one bonded to the oxygen atom ("alkyl") and one bonded to the carbonyl group ("alkanoate"). Esters are named by combining these two components. 4. omenclature of Amides a. Primary amides are named by replacing the "oic acid" or "ic acid" ending of the corresponding with "amide". b. Secondary and tertiary amides are named as "-alkyl-" or ",-dialkyl-" amides. The parent is determined as for primary amides.

2 rganic hemistry hapter 21: arboxylic Acid Derivatives and u Acyl Substitutions Lecture utline II. PPETIES F ABXYLI AID DEIVATIVES A Boiling points arboxylic acid derivatives that cannot -bond tend to have lower boiling points than those that can -bond. arboxylic acids and primary and secondary amides tend to have higher boiling points. B. Leaving groups The leaving groups associated with nucleophilic acyl addition reactions of derivatives include: chlorides, carboxylate and s, alkoxides and s, hydroxides and water, and amines.. Primary imides are acidic D. ELATIVE EATIVITIES F ABXYLI DEIVATIVES WIT ULEPILES (21.2) Inductive and resonance effects help to predict the relative reactivity of s and derivatives. acyl halide acid anhydride amide very strong inductive effect due to electronegative > δ > ' ~ inductive effect due to electronegative oxygen but less reactive than > ' 2 δ strong inductive effect enhanced by resonance effect IV. ULEPILI AYL SUBSTITUTIS F ABXYLI AIDS AD ABXYLI AID DEIVATIVES (21.2) A. MEAISM F TE ULEPILI AYL SUBSTITUTI EATI arboxylic acids and derivatives react with nucleophiles via the nucleophilic acyl substitution reaction either under basic conditions or acidic conditions. Base-atalyzed u Acyl Substitution u: u X X u X = halogen, oxygen, nitrogen

3 rganic hemistry hapter 21: arboxylic Acid Derivatives and u Acyl Substitutions Lecture utline Acid-atalyzed u Acyl Substitution X X = halogen, oxygen, nitrogen u: X u X u u u X V. PEPAATI F ABXYLI AID DEIVATIVES A. Preparation of Acyl halides 1. Acyl halides are usually prepared from s with S 2. B. Preparation of Anhydrides 1. Anhydrides are usually prepared by reacting acyl chlorides with s in the presence of pyridine.. Preparation of Esters: Esters can be prepared in three ways. 1. Fisher Esterification: eaction of s with a in the presence of an acid catalyst. 2. eaction of s with acyl chlorides in the presence of pyridine. 3. eaction of s with anhydrides in the presence of pyridine. D. Preparation of Amides 1. Primary amides are usually prepared by reaction of two moles of ammonia with acyl halides, anhydrides or s. 2. Secondary and tertiary amides are usually prepared by reaction of two moles either a primary amine (to give a secondary amide) or a secondary amine (to give a tertiary amide) with acyl halides, anhydrides or s. E. Preparation of itriles: itriles can be prepared in two ways. 1. ucleophilic substitution of an alkyl halide 2. ucleophilic addition of with aldehydes & ketones VI. EATIS F ABXYLI AID DEIVATIVES A. EATIS WIT AYL ALIDES (atalyst usually not needed) 1. Acyl halide reactions with oxygen nucleophiles (carboxylates, s/phenols, water) to generate anhydrides, s and s respectively. eaction with a arboxylate acyl halide ' anhydride product carboxylate ion

4 rganic hemistry hapter 21: arboxylic Acid Derivatives and u Acyl Substitutions Lecture utline eaction with an Alcohol acyl halide product eaction with a Phenol acyl halide product phenol 2. Acyl halides react with primary and secondary amines to generate amides. acyl halide secondary amide primary amine B. EATIS F AYDIDES (atalyst usually not needed) 1. Acid anhydride reactions with oxygen nucleophiles (s/phenols, water) to generate s and s eaction with Alcohol acid anhydride 1 ' ' product

5 rganic hemistry hapter 21: arboxylic Acid Derivatives and u Acyl Substitutions Lecture utline eaction with Phenol acid anhydride 1 ' product ' phenol 2. Acid anhydrides react with primary and secondary amines to generate amides. eaction with Primary Amine acid anhydride 1 ' amide product ' amine. eactions of Esters 1. Ester reactions with oxygen nucleophiles (s/phenols, water). Acid atalyzed eaction with Alcohols (Transification) ' ' ' ' " " " ' " new " '

6 rganic hemistry hapter 21: arboxylic Acid Derivatives and u Acyl Substitutions Lecture utline Acid atalyzed ydrolysis ' ' ' ' ' ' Base-atalyzed ydrolysis ' ' ' alkoxide ' 2. Ester reactions with primary and secondary amines to generate amides. Primary amines give secondary amides and secondary amines give tertiary amides. eaction of Esters with Amines ' " " ' amide ' ' 3. Ester reactions with carbon nucleophiles and hydrides. a. Esters react with Grignard reagents and primary or secondary alkyl lithiums to form s i. Two equivalents of reagent is needed to convert s to s.

7 rganic hemistry hapter 21: arboxylic Acid Derivatives and u Acyl Substitutions Lecture utline eaction of Esters with rganometallic eagents "intermediate ketone" " 3 " 3 alkoxide " " 3 (from Grignard or alkyl lithium) 3 (second equivalent of reagent) Tertiary b. Esters are reduced with hydrides to s with LiAl 4 to s or to an and aldehyde with DIBAL i. eaction with DIBAL gives an aldehyde and and. ii. If LiAl4 is used as hydride reagent, the aldehyde continues to undergo reduction to a primary. Two s (one primary, the other from the original ) result as products of the reaction. eaction of Esters with ydrides aldehyde product if DIBAL " " " alkoxide "intermediate aldehyde" if LiAl DIBAL or LiAl 4 4 (second equivalent of hydride if LiAl4) " Primary with LiAl 4 E. eactions of arboxylic Acids (Either activated or acid catalyzed) 1 Activation with S 2 Alcohols can be "activated" or converted to an acyl chloride with thionyl chloride prior to reaction with nucleophiles.

8 rganic hemistry hapter 21: arboxylic Acid Derivatives and u Acyl Substitutions Lecture utline eaction of arboxylic Acid with Thionyl hloride LG S S S LG acid chloride S 2. eaction with s (acid catalyzed) (Fisher ification) eaction of arboxylic Acids with Alcohols (Acid-atalyzed) ' ' ' 2 water ' ' 3. eaction with hydrides (1) LiAl 4 2) ) eaction of arboxylic Acid with ydride LiAl 4 hydroxide "intermediate aldehyde" (second equivalent of hydride if LiAl4) 2 water Primary with LiAl 4

9 rganic hemistry hapter 21: arboxylic Acid Derivatives and u Acyl Substitutions Lecture utline F. eactions of Amides 1. eaction with s and water (acid- catalyzed) eaction of Amides with Alcohols (Acid-atalyzed) " " " ' ' ' 2 " amine ' ' " Acid-atalyzed ydrolysis of Amides " " " water 2 " amine " Base-atalyzed ydrolysis of Amides " " " "2 amine 2. eaction with hydrides i. LiAl4 can be used to reduce amides to amines ii. eduction of a primary amide gives a primary amines; reduction of a secondary amide gives a secondary amine and reduction of a tertiary amide gives a tertiary amine.

10 rganic hemistry hapter 21: arboxylic Acid Derivatives and u Acyl Substitutions Lecture utline eaction of Amides with ydrides "" " " " LiAl 4 intermediate imine - " " " amine G. ydrolysis of Imides and itriles 1. ydrolysis of Imides: Gabriel Synthesis a. Imides can be used to synthesize amines through the Gabriel synthesis. b. The Gabriel synthesis is a multi-step reaction involving acid/base chemistry, an S2 reaction followed by basecatalyzed hydrolysis to synthesize primary amines. Acid-Base eaction (alkyl halide) -X phthalimide phthalimide ion S2 eaction ydrolysis -substituted phthalimide 2 primary amine

11 rganic hemistry hapter 21: arboxylic Acid Derivatives and u Acyl Substitutions Lecture utline 2. ydrolysis of itriles itriles can be hydrolyzed under acidic or basic conditions to provide primary amides. Acid-atalyzed ydrolysis of itriles water 2 2 Primary amide Base-atalyzed ydrolysis of itriles 2 Primary amide

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