CHM247H1 Jasmyn Lee Chapter 21: Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Reactions 21.1 Naming Carboxylic Acid Derivatives Naming Acid Halides, RCOX Naming Acid Anhydrides, RCO2COR’ Naming Esters, RCO2R’

1. Name the alkyl group - ethyl 2. Name the acyl group - acetate (ethanoate)

o Replace “ic acid” with “ate” Naming 1° Amides, RCONH2 For all 1° amides

o Replace ic acid, oic acid, ylic acid with amide

Naming 2° and 3° Amides 1. Name the alkyl group (groups) bonded to N first 2. Use N as a prefix before each alkyl group name 3. In a 3° amide, if two groups are the same, use “N,N-dialkyl”

Some Interesting Amides

Thiesters, RCOSR’ Acyl Phosphates, RCO2PO3

2- and RCO2PO3R’

CHM247H1 Jasmyn Lee 21.10 Spectroscopy of Carboxylic Acid Derivatives Infrared Spectroscopy IR Absorption of Acid Derivatives

o As the C=O π bond becomes more delocalized, adsorption shifts to lower frequency o Conjugation also shifts C=O absorption to lower frequencies

Other IR Adsorptions o 1° and 2° Amines

3200-3400 cm-` (one or two; stretching)

~1640 cm-1 (bending)

Nitrile adsorption at 2250 cm-1 Typical NMR Signals 1H NMR

o α proton signal at 2-2.5 ppm Identity of the carbonyl group cant be determined by 1H NMR because α

hydrogen’s of all acid derivatives absorb in the same range o Protons of 1° and 2° amides adsorb at 7.5-8.5 ppm

13C NMR o C=O peak at 160-180 ppm o C≡N peak at 115-120 ppm

21.2 Nucleophilic Acyl Substitution Reactions Recall: when a nucleophile adds to an ald/ket, the initially formed tetrahedral intermediate can be protonated to yield an

alcohol When a nucleophile adds to a carboxylic acid derivative, the initially formed tetrahedral intermediate eliminated one of the

two substituents originally bonded to the carbonyl carbon – leads to a net nucleophilic acyl substitution reaction Difference between ald/ket and c. acid derivative is a consequence of structure

o Carboxylic acid derivatives have an acyl carbon bonded to a group –Y than can act as a leaving group, often as a stable anion – tetrahedral formed, leaving group is expelled to generate new carbonyl compound

o Ald/ket do not have a leaving group – don’t undergo substitution

Nucleophilic Acyl Substitution is characteristic o General Mechanism

1. Nu attacks breaks π bond, new C-Nu bond forms tetrahedral

intermediate 2. Leaving group eliminated, substitution product made o Overall: Adding Nu, eliminating Z

i.e. substituting Nu for Z; Z = -X, -OCOR, -OR, -NR2

Oxygen Nucleophiles

OH_

OH2 ROHR

CO

O_

Nitrogen Nucleophiles

NH3 RNH2 R2NH

CHM247H1 Jasmyn Lee Reactivity of Acid Derivatives Any factor that makes the carbonyl group more reactive toward nucleophile favors substitution Steric and electronic factors are important in determining reactivity

o Sterically – unhindered, accessible carbonyl groups react with nucleophiles more readily than sterically hindered groups

o Electronically – strongly polarized acyl compounds react more readily than less polar Acid Halide > Acid Anhydride > Thioester > Ester > Amide Eg/ Cloride substituent is an EWG – inductively withdraws electrons from an acyl group Eg/ Amino, methoxyl and methylthio substituents donate electrons to acyl group

What determines derivative reactivity?

Physical Properties of Acid Derivatives

Types of Reactions Hydrolysis – reaction with H2O to yield a carboxylic acid Alcoholysis – reaction with an alcohol to yield an ester Aminolysis – reaction with ammonia or an amine to yield an amide Reduction – reacation with a hydride reducing agent to yield an ald/ket Grignard Reaction – reaction with an organometallic reagent to yield an ald/ket

21.3 Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Conversion of Carboxylic Acids in to Acid Chlorides Conversion of Carboxylic Acids into Acid Anhydrides

Conversion of Carboxylic Acids into Esters SN2 reaction of a carboxylate anion with a primary alkyl halide Fischer Esterification starts with carboxylic acid

o Need to force it o Only works with 1° and methyl alcohols

Leaving Group Stability Interconversion of Acid Derivatives

C=O undergoes Nucleophilic Acyl Substitution

CHM247H1 Jasmyn Lee

o Mechanism Part A – addition of nucleophile

1. Protonation makes C=O more electrophilic 2. Nucleophilic addition of R’OH forms tetrahedral intermediate 3. Deprotonation for neutral intermediate

Part B – elimination of leaving group

4. Protonate an OH to make good leaving group (H2O) 5. Leaving group eliminated 6. Deprotonation for neutral product ester

o All steps are reversible – equilibrium constant close to 1 reaction can be driven in either direction by reaction conditions

o Ester formation is favored when large excess of alcohol is used as solvent o Carboxylic Acid formation is favored when a large excess of water is present

Conversion of Carboxylic Acids into Amides Conversion of Carboxylic Acids into Alcohols Biological Conversions of Carboxylic Acids 21.4 Chemistry of Acid Halides Preparation of Acid Halides Reactions of Acid Halides Hydrolysis: Conversion of Acid Halides into Acids Conversion of Acid Halides into Anhydrides Alcoholysis: Conversion of Acid Halides into Esters Aminolysis: Conversion of Acid Halides into Amides Reduction and Grignard Reaction: Conversion of Acid Chlorides into Alcohols Diorganocopper Reaction: Conversion of Acid Chlorides into Ketones 21.5 Chemistry of Acid Anhydrides Preparation of Acid Anhydrides Reactions of Acid Anhydrides

Conversion of Acid Anhydrides into Esters Prepare an Ester with a more reactive acid derivative (compared to Fischer Esterification)

o Use milder reaction conditions o Even with less reactive alcohol

Conversion of Acid Anhydrides into Amides

CHM247H1 Jasmyn Lee 21.6 Chemistry of Esters Sweet smelling liquids; responsible for fragrant odors of fruits and flowers Preparation of Esters Reactions of Esters Hydrolysis: Conversion of Esters into Carboxylic Acids Hydrolysis can occur in acid or base Under acidic conditions the mechanism is exactly the reverse of Fischer Esterification (refer to mechanism

above)

Base Promoted Ester Hydrolysis (saponification)

1. Nucleophile attacks C=O forming tetrahedral intermediate 2. Elimination of leaving group, R’ O- 3. Acid-base reaction between carboxylic acid and alkoxide ion, yields a carboxylate ion 4. Addition of acid in a separate step protonates carboxylate and gives carboxylic acid

Application: Lipid Hydrolysis

o Natural fats are triaglycerols o The fatty acid esters of the triol, glycerol o Ester hydrolysis is catalyzed by enzymes (lipases) o The acids are usually different, R can have 11-19 C’s o Olestra, A synthetic fat

A polyester of sucrose Steric hindrance prevents ester hydrolysis by lipases R groups contain 11 to 19 C’s

Aminolysis: Conversion of Esters into Amides

Base Protonated Amide Hydrolysis

1. Nucleophile attacks C=O forming tetrahedral intermediate 2. Elimination of leaving group, -NH2 3. Acid-base reaction between carboxylic acid and amide ion

Application: The Mechanism of Action of β-Lactam Antibiotics

OO

O

OOCR

RCOO

OOCR

OOCR

RCOOOOCR

RCOORCOO

CHM247H1 Jasmyn Lee

o Penicillin interferes with synthesis of bacterial cell wall Transpeptidase enzyme forms peptide bonds to link carbohydrate chains in bacterial cell wall

Enzyme reacts irreversibly with strained amide of penicillin and becomes inactive

Reduction: Conversion of Esters into Alcohols Reduction of Estes (a)

o Using an aggressive reagent o Work up in aqueous acid o Converts the acyl group to a 1° alcohol

Reduction of Esters (b) – aldehyde intermediate can be isolated if 1 equiv. of DIBAH is used as reducing agent

o Using a bulky reagent with only one hydride o Converts the acyl group to an aldehyde

Grignard Reaction: Conversion of Esters into Alcohols Using two equivalents of Grignard reagent Converts to acyl group to a 3° alcohol (same as acid chlorides)

CHM247H1 Jasmyn Lee 21.7 Chemistry of Amides Amides are abundant in all living organisms due to their stability in aqueous conditions found in living organisms Amides are the least reactive of the common acid derivatives and undergo few nucleophilic acyl substitution reactions

Preparation of Amides Reactions of Amides Hydrolysis: Conversion of Amides into Carboxylic Acids Acid Promoted Hydrolysis of Amides Part A – Addition of Nucleophile

1. Protonation makes C=O more electrophilic 2. Nucleophilic addition of H2O forms tetrahedral intermediate 3. Proton transfer; NH3 leaving group

Part B – Elimination of Leaving Group

4. Deprotonate an OH to push out leaving group (NH3)

Steps are reversible – reaction needs to be forced toward product by protonation of NH3 Heat amide at high [H+]

Basic hydrolysis (not included in class notes) o Occurs by nucleophilic addition of –OH to the amide carbonyl group, followed by elimination of amide ion (-NH2)

and subsequent deprotonation of the initially formed carboxylic acid by ammonia o Reversible – equilibrium favors products by final deprotonation of carboxylic acid o More difficult than acid catalyzed –because amide ion is poor leaving group; elimination step is difficult

Hydrolysis of amides is initial step in digestion of dietary proteins o Catalyzed by protease enzyme

Reduction: Conversion of Amides into Amines Using an aggressive reagent and aqueous work-up Converts the amide to a 1° amine Full C=O reduction with LiAlH4 is specific for amides

Good way to convert lactam to cyclic amine

CHM247H1 Jasmyn Lee Nitrile Hydrolysis Mechanism of Nitrile Hydrolysis in Base

1. Nucleophilic Addition 2. Tautomerization 3. Amide Hydrolysis

Mechanism of Nitrile Hydrolysis in Acid

1. Activation and Nucleophilic Addition 2. Tautomerization 3. Amide Hydrolysis Practice

C4H7O2Br

CHM247H1 Jasmyn Lee