CHEM 215 - Exam 2

Carb

How are Carboxylic Acids mades?

Via ozonolysis (sometimes works) and oxidation

Carboxylic Acid Structure

Carboxylate Structure

Conjugates base of Carboxylic Acid

Ester Structure

Thioester Structure

Acyl Group Structure

Anhydride Structure

Acid Chloride Structure

Amide Structure

If something is an acylating agent AND acid, and the reagent is a good nuc and base….

An A-B reaction will trump the acylation reaction!

Acylation Mechanism: TLDR

Substitution @ sp2 carbon via addition + elimination

What is a tetrahedral intermediate?

Acylation: Strong Base Mechanism Conditions

1. Anions for nucleophile: -OCH3, -OH, -SCH3 (all ready to go, no need for deprotonation!)

2. No strong acids present

Acylation: Strong Base Mechanism Steps

Acylation: Acid-Catalyzed Mechanism Conditions

Acylation: Acid-Catalyzed Mechanism Steps

Acylation: Weak Base Mechanism Conditions

Acylation: Weak Base Mechanism Steps

Acylation: OTHER Weak Base Mechanism Conditions

Acylation: OTHER Weak Base Mechanism Steps

Carboxylic Acid to Carboxylate: Reagents

Carboxylate to Carboxylic Acid: Reagents

Carboxylic Acid to Acid Chloride: Reagents

Carboxylic Acid to Acid Anhydride: Reagents

Carboxylic Acid to Thioester: Reagents

Carboxylic Acid to Ester: Reagents

Carboxylic Acid to Amide?

Acid Chloride/Acid Anyhydride/Thioester/Ester/Amide —> Carboxylic Acid: Reagents

Acid Chloride/Thioester/Ester/Amide —> Acid Anhydride: Reagents

Acid Chloride/Acid Anhydride/Ester/Amide —> Thioester: Reagents

Acid Chloride/Acid Anyhydride/Thioester/Amide —> Ester: Reagents

Acid Chloride to Amide: Reagents

Ways to make Carboxylic Acids from this compound?

OZONOLYSIS

Reagents: 1. O3, 2. H202 (oxidative work-up)

Ways to make Carboxylic Acids from this compound?

1. Wet Cr6+ oxidation (Jones reagent)

2. Weaker conditions in Oxygen

3. Peroxidation w/mCPBA (peroxyacid)

Ways to make Carboxylic Acids from this compound: organometallic?

1. CO2, 2. H3O+

Ways to make Carboxylic Acids from this compound: CADs

H2O and acid/base

• Acid chloride reacts much faster (and at RT) compared to amide (takes hours and at 100C)

Reactions of Carboxylic Acids?

1. Deprotonation

2. Convert to other CADS (Fischer esterfication, make acid chloride, anhydrides)

Mechanism for Deprotonation of Carboxylic Acids

Mechanism for Fischer Esterfication of Carboxylic Acids

Mechanism for Making Acid Chloride from Carboxylic Acid

Mechanism for Making Anhydrides from Carboxylic Acids (Dehydration)

Reactions of Anhydrides

1. Making Amide

2. Making Thioester

3. With Alcohols

Ways to make Esters?

1. VIA ACYLATION (from acid chloride, thioester, carboxylic acids, etc)

2. Non-Acylations (Carboxylic Acid with nonhindered and hinder carbon conditions)

Acylation Mechanisms to make Esters

Non-Acylation Mechanism: Making Ester w/ primary carbon (nonhindered)

1. Deprotonation

2. SN2

Non-Acylation Mechanism: Making Ester w/ tertiary carbon (hindered)

Reagents: Carbon group and acid to make the OH a good LG

SN1 Mechanism: Protonation, LG leaves, Subsitution, Deprotonation

Reactions of Esters: Acylation

1. Transesterification

2. Basic Hydrolysis

3. H2O, H2SO4

Transesterification Mechanism

Basic Hydrolysis Mechanism of Esters

Mechanism for making Carboxylic Acid from Ester

How to make Amides?

VIA ACYLATIONS —> all weak base mechanisms

Acylation Mechanism to make Amides from Acid Chloride

Acylation Mechanism to make Amides from Thioester

Acylation Mechanism to make Amides from Ester

Acylation Mechanism to make Amides from Acid Anhydride

Acylation Mechanism to make Amides from Carboxylic Acid?

NOT POSSIBLE —> excess H-N reagent would just do Bronsted A-B rxn, deprotonating OH on carboxylic acid

Possible Reactions of Amides: All Acylations

1. Acylations (also making Carboxylic Acids)

2. Transamidation

Acylation of Amides Mechanism: Making Carboxylic Acid

Acidic conditions, hydrolysis

Transamidation mechanism

4 steps: addition, deprotonate the nuc, protonate the LG, elimination via assisted ionization

Ester + Organometallic = what product?

Tertiary alcohol

Ester + LiAlHy = what product?

Primary alcohol

Ester + Organometallic: Mechanism

Double Addition

Ester + LiAlHy: Mechanism

Double Addition

Carboxylic Acid + Organometallic = product?

Ketone (CARBOXYLIC ACIDS DONT REACT W/ GRIGNARD)

*Carboxylic Acid + Organometallic: Mechanism

Single Addition w/Organolithium (Stabilizing the T.I)

Reagents: 1. 2 equiv of RLi, 2. H3O+

1. Deprotonate

2. Addition of 2nd nuc

3. Protonate stabilized T.I (because can’t elimiate because no good LG)

4. Hydrate of Ketone is protonated

5. Elimination

6. Deprotonate

Carboxylic Acid + LiAlHy: Mechanism

Double Addition

1. Deprotonate

2. Complexation

3. Addition of hydride

4. Elimination via assisted ionization

5. 2nd addition

6. Protonate (killing any LiAlHy still around through A-B chemistry)

Tertiary Amides + LiAlHy: Mechanism

Double Addition

1. Addition

2. Complexation

3. Elimination via assisted ionization (electrongs coming off N to push OAlH3 group off)

4. Addition of Hydride

Tertiary Amides + Organometallics: Mechanism?

NO PREDICTABLE RXN

What is Weinreb Amide? How to make it?

*Weinreb Amide + LiAlHy: Mechanism

Single Addition

*Weinreb Amide + Organometallics: Mechanism

Single Addition (Stabilize the T.I.)

1. Addition

2. Protonate T.I. stabilized by 5-member ring + low temp

3. Hemiaminal is protonated

   1. Hemiaminal can only dissociate back into ketone because can’t make imine with no Hs on N

4. Protonate

5. Elimination

6. Deprotonate

Ketones & Aldehydes are MORE electrophilic than most CADs

TRUE

Most CADs given double addition in rxns w/organometallics + hydrides, except…

Carboxylic Acids: Single addition with RLi, no rxn with Gringnard

Tertiary Amides: No predictable rxn with Organometallics

Weinreb Amides: Do single additions only

Primary and Secondary Amides just deprotonate in presence of Carbon/Hydrogen Nuc.

TRUE

• Can be exploited so you deprotonate and then do a SN2 rxn to do complexation at N