Carboxylic acids + derivatives

Two principles guiding carbonyl mechanisms

1. carbonyl group is vulnerable to attack (flat + polar)

2. reform carbonyl, if possible, but never kick off C- or H-

Carboxylic acid vs deritatives

Carboxylic acids: you know this…. i hope

derivates: are like cabroxylic acids except the OH is an LG. Aldehydes and ketones dont have this

Carboxylic acid/dervatives + H nucleophile

Ex. H nucleophile = LAH

attacks twice

Carboxylic acid/derivatives + C nucleophiles

Ex. RMgBR or RLi

attacks twice

Carboxylic acid/derivatives + ‘other’ nucleophiles

only attack once

Nu just replaces the LG

Reactivity ladder top to bottom + Pka

Top:

Acid chloride — <0

Acid anhydride — 5

Ester — 15
Carboxylic acid — 15ish
Amide — 35

Most stable

Important note about the stability ladder

can go down in one step but to go up you must first hydrolize to get to a carboxylic acid and then proceed up the ladder. This is because higher stability means weaker acidity.

Preparing carboxylic acids

all derivatives can be hydrolyzed to COOH in acid or base, some easier than others

Preparing carboxylic acids with gringard

R-MgBr —> 1. CO₂ 2. H₂O —> makes a carboxylic acid

Preparing carboxylic acids with nitrile hydrolysis

R-C (triple) N —> H₃O+ —> makes a derviate with NH₂ (where the OH would be) —> heat —> carboxylic acid

Preparing carboxylic acids ozonolysis

triple bonded R group —> 1. O₃ 2. H₂O —> carboyxlic aicd

Preparing carboxylic acids with oxidizing an alchol or benzylic alkane group

strong oxidizers = KMNO₄

Acyl chlordies (acid chlorides)

can undergo hydrolysis to COOH or be converted to anhydride, ester or amide

Acid chlordie + H₂O

makes a carboxylic acid

Acid chlordie + ROH

makes an ester with the R group hanging off the next O

Acid chlordie + R₂NH

Makes a deriviative with NR₂ (the H leaves)

• R can be H or an R group

Acid chlordie + carboxylic acid

results in anhydride

Preparation of acid chloride

Carboxylic acid + SOCl₂

• Double bonded O attacks S

• OH becomes new =O

Acid chloride + Gringard regent or lithium regeant

Gringard: Double bonded O turns into an OH and R group gets added twice

organocuprates (CuLi): only attack once, double bonded O stays

Reduction of acyl chlorides

Attacks twice

Double-bonded O turns into a single bonded OH

Adds two hydrogens

Anhydrides preparation

two options:

• 1. Acid chloride + carboxylic acid

• 2. two carboxylic acids + heat

Anhydrides + ROH

Makes an ester group basically

get rid of the OCOR group and replace it with the OR group

Anhydrides + H₂O / H⁺ heat

makes a carboxylic acid

Anhydrides + R₂NH

LG leaves (the OCOR group) and is replaced by NR₂ (make sure H leaves)

Preparation of Esters

three methods:

1. Acid chloride + R₁OH (preferred)

2. Anhydride + R₁OH

3. Carboxylic acid + R₁OH

Ester + H₂O

makes carboxylic acid

Ester + NaOH/Heat

“saponification” (soap)

O- repalces the OR from the ester

Ester + HNR₂ / base or 2 eq.

amide

NR₂ replaces where the OR was in the ester

Tranesterification

Conversion to anothe rester

Ester + NaOEt/EtOH —> Ester but the OEt is the next OR group

Ester and reductions

LAH: turns double bonded O into single bonded OH and adds two H

NaBH_4: to weak for an ester

DIBAL-H: reduces ester to an aldehyde

Ester with Gringard

turns double bonded O into single bonded OH and adds two R groups

Amides

• Do not undergo acyl substiution (bottom of the ladder)

• Can be hydrozled to COOH

• Very stable / not very reactive

Preparation of Amides

Three methods:

1. Acid chloride + HNR₂/Base or 2 eq. (preferred)

2. Anhydride + HNR₂/Base or 2 eq.

3. Ester + HNR₂/Base or 2 eq.

Reduction of amides

Two types

i. LiALH₄ followed by H₂O or H₂/Pt: the double bonded O leaves and is repalced by two H (only one where carbonyl O atom leaves)

ii. SOCl₂ or P₂O₅ to make a nitrile (basically a dehydration where the H₂O leaves) —> R-C(triple bond) N

Amides + H⁺, H₂O

Carboxylic acid

Nitriles

contain a CN (triple bonded)

Prepartion of Nitriles

Two methods:

1. R-C-Br + NaCN —> R-C-CN

2. amide + SOCl₂ (or P₂O₅) to make R-C (triple bond) N

Hydrolysis of Nitriles

1. R-C(triple)N → H⁺, H₂O with heat → carboxylic aicd (acid)

2. R-C(triple)N → 1. NaOH 2. H₃O+ → carboxylic acid (base)

Nitriles reduction

LAH: takes away triple bond and adds two H to the C connected to the N and the N gains two H to make NH₂

H₂: takes away triple bond and adds two H to the C connected to the N and the N gains two H to make NH₂

Nitriles reaction with Gingard

Turns it into a ketoneish? except one R group is the orginal R group and the other R group is the new R group (from the gringard)

• N atom disspaears