Carbonyl Chemistry Part 1: Additions and Carboxylic Acids

Chapter 16-18 - Jones

carbonyl

an oxygen double-bonded to a carbon (C=O) in an organic compound

ketone

a carbonyl group bonded to two R groups

aldehyde

a carbonyl group bonded to one R group and one hydrogen; terminal group

carboxylic acid

a carbonyl group bonded to one R group and one hydroxyl group (-OH); terminal group

acetone

simplest ketone

resonance forms of carbonyl compounds

allows carbonyl groups to be both nucleophiles and electrophiles

nucleophlic addition of alcohol to carbonyl (acidic)

acetal product (via hemiacetal ‘crossroads’); fully reversible with water

nucleophlic addition of alcohol to carbonyl (acidic) mechanism

double bond attacks proton → hydroxyl formation

resonance forms

alcohol attacks (electrophlic) carbonyl carbon

proton removal → hemiacetal formation

hydroxyl attacks proton → water leaves

alcohol attacks (electrophlic) carbonyl carbon

proton removal → acetal formation

nucleophlic addition of alcohol to carbonyl (basic)

hemiacetal; no protonation, no leaving group; prefers carbonyl; equilibrium

nucleophlic addition of alcohol to carbonyl (basic) mechanism

resonance forms

nucleophile attacks (electrophlic) carbonyl carbon

proton gain → hemiacetal formation

no more protons - only nucleophile left

hydration of carbonyl (acidic)

hydrate/geminal alcohol; fully reversible

hydration of carbonyl (acidic) mechanism

replace R’ with H

hydration of carbonyl (basic)

hydrate/geminal alcohol; fully reversible

hydration of carbonyl (basic) mechanism

replace R’ with H

imine

compound containing carbon–nitrogen double bond (C=N)

addition of primary amine (NH₂R) to carbonyl

imine/Schiff base; reversible with acid and water

addition of primary amine (NH₂R) to carbonyl mechansim

double bond attacks proton (from catalytic HCl)

amine attacks (electrophlic) carbonyl carbon

proton removal

hydroxyl attacks proton → water leaves

proton removal → imine formation

addition of secondary amine (NR₂H) to carbonyl

enamine; mixture possible based on R groups; reversible with acid and water

addition of secondary amine (NR₂H) to carbonyl mechanism

double bond attacks proton (from catalytic HCl)

amine attacks (electrophlic) carbonyl carbon

proton removal

hydroxyl attacks proton → water leaves

proton removal from α-carbon by base → enamine formation

enamine

carbon-carbon couble bond (C=C) and amine

organolithium or Grignard addition to carbonyl

tertiary oxygen anion; alcohol with protonation with water/proton source; via nucleophlic attack of (electrophillic) carbonyl carbon

lithium aluminium hydride addition to carbonyl (reduction)

secondary oxygen anion; alcohol with protonation with water/proton source; via hydride attack of (electrophillic) carbonyl carbon; irreversible

sodium borohydrate addition to carbonyl (reduction)

secondary oxygen anion; alcohol with protonation with water/proton source; via hydride attack of (electrophillic) carbonyl carbon; irreversible

chromate salt addition to 1° alcohol in water (oxidation)

carboxylic acid; irreversible

chromate salt addition to 1° alcohol in dry pyridine (oxidation)

aldehyde; irreversible

chromate salt addition to 2° alcohol (oxidation)

ketone; irreversible

chromate salt addition to 3° alcohol (oxidation)

no reaction; sterics

chromate salt addition to 2° alcohol (oxidation) mechanism

hydroxyl oxygen attacks chromium

water takes hydrogen

chromate ester formation

hydronium donates proton

proton transfer from carbonyl carbon → separation

addition of weak oxidant (PCC/PDC) to alcohol (oxidation)

aldehyde; cannot go to carboxylic acid; irreversible

Witting Reaction: addition of phosphorus ylide to ketone

alkene; carbon-carbon bond; reverse ozonolysis; irreversible

Witting Reaction: addition of phosphorus ylide to ketone mechanism

form and break a square

ylide

neutral dipolar molecule containing a negative charge adjacent to a positive charge

formation of phosphorus ylide

SN2

deprotonation

Swern Oxidation - DMSO, oxalyl dichloride, triethyl amine on alcohol

carbonyl; does not work on tertiary alcohols; irreversible; also makes CO, CO2, dimethyl sulfoxide and 2 x HCL

Preparation of Swern catalyst mechanism

Swern oxidation mechanism

oxygen attacks (electrophlic) sulfur

deprotonation x 2

Oxidative Cleavage of vicinal diols - HIO₄/H₂SO₄

two carbonyl-containing groups; irreversible

Oxidative Cleavage of vicinal diols - HIO₄/H₂SO₄

note cyclic intermediate/transition state

carboxylic acids in basic organic environment

deprotonates; resonance; spectator ion

carboxylic acids in basic aqueous environment

deprotonates; resonance; spectator ion

carboxylic acids in acidic organic environment

Fischer’s esterification; reversible; equilibrium

carboxylic acids in acidic aqueous environment

no change; exchangable protons

carboxylic acids in base mechanism

deprotonation

Fischer’s esterification mechanism

carbonyl oxygen attacks acid → protonation

forms hemiacetal

protonation and dehydration

reform carbonyl via deprotonation

transesterifcation

switch R group on ester; essentially Fischer’s esterification mechanism

ester

carbonyl + ester; formed from carboxylic acids

ester hydrolysis

reverse of Fischer esterification; reversible

ozonolysis and oxidation of an alkene

2x carboxylic acid

addition of KMnO4 to substituted benzene

benzoic acid

strong oxidants

HNO3, KMnO4, CrO3, K2Cr2O7, RuO4

addition of chromate salt to aldehyde

carboxylic acid

Reaction of Organometallic Reagents with Carbon Dioxide

carboxylic acid

Reaction of Organometallic Reagents with Carbon Dioxide

attack on carbon of CO2

protonation

decarboxylation

removes one acid; needs one carboxylic acid at the beta position of another

decarboxylation mechanism

proton transfer

enol → keto

keto-enol tautomerization

many aldehydes and ketones are in equilibrium with a structural isomer known as the enol form; not resonance forms but structural isomers that can interconvert

addition of DCC and amine to carboxylic acid

amide synthesis; reversible; urea side product

addition of DCC and amine to carboxylic acid mechanism

carbonyl oxygen attack on carbon

nitrogen deprotonates

amine addition

nitrogen deprotonates

addition of sulfurous dichloride to carboxylic acid

acid chloride; reversible with NaOH and acid

addition of sulfurous dichloride to carboxylic acid mechanism

make carbonyl a good leaving group

make alcohol a carbonyl

addition of organolithium to carboxylic acid

carbonyl

addition of organolithium to carboxylic acid mechanism

addition of lithium aluminium hydride to carboxylic acid

reduction to primary alcohol; also turns aldehyde into primary alcohol, ketone into secondary alcohol; ester into primary alcohol; amide into amine, nitrile into primary amine

addition of lithium aluminium hydride to carboxylic acid

addition of sodium borohydride to carboxylic acid

doesn’t work, only reduces aldehydes and ketones

addition of nucleophile to acid chloride

SN1 type reaction

addition of base to acid chloride

ester

addition of hydroxide to acid chloride

carboxylic acid

addition of secondary amine to acid chloride

amide

addition of benzene and aluminum chloride to acid chloride

Friedel-Crafts acylation

addition of organolithium/Grignard reagent to acid chloride

tertiary alcohol

addition of organolithium/Grignard reagent to acid chloride mechanism

addition of organocuprate to acid chloride

ketone; like RLi but more selctive; will not react with ketone/aldehyde

addition of lithium aluminium hydride to acid chloride

tertiary alcohol

addition of lithium tri-tert-butoxyaluminum hydride to acid chloride

aldehyde; doesn’t react with aldehydes/ketones

addition of diazomethane to carboxylic acid

methyl ester

addition of aqueous sodium hydroxide to ester

saponification, deprotonated

combination of two carboxylic acids @ 300°C

anhydride and water

addition of deprotonated acid to acid chloride

anhydride and salt

addition of DIBAL-H to ester @ -78°C

aldehyde

addition of organolithium/Grignard reagent to ester

tertiary alcohol

addition of amine to anhydride

amide

addition of amine to anhydride mechanism

resonance of amide

stability

amide in basic aqueous environment

deprotonated carboxylic acid and neutral amine; electrophlic attack from carbonyl oxygen

amide in acidic aqueous environment

carboxylic acid and positive amine; nucleophilic attack on carbonyl carbon

lithium aluminium hydride reduction on amide

amine; could use deuterated reagent

resonance for nitrile

addition of potassium cynaide to alkyl halide

nitrile; SN2

acidic workup of nitrile

carboxylic acid and ammonium; begins with protonation of nitrogen

basic workup of nitrile

deprotonated carboxylic acid and ammonia

addition of organolithium to nitrile

ketone; nucleophlic attack on nitrile carbon; iminium ion

addition of organolithium to nitrile mechanism

lithium aluminium hydride reduction of nitrile

amine

amine

Bayer-Villager rearrangement general formula

transfers one side group of a ketone to an ester

Bayer-Villager rearrangement mechanism

proton attack → more suitable R group moves to oxygen

rate of migration for different side groups in rearrangement

H > 3° > 2° > 1° > CH₃

Bayer-Villager rearrangement example 1

Bayer-Villager rearrangement example 2