Chapter 11- Reactions of Alcohols Organic Chemistry

Oxidation

Loss of H2

Gain of O, O2 or X2 bonds

Reduction

Loss of O, O2, or X2

Gain of H2 or H

Primary Alcohol Oxidation States

Alkane → 1° Alcohol → Aldehyde → Carboxylic Acid

Secondary Alcohol Oxidation States

Alkane → 2° Alcohol → Ketone

Tertiary Alcohol Oxidation States

Alkane → 3° Alcohol

Sodium Hypochlorite (NaOCl) in the presence of acetic acid

-Oxidizes 2° Alcohols to ketones

-Acetic acid protonates NaOCL to hypochlorous acid and then activates hypochlorous acid to become a strong electrophile

-Oxygen in alcohol attacks the Cl

-Acetate ion removes a proton and chlorine leaves

Chromic Acid (H2CrO4)= Sodium dichromate (Na2Cr2O7) + Sulfuric Acid (H2SO4) and Water

-Oxidizes 2° Alcohols to ketones

-Alcohol oxygen attacks chromic acid oxygen to create a chromic ester and water

-Water protonates Chromate ester to form water as a leaving group to create a ketone and Chromic acid

Sodium hypochlorite (NaOCl) plus TEMPO (stable free radical)

-Oxidizes 1° Alcohol to an aldehyde

-When sodium hypochlorite plus TEMPO is in excess it oxidizes to carboxylic acid

Pyridinium Chlorochromate (PCC) (usually in dichloromethane [CH2Cl2])

-Oxidizes 1° Alcohols to an aldehyde

Summarize Alcohol Oxidations

What does it oxidize to?

a) Octan-1-ol with sodium dichromate in the presence of sulfuric acid

b)Octan-1-ol with PCC

c) octan-3-ol with PCC

d) 4-Hydroxydecanal with PCC

How to oxidize a 3° alcohol?

Nothing, it has no oxidation

Ethanol + ADH

-ADH catalyzes oxidation of ethanol by NAD to an aldehyde

Ethanol + ALDH

-ALDH catalyzes the oxidation of ethanol by NAD to carboxylic acid (acetic acid)

Methanol + ADH

-ADH catalyzes oxidation of methanol to formaldehyde (Aldehyde)

-TOXIC

Methanol + ALDH

-ALDH catalyzes the oxidation of formaldehyde to formic acid (Carboxylic acid)

-EVEN MORE TOXIC

How is methanol poisoning treated?

Treated by ethanol intravenous infusion because the ethanol will compete for ADH and ALDH to slow/stop the oxidation of methanol into toxic substances

When can Alcohol act as a nucleophile?

1) Alcohol can react as a weak nucleophile when there is a strong electrophile to attack

2) Alcohol can be converted to a strong nucleophile by forming its alkoxide ion to attack a weak electrophile

When can alcohol act as an electrophile?

1) Protonation can make alcohol a good leaving group, hence a good electrophile

2) In a Aprotic solution

→ Alcohol is weak as an electrophile because the hydroxy group is a poor leaving group

→ Cannot in a protic solution because Halide ions, which become the nucleophile after protonating the alcohol, are strong bases which would themselves be protonated

Tosylate

-A great leaving group because the tosylate ion is stabilized by resonance

-Alcohol can react with TsCl in the presence of pyridine to add in nucleophilic substitution

→Ts bonds to the O in the alcohol and displaces the H then since Tosylate is a great leaving group, a Nucleophile can attack the carbon from the back and the OTs will leave

Predict the major products:

a) Potassium ter-butoxide + ethyl tosylate

b) (R)-2-hexyl tosylate + sodium cyanide

Alcohol to Alkane

-Reduction

1) Dehydrate with conc. H2SO4 (produces an alkene) and then Add H2 using Pt Catalyst

→ Protonation to alkene and then addition of hydrogens to break double bond

2) React alcohol with TsCl and Reduce with LiAlH4

→ Make OH a leaving group and then add Hydride

3° and 2° alcohols + HBr

Alcohol to Alkyl Halide

SN1

-Used for 3° and 2° alcohols

→ Protonation converts the hydroxy group into a good leaving group, water leaves forming carbocation and bromide ion attacks carbocation

1° alcohols + HBr

Alcohol to alkyl halide

→ Protonation converts hydroxy group into a good leaving group and bromide displaces the water to give the alkylbromide

3° and 2° alcohols + HCl in the presence of ZnCl2 or Lucas Reagents

Alcohol to alkyl halide

SN1

-Chloride is a weaker nucleophile than bromide and needs ZnCl2 which is stronger than a proton

→ZnCl2 binds to oxygen in alcohol to create a good leaving group, when it leaves with the -OH it produces a stable carbocation that the chlorine ion attacks

1° Alcohols + HCl

Alcohol to alkyl halide

SN2

→ZnCl2 creates a leaving group and at the same time it leaves the chlorine ion attacks from the back

Limitations of HX Reactions

1) HI does not react with alcohol

2) 1° and 2° alcohols react very slowly

3) Elimination reactions will produce alkenes instead of alkyl halides because of water acting as a base and deprotonating

4) Carbocation intermediate may rearrange to become most stable

Alcohol + PBr3

Alcohol to Alkyl Bromide

-PBr3 is a strong electrophile

-Alcohol displaces bromide ion from PBr3 to create a bond

-Bromide ion does SN2 attack on alkyl group displacing the hydroxy-PBr2 group and forming alkyl bromide

Alcohol + (PCl3/PCl5)

Alcohol to alkyl chloride

Chlorine from phosphorus molecule attacks alkyl group at the same time oxygen in alcohol attacks phosphorus to create a cleaving group

Alcohol + PI3

To convert alcohol to alkyl iodide

→PI3 is not stable to be stored

→Generated in reaction by the reaction of phosphorus with iodine

Alcohol + SOCl2 (Thionyl Chloride)

To convert Alcohol to Alkyl Chlorides

-Oxygen attacks the electrophilic sulfur atom of SOCl2

-Chloride ion is expelled

-Intermediate is deprotonated to give the chlorosulfite ester which ionizes and produces a carbocation

-chloride quickly attacks carbocation

a) Trans-4-methylcyclohexanol + SOCl2

b) butan-1-ol + HBr

c) butan-1-ol + P/I2

d) butan-1-ol + PBr3

Acid-Catalyzed Dehydration of an Alcohol

H2SO4

-Protonation converts the hydroxy group to a good leaving group

-Water leaves forming a good carbo cation

-Water removes a proton to produce the alkene (most substituted)

Zaitsev's Rule

The most substituted alkene is formed preferentially by deprotonating the least substituted carbon adjacent to the carbocation

Bimolecular Condensation

Forms Ethers

-Protonated 1° alcohols can be attacked by another molecule of the alcohol and undergo an SN2 displacement

(Two alcohols combining and then being deprotonated)

Pinacol Rearrangement

Unique reaction of diols

-One of the hydroxy oxygens get protonated

-A water molecule leaves forming a carbocation

-A methyl migrates to form a resonance-stabilized carbocation

-Deprotonation give s the pinacolone product

Esterification

Addition of an alcohol to an acid

Mechanism:

1) protonation of acid O

2) Electron movement creates a carbocation where alcohol can attack

3) Alcohol attached to acid is deprotonized and acid oxygen is protonized

4) water leaves

5) Resonance stabilization with O + to make acid O positive

6) Acid Oxygen is deprotonated

Fischer Esterification

1) Alcohol reacts with a carboxylic acid to make a carboxylic acid ester (acid-catalyzed)

2) Alcohol reacts with an acid chloride to produce an ester in the presence of pyridine which neutralizes the HCl byproduct

Tosylate Esterification

1) Alcohol reacts with p-Toluenesulfonic acid (TsOH)

2) Alcohol reacts with para-toluenesulfonyl chloride (TsCl)

→reaction is pyridine catalyzed

→ H and Cl become a molecule with pyridine

Sulfate Esterification

Alcohol + sulfuric acid

- sulfur atom in the acid is not bound to an alkyl group

-sulfate ester can react with another alcohol molecule

-sulfate ions are great leaving groups

Nitrate Esterification

Alcohol + Nitric Acid

Phosphate Esterification

Alcohol + Phosphoric Acid

→ The central phosphorus can bing three alkoxy groups

Williamson Ether Synthesis

An Alkoxide ion reacts with 1° alkyl halides or tosylates to produce an ether

Mechanism:

1) Alkoxide ion is formed using alcohol + NaH in the presence of THF

→Hydride attacks alcohol H to create gas

2) Alkoxide ion attacks the carbon and displaces the leaving group in an SN2 mechanism

→ One step with a highly unstable transition state (Bonds break and form at the same time)

How can Ethanol and Cyclohexanol be used to synthesize cyclohexyl ethyl ether

Williamson Ether Synthesis

-Need to form a primary tosylate and an alkoxide ion