Reactions of Alcohols oxidation tosylation and reactions of tosylates substitutions to form alkyl halides dehydration to form alkenes and ethers pinacol rearrangement esterification cleavage of glycols ether synthesis

Classification of Reactions

Oxidations addition of O or O2

addition of X2

loss of H2

Reductions loss of O or O2

loss of X2

addition of H2 or H-

Classification of Reactions

Neither an oxidation nor a reduction Addition or loss of H+

Addition or loss of OH-

Addition or loss of H2O Addition or loss of HX

Classification of Reactions

Oxidations count C-O bonds on a single C the more C-O bonds, the more

oxidized the C

increasing level of oxidation

OHH

OO

OH

OH

OH

Reactions of Alcohols - Oxidation For alcohols, the oxidation comes from the loss of

H2. Oxidation of a 2° alcohol gives a ketone. Chromic acid reagent used in lab oxidations.

Na2Cr2O7 + H2SO4 + H2O 2H2CrO4 + 2NaHSO4 CrO3 + H2O (dil H2SO4) H2CrO4

Reactions of Alcohols - Oxidation Oxidation of a 1° alcohol gives

a carboxylic acid if chromic acid reagent is used.

an aldehyde if pyridinium chlorochromate (PCC) is used.

Reactions of Alcohols - Oxidation

Two other reagents behave like the chromic acid reagent: KMnO4 (will attack C=C, too)

HNO3

These two oxidizing agents are so strong that C-C bonds may be cleaved.

Bleach (OCl-) also oxidizes alcohols.

Reactions of Alcohols – Swern Oxidation

Uses dimethyl sulfoxide (DMSO), oxalyl chloride (COCl)2 and a hindered base. The reactive species is (CH3)2SCl+. The result is a ketone or an aldehyde

(the same as for PCC).

Reactions of Alcohols – Swern Oxidation

Uses dimethyl sulfoxide (DMSO), oxalyl chloride (COCl)2 and a hindered base.

OH + H3C S CH3

O

+ Cl C C Cl

O O (CH3CH2)3N

CH2Cl2

H

O

+ H3C S CH3 + CO2 CO 2HCl+ +

-60°C

Reactions of Alcohols – Oxidation with DMP

Uses Dess-Martin periodinane (DMP). Mild conditions: room temperature

and neutral pH with excellent yields The result is a ketone or an aldehyde

(the same as for PCC and the Swern oxidation).

Reactions of Alcohols – Oxidation with DMP

Uses Dess-Martin periodinane (DMP).

OH + H

O

+ 2HOAcOI

O

AcO OAcOAc

....OI

O

OAc

+

..

Reactions of Alcohols - Biological Oxidation Ethanol is the least toxic alcohol, but it is still

toxic. The body detoxifies ethanol with NAD catalyzed

first by alcohol dehydrogenase (ADH) and second by aldehyde dehydrogenase (ALDH): ethanol acetic acid

The reason methanol and ethylene glycol are so toxic to humans is that, when they react with NAD/ADH/ALDH, the products are more toxic than the original alcohols. methanol formic acid ethylene glycol oxalic acid

Reactions of Alcohols - Oxidation

3° alcohols will not oxidize, because there is no H on the carbinol C atom.

The chromic acid test capitalizes on this fact: orange chromic acid reagent turns

green or blue (due to Cr3+) in the presence of 1° or 2° alcohols, but doesn’t change color in the presence of a 3° alcohol.

Reactions of Alcohols - Tosylation

In order to perform an SN2 reaction on an alcohol, i.e., with the alcohol as the substrate, the -OH group must leave the alcohol: R-OH + Nuc:- R-Nuc + OH-

OH- is a poor leaving group H2O is a better leaving group, but this requires

protonation of the alcohol which, in turn, requires an acidic solution. Most nucleophiles are strong bases and cannot exist in acidic solutions.

We need to convert the alcohol to an electrophile that is compatible with basic nucleophiles.

Reactions of Alcohols - Tosylation Converting the alcohol to an alkyl halide (already

discussed) or an alkyl tosylate lets it act as an electrophile.

Stereochemical configuration of alcohol is

retained.

A Tosylate Ion is an EXCELLENT LEAVING GROUP

As good as or better than a halide.

A Tosylate Ion is an EXCELLENT LEAVING GROUP

As such, tosylates (just like halides) are candidates for SN2 reactions E2 reactions SN1 reactions E1 reactions

Just like the halides

SN2 Reactions of Tosylates

R-OTs + OH- ROH (alcohol) + -OTs

R-OTs + CN- RCN (nitrile) + -OTs

R-OTs + Br- RBr (alkyl halide) + -OTs

R-OTs + R’O- ROR’ (ether) + -OTs

R-OTs + NH3 RNH3+ -OTs (amine salt)

R-OTs + LiAlH4 RH (alkane) + -OTs

SN2 Reactions of Tosylates - Mechanism

Single step Inversion of configuration

Alcohols to Alkyl Halides: Hydrohalic Acids (HX)

Hydrohalic acids are strong acids, existing in aqueous solution as H+ and X-. Recognize a hydrohalic acid: NaBr/H2SO4

The H+ is need to convert the -OH of the alcohol into a good leaving group (H2O).

The reaction mechanism, SN1 or SN2, depends on the structure of the alcohol.

Alcohols to Alkyl Halides: Hydrohalic Acids (HX)

The structure of the alcohol dictates whether the mechanism is SN1 or SN2.

Cl- is a weaker nucleophile than Br-. ZnCl2 coordinates with the -OH of the

alcohol (like H+ does) to form a better leaving group (HOZnCl2

-) than water. ZnCl2 is a better Lewis acid than H+.

This promotes the SN1 reaction between HCl and 2° and 3° alcohols.

HCl/ZnCl2 is called the Lucas reagent.

Alcohols to Alkyl Chlorides: The Lucas Reagent

Add the Lucas reagent to a solution of the unknown alcohol and time the formation of a second phase.

3° alcohols react immediately. 2° alcohols take 1-5 minutes. 1° alcohols take >6 minutes.

Alcohols to Alkyl Chlorides: The Lucas Test

This reaction does not always give good yields of RX. 1° and 2° alcohols react slowly with

HCl, even with ZnCl2 added. Heating an alcohol with HCl or HBr can

give the elimination product, an alkene.

Rearrangements can occur with SN1 (this is not necessarily bad).

HI does not give good yields of alkyl iodides, a valuable class of reagents.

Alcohols to Alkyl Halides: Limitations of Using HX

Can give good yields of 1° and 2° alkyl bromides and iodides without the acidic conditions that go with HX. 3 R-OH + PBr3 3RBr + P(OH)3

PI3 is unstable and must be made in situ: 6 R-OH + 2P + 3I2 6RI + 2P(OH)3

PBr3 and P/I2 do NOT work well with 3° alcohols.

Alcohols to Alkyl Halides: PBr3 and P/I2

A double SN2 mechanism, which is why it does not work on 3° alcohols.

Inversion of configuration, but no rearrangements.

Alcohols to Alkyl Halides: PBr3 Mechanism

Alcohols to Alkyl Halides: Thionyl Chloride, SOCl2

Often the best way to make an alkyl chloride from an alcohol.

ROH + SOCl2 RCl + HCl(g) + SO2(g)

Gaseous by-products keep the equilibrium well to the right.

heat

dioxane

Alcohols to Alkyl Halides: Best Reagents

Alcohol Alkyl chloride

Alkyl bromide

Alkyl iodide

1° SOCl2 PBr3 P/I2

2° SOCl2 PBr3 (P/I2)

3° HCl HBr (HI)

Alcohols to Alkenes: Acid-Catalyzed Dehydration

We studied this in the formation of alkenes.

E1 elimination of a protonated alcohol

Best for 3° and 2° alcohols Rearrangements common for 1°

alcohols due to the carbocation intermediate

Zaitsev product predominates.

Step 1: protonation of the alcohol Fast equilibrium Converts OH to a good leaving

group

Alcohols to Alkenes: Acid-Catalyzed Dehydration

Step 2: ionization to a carbocation slow, rate-limiting leaving group is H2O

Alcohols to Alkenes: Acid-Catalyzed Dehydration

Step 3: deprotonation to give alkene fast The carbocation is a strong acid: a weak

base like water or bisulfate can abstract the proton.

Alcohols to Alkenes: Acid-Catalyzed Dehydration

Competes with alkene formation. Lower temperatures favor ether formation, a ΔS thing. After protonation, the alcohol can undergo an SN2 attack

by another alcohol molecule to form a symmetric ether.

Alcohols to Symmetric Ethers:

Bimolecular Dehydration

3° Vicinal Diols to Ketones: The Pinacol Rearrangement

Acid-catalyzed dehydration of a 3° vicinal diol to form a ketone.

Involves a methyl migration, ~CH3

3° carbocation

resonance-stabilized carbocation

3° Vicinal Diols to Ketones: The Pinacol Rearrangement

3° Vicinal Diols to Ketones: The Pinacol Rearrangement

Vicinal Diols to Carbonyls: Periodic Acid Cleavage of Glycols

Periodic acid is HIO4. Products are aldehydes and ketones. Products the same as for ozonolysis.

HIO4

Alcohols to Esters: Acids

When the acid is a carboxylic acid, the reaction is called Fischer esterification.

This is an equilibrium, and it does not always favor the ester.

When the acid is sulfuric acid, the product is a sulfate ester.

Alcohols to Esters: Acids

When the acid is nitric, and propane-1,2,3-triol (glycerine) is the alcohol, what is the product?

When the acid is phosphoric acid, the product is a phosphate ester.

Phosphate esters are the links between nucleotides in RNA and DNA.

Alcohols to Esters: Acids

DNA

image from Wikipedia

Oxidation or Reduction?

O OHHO O OH

COHO

CH3

COHO

H2COH

Predict the Product

CH2OH

H2SO4 , heat

OHNa2Cr2O7

H2SO4

OHSOCl2

Predict the Product

OH1.

2.

TsCl/pyridine

NaCN

OH1.

2.

TsCl/pyridine

NaOCH3/CH3OH

1.

2.

TsCl / pyridineOH

NaI / acetone

Predict the Product

CH3CH2OHH2SO4

140°C

OH

P/I2

As opposed to 180°C.

Predict the Product

CO Cl

+

OH

O

+

OHCOH

H+

Conversions

Br CHO

Br CCH3H3C

Br

CH3OH

CH3

Conversions

OH CH3HO

CH2OH CO2CH2CH3