Alcohols

Have seen many reactions to synthesize alcohols:

In this chapter we will study reactions of the alcohols

Oxidation

Need to understand the nomenclature of organic reduction/oxidation

In general chemistry learn that reduction is gain of electrons and oxidation is loss of electrons

Definition works well with transition metals, but it is hard to distinguish RED/OX reactions in organic reactions by this definition

It is very important that one recognizes whether two compounds are of the same oxidation level or whether one is “oxidized” relative to the other

For organic compounds want to compare oxidation level of different compounds

Anytime two compounds can be converted with only water, basic water (NaOH) or acidic water (H+) then the two compounds are at the same oxidation level

For example:

All compounds are at the same oxidation level

oxidized form reduced form

Using LAH, however, creates two compounds at different oxidation levels

Comparison of Oxidation States

We can use a bookkeeping technique to assign oxidation states

In this technique assume every bond is ionic and the electrons are closer to the more electronegative atom

This is obviously just for convenience – does not correspond to actual system with covalent bonds (where electrons are shared between two atoms)

Consider bonds to carbon:

C H

C Cl

C O

C H

C Cl

C O

Used only for bookkeeping - C-H bond is not ionic

Comparison of Oxidation States

With this bookkeeping technique, oxidation states can be compared

Oxidation state

compound

CnHx

CHnClx

CHnOx

CHnNx

-4 -2 0 +2 +4

alkane alkene alkyne CH4 C2H4 C2H2

alkyl halide dihalide trihalide tetrahalide CH3Cl CH2Cl2 CHCl3 CCl4

alcohol aldehyde acids carbon dioxide CH3OH CH2O HCO2H CO2

amine imine nitrile diimide CH3NH2 CH2NH HCN C(NH)2

Oxidation

Reduction

Oxidation States Relative to Reactions

Oxidation state

CH3CH3 H2C=CH2 C2H2

CH3CH2Cl CH3CHCl2 CH3CCl3 CCl4

CH3CH2OH CH3CHO CH3CO2H CO2

CH3CH2NH2 CH3CHNH CH3CN C(NH)2

Interconversions between same oxidation state can occur with water or acidic/basic conditions

HCl

Interconversions between different oxidation states need an oxidizing (if going to the right) or reducing agent (if going to the left)

LAH

Choosing Reagents for an Organic Reaction

The proper choice of reagents therefore involves deciding whether a reaction changes oxidation states

If a reaction is more oxidized, then an oxidizing agent is required If a reaction is more reduced, then a reducing agent is required

H3CCO

CH3H3CC CH3

HO H

Assign oxidation state to each carbon

-3 -3 -3 -3 0 +2

The middle carbon changes from 0 to +2 oxidation state, Therefore the carbon has been oxidized

Need oxidizing agent

Oxidation of Alcohols

Typical procedure to oxidize an alcohol is to use a chromium (VI) reagent e.g. CrO3, H2Cr2O7, H2CrO4

The alcohol reacts with Cr(VI) to form a chromate ester

OH HO CrO

OOH O Cr

O

OOH

HO

Cr(IV)

B

The chromate ester then reacts with base (usually water) to oxidize the alcohol [and reduce the chromium reagent]

With 1˚ alcohols the initially formed aldehyde reacts further

The aldehyde equilibrates to the geminal diol form, called acetal (which is further promoted in acidic conditions)

This acetal can behave like an alcohol to oxidize in a second step

1˚ alcohols therefore give almost exclusively carboxylic acids (especially in acidic conditions)

One way to avoid this overoxidation is to use a Cr(VI) reagent in nonacidic conditions

The pyridine acts as a base and therefore there is less acetal formation and hence oxidation of 1˚ alcohols stop at the aldehyde stage

Other Oxidants

Cr(VI) is not the only oxidant for alcohols

Swern Oxidation -another method to synthesize aldehydes from 1˚ alcohols

Advantages: mild method, easy to separate and purify products, 1˚ alcohol stops at aldehyde

In addition to oxidation, can also react alcohols as either nucleophiles or electrophiles

To make alcohols more nucleophilic, need to abstract the acidic hydrogen (remember pKa’s!)

With this method, can make nucleophilic oxygen that can react through any SN2 type reaction already studied

Esterification

To form esters the alcohol can react as a nucleophile without forming the alkoxides - generally need to activate the carbonyl first (through protonation)

to make it more electrophilic

Esters can also be formed with alcohols by reacting alcohol with more reactive carbonyl groups

The better leaving group (chloride) allow the alcohol to react at the carbonyl without first protonating

Formation of Inorganic Esters

- Same type of mechanisms already observed

Tosylates are typically formed by reacting alcohols and tosyl chlorides

Using common abbreviations:

Other Common Ester Types

Follow same mechanism as seen earlier for ester formation (alcohol reacts at carbonyl site {N=O or P=O in these examples} followed by loss of water)

OHH

HH

NUC

Alcohols Reacting as Electrophiles

In these reactions the alcohol is the leaving group (the C-O bond is broken during the reaction)

NUCH

HHOH

Usually the hydroxide, or alkoxide, is a BAD leaving group, therefore we need to convert the alcohol into a GOOD leaving group

One Method is Tosylate Formation

The tosylate, which was seen earlier, is commonly used as a way to make the alcoholic oxygen a good leaving group

OTsH

HH

NUCNUC

H

HHOTs

Another method we have already observed is protonation to form water as the leaving group

OH OH2 XH+

X

With either an SN1 or SN2 reaction the alcohol would need to be protonated first in order to make a better leaving group

For alcohol reactions what type of reaction that will occur (SN1 or SN2) depends upon the order of the attached carbon

3˚ alcohols must be SN1 (cannot undergo SN2) 2˚ alcohols mainly SN1 1˚ alcohols SN2 (1˚ carbocations are high in energy)

Lucas Reagent

Chloride reacts slower than bromide (less nucleophilic)

Therefore often need to add an additional Lewis acid to convert an alcohol to alkyl chloride (even with 2˚ and 3˚ alcohols that proceed through SN1)

-with Lucas reagent need to add ZnCl2 to increase reaction rate

While it is relatively easy to react alcohols with hydrobromic or hydrochloric acid, to generate alkyl bromides or alkyl chlorides,

both HF and HI are difficult to react in this manner

Need different routes to these compounds

Alkyl iodides can be prepared with phosphorous halides

An example with PCl3:

SN2 reaction – works well for 1˚ and 2˚ alcohols, not a choice for 3˚ alcohols

Method of choice for Iodides

PI3 can be used Often in practice PI3 is generated in situ from P/I2

Another method for conversion of alcohols to alkyl halides is thionyl chloride

Due to rapidity of the last step, these is retention of stereochemistry

In practice almost any alcohol can be converted into an alkyl halide

Type of alcohol and desired halide often determine which method is best

Best reagents for interconversions:

Type of alcohol chloride bromide iodide primary

secondary tertiary

SOCl2

SOCl2

HCl HBr HI

PBr3

PBr3

P/I2

P/I2

Stereochemistry, and possibility of rearrangements, depends on mechanism for each reaction

Diol Reactions

Some reactions are unique to vicinal diols (glycols)

Pinacol rearrangement:

O

H

HO

H

HO

H

HOHH OCH3

OH

methyl-!-D-glucopyranoside

Periodic Cleavage of Glycols

HIO4 will react with glycols

Very important reaction to determine sugar structures

Only vicinal diols react

O

H

OH

HH OCH3

OH

HIO4

O

H

O

OH