In This Chapter We Will Study Reactions of the Alcohols Oxidation

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

For organic compounds want to compare oxidation level of different compounds

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 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 H

C Cl C Cl

C O 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 -4 -2 0 +2 +4

CnHx alkane alkene alkyne

CH4 C2H4 C2H2

CHnClx alkyl halide dihalide trihalide tetrahalide

CH3Cl CH2Cl2 CHCl3 CCl4

CHnOx alcohol aldehyde acids carbon dioxide CH3OH CH2O HCO2H CO2

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

Oxidation

Reduction Oxidation States Relative to Reactions

Oxidation state

CH3CH3 H2C=CH2 C2H2 HCl

CH3CH2Cl CH3CHCl2 CH3CCl3 CCl4 LAH

CH3CH2OH CH3CHO CH3CO2H CO2

CH3CH2NH2 CH3CHNH CH3CN C(NH)2

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

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

Need HO H O oxidizing agent C C H3C 0 CH3 H3C +2 CH3 -3 -3 -3 -3

Assign oxidation state to each carbon

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

Typical procedure to oxidize an alcohol is to use a chromium (VI) reagent

e.g. CrO3, H2Cr2O7, H2CrO4

B O H O O HO Cr OH OH O Cr OH Cr(IV) O O

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

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) Alcohols Reacting as Electrophiles

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

NUC H H OH NUC OH H H H H

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

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

OH H+ OH2 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 SOCl2 PBr3 P/I2

secondary SOCl2 PBr3 P/I2

tertiary HCl HBr HI

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

Some reactions are unique to vicinal diols (glycols)

Pinacol rearrangement: Periodic Cleavage of Glycols

HIO4 will react with glycols

Very important reaction to determine sugar structures

H OH H OH

H O H O HO HIO4 O HO OCH3 OCH3 H OH O H O H H H H OH methyl-!-D-glucopyranoside

Only vicinal diols react