Reactions of Alcohols Alcohols are versatile organic compounds since they undergo a wide variety of transformations the majority

y of which are either oxidation or reduction type reactions. Oxidation is a loss of electrons Reduction is a gain of electrons. But in organic terms: Oxidation: loss of H2; addition of O or O2; addition of X2 (halogens). Reduction: addition of H2 or H-; loss of O or O2; loss of X2. (Neither an oxidation or reduction: Addition or loss of H+, H2O, HX). Oxidation-Reduction Chart:
Oxidation OH H R H R H primary alcohol OH H R R H R R secondary alcohol OH R R R tertiary alcohol

H R H alkane

O H R

O OH acid

aldehyde

H R

O R ketone

H R R H

Reduction

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Oxidation of Alcohols Primary and secondary alcohols are easily oxidized by a variety of reagents. Secondary Alcohols The most common reagent used for oxidation of secondary alcohols to ketones is chromic acid, H2CrO4.
OH R H R secondary alcohol Na2Cr2O7, H2SO4 R O R ketone

Chromic acid is produced in situ by reaction of sodium dichromate, sulfuric acid and water. Na2Cr2O7 + H2O + 2H2SO4 2 H2CrO4 + 2 NaHSO4 Mechanism of oxidation
R R H OH O HO Cr OH O chromic acid (CrVI) O R O Cr OH H O H2O: R R O R O R O Cr OH H O chromate ester OH O Cr O(CrIV) R

+ H2O

H3O+

The alcohol and chromic acid produce a chromate ester, which then reductively eliminates the Cr species. The Cr is reduced (VI IV), the alcohol is oxidized.

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Oxidation of Primary Alcohols Primary alcohols are easily oxidized just like secondary alcohols, but the product of oxidation is an aldehyde.
OH R H H primary alcohol [O] O R H [O] O R acid OH

aldehyde

However, the aldehyde can also be easily oxidized to an acid, and this overoxidation is a practical problem. E.g.
CH2OH Na2Cr2O7, H2SO4 CO2H

A common reagent that selectively oxidizes a primary alcohol to an aldehyde (and no further) is pyridinium chlorochromate, PCC.
N: CrO3, HCl (PCC)

E.g.
H OH PCC O aldehyde

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Tertiary Alcohols These are resistant to oxidation because they have no hydrogen atoms attached to the oxygen bearing carbon (carbinol carbon). Other Oxidizing Reagents Potassium permanganate is a cheaper but stronger oxidizing agent, and conditions must be controlled carefully.
KMnO4, base OH O

OH

Thermal dehydrogenation is the cheapest method of oxidation but the high temperatures involved limit the applicability of this method.
H OH CuO, 300 C
o

Reduction of Alcohols Normally an alcohol cannot be directly reduced to an alkane in one step.
H OH LiAlH4 H H

The OH group is a poor leaving group so hydride displacement is not a good option however the hydroxyl group is easily converted into other groups that are superior leaving groups, and allow reactions to proceed. One such conversion involves tosyl chloride, and the formation of a tosylate.

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Ts-Cl, py OH

O O S O CH3 LiAlH4

H H

Ts or Tosylcyclohexyl tosylate

Cyclohexanol will not reduce with LiAlH4, but the corresponding tosylate reduces to cyclohexane very easily. Tosylate Esters These compounds undergo substitution and elimination very easily (often more reactive than alkyl halides).

R O H N

R O+N H OR O S O ClCH3 Ts-Cl CH3 Tosylate Ester RO-Ts

Cl O S O R O-

Tosylate esters (tosylates) are typically formed from alcohols with reaction with Ts-Cl and pyridine (py).
CH3CH2 I:
-

H H3C (S)

O-Ts

SN2

CH2CH3 I H CH3 (R)

-

OTs

Tosylate groups undergo a variety of SN2 reactions. The tosylate is such a good leaving group because it is a stable anion.

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OO S O
-

O -O S O

O O S O-

OTs =

CH3

CH3

CH3

Common SN2 transformations of Tosylates:

R OTs
-

O H C N Br-

R-OH R-CN R-Br

-

R'

R-OR' R-NH2 R-H

:NH3 LiAlH4

Alcohols and Hydrohaloic Acids Alkyl halides can also be formed by reaction of alcohols with H-X acids. R-OH + H-Br R-Br + H2O In acidic media, the alcohol is in equilibrium with its protonated form.
R O-H + H
+

H R O H +

Br SN1 or SN2

R Br

+ H2O

The OH is a poor leaving group, but OH2+ is an excellent leaving group, and once the -OH is protonated the molecule may take place in a variety of substitution and/or elimination reactions.

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The nature of R determines whether the reactions proceed via SN1 or SN2 mechanisms. (If R is primary alkyl SN2 If R is bulky tertiary alkyl SN1). Hydrochloric Acid H-Cl reacts in the same way, although often Zinc (II) chloride (a Lewis acid) is added to help compensate for the lower nucleophilicity of chloride ion. The mixture of HCl and ZnCl2 is called the Lucas Reagent. Secondary and tertiary alcohols react via the SN1 mechanism with the Lucas reagent.
CH3 H OH CH3 ZnCl2 H CH3
3

O + CH H

_ ZnCl2

CH3 H + CH3

Cl

CH3 H Cl CH3

The ZnCl2 coordinates to the hydroxyl oxygen, and this generates a far superior leaving group.
H H OH CH3 Cl
-

ZnCl2 H

H
3

O + CH H

_ ZnCl2

_ Cl

O + H H CH3

_ ZnCl2

H H Cl CH3

Primary alcohols react in a similar fashion except the free cation is not generated, and the substitution is of SN2 type. Limitations of use of H-X 1) Only works for H-Cl and H-Br 2) Low chemical yields for primary and secondary alcohols 3) Often observe competing elimination 4) Carbocations can lead to rearranged products

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Phosphorous Halides Phosphorous halides can convert alcohols to alkyl halides. E.g. 3 R-OH + PCl3 3 R-Cl + P(OH)3 3 R-OH + PBr3 3 R-Br + P(OH)3 R-OH + PCl5 R-Cl + POCl3 + HCl PI3 has to be generated in situ via reaction of iodine and phosphorous. E.g. CH3(CH2)14CH2-OH + P/I2 CH3(CH2)14CH2-I This type of reaction does not work well for tertiary alcohols, and also does not lead to rearranged products. These observations are explained by the reaction mechanism. Mechanism The hydroxyl oxygen displaces a halide (good leaving group) from the Phosphorous.
Br R OH P Br Br Br
-

Br + R O P Br H

Br R

The liberated halide performs an SN2 type attack on the back side of the R group. The positively charged oxygen is a good leaving group.

Thionyl Chloride Thionyl chloride (SOCl2) is the usual method of choice for preparing alkyl chlorides from alcohols.
Cl S O Cl

R OH

R Cl + SO2 + HCl

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The mechanism is interesting: The hydroxyl oxygen attacks the electrophilic Sulfur, and from the tetrahedral intermediate a chloride is ejected.
Cl S O Cl Cl + R O S OH Cl O + R O S Cl H -H+ R-Cl + SO2 R+ O -O S Cl R O S Cl O

R OH

The chlorosulfite ester rearranges with the breaking of the C-O and S-Cl bonds and the formation of the R-Cl bond and a new S-O bond. When R is secondary or tertiary, the ionization to a cation probably precedes the Chloride attack, whereas if R is primary the process is probably concerted (Bond breaking and forming at the same time).

Summary of Best Alcohol to Alkyl Halide Transformations Class Primary Secondary Tertiary Chloride SOCl2 SOCl2 HCl Bromide PBr3 PBr3 HBr Iodide P/I2 P/I2 HI

Dehydration Reactions of Alcohols Dehydration of alcohols requires an acidic catalyst to convert the hydroxyl into a good leaving group this is an equilibrium reaction.
H OH + H2O

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It is possible to force the equilibrium to the right (alkene) by removing one or both of the products. This is normally achieved either by distillation (alkene is lower boiling than alkyl halide) or the addition of a dehydrating agent. Alcohol dehydration usually occurs via the E1 mechanism.
OH H
+

+ OH2

+ H H H2O:

The first step is the exothermic protonation of the hydroxyl, followed by the slow, endothermic, rate determining ionization to generate the cation. The fast deprotonation is exothermic and produces the alkene.

Figure 11-2

Since the RDS is the formation of the carbocation, the ease of formation dictates the reaction rates of 3 > 2 > 1. Rearrangements are common since a free carbocation is involved.

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E.g. CH3CH2CH2CH2-OH CH3CH=CHCH3 + CH2=CHCH2CH3

H H H H H H H2O H H H + H H + Ha H Hb H -Ha
+

H H H

-Hb

H H3C

CH3 H

major product disubstituted alkene

H CH2 CH2CH3

minor product mono substituted alkene

After 1-butanol is protonated, the ionization is accompanied by a hydride shift to produce a secondary carbocation. There is a choice of protons to be eliminated, and Saytzeffs rule applies. Bimolecular Dehydration to form Ethers In certain cases, a protonated primary alcohol may be attacked by another molecule of alcohol. The net result is a dehydration and a formation of an ether. E.g.
H3C CH3CH2 OH H H + O H H CH3CH2 + O H -H+ CH3CH2 O CH2CH3 CH3 H H

Bimolecular dehydration is best used for the synthesis of symmetrical dialkyl ethers from unhindered primary alcohols.

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Unique Reactions of Diols (Pinacol Rearrangement)

CH3 CH3 H3C OH OH pinacol CH3 H2SO4 H3C CH3 CH3 O CH3 pinacolone + H2O

The pinacol rearrangement is a formal dehydration. Mechanism

CH3 CH3 H3C OH OH CH3 CH3 CH3 CH3 H3C H2O OH + H3C CH3 CH3 + OH methyl shift CH3 H3C CH3 OH + CH3 H3C CH3 + CH 3 CH3 O H H2O: CH3 H3C CH3 O CH3 CH3

The protonation of the hydroxyl is followed by ionization. The tertiary carbocation rearranges with a methyl shift to produce a tertiary cation which has the extra benefit of resonance stabilization. The rearranged product is deprotonated to generate the final product.

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Cleavage of Glycols Periodic acid will cleave 1,2 diols to give aldehyde and ketone products.
OsO4 H2O2 HIO4 HO OH syn diol O O

(The treatment of an alkene to syn hydroxylation followed by periodic acid cleavage is an alternative to the ozonolysis-reduction procedure described earlier). Mechanism
H HO H H O H = O O O O O O I OH O

HIO4

OH

The mechanism involves the formation of a cyclic periodate ester, which cleaves to generate to carbonyl groups. Esterification of Alcohols Usually the term ester means the ester of a carboxylic acid. In general, an acid and alcohol generate an ester and water. This is called a Fischer esterification.
O C OH acid H+ O R O C R' + H2O ester

R OH + R' alcohol

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Acid chlorides provide another route to producing esters.

O C Cl acid chloride O R O C R' + HCl ester

R OH + R' alcohol

Esters of Inorganic Acids Just as alcohols form esters with carboxylic acids, they also form esters with inorganic acids.
O R OH + HO S O O CH3 RO S CH3 + H2O O p-toluenesulfonate ester ROTs O RO S OH O methylsulfate (sulfate ester) O RO N+ Oalkyl nitrate ester

p-toluenesulfonic acid TsOH O HO S OH O sulfuric acid O HO N+ Onitric acid

R OH +

+ H2O

R OH +

+ H2O

Phosphate esters are important in nature since they link the nucleotide bases together in DNA.
R OH + O HO P OH OH phosphoric acid O RO P OH + H2O OH methylphosphate (phosphate ester)

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Reactions of Alkoxides Alkoxide ions are produced when metals like Na or K are added to alcohols. R-OH + Na RO- +Na + H2 The sodium (or potassium) alkoxides are strong bases and nucleophiles. Alkoxides can react with primary alkyl halides (or tosylates) to produce ethers. This is the Williamson Ether synthesis, and it involves SN2 displacement with back side attack of the alkoxide.
CH3CH2 O:Na
+

H3C I

CH3CH2 O-CH3 ether

+ NaI

Normally this reaction is limited to unhindered primary alkyl halides, otherwise elimination tends to be the preferred mode of reaction.

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