Chapter 15 Alcohols, Diols, and Thiols

15.1 Sources of Alcohols

Methanol is an industrial chemical: solvent, antifreeze, fuel. Principal use: preparation of formaldehyde. Prepared by hydrogenation of carbon monoxide. CO + 2H 2  CH 3 OH Methanol

Ethanol is an industrial chemical. Most ethanol comes from fermentation. Synthetic ethanol is produced by hydration of ethylene. Synthetic ethanol is denatured by adding: methanol, benzene, pyridine, castor oil, gasoline, etc. Ethanol

Isopropyl alcohol is prepared by hydration of propene. All alcohols with four carbons or fewer are readily available. Most alcohols with five or six carbons are readily available. Other alcohols

Natural Product Alcohols Natural product - Any organic substance isolated from living organisms or material derived from living organisms.

Review - Preparation of Alcohols Hydroboration-oxidation of alkenes Nucleophilic 1,2-addition of organometallic reagents to carbonyl compounds Hydration of alkenes

Reduction of aldehydes and ketones. Reduction of carboxylic acids. Reduction of esters. Reaction of Grignard reagents with epoxides. 1,2-Diols by dihydroxylation of alkenes. New Ways to Prepare Alcohols

15.2 Preparation of Alcohols by Reduction of Aldehydes and Ketones

CRH OHOHOHOH H CRH O Reduction of Aldehydes Gives Primary Alcohols

Pt, ethanol (92%) Example: Catalytic Hydrogenation CH 3 O CH 2 OH O CH 3 O CH + H2H2H2H2

CRH OHOHOHOH R' C R R' O Reduction of Ketones Gives Secondary Alcohols

(93-95%) Example: Catalytic Hydrogenation + H2H2H2H2OPt ethanol HOH

H:–H:–H:–H:– CRH OHOHOHOH H CRH O H:–H:–H:–H:– CRH OHOHOHOH R' C R R' O Retrosynthetic Analysis

Sodium borohydride Na+ – B HHHH Lithium aluminum hydride Li + – Al HHHH Metal Hydride Reducing Agents Both act as hydride (H: – ) donors.

Sodium Borohydride O CH O2NO2NO2NO2N O NaBH 4 methanol (82%) CH 2 OH O2NO2NO2NO2NHOH (84%) NaBH 4 ethanol Aldehyde Ketone

More reactive than sodium borohydride. Cannot use water, ethanol, methanol, etc. as solvents. Diethyl ether is most commonly used solvent. Lithium Aluminum Hydride

Aldehyde KetoneO CH 3 (CH 2 ) 5 CH 1.LiAlH 4, diethyl ether 2. H 2 O O (C 6 H 5 ) 2 CHCCH 3 1.LiAlH 4, diethyl ether 2. H 2 O (84%) CH 3 (CH 2 ) 5 CH 2 OH (86%) OH (C 6 H 5 ) 2 CHCHCH 3

Neither NaBH 4 or LiAlH 4 reduces carbon-carbon double bonds. O HOH 1.LiAlH 4, diethyl ether 2. H 2 O (90%) Selectivity

15.3 Preparation of Alcohols By Reduction of Carboxylic Acids and Esters

Lithium aluminum hydride is only effective reducing agent. Reduction of Carboxylic Acids Gives Primary Alcohols CRH OHOHOHOH H C R HO O

Reduction of a Carboxylic Acid 1.LiAlH 4, diethyl ether 2. H 2 O COH O CH 2 OH (78%)

Lithium aluminum hydride preferred for laboratory reductions. Catalytic hydrogenation used in industry but conditions difficult or dangerous to duplicate in the laboratory (special catalyst, high temperature, high pressure). Reduction of Esters Gives Primary Alcohols

Reduction of an Ester 1.LiAlH 4, diethyl ether 2. H 2 O (90%)O COCH 2 CH 3 CH 3 CH 2 OH CH 2 OH +

15.4 Preparation of Alcohols From Epoxides

CH 3 (CH 2 ) 4 CH 2 MgBr H2CH2CH2CH2C CH 2 O + 1. diethyl ether 2. H 3 O + CH 3 (CH 2 ) 4 CH 2 CH 2 CH 2 OH (71%) Reaction of Grignard Reagents with Epoxides

Epoxide rings are strained (~29 kcal mol -1 ) and prone to nucleophilic attack at the carbon centers.

15.5 Preparation of Diols

OO HCCH 2 CHCH 2 CH CH 3 H 2 (100 atm) Ni, 125°C HOCH 2 CH 2 CHCH 2 CH 2 OH CH 3 3-Methyl-1,5-pentanediol (81-83%) Example: Reduction of a Dialdehyde

Vicinal diols have hydroxyl groups on adjacent carbons. Ethylene glycol (HOCH 2 CH 2 OH), an antifreeze, is a familiar example. Hydroxylation of Alkenes Gives Vicinal Diols

Osmium Tetraoxide is Key Reagent C C HOHOHOHO OHOHOHOH C C OsO 4 O O Os OO C C Cyclic osmate ester

Example CH 2 CH 3 (CH 2 ) 7 CH (CH 3 ) 3 COOH, OsO 4 (cat), tert-Butyl alcohol, HO – (73%) CH 3 (CH 2 ) 7 CHCH 2 OH OHOHOHOH

Dihydroxylation with OsO 4 Is a Sterespecific Reaction Only the cis-1,2-diol obtained because of the mechanism of initial cycloaddition step: both oxygen atoms on OsO 4 attack same face of the alkene.

15.6 Reactions of Alcohols: A Review and a Preview

Review of Reactions of Alcohols Reaction with hydrogen halides (alkyl halides). Reaction with thionyl chloride (alkyl chlorides). Reaction with phosphorous tribromide (alkyl bromides). Acid-catalyzed dehydration (alkenes). Conversion to p-toluenesulfonate esters (tosylates).

New Reactions of Alcohols Conversion to ethers Esterification Esters of inorganic acids Oxidation Cleavage of vicinal diols

15.7 Conversion of Alcohols to Ethers

Conversion of Alcohols to Ethers Acid-catalyzed condensation of alcohols is an equilibrium reaction; most favorable for primary alcohols and works best if water is removed.

Example

Step 1: CH 3 CH 2 O H H OSO 2 OH CH 3 CH 2 O H OSO 2 OH H + – + Mechanism of Formation of Diethyl Ether

Step 2: CH 3 CH 2 HH+ O CH 3 CH 2 O H + + CH 3 CH 2 CH 3 CH 2 O H HHO Unlike hydroxide (HO - ), H 2 O is an excellent leaving group, so acid catalysis is the key.

Mechanism of Formation of Diethyl Ether Step 3: + CH 3 CH 2 CH 3 CH 2 O H OCH 2 CH 3 H + CH 3 CH 2 CH 3 CH 2 O OCH 2 CH 3 H H +

Intramolecular Etherification

15.8 Esterification

Esterification: A Reversible Process 1) Fischer esterification (a classical transformation). 2) Condensation process (H 2 O produced). 3) Acid-catalyzed (H 2 SO 4 is source of H + and dehydrating agent). 4) Reversible - aqueous acid hydrolyzes esters to carboxylic acids. Acidic Dehydration Acidic Hydrolysis Acid + Alcohol Ester + Water

Example of Fischer Esterification

Reaction of Alcohols with Acyl Chlorides Advantages over Fischer Esterification? Fast, high yields, mild conditions and not reversible.

Example

Reaction of Alcohols with Acid Anhydrides Note similar behavior of acid anhydrides to acyl chlorides.

Example

15.10 Oxidation of Alcohols

Primary alcohols from H 2 O Oxidation of Alcohols RCH 2 OH ORCHORCOH Secondary alcohols O RCR'RCHR' OH

Aqueous solution Mn(VII) Cr(VI) KMnO 4 H 2 CrO 4 KMnO 4 H 2 CrO 4 Na 2 Cr 2 O 7 K 2 Cr 2 O 7 Typical Oxidizing Agents

Aqueous Cr(VI) FCH 2 CH 2 CH 2 CH 2 OH K 2 Cr 2 O 7 H 2 SO 4, H2OH2OH2OH2O FCH 2 CH 2 CH 2 COH (74%)O Na 2 Cr 2 O 7 H 2 SO 4, H2OH2OH2OH2O (85%) H OH O

Mechanism Involves formation and elimination of a chromate ester. C OHOHOHOH HOCrOH OO H C OHO O CrOH CO O HH

All are used in CH 2 Cl 2. Pyridinium dichromate (PDC) (C 5 H 5 NH + ) 2 Cr 2 O 7 2– Pyridinium chlorochromate (PCC) C 5 H 5 NH + ClCrO 3 – Nonaqueous Sources of Cr(VI)

PDC CH 2 Cl 2 O(94%) CH 2 OH (CH 3 ) 3 C CH Oxidation of a Primary Alcohol with PDC

Oxidation of a Primary Alcohol with PCC CH 3 (CH 2 ) 5 CH 2 OH PCC CH 2 Cl 2 O CH 3 (CH 2 ) 5 CH (78%) ClCrO 3 – N H +

15.11 Biological Oxidation of Alcohols

alcoholdehydrogenase Enzyme-Catalyzed CH 3 CH 2 OH + NAD H NAD H CH 3 CH O

Nicotinamide adenine dinucleotide (oxidized form) HO HO O O N N NH 2 P O P O O HO OH H C O N O O OO + __ Structure of NAD +

Enzyme-Catalyzed CH 3 CH 2 OH + N H CNH 2 O+ R N H OR CH 3 CH OH +H ++

15.12 Oxidative Cleavage of Vicinal Diols

Cleavage of Vicinal Diols by Periodic Acid CC HO OH HIO 4 C O O C +

Cleavage of Vicinal Diols by Periodic Acid

Cyclic Diols Are Cleaved

15.13 Thiols

Nomenclature of Thiols 1) Analogous to alcohols, but suffix is -thiol rather than -ol 2) Final -e of alkane name is retained, not dropped as with alcohols CH 3 CHCH 2 CH 2 SH CH 3 3-Methyl-1-butanethiol

1) Hydrogen bonding is much weaker in thiols than in alcohols (S—H bond is less polar than O—H). 2) Low molecular weight thiols have foul odors. 3) Thiols are stronger acids than alcohols. 4) Thiols are more easily oxidized than alcohols; oxidation takes place at sulfur. Properties of Thiols

Thiols Are Less Polar than Alcohols MethanolMethanethiol bp: 65°C bp: 6°C

Have pK a s of about 10-11; can be deprotonated in aqueous base... Thiols Are Stronger Acids than Alcohols Stronger acid (pK a = 10-11) Weaker acid (pK a = 15.7) H RS OHOHOHOH – RS H OHOHOHOH –++

RS – and HS – Are Weakly Basic and Good Nucleophiles HClH C6H5SC6H5SC6H5SC6H5S C 6 H 5 SNa SN2SN2SN2SN2 (75%) KSH SN2SN2SN2SN2 (67%) BrSH

Oxidation of Thiols Takes Place at Sulfur ThiolDisulfide RS H RS SR Thiol-disulfide redox pair is important in biochemistry. Other oxidative processes place 1, 2 or 3 oxygen atoms on sulfur.

Oxidation of Thiols Takes Place at Sulfur ThiolDisulfide RS H RS SR Sulfenic acid RS OH Sulfinic acid RS OH O –+ Sulfonic acid RS OH O –2+ O –

HSCH 2 CH 2 CH(CH 2 ) 4 COH SHSHSHSH O 2, FeCl 3 Sulfide-Disulfide Redox Pair O (CH 2 ) 4 COH  -Lipoic acid (78%) OS S 6,8-Dimercaptooctanoicacid

15.14 Spectroscopic Analysis of Alcohols

O—H stretching: cm –1 (broad) C—O stretching: cm –1 Infrared Spectroscopy

Infrared Spectrum of Cyclohexanol

S—H stretching: cm –1 (weak) Infrared Spectroscopy Example: 2-Mercaptoethanol HOCH 2 CH 2 SH HOCH 2 CH 2 SH

Chemical shift of O—H proton is variable; depends on temperature and concentration. O—H proton can be identified by adding D 2 O; signal for O—H disappears (converted to O—D). H—C—O signal is less shielded than H—C—H. 1 H NMR C O HH  ppm  ppm

Chemical shift ( , ppm) 2-Phenylethanol CH2CH2OHCH2CH2OHCH2CH2OHCH2CH2OH

Sulfur is less electronegative than oxygen, so it is less deshielding. 1 H NMR CH 3 CH 2 CH 2 CH 2 OH CH 3 CH 2 CH 2 CH 2 SH  3.6  2.5

Chemical shift of C—OH is  ppm. Deshielding effect of O is much larger than that of S. 13 C NMR CH 3 — CH 2 — CH 2 — CH 2 — OH  14  19  35  62 CH 3 — CH 2 — CH 2 — CH 2 — SH  13  21  36  24