Alcohols Biological Activity Nomenclature Preparation Reactions

Some Alcohols

Alcohols are Found in Many Natural Products

Paralytic Shellfish Poisoning

Ethanol: the Beverage

Methanol: Not a Beverage

Oxidation levels of oxygen- halogen- and nitrogen- containing molecules

Acidity of Alcohols Due to the electronegativity of the O atoms, alcohols are slightly acidic (pKa 16-18). The anion dervived by the deprotonation of an alcohol is the alkoxide. Alcohols also react with Na (or K) as water does to give the alkoxide (red-ox):

Withdrawing Groups Enhance Acidity alcoholpKa CH 3 OH15.54 CH 3 CH 2 OH16.00 CF 3 CH 2 OH12.43 (CH 3 ) 3 COH18.00 (CF 3 ) 3 COH 5.4

Phenols are more acidic than alcohols

Physical Properties CH 3 CH 2 CH i CH 3 OCH ss CH 3 CH 2 OH781.7 vs b.p. o C  Dsol. in H 2 O

Intermolecular H-Bonding

Alcohol Nomenclature

Nomenclature

Preparation of Alcohols Reduction of ketones and aldehydes Reduction of esters and carboxylic acids Hydration of Alkenes Nucleophilic addition –Grignard reaction –Acetylide addition Substitution Epoxide opening

NaBH 4 Reduction

Some Examples

Two Alcohol Products Form in Lab

LiAlH 4 Reduction a Stronger Reducing Agent

LiAlH 4 is a much stronger reducing agent

NaBH 4 is More Selective

Oxymercuration Hydration Markovnikov

Hydroboration Hydration Anti-Markovnikov

Base Catalyzed Ring-Opening of Epoxides

Acid Catalyzed Ring-Opening Aqueous and in Alcohol

Nucleophilic addition to Carbonyl Compounds Acetylides

Organometallic Chemistry Grignard Reaction

Grignard Reagents React With Ketones to form tertiary alcohols

Grignard Reagents React With Aldehydes to form secondary alcohols

Grignard Reagents React With Formaldehyde to form primary alcohols

Grignard Reagents react (twice) with Esters to form 3 o Alcohols

Grignard Summary

Grignard Reagents are exceptionally strong bases

Synthesis

Retrosynthetic Analysis

4-Step Synthesis

Synthesize Using Only 1,2, or 3-Carbon Reagents

Retrosynthesis

Reactions of Alcohols Oxidation R-X, Ether, and Ester Preparation Protection of Alcohols Synthesis The Logic of Mechanisms

Alcohols are Synthetically Versatile

Oxidation - Reduction

Oxidation of 2 o Alcohols with Cr(VI)

Mechanism

Oxidation of 1 o Alcohols

PCC oxidizes 1 o Alcohols to Aldehydes

Oxidation of 1 o Alcohols to Aldehydes: PCC

Oxidation Summary

Reduction Summary

Conversion of Alcohol into a Leaving Group Form Tosylate (p-TsCl, pyridine) Use strong acid (H 3 O + ) Convert to Alkyl Halide (HX, SOCl 2, PBr 3 )

Formation of p-Toluenesulfonate Esters

Best to use p-TsCl with pyridine

Reactions of Tosylates: Reduction, Substitution, Elimination

Alcohols to Alkyl Halides

Lucas Test

Qualitative test for Alcohol Characterization

Other Simple Qualitative Tests

1 o and 2 o Alcohols: best to use SOCl 2, PBr 3, or P/I 2

Thionyl chloride mechanism in Pyridine – S N 2, Inversion

Dehydration of Alcohols – E1

Propose a Mechanism

Both approaches seem logical

Take the Blue Route

Problem Set: Road Map Problem

Ethers

Dimerization of Alcohols: Symmetrical Ethers

Mechanism

Williamson Ether Synthesis Preparation of Unsymmetrical Ethers

Mechanism, S N 2

Alkoxides are strong bases so there is competition with E2 reactions. Bulky alkoxides reacting with primary alkyl halides favor Williamson ether synthesis(S N 2). How would you prepare the following ethers starting from an alcohol and an alkyl halide?

Alkene Oxides, Oxiranes or Epoxides

Epoxides are Extremely Reactive

Cleavage of Unsymmetrical Ethers

Size 1, Pairwork 8.28 b,d 8.29 a,d 8.33 e,f 8.44 a-e