Chapter 12: Alcohols

15−18

• Resonance- phenols are more acidic (pKa = 10) than alcohols because they are resonance stabalized • Induction- a conjugate base that is resonance stabilized by the electron withdrawling effects of nearby atoms will be more stable • Solvation effects- a smaller alcohol such as ethanol will be better solcated and will be more stable than a larger alcohol such as tert-butanol (pKa 16 vs. 18)

Alcohols can be prepared by substitution reactions in which a leaving group is replaced by a hydroxyl group A primary substrate will require SN2 conditions; a strong nucleophile (NaOH) A tertiary substrate will require SN1 conditions; a weak nucleophile (H2O) A secondary substrate is not effective for preparing a secondary alcohol

Reagents H2 & Pt, Pd, or Ni Catalytic hydrogenation does NOT selectively reduce carbonyl groups; will also reduce C=C bonds present in molecule or NaBH4 (sodium borohydride) & EtOH, MeOH, or H2O NaBH4 serves as a hydride delivery device and the solvent functions as a proton source; results in a racemic mixture if a chiral center is present or • LiAlH4 (lithium aluminum hydride) • H3O+ LiAlH4 serves as a hydride delivery device, a proton source is subsequently added in a work-up step; results in a racemic mixture • LiAlH4 can also reduce carboxylic acids and esters

Diols are compounds with TWO hydroxyl groups

Reagents • RMgX • H3O+ Mechanism A Grignard reagent is formed by the reaction between an alkyl halide and magnesium characterized by a C−Mg bond; acts as a nucleophile and attacks a carbonyl carbon CANNOT be used in the presence of a mildy acidic proton as it will just deprotonate the substrate; NOT compatible with carboxylic acids Regeoselectivity Attaches the R group to the carbonyl carbon; subsequent workup protonates the carbonyl oxygen creating a hydroxyl group Stereospecificity Nuclephilic attack can occur form either side; forms a mixture of enantiomers when a chiral center is present

Reagents • TMSCl & Et3N (triethylamine) • TBAF Mechanism Allow Grignard reaction to be performed in the presence of acidic protons by replacing them with a protecting group which can subsequently be removed and converted back to its initial group

Reagents HX Mechanism A tertiary alcohol will undergo a substitution reaction when treated with a halogen halide; not effective for primary or secondary alcohols; results in a mixture of enatiomers

Reagents HBr or • TsCl (toluenesulfonyl chloride) & py (pyridine) • NaBr or PBr3 (phosphorus tribromide) Mechanism Occur via “backside attack” leading to inversion of configuration

Reagents HCl and ZnCl2 Due to its ionic nature can only be used with alcohols that are water-soluble- alcohols with less than eight carbon atoms or SOCl2 (thionyl chloride) & py (pyridine) or • TsCl (toluenesulfonyl chloride) & py • NaCl Mechanism Occur via “backside attack” leading to inversion of configuration

Reagents conc H2SO4 & heat ONLY works for tertiary alcohols; favors the more substituted Zaitsev product or • TsCl (toluenesulfonyl chloride) & py (pyridine) • Strong base • Choice of base determines Hofmann vs. Zaitsev product

Carboxylic Acid as the Product Na2Cr2O7 (sodium dichromate) & H2SO4/H2O or xs CrO3 (chromium trioxide) & H3O+/acetone Aldehyde as the Product PCC & CH2Cl2 (dichloromethane) or Swern oxidation 1. DMSO & (COCl)2 (oxalyl chloride) 2. Et3N (triethylamine) or Des-Martin periodinane (DMP) oxidation DMP and CH2Cl2

Reagents All processes reduce the secondary alcohol to a ketone Na2Cr2O7 (sodium dichromate) & H2SO4/H2O or xs CrO3 (chromium trioxide) & H3O+/acetone or PCC & CH2Cl2 (dichloromethane) or Swern oxidation 1. DMSO & (COCl)2 (oxalyl chloride) 2. Et3N (triethylamine) or Des-Martin periodinane (DMP) oxidation DMP & CH2Cl2 (dichloromethane)

Reagents • DMSO & (COCl)2 (oxalyl chloride) • Et3N (triethylamine) Mechanism Converts a primary alcohol to an aldehyde Converts a secondary alcohol to a ketone

Reagents DMP and CH2Cl2 (dichloromethane) Mechanism Converts a primary alcohol to an aldehyde Converts a secondary alcohol to a ketone

Reagents Na2Cr2O7 (sodium dichromate) & H2SO4/H2O or xs CrO3 (chromium trioxide) & H3O+/acetone Mechanism Although there is no alpha proton, phenol still undergos oxidation to form a benzoquinone