Alcohol and Thiol Reactions

Grignard Reagents: Can’t Do’s

• Grignard reagents = great bases so they can’t react with substances that are very acidic

  • R-OH

  • R-NH₂ (primary or secondary)

  • R-SH

• Also will also react w/ lots of functional groups

  • Epoxides

  • Nitriles

  • Nitro groups

• If you react an organometallic with one of those acids or functional groups, you won’t get a useful product (reacts with itself

Alcohols as a Nu

Poor nucleophiles; unlikely to be able to kick out a LG

• React the ROH with a base (NaH or NaNH₂) to turn it into R-O^-

• Now the R-O^- can attack something with a primary LG and kick out the LG

Alcohols as LG

Bad leaving groups

• Can turn into a good LG using concentrated acids, sulfonates, phosphorous halides, and thionyl chloride

• Know all of these reactions/mechanisms

Substitution: Primary Alcohols

• Stereochemistry = irrelevant

• Cl reagent: SOCl₂ or PCl₃

• Br reagent: PBr₃

• I reagent: P/I₂

Substitution: Secondary Alcohols

• Cl reagent: SOCl₂ to retain stereochemistry, PCl₃ to invert it

• Br reagent: PBr₃ inverts stereochemistry

• I reagent: P/I₂ inverts stereochemistry

Substitution: Tertiary Alcohols

• Scrambling of stereochemistry due to planar carbocation intermediate (no retention or inversion → racemic mixture)

• Cl reagent: HCl

• Br reagent: HBr

• I reagent: HI (sometimes)

Alcohol Oxidations

Gain of bonds to an oxygen and/or the loss of bonds to H

PCC (Chromium Rxns)

Pyridinium chlorochromate

• A strong oxidant that has been “poisoned” by the pyridine salt so it becomes a weaker oxidant

• Allows primary alcohols to stop oxidation at the aldehyde (instead of proceeding to a carboxylic acid)

TEMPO

Free radical oxygen that helps catalyze the oxidation in bleach reactions

DMP and Swern Reactions

Have the same reactant and same product (interchangeable on exams/quizzes for RRP or mechanism problems)

Silyl Protecting Groups

• Trimethylsilyl (TMS): the weakest; can deprotect with H₃O⁺

• Triisopropylsilyl (TIPS)

• Tert-butyldimethylsilyl (TBS)

  • TIPS and TBS require a source of F^- to deprotect

  • CsF or TBAF (F^- N⁺(Bu)₄)

• Using protecting groups allows us to use Grignard reagents in synthesis problems (recall that Grignard’s can’t react with alcohols b/c they’re too strong of an acid)