Synthesis of 2

1
Synthesis of 2º Alcohols

• Grignard aldehyde yields a secondary alcohol.

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Synthesis of 3º Alcohols

• Grignard ketone yields a tertiary alcohol.

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How would you synthesize
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Grignard Reactions with Acid Chlorides and
Esters

• Use two moles of Grignard reagent.
• The product is a tertiary alcohol with two
  identical alkyl groups.
• Reaction with one mole of Grignard reagent
  produces a ketone intermediate, which reacts with
  the second mole of Grignard reagent.
  gt

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Grignard Acid Chloride (1)

• Grignard attacks the carbonyl.
• Chloride ion leaves.

Ketone intermediate gt
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Grignard and Ester (1)

• Grignard attacks the carbonyl.
• Alkoxide ion leaves! ? !

Ketone intermediate gt
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Second step of reaction

• Second mole of Grignard reacts with the ketone
  intermediate to form an alkoxide ion.
• Alkoxide ion is protonated with dilute acid.

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How would you synthesize...

• Using an acid chloride or ester.

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Grignard Reagent Ethylene Oxide

• Epoxides are unusually reactive ethers.
• Product is a 1º alcohol with 2 additional carbons.

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Limitations of Grignard

• No water or other acidic protons like O-H, N-H,
  S-H, or -CC-H. Grignard reagent is destroyed,
  becomes an alkane.
• No other electrophilic multiple bonds, like CN,
  CN, SO, or NO.
  gt

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Reduction of Carbonyl

• Reduction of aldehyde yields 1º alcohol.
• Reduction of ketone yields 2º alcohol.
• Reagents
• Sodium borohydride, NaBH4
• Lithium aluminum hydride, LiAlH4
• Raney nickel
  gt

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Sodium Borohydride

• Hydride ion, H-, attacks the carbonyl carbon,
  forming an alkoxide ion.
• Then the alkoxide ion is protonated by dilute
  acid.
• Only reacts with carbonyl of aldehyde or ketone,
  not with carbonyls of esters or carboxylic acids.

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Lithium Aluminum Hydride

• Stronger reducing agent than sodium borohydride,
  but dangerous to work with.
• Converts esters and acids to 1º alcohols.

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Comparison of Reducing Agents

• LiAlH4 is stronger.
• LiAlH4 reduces more stable compounds which are
  resistant to reduction.
  gt

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Catalytic Hydrogenation

• Add H2 with Raney nickel catalyst.
• Also reduces any CC bonds.

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Thiols (Mercaptans)

• Sulfur analogues of alcohols, -SH.
• Named by adding -thiol to alkane name.
• The -SH group is called mercapto.
• Complex with heavy metals Hg, As, Au.
• More acidic than alcohols, react with NaOH to
  form thiolate ion.
• Stinks!
  gt

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Thiol Synthesis

• Use a large excess of sodium hydrosulfide with
  unhindered alkyl halide to prevent dialkylation
  to R-S-R.

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Thiol Oxidation

• Easily oxidized to disulfides, an important
  feature of protein structure.

• Vigorous oxidation with KMnO4, HNO3, or NaOCl,
  produces sulfonic acids.