Synthesis of 2º Alcohols

Grignard + aldehyde yields a secondary alcohol.

MgBrCH3 CH

CH3

CH2 CH2 C

CH3

H

OC

CH3

H3C CH2 C MgBr

H

HH

C OH

H3C

CH3 CH

CH3

CH2 CH2 C

CH3

H

O HHOH

=>

Synthesis of 3º Alcohols

Grignard + ketone yields a tertiary alcohol.

MgBrCH3 CH

CH3

CH2 CH2 C

CH3

CH3

OC

CH3

H3C CH2 C MgBr

H

HH

C OH3C

H3C

CH3 CH

CH3

CH2 CH2 C

CH3

CH3

O HHOH

=>

How would you synthesize…

CH3CH2CHCH2CH2CH3

OH CH2OH

OH

CH3C

OH

CH2CH3

CH3 =>

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. =>

Grignard + Acid Chloride (1)

C OCl

H3C

MgBrR MgBr C

CH3

Cl

OR

C

CH3

Cl

OR MgBr C

CH3

RO

+ MgBrCl

Ketone intermediate =>

• Grignard attacks the carbonyl.• Chloride ion leaves.

Grignard and Ester (1)

• Grignard attacks the carbonyl.

• Alkoxide ion leaves! ? !

C OCH3O

H3C

MgBrR MgBr C

CH3

OCH3

OR

C

CH3

OCH3

OR MgBr C

CH3

RO

+ MgBrOCH3

Ketone intermediate =>

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.

C

CH3

RO

R MgBr + C

CH3

R

OR MgBr

HOH

C

CH3

R

OHR

=>

How would you synthesize...

CH3CH2CCH3

OH

CH3

C

OH

CH3

Using an acid chloride or ester.

CH3CH2CHCH2CH3

OH

=>

Grignard Reagent + Ethylene Oxide

• Epoxides are unusually reactive ethers.

• Product is a 1º alcohol with 2 additional carbons.

MgBr + CH2 CH2

OCH2CH2

O MgBr

HOH

CH2CH2

O H

=>

Limitations of Grignard

• No water or other acidic protons like O-H, N-H, S-H, or -C—C-H. Grignard reagent is destroyed, becomes an alkane.

• No other electrophilic multiple bonds, like C=N, C—N, S=O, or N=O.

=>

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

=>

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.

HC

O

HC

H

OHC

H

OH HH3O+

=>

Lithium Aluminum Hydride

• Stronger reducing agent than sodium borohydride, but dangerous to work with.

• Converts esters and acids to 1º alcohols.

CO

OCH3C

OH H

HH3O+

LAH =>

Comparison of Reducing Agents

• LiAlH4 is stronger.

• LiAlH4 reduces more stable compounds which are resistant to reduction. =>

Catalytic Hydrogenation

• Add H2 with Raney nickel catalyst.

• Also reduces any C=C bonds.

O

H2, Raney Ni

OH

NaBH4

OH

=>

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>= !

Thiol Synthesis

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

H S_

R X R SH +_

X

=>

Thiol Oxidation

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

R SH + RHSBr2

Zn, HClR S S R + 2 HBr

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

SHHNO3

boilS

O

O

OH

=>