Download Synthesis of 2º Alcohols Grignard + aldehyde yields a secondary alcohol. =>

Synthesis of 2º Alcohols Grignard + aldehyde yields a secondary alcohol. CH3 H3C C CH2

C

H

H

CH3

H3C

H MgBr

C O

CH3

CH CH2

CH3 CH2

H

MgBr

H

CH3 CH3

C O

CH CH2

CH3 CH2

HOH

C O H H

=>

Synthesis of 3º Alcohols Grignard + ketone yields a tertiary alcohol. CH3 H3C C CH2

C

H

H

CH3

H3C

H MgBr

C O

CH3

CH CH2

CH3 CH2

H3C

MgBr

CH3

CH3 CH3

C O

CH CH2

CH3 CH2

HOH

C O H CH3

=>

How would you synthesize… OH

CH2OH

CH3CH2CHCH2CH2CH3

OH

OH

CH3

C CH3 CH2CH3

=>

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) • Grignard attacks the carbonyl. • Chloride ion leaves. CH3

H3C R

MgBr

C O Cl

CH3 R C O Cl

R C O

MgBr

Cl CH3

MgBr

R C

+

MgBrCl

O

Ketone intermediate

=>

Grignard and Ester (1) • Grignard attacks the carbonyl. • Alkoxide ion leaves! ? ! CH3

H3C R

MgBr

C O CH3O

CH3 R C O OCH3

R C O

MgBr

OCH3 CH3

MgBr

R C

+ O

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. CH3

CH3 R

MgBr

+

R C

R C O O

MgBr

R

HOH CH3 R C OH R

=>

How would you synthesize... Using an acid chloride or ester.

OH

CH3

CH3CH2CCH3

C

CH3

OH

OH CH3CH2CHCH2CH3

=>

Grignard Reagent + Ethylene Oxide • Epoxides are unusually reactive ethers. • Product is a 1º alcohol with 2 additional carbons. O

O MgBr

+

CH2

CH2CH2

CH2

HOH O H CH2CH2

=>

MgBr

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. O C H

H

H C

H

O +

H

H3O

O H

C

H

=>

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

OCH3

H LAH

H3O+

C

O H H

=>

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. OH

O

NaBH4

OH H2, Raney Ni

=>

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. Br2 R

SH

+ HS

R

R

S

S

R +

2 HBr

Zn, HCl

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

SH

HNO3 boil

O S O

OH

=>