Chapter 12

Alcohols fromCarbonyl CompoundsOxidation-Reduction &

OrganometallicCompounds

Ch. 12 - 2

O

1. Structure of the Carbonyl Group

Carbonyl compounds

O

R HAldehyde Ketone

O

R R'

Carboxylic acid

O

R OH

Ester

O

R OR'

Amide

O

R NR'

R"

Ch. 12 - 3

Structure

O

C

~ 120o

~ 120o

~ 120o

●Carbonyl carbon: sp2 hybridized

●Planar structure

Ch. 12 - 4

Polarization and resonance structure

O

C

O

C

Ch. 12 - 5

1A.Reactions of Carbonyl Compoundswith Nucleophiles One of the most important

reactions of carbonyl compounds is nucleophilic addition to the carbonyl group

Nu

O

C

nucleophilic

addition

O

CNu

Ch. 12 - 6

Two important nucleophiles:●Hydride ions (from NaBH4 and

LiAlH4)●Carbanions (from RLi and

RMgX) Another important reactions:

O

CR H

OH

R HH

oxidation

reduction

1o alcohol aldehyde

Ch. 12 - 7

Overall order

O

C

O

H

C

H

H H

H

C

H

H OH

O

CH OH

O

CH H

< < < <

- 4 - 2 0 +2 +4

lowest oxidatio

nstate of carbon

highest oxidatio

nstate of carbon

oxidationstate

Ch. 12 - 8

3. Alcohols by Reduction of Carbonyl Compounds

R OH

H H(1o alcohol)

[H]

R R'

O

R R'

HO H

H

R O

[H]

[H]OH

R O

[H]OR'

R O

Ch. 12 - 9

3A.Lithium Aluminum Hydride

LiAlH4 (LAH)●Not only nucleophilic, but also

very basic●React violently with H2O or

acidic protons (e.g. ROH)●Usually reactions run in

ethereal solvents (e.g. Et2O, THF)

●Reduces all carbonyl groups

Ch. 12 - 10

Examples

O

R OH

OH

R HH

1. LiAlH4, Et2O

2. H+, H2O(1)

O

R OR'

1. LiAlH4, Et2O

2. H+, H2O(2)

OH

R HH

+ HOR'

O

R H

OH

R HH

1. LiAlH4, Et2O

2. H+, H2O(3)

Ch. 12 - 11

3B.Sodium Borohydride

NaBH4

●less reactive and less basic than LiAlH4

●can use protic solvent (e.g. ROH)

●reduces only more reactive carbonyl groups (i.e. aldehydes and ketones) but not reactive towards esters or carboxylic acids

Ch. 12 - 12

Examples

O

R H

OH

R HH

(1)NaBH4

H2O

O

R R'

OH

R R'H

(2)NaBH4

H2O

Ch. 12 - 13

3C. Overall Summary of LiAlH4 and NaBH4 Reactivity

O

R O<

O

R OR'

O

R R'<

O

R H<

ease of reduction

reduced by NaBH4

reduced by LiAlH4

Ch. 12 - 14

5. Organometallic Compounds

Compounds that contain carbon-metal bonds are called organometallic compounds

C M

primarily ionic(M = Na or K)

C : M

(M = Mg or Li)

C M

primarily covalent(M = Pb, Sn, Hg or Tl)

Ch. 12 - 15

6. Preparation of Organolithium &Organomagnesium Compounds

R 2 Li RLi LiXEt2O

(or THF)++X

6A.Organolithium Compounds

Order of reactivity of RX●RI > RBr > RCl

Preparation of organolithium compounds

Ch. 12 - 16

2 Li

+Br Li

LiBr

+

Et2O

-10oC

(80% - 90%)

Example

Ch. 12 - 17

R RMgXEt2O

+X Mg

Ar ArMgXEt2O

+X Mg

6B.Grignard Reagents

Order of reactivity of RX●RI > RBr > RCl

Preparation of organomagnesium compounds (Grignard reagents)

Ch. 12 - 18

7B.Reactions of Grignard Reagentswith Epoxides (Oxiranes)

Grignard reagents react as nucleophiles with epoxides (oxiranes), providing convenient synthesis of alcohols

then H2OOR

OH+RMgBr

Ch. 12 - 19

Via SN2 reaction

OR RO

H+, H2O

ROH

(1o alcohol)

Ch. 12 - 20

Also work for substituted epoxides

then H2OO+RMgBr

R'

H

R OH

R'

H

(2o alcohol)

then H2OO+RMgBr

R'

R"

R OH

R'

R"

(3o alcohol)

Ch. 12 - 21

7C. Reactions of Grignard Reagentswith Carbonyl Compounds

O

R R'

1. Et2O

2. H3O++ R"MgX

OH

RR"

R'

R' = H (aldehyde)R' = alkyl (ketone)

Ch. 12 - 22

Mechanism

O

R R'MgXR"+

H O H

HOH

RR'

R"

O MgX

RR'

R"

Ch. 12 - 23

8. Alcohols from Grignard Reagents

O

R R'

1. Et2O

2. H3O++ R"MgX

OH

RR"

R'

R' = H (aldehyde)R' = alkyl (ketone)

Ch. 12 - 24

R, R’ = H (formaldehyde)●1o alcohol

O

H HMgXR +

formaldehyde

O MgX

RH

H

OH

RH

H

H3O+

1o alcohol

Ch. 12 - 25

R = alkyl, R’ = H (higher aldehydes)●2o alcohol

O

R' HMgXR +

higheraldehyde

O MgX

RH

R'

OH

RH

R'

H3O+

2o alcohol

Ch. 12 - 26

R, R’ = alkyl (ketone)●3o alcohol

O

R' R"MgXR +

ketone

O MgX

RR"

R'

OH

RR"

R'

NH3ClH2O

3o alcohol

Ch. 12 - 27

Reaction with esters●3o alcohol

O

R OR'

1. Et2O

2. H3O++ R"MgX

OH

RR"

R"

+ R'OH

Ch. 12 - 28

O

R R"+R'O

O

RR"

OR'

MgX

O

RR"

R"

MgX

Mechanism

O

R OR'MgXR"+

H O H

HOH

RR"

R"

MgXR"

Ch. 12 - 29

Examples

O

H H(1)

MgBr

+Et2O

H

OMgBr

H

OH

H3O+

(1o alcohol)

Ch. 12 - 30

Examples

O

H3C H(2)

MgI

+Et2O

CH3

OMgI

H

OH

H3O+

(2o alcohol)

CH3

Ch. 12 - 31

Examples

O

Ph Ph(3) +

Et2O

OMgBr

PhH3O

+

(3o alcohol)

MgBr

Ph

OH

Ph

Ph

Ch. 12 - 32

Examples

O

Ph OMe(4) +

Et2O

H3O+

(3o alcohol)

OMgI

Ph

MgI

O

PhOMe

MgI

O

Ph

OH

Ph

MgI

Ch. 12 - 33

8A.How to Plan a Grignard Synthesis

OH

MeMe

Synthesis of

Ch. 12 - 34

OH

MeMe

disconnection

MgBr

+O

Me Me

Method 1●Retrosynthetic analysis

●Synthesis OH

MeMeMgBr

+O

Me Me

1. Et2O

2. H3O+

Ch. 12 - 35

OH

MeMe

disconnection

+MeMgBrMe

O

Method 2●Retrosynthetic analysis

●SynthesisOH

MeMe

+MeMgBrMe

O

1. Et2O

2. H3O+

Ch. 12 - 36

OH

MeMe

disconnection

+ 2 MeMgBrOEt

Odisconnection

Method 3●Retrosynthetic analysis

●SynthesisOH

MeMe1. Et2O

2. H3O+

+ 2 MeMgBr

OEt

O

Ch. 12 - 37

8B.Restrictions on the Use ofGrignard Reagents

Grignard reagents are useful nucleophiles but they are also very strong bases

It is not possible to prepare a Grignard reagent from a compound that contains any hydrogen more acidic than the hydrogen atoms of an alkane or alkene

Ch. 12 - 38

A Grignard reagent cannot be prepared from a compound containing an –OH group, an –NH– group, an –SH group, a –CO2H group, or an –SO3H group

Since Grignard reagents are powerful nucleophiles, we cannot prepare a Grignard reagent from any organic halide that contains a carbonyl, epoxy, nitro, or cyano (–CN) group

Ch. 12 - 39

Grignard reagents cannot be prepared in the presence of the following groups because they will react with them:

OH, NH2, NHR, CO2H,

SO3H, SH, C C H,

O

H,

O

R,

O

OR,

O

NH2,

NO2, C N, O

Ch. 12 - 40

8C. The Use of Lithium Reagents

Organolithium reagents have the advantage of being somewhat more reactive than Grignard reagents although they are more difficult to prepare and handle

OLiR +

organo-lithiumreagent

aldehydeor

ketone

OH

R

OLi

R

lithiumalkoxide

alcohol

H3O+

Ch. 12 - 41

8D.The Use of Sodium Alkynides Preparation of sodium alkynides

R H RNaNH2

-NH3Na

Reaction via ketones (or aldehydes)O

+OHONa H3O

+

R Na

RR

Ch. 12 - 42

9. Protecting Groups

HOI

HO

OHHow?

Ch. 12 - 43

Retrosynthetic analysis

HO

OH O

HOMgBr +

disconnection

HOBr

However

HOBr

Mg

Et2O OMgBr

H

BrMg OHacidic proton powerful

base

Ch. 12 - 44

Need to “protect” the –OH group first

HOBr (protection)

"P"OBr

"P"OMgBr

Mg, Et2O

(no acidic OH group)

O

"P"O

OH

2. H3O+

1.

HO

OH

(deprotection)