Chapter 12

Alcohols from Carbonyl CompoundsOxidation-Reduction & Organometallic Compounds

Ch. 12 - 1

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

δ−

δ+

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

δ−

δ+ 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

2. Oxidation-Reduction Reactions inOrganic Chemistry

Reduction of an organic molecule usually corresponds to increasing its hydrogen content or decreasing its oxygen content

carboxylicacid

reduction

[H] O

R H

O

R OH

aldehyde

oxygen contentdecreases

reduction

[H] OH

R H

O

R HH

hydrogen contentdecreases

Ch. 12 - 8

The opposite reaction of reduction is oxidation. Increasing the oxygen content of on organic molecule or decreasing its hydrogen content is oxidation

OH

R HH

O

R OH

O

R H

[O]RCH3

[H]

[O]

[H]

[O]

[H]

lowestoxidation

state

highestoxidation

state

Ch. 12 - 9

Oxidation of an organic compound may be more broadly defined as a reaction that increases its content of any element more electronegative than carbon

[O]

[H]

[O]

[H]

[O]

[H]Ar CH3 Ar CH2Cl Ar CHCl2 Ar CCl3

Ch. 12 - 10

2A. Oxidation States in Organic Chemistry Rules

● For each C–H (or C–M) bond -1● For each C–C bond 0● For each C–Z bond +1

(where M = electropositive element and is equivalent to H, e.g. Li, K, etc.; Z = electronegative heteroatom, e.g. OR, SR, PR2, halogen, etc.)

Calculate the oxidation state of each carbon based on the number of bonds it is forming to atoms more (or less) electronegative than carbon

Ch. 12 - 11

Examples

H

C

H

H H(1)Bonds to C:4 to H = (- 1) x 4 = - 4

Total = - 4

Oxidation state of C = - 4

Ch. 12 - 12

Examples

H

C

H

H OH(2)Bonds to C:

3 to H = - 3

Total = - 2

Oxidation state of C = - 2

1 to O = +1

Ch. 12 - 13

Examples

O

CH H

(3)Bonds to C:

2 to H = - 2

Total = 0

Oxidation state of C = 0

2 to O = +2

Ch. 12 - 14

Examples

O

CH OH

(4)Bonds to C:

1 to H = - 1

Total = +2

Oxidation state of C = +2

3 to O = +3

Ch. 12 - 15

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 oxidationstate of carbon

highest oxidationstate of carbon

oxidationstate

Ch. 12 - 16

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 - 17

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 - 18

ExamplesO

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 - 19

MechanismO

R OR'

H

Al HH

H

+

O

OR'R

HO

R HR'O +

H

Al HH

HO

RH

H

OH H

OH

RH

H

Esters are reduced to 1o alcohols

Ch. 12 - 20

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 - 21

Examples

O

R H

OH

R HH

(1)NaBH4

H2O

O

R R'

OH

R R'H

(2)NaBH4

H2O

Ch. 12 - 22

Mechanism

O

R R'

H

B HH

H

+

δ−

δ+

O

R'R

H

OH HOH

RH

R'

Aldehydes are reduced to 1° alcohols & ketones are reduced to 2° alcohols

Ch. 12 - 23

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 - 24

4. Oxidation of Alcohols

[O]R OH

O

R OH

O

R H

[O]

1o alcohol aldehyde carboxylicacid

4A. Oxidation of Primary Alcohols to Aldehydes

The oxidation of aldehydes to carboxylic acids in aqueous solutions is easier than oxidation of 1o alcohols to aldehydes

It is, therefore, difficult to stop the oxidation of a 1o alcohol to the aldehyde stage unless specialized reagents are used

Ch. 12 - 25

PCC oxidation● Reagent

(Pyridinium chlorochromate)

N

H

[CrO3Cl]PCC =

CrO3 + HCl N+

Pyridine(C5H5N)

Pyridiniumchlorochromate

(PCC)

N H [CrO3Cl]

Ch. 12 - 26

PCC oxidation

R OHPCC

CH2Cl2

O

R H

R R'

O

R R'

OH PCC

CH2Cl2

R R'

OH

R

No ReactionPCC

CH2Cl2

Ch. 12 - 27

4B. Oxidation of Primary Alcohols toCarboxylic Acids

R OHR OH

O

R O

O

K

H3O+KMnO4, OH-

H2O, heat

Chromic acid (H2CrO4) usually prepared by[CrO3 or Na2Cr2O7] + aqueous H2SO4

Jones reagent

H2CrO4(chromic acid)

Ch. 12 - 28

Jones oxidation● Reagent: CrO3 + H2SO4● A Cr(VI) oxidant

R OH

O

R OH

CrO3

H2SO4(orange solution)

+ Cr(III)

(green)

R R'

O

R R'

CrO3

H2SO4(orange solution)

+ Cr(III)

(green)

OH

RR'

CrO3

H2SO4

OH

R"No Reaction

Ch. 12 - 29

4D. Mechanism of Chromate Oxidations

CH3C

HH3C

O

H

Cr

O

O

+ HO O

H O H

H

Formation of the Chromate Ester

Cr

O

O OO

H

O

H

H

CH3C H

H3C

H

OH

H O H

H

Cr

O

O OO

H

O

H

CH3C H

H3CH

Cr

O

OC

H3C H

H3C

OH

O

H

OH

+

Ch. 12 - 30

The oxidation step

Cr

O

OC

H3C H

H3C

OH

O

H

OH

+ H O H

H

OC

H3C

H3CCr

O

OH

O+

+

Ch. 12 - 31

4E. A Chemical Test for Primary andSecondary Alcohols

R OH

O

R OH

CrO3

H2SO4(orange solution)

+ Cr(III)

(green)

R R'

O

R R'

CrO3

H2SO4(orange solution)

+ Cr(III)

(green)

OH

RR'

CrO3

H2SO4

OH

R"No Reaction

Ch. 12 - 32

4F. Spectroscopic Evidence for Alcohols

Alcohols give rise to broad O-H stretching absorptions from 3200 to 3600 cm-1 in IR spectra

The alcohol hydroxyl hydrogen typically produces a broad 1H NMR signal of variable chemical shift which can be eliminated by exchange with deuterium from D2O

Hydrogen atoms on the carbon of a 1o or 2o

alcohol produce a signal in the 1H NMR spectrumbetween δ 3.3 and δ 4.0 ppm that integrates for 2 and 1 hydrogens, respectively

The 13C NMR spectrum of an alcohol shows a signal between δ 50 and δ 90 ppm for the alcohol carbon

Ch. 12 - 33

5. Organometallic Compounds

Compounds that contain carbon-metal bonds are called organometallic compounds

C M

primarily ionic(M = Na or K)

δ− δ+C : M

(M = Mg or Li)

C M

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

Ch. 12 - 34

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 - 35

2 Li

+Br Li

LiBr

+

Et2O

-10oC

(80% - 90%)

Example

Ch. 12 - 36

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 - 37

THF+ Mg

Br MgBr

Example

Ch. 12 - 38

7. Reactions of Organolithium andOrganomagnesium Compounds

7A. Reactions with Compounds Con-taining Acidic Hydrogen Atoms

Grignard reagents and organolithium compounds are very strong bases

RMgX ~ R:MgX RLi ~ R:Liδ− δ+ δ− δ+

δ− δ+R MgX H Y+

(or RLi) (Y = O, N or S)

δ−δ+++ XR H Y Mg2+ +

Ch. 12 - 39

Examples● As base

CH3OH+

MgBr

+ Mg2+ + Br−

+ CH3O−(2)

CH3MgBr + H2O + OH−H3C H(1)

+ Mg2+ + Br−

Ch. 12 - 40

Examples● As base

(3) H + H3C MgBr

MgBr H CH3+

A good method for the preparationof alkynylmagnesium halides

Ch. 12 - 41

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 - 42

Via SN2 reaction

OR RO

H+, H2O

ROH

(1o alcohol)

Ch. 12 - 43

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 - 44

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 - 45

Mechanism

O

R R'MgXR"+δ+δ−

H O H

HOH

RR'

R"

O MgX

RR'

R"

Ch. 12 - 46

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 - 47

R, R’ = H (formaldehyde)● 1o alcohol

O

H HMgXR +δ+δ−

formaldehyde

O MgX

RH

H

OH

RH

H

H3O+

1o alcohol

Ch. 12 - 48

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

O

R' HMgXR +

δ− δ+

higheraldehyde

O MgX

RH

R'

OH

RH

R'

H3O+

2o alcohol

Ch. 12 - 49

R, R’ = alkyl (ketone)● 3o alcohol

O

R' R"MgXR +δ+δ−

ketone

O MgX

RR"

R'

OH

RR"

R'

NH3ClH2O

3o alcohol

Ch. 12 - 50

Reaction with esters● 3o alcohol

O

R OR'

1. Et2O

2. H3O++ R"MgX

OH

RR"

R"

+ R'OH

Ch. 12 - 51

O

R R"+R'O

O

RR"

OR'

MgX

O

RR"

R"

MgX

Mechanism

O

R OR'MgXR"+δ+δ−

H O H

HOH

RR"

R"

MgXR"δ+δ−

Ch. 12 - 52

Examples

O

H H(1)

MgBr

+Et2O

H

OMgBr

H

OH

H3O+

(1o alcohol)

Ch. 12 - 53

Examples

O

H3C H(2)

MgI

+Et2O

CH3

OMgI

H

OH

H3O+

(2o alcohol)

CH3

Ch. 12 - 54

Examples

O

Ph Ph(3) +

Et2O

OMgBr

PhH3O

+

(3o alcohol)

MgBr

Ph

OH

Ph

Ph

Ch. 12 - 55

ExamplesO

Ph OMe(4) +

Et2O

H3O+

(3o alcohol)

OMgI

Ph

MgI

O

PhOMe

MgI

O

Ph

OH

Ph

MgI

Ch. 12 - 56

8A. How to Plan a Grignard Synthesis

OH

MeMe

Synthesis of

Ch. 12 - 57

OH

MeMe

disconnection

MgBr

+O

Me Me

Method 1● Retrosynthetic analysis

● Synthesis OH

MeMeMgBr

+O

Me Me

1. Et2O

2. H3O+

Ch. 12 - 58

OH

MeMe

disconnection

+MeMgBrMe

O

Method 2● Retrosynthetic analysis

● SynthesisOH

MeMe

+MeMgBrMe

O

1. Et2O

2. H3O+

Ch. 12 - 59

OH

MeMe

disconnection

+ 2 MeMgBrOEt

Odisconnection

Method 3● Retrosynthetic analysis

● SynthesisOH

MeMe1. Et2O

2. H3O+

+ 2 MeMgBr

OEt

O

Ch. 12 - 60

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 - 61

A Grignard reagent cannot be prepared from a compound containing an –OHgroup, 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 - 62

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 - 63

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 +δ+δ−

organo-lithiumreagent

aldehydeor

ketone

OH

R

OLi

R

lithiumalkoxide

alcohol

H3O+

Ch. 12 - 64

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 - 65

9. Protecting Groups

HOI

HO

OHHow?

Ch. 12 - 66

Retrosynthetic analysis

HO

OH O

HOMgBr +

disconnection

HOBr

However

HOBr

Mg

Et2O OMgBr

H

δ+

δ−

BrMg OHacidic proton powerful

base

Ch. 12 - 67

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)

Ch. 12 - 68

Synthesis

HOBr

(protection) TBSOBr

TBSClimidazole

DMF

TBSCl =

Me

SitBu Cl

Me

Imidazole =N

N H

O

H NMe

Me

DMF =

(a polar aprotic solvent)

TBSOMgBr

Mg, Et2O

O

TBSO

OH

2. H3O+

1.

HO

OH Bu4N FTHF

(deprotection)