Alcohols, Carbonyls and REDOX

• The Carbonyl Group (Section 12.1)

• Oxidation/Reduction Reactions: Review (Section 12.2)

• Reduction of Carbonyls to Alcohols (Section 12.3)

• Oxidation of Alcohols (Section 12.4)

• Organometallic Compounds (Section 12.5)

• Organolithium and Magnesium Compounds (Section 12.6)

• Reactions of Organolithium/Magnesium Species (Section 12.7)

• Alcohols from Grignard Reactions (Section 12.8)

• Lithium Dialkylcuprates (Section 12.9)

The Carbonyl Functional Group

O

RR

120o

O O

HR

O

R'R

O

OHR

O

OR'R

Carbonyl Aldehyde Ketone CarboxylicAcid

CarboxylateEster

Planar, sp2 Hybridized Carbon

• Carbonyl Features 1 and 1 Bond

• Carbonyl Group Quite Polarized (C+, O-)

Resonance Structure for Carbonyl Reflecting Bond Polarization??

General Reactions of Carbonyls

Carbonyl

ONu

Nucleophile

Nu

O

Addition Product:TETRAHEDRAL

Nucleophilic Addition to Carbonyl Groups:

Oxidation of Alcohols/Reduction of Carbonyls:

R OHR H

O

PrimaryAlcohol

Aldehyde

Oxidation

Reduction

LessHydrogenContent

MoreHydrogenContent

Oxidation/Reduction Reactions

• Commonly Termed ‘REDOX’ Reactions

• From General Chemistry, we Will Recall Oxidation: Loss of Electrons Reduction: Gain of Electrons

• Organic Chemists will Typically use Different Definitions Reduction: Increase Hydrogen Content (Decrease Oxygen) Oxidation: Decrease Hydrogen Content (Increase Oxygen)

• Oxidizing/Reducing Agents: Usually Inorganic Compounds (M+)

• We will also Recall that in REDOX Reactions: Oxidizing Agents get Reduced Reducing Agents get Oxidized

Oxidation States of Carbon: Organics

• +1 For More Electronegative, -1 For Less, 0 For Bonded Carbon

H

CHH

HCH3

CHH

HCH3

CCH3H

HCH3

CCH3H

H3C

CH3

CCH3H3C

H3C

Br

CCH3H3C

H3CO

CCH3H3C

O

COHH3C

O

C

O

-4 -3 -2 -1

0

1 2 3 4

Alcohol Synthesis: Carbonyl ReductionO

OMeR

O

OHR

O

HR

O

MeR

[H]

Reduction

[H]

Reduction

[H]

Reduction

[H]

Reduction

ROH

ROH

ROH

OH

MeR

1o Alcohol

1o Alcohol

1o Alcohol

2o Alcohol

Carboxylic Acids, Esters,Aldehydes Reduced to

1° Alcohols

Ketones Reduced to2° Alcohols

Several Hydrogen SourcesAre Used In Organic

Reactions: We’ve AlreadySeen NaBH4

Reducing Agents: 1° and 2° Alcohols• Sodium Borohydride: NaBH4

• Lithium Aluminum Hydride: LiAlH4 (LAH)

• H2/Transition Metal Catalyst (z.b. CuO•CuCr2O4)

• NaBH4 and LiAlH4 are Hydride Transfer Agents

• Hydride (H¯) Acts as a Nucleophile

• Carbonyls Have Varying Degrees of Ease of Reduction:O

OR'R

O

OR

O

HR

O

R'R

> > >

Hardest Easiest

Selection of a Reducing Agent

Carboxylate Ester Ketone Aldehyde

LiAlH4 1° Alcohol 1° Alcohol 2° Alcohol 1° Alcohol

NaBH4 No Reaction No Reaction 2° Alcohol 1° Alcohol

• Choice of Reducing Agent Impacts Reaction Products

• For Ketones/Aldehydes Either Reductant Suffices

• Carboxylates/Esters Only Reduced by LiAlH4

• For Compounds w/ Multiple Carbonyl F.G.s; Select Basedon Which Group(s) Need to be Reduced

NaBH4/LiAlH4 Reduction ExamplesO

1. LAH/Et2O

2. H2O/H2SO4

NaBH4

H2O

OHOH

OH

O

1. LAH/Et2O

2. H2O/H2SO4

NaBH4

H2ONO REACTION

OH

O

OHO

1. LAH/Et2O

2. H2O/H2SO4

OH

OH

NaBH4

H2O

OH

OHO

Oxidizing Agents in Organic Chemistry

• PCC Generally a Mild Oxidant (1° Alcohol Aldehyde)

• Jones Reagent Harsher Oxidant (1° Alcohol Carboxylic Acid)

• Alcohol Often Dissolved in Acetone While Jones Reagent Added

• Choose Oxidant Based on Desired Carbonyl Functional Group

N H CrO3Cl

Pyridinium chlorochromate(PCC)

H2CrO4

Chromic Acid(Jones Reagent)

CrO3/H2SO4

General Oxidizing Agent Selection

MeOH 1° Alcohol 2° Alcohol 3° Alcohol

PCC H2C=O Aldehyde KetoneNo

Reaction

Cr6+

H2SO4

HCO2HCarboxylic

AcidKetone

No Reaction

• Just as in Reductions, Oxidation Products Depend on Reagent

• Generally Don’t Oxidize 3° Alcohols (No Texas Carbons)

• PCC Good For Aldehydes From Primary Alchols

• Cr6+/H2SO4 Reagents, KMNO4 Primary Carboxylic Acids

• Use What You Like For Most Ketones

Oxidation of 1°, 2° Alcohols

OH PCC H

O

CH2Cl2, 25 oC

OHH2CrO4

acetone, 35 oC

O

OH KMnO4, H2O

NaOH, Heat

OH

O

Oxidation Mechanisms: Chromate Esters

O

Cr O

O

HO

O

H H

H

Cr

O

O

OO

O

HH

H

H

Cr

O

O

OH

O

H

H2O

Protonation, Followed by Lossof Water (Combined Here)

Chromate Ester

O +

O

Cr

OH

O + H3O

Organometallic Compounds• Organic Compounds Containing Carbon—Metal Bonds

• Bonds Range From Ionic to Primarily Covalent

• Ionic C—M Bonds: C—Na C—K

• Primarily Covalent C—M Bonds: C—Pb C—Sn C—Hg

• Inetermediate C—M Bonds Include C—Mg and C—Li

• Reactivity Increases with Ionic Character of C—M Bond

Organolithium Reagents

O

ODiethyl Ether Tetrahydrofuran

Br 2Li, -10 oC

Et2O

Li+ LiBr

Butyllithium(Alkyl Lithium Reagent)

Common Solvents for Organolithium Reagents:

Preparation of Organolithium Reagents:

• Reactive, Carbanion-Like Species (React Slowly w/ Ethers)

• Halide Reactivity: RI > RBr > RCl (F Not Often Used)

Grignard Reagents

BrEt2O

MgBr

Butylmagnesium Bromide(Grignard Reagent)

Preparation of Grignard Reagents:

Mg

Et2O

Mg

Br MgBr

Phenylmagnesium Bromide(Grignard Reagent)

• Reactivity of Halides Same as for Organolithium Reagents

• Generally Exist as Complexes, We’ll Use RMgX for Simplicity

Organometallic Reactions: Notes

• Can Act as Nucleophiles Towards Polarized Carbonyl Groups

• Very Strong Lewis Bases (React with Acidic Protons)

• Basicity Necessitates Dry Conditions (Avoid Reaction w/ H2O)

• Reason For Basicity: Carbanion-Like Behavior (pKa??)

• Strong Enough Bases to Deprotonate Terminal Alkynes (pKa??)

• With No Acidic Protons, Can Do Nucleophilic Substitution

Let’s Look at Some Representative Grignard Reactions

Grignard Reactions: Epoxides

MgBrO

+1. Et2O

2. H3O+OH

MgBrO

+1. Et2O

2. H3O+OH

• Grignard Reagents Nucleophilically Open Epoxides

• Generally Attack Less Substituted Carbon (Steric Hindrance)

• View This as Carbanion Attacking in SN2 Reaction (O L.G.)

Grignard Reactions w/ Carbonyls

Let’s Look at Some Specific Grignard Reactions w/ Carbonyls

• Grignard Reagents React With a Variety of Carbonyls

Formaldehyde 1° Alcohols

Higher Aldeydes 2° Alcohols

Ketones 3° Alcohols

Ester 3° Alcohols

• Attack of Grignard Generates Alkoxide; Protonate to get OH

Grignard Reactions: Carbonyls

MgBr

H

O

H

+

MgBr

H3C

O

H

+

MgBr

H3C

O

CH3

+

Et2O

Et2O

Et2O

OH

OH

OH

Me

MeMe

Grignard Reactions: Esters

MgBr

H3C

O

OCH3

+Et2O

Me OH

• Grignard Reagents React Twice w/ Esters 3° Alcohols

• Two Alkyl Groups of Alcohol Correspond to Grignard Reagent

• Grignard Reactions Quite Useful in Wide Range of AlcoholSyntheses (w/ Varying Degrees of Substitution)

Reactions of Organolithium Compounds

• Organolithium Reagents React Similarly to Grignards

• Also Strong Bases, Same Limitations Apply

• More Reactive Species Than Grignard Reagents

• Routine Syntheses: Prefer to use Grignard Reagents

• Sodium Alkynides (Triple Bond Anions) React in Same Mannerw/ Aldehydes and Ketones

Now We’ll Look at One More Organometallic: LithiumDialkylcuprates (A Coupling Reagent)

Lithium DialkylcupratesI

(CH3)2CuLi

Et2O

Me

CH3Br2Li, Et2O

2 CH3Li CuI (CH3)2CuLi

Br

(CH3)2CuLi

Et2O

Me

Quite Versatile C—C Bond Forming Reaction