Chapter 12

Alcohols from Carbonyl Compounds Oxidation-Reduction & Organometallic Compounds

Ch. 12 - 1 1. Structure of the Carbonyl Group

O  Carbonyl compounds

O O

R H R R' Aldehyde Ketone O O O R' R OH R OR' R N Carboxylic acid Ester Amide R" Ch. 12 - 2  Structure

o ~ 120 O ~ 120o C ~ 120o

● Carbonyl carbon: sp2 hybridized ● Planar structure

Ch. 12 - 3  Polarization and resonance structure

δ− O O + Cδ C

Ch. 12 - 4 1A. Reactions of Carbonyl Compounds with Nucleophiles

 One of the most important reactions of carbonyl compounds is nucleophilic addition to the carbonyl group

− Oδ O + nucleophilic Nu C δ C addition Nu

Ch. 12 - 5  Two important nucleophiles:

● Hydride ions (from NaBH4 and LiAlH4) ● Carbanions (from RLi and RMgX)

 Another important reactions:

O OH oxidation C R R H H reduction H 1o alcohol aldehyde Ch. 12 - 6 2. Oxidation-Reduction Reactions in Organic Chemistry

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

oxygen content hydrogen content decreases decreases

O [H] O O [H] OH

R OH reduction R H R H reduction R H H carboxylic aldehyde acid Ch. 12 - 7  The opposite reaction of reduction is oxidation. Increasing the oxygen content of on organic molecule or decreasing its hydrogen content is oxidation

[O] OH [O] O [O] O RCH3 [H] R H [H] R H [H] R OH H lowest highest oxidation oxidation state state

Ch. 12 - 8  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] [O] [O] Ar CH3 Ar CH2Cl Ar CHCl2 Ar CCl3 [H] [H] [H]

Ch. 12 - 9 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 - 10  Examples

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

Oxidation state of C = - 4

Ch. 12 - 11  Examples

H Bonds to C: (2) H C OH 3 to H = - 3 H 1 to O = +1 Total = - 2

Oxidation state of C = - 2

Ch. 12 - 12  Examples

O Bonds to C: (3) C 2 to H = - 2 H H 2 to O = +2 Total = 0

Oxidation state of C = 0

Ch. 12 - 13  Examples

O Bonds to C: (4) C 1 to H = - 1 H OH 3 to O = +3 Total = +2

Oxidation state of C = +2

Ch. 12 - 14  Overall order

H H O O O H C H < H C OH < C < C < C H H H OH H H O oxidation - 4 - 2 0 +2 +4 state lowest highest oxidation oxidation state of state of carbon carbon

Ch. 12 - 15 3. Alcohols by Reduction of Carbonyl Compounds H [H]

R O

OH [H] H H (1o alcohol) R O R OH OR' [H] R O O [H] HO H

R R' R R' Ch. 12 - 16 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 - 17  Examples O OH 1. LiAlH4, Et2O (1) R OH 2. H+, H O R H 2 H

O OH 1. LiAlH4, Et2O (2) + HOR' R OR' 2. H+, H O R H 2 H

O OH 1. LiAlH4, Et2O (3) R H 2. H+, H O R H 2 H Ch. 12 - 18  Mechanism O H O + H Al H R OR' R OR' H H O R'O + R H H H Al H OH O O H H H R H R H H H Esters are reduced to 1o alcohols Ch. 12 - 19 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 - 20  Examples

O NaBH4 OH (1) H R H H2O R H

O NaBH4 OH (2) R' R R' H2O R H

Ch. 12 - 21  Mechanism

δ− O H O + H B H R R' R δ+ R' H H

O OH H H

R R' H Aldehydes are reduced to 1° alcohols & ketones are reduced to 2° alcohols Ch. 12 - 22 3C. Overall Summary of LiAlH4 and NaBH4 Reactivity

reduced by LiAlH4

reduced by NaBH4

O O O O < < < R O R OR' R R' R H

ease of reduction

Ch. 12 - 23 4. Oxidation of Alcohols 4A. Oxidation of Primary Alcohols to Aldehydes O O [O] [O] R OH R H R OH 1o alcohol aldehyde carboxylic acid

 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 - 24  PCC oxidation ● Reagent

PCC = [CrO3Cl] N H (Pyridinium chlorochromate)

CrO3 + HCl + N N H [CrO3Cl]

Pyridine Pyridinium (C5H5N) chlorochromate (PCC) Ch. 12 - 25  PCC oxidation

PCC O R OH CH2Cl2 R H

OH PCC O

R R' CH2Cl2 R R'

OH PCC R' No Reaction R CH2Cl2 R

Ch. 12 - 26 4B. Oxidation of Primary Alcohols to Carboxylic Acids - O + KMnO4, OH H3O

H2O, heat R O K O R OH H2CrO4 R OH (chromic acid)

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

Jones reagent Ch. 12 - 27  Jones oxidation

● Reagent: CrO3 + H2SO4 ● A Cr(VI) oxidant O CrO3 + Cr(III) R OH H SO 2 4 R OH (orange solution) (green) OH O CrO3 + Cr(III) H SO R R' 2 4 R R' (orange solution) (green) OH CrO3 No Reaction H SO R R" 2 4 R' Ch. 12 - 28 4D. Mechanism of Chromate Oxidations

 Formation of the Chromate Ester H H O O H H O H3C O C + HO Cr O H3C O Cr O H C H 3 O C O O H C H H O H 3 H H H O H H H

H O O O H3C O Cr O H H3C O Cr O C C O O H + OH H C H H3C H 3 H H Ch. 12 - 29  The oxidation step

O O H3C H3C O Cr O C O + Cr O C OH H3C OH H3C H + + H O H H H O H

Ch. 12 - 30 4E. A Chemical Test for Primary and Secondary Alcohols O CrO3 + Cr(III) R OH H SO 2 4 R OH (orange solution) (green) OH O CrO3 + Cr(III) H SO R R' 2 4 R R' (orange solution) (green) OH CrO3 No Reaction H SO R R" 2 4 R' Ch. 12 - 31 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 spectrum between 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 - 32 5. Organometallic Compounds

 Compounds that contain carbon-metal bonds are called organometallic compounds

δ− δ+ C M C : M C M primarily ionic primarily covalent (M = Na or K) (M = Mg or Li) (M = Pb, Sn, Hg or Tl)

Ch. 12 - 33 6. Preparation of Organolithium & Organomagnesium Compounds 6A. Organolithium Compounds  Preparation of organolithium compounds

Et2O R X + 2 Li RLi + LiX (or THF)

 Order of reactivity of RX ● RI > RBr > RCl Ch. 12 - 34  Example (80% - 90%) Et2O Br -10oC Li + + 2 Li LiBr

Ch. 12 - 35 6B. Grignard Reagents

 Preparation of organomagnesium compounds (Grignard reagents)

Et2O R X + Mg RMgX

Et2O Ar X + Mg ArMgX

 Order of reactivity of RX ● RI > RBr > RCl

Ch. 12 - 36  Example

Br MgBr THF + Mg

Ch. 12 - 37 7. Reactions of Organolithium and Organomagnesium Compounds 7A. Reactions with Compounds Con- taining Acidic Hydrogen Atoms δ− δ+ δ− δ+ RMgX ~ R:MgX RLi ~ R:Li

 Grignard reagents and organolithium compounds are very strong bases

δ− δ+ δ+ δ− R MgX + H Y R H + Y + Mg2+ + X (or RLi) (Y = O, N or S) Ch. 12 - 38  Examples ● As base − (1) CH3MgBr + H2O H3C H + OH + Mg2+ + Br−

MgBr − (2) + CH3OH + CH3O

+ Mg2+ + Br−

Ch. 12 - 39  Examples ● As base

(3) H + H3C MgBr

MgBr + H CH3

A good method for the preparation of alkynylmagnesium halides

Ch. 12 - 40 7B. Reactions of Grignard Reagents with Epoxides (Oxiranes)

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

then H2O RMgBr O OH + R

Ch. 12 - 41  Via SN2 reaction

O O R R

+ H , H2O

OH R (1o alcohol)

Ch. 12 - 42  Also work for substituted epoxides

R OH O then H2O RMgBr + H H R' R' (2o alcohol)

R OH O then H2O RMgBr + R" R" R' R' (3o alcohol) Ch. 12 - 43 7C. Reactions of Grignard Reagents with Carbonyl Compounds

O OH 1. Et2O + R"MgX R' 2. H O+ R R R' 3 R"

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

Ch. 12 - 44  Mechanism

O MgX O δ− δ+ + R" MgX R" R R R' R'

H O H OH H R" R R'

Ch. 12 - 45 8. Alcohols from Grignard Reagents

O OH 1. Et2O + R"MgX R' 2. H O+ R R R' 3 R"

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

Ch. 12 - 46  R, R’ = H (formaldehyde) ● 1o alcohol

O MgX δ− δ+ O R MgX + H H H R H formaldehyde H O+ OH 3 H R H 1o alcohol Ch. 12 - 47  R = alkyl, R’ = H (higher aldehydes) ● 2o alcohol

O MgX δ− δ+ O R MgX + R' R' H R H higher aldehyde H O+ OH 3 R' R H 2o alcohol Ch. 12 - 48  R, R’ = alkyl (ketone) ● 3o alcohol

O MgX δ− δ+ O R MgX + R' R' R" R R" ketone

NH3Cl OH H2O R' R R" 3o alcohol Ch. 12 - 49  Reaction with esters ● 3o alcohol

O OH 1. Et2O + R"MgX R" 2. H O+ R R OR' 3 R"

+ R'OH

Ch. 12 - 50  Mechanism MgX O O δ− δ+ + R" MgX OR' R R OR' R" O R'O + R R"

− + H O H MgX δ δ OH O R" MgX H R" R" R R R" R" Ch. 12 - 51  Examples

MgBr O Et2O (1) + H H

OH OMgBr

+ H H3O H

(1o alcohol)

Ch. 12 - 52  Examples

MgI O Et2O (2) + H3C H

OH OMgI

+ CH3 CH H3O 3 H

(2o alcohol)

Ch. 12 - 53  Examples

O Et2O (3) MgBr + Ph Ph

Ph + Ph H3O Ph Ph OH OMgBr (3o alcohol)

Ch. 12 - 54  Examples MgI O O Et2O (4) MgI + OMe Ph OMe Ph

MgI OMgI O

Ph Ph

OH (3o alcohol) + H3O Ph

Ch. 12 - 55 8A. How to Plan a Grignard Synthesis

 Synthesis of

OH Me Me

Ch. 12 - 56  Method 1 ● Retrosynthetic analysis OH

Me MgBr O Me + Me Me

disconnection

● Synthesis OH MgBr Me O 1. Et2O + Me + Me Me 2. H3O Ch. 12 - 57  Method 2 ● Retrosynthetic analysis OH O Me Me Me MeMgBr +

disconnection ● Synthesis O OH

1. Et O Me Me 2 MeMgBr + Me + 2. H3O Ch. 12 - 58  Method 3 ● Retrosynthetic analysis OH disconnection O Me OEt Me + 2 MeMgBr

disconnection ● Synthesis O OH

1. Et O Me OEt 2 Me + 2. H3O + 2 MeMgBr Ch. 12 - 59 8B. Restrictions on the Use of Grignard 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 - 60  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 - 61  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 O O O

H, R, OR, NH2,

O NO2, C N, Ch. 12 - 62 8C. The Use of Lithium Reagents − + O OLi + OH δ δ H3O R Li +

R R organo- aldehyde lithium alcohol lithium or alkoxide reagent ketone  Organolithium reagents have the advantage of being somewhat more reactive than Grignard reagents although they are more difficult to

prepare and handle Ch. 12 - 63 8D. The Use of Sodium Alkynides  Preparation of sodium alkynides NaNH2 R H R Na -NH3

 Reaction via ketones (or aldehydes) O ONa + OH H3O R Na +

R R Ch. 12 - 64 9. Protecting Groups

OH How? I HO HO

Ch. 12 - 65  Retrosynthetic analysis OH O MgBr + HO HO

disconnection Br HO  However Mg δ+ Br MgBr HO H O Et2O δ−

powerful acidic proton base H BrMg O Ch. 12 - 66  Need to “protect” the –OH group first

Br (protection) Br HO "P"O

Mg, Et2O OH O 1. MgBr "P"O + "P"O 2. H3O (no acidic OH group) (deprotection)

OH

HO Ch. 12 - 67 TBSCl  Synthesis imidazole Br DMF Br HO (protection) TBSO Me t TBSCl = Bu Si Cl Mg, Et2O Me

Imidazole = N H MgBr N TBSO O O Me DMF = H N 1.

Me + (a polar aprotic solvent) 2. H3O OH OH Bu4N F THF HO TBSO (deprotection) Ch. 12 - 68