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Chapter 12. Alcohols from Carbonyl Compounds Oxidation-Reduction & Organometallic Compounds. About The Authors. These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang. - PowerPoint PPT Presentation
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Created byProfessor William Tam & Dr. Phillis
Chang Ch. 12 - 1
Chapter 12Alcohols from
Carbonyl CompoundsOxidation-Reduction &
OrganometallicCompounds
Ch. 12 - 2
About The Authors
These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang.
Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.
Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.
Ch. 12 - 3
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 - 4
Structure
O
C
~ 120o
~ 120o
~ 120o
●Carbonyl carbon: sp2 hybridized
●Planar structure
Ch. 12 - 5
Polarization and resonance structure
O
C
O
C
Ch. 12 - 6
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 - 7
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 - 8
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 - 9
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 - 10
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 - 11
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 - 12
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 - 13
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 - 14
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 - 15
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 - 16
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 - 17
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 - 18
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 - 19
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 - 20
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 - 21
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 - 22
Examples
O
R H
OH
R HH
(1)NaBH4
H2O
O
R R'
OH
R R'H
(2)NaBH4
H2O
Ch. 12 - 23
Mechanism
O
R R'
H
B HH
H
+
O
R'R
H
OH HOH
RH
R'
Aldehydes are reduced to 1° alcohols & ketones are reduced to 2° alcohols
Ch. 12 - 24
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 - 25
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 - 26
PCC oxidation●Reagent
(Pyridinium chlorochromate)
N
H
[CrO3Cl]PCC =
CrO3 + HCl N+
Pyridine(C5H5N)
Pyridiniumchlorochromate
(PCC)
N H [CrO3Cl]
Ch. 12 - 27
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 - 28
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 - 29
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 - 30
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 O
O
H
O
H
CH3C H
H3C
HCr
O
OC
H3C H
H3C
OH
O
H
OH
+
Ch. 12 - 31
The oxidation step
Cr
O
OC
H3C H
H3C
OH
O
H
OH
+ H O H
H
OC
H3C
H3C
Cr
O
OH
O+
+
Ch. 12 - 32
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 - 33
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 d 3.3 and d 4.0 ppm that integrates for 2 and 1 hydrogens, respectively
The 13C NMR spectrum of an alcohol shows a signal between d 50 and d 90 ppm for the alcohol carbon
Ch. 12 - 34
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 - 35
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 - 36
2 Li
+Br Li
LiBr
+
Et2O
-10oC
(80% - 90%)
Example
Ch. 12 - 37
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 - 38
THF+ Mg
Br MgBr
Example
Ch. 12 - 39
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:Li
R MgX H Y+
(or RLi) (Y = O, N or S)
++ XR H Y Mg2+ +
Ch. 12 - 40
Examples●As base
CH3OH+
MgBr
+ Mg2+ + Br
+ CH3O(2)
CH3MgBr + H2O + OHH3C H(1)
+ Mg2+ + Br
Ch. 12 - 41
Examples●As base
(3) H + H3C MgBr
MgBr H CH3+
A good method for the preparationof alkynylmagnesium halides
Ch. 12 - 42
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 - 43
Via SN2 reaction
OR RO
H+, H2O
ROH
(1o alcohol)
Ch. 12 - 44
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 - 45
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 - 46
Mechanism
O
R R'MgXR"+
H O H
HOH
RR'
R"
O MgX
RR'
R"
Ch. 12 - 47
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 - 48
R, R’ = H (formaldehyde)●1o alcohol
O
H HMgXR +
formaldehyde
O MgX
RH
H
OH
RH
H
H3O+
1o alcohol
Ch. 12 - 49
R = alkyl, R’ = H (higher aldehydes)●2o alcohol
O
R' HMgXR +
higheraldehyde
O MgX
RH
R'
OH
RH
R'
H3O+
2o alcohol
Ch. 12 - 50
R, R’ = alkyl (ketone)●3o alcohol
O
R' R"MgXR +
ketone
O MgX
RR"
R'
OH
RR"
R'
NH3ClH2O
3o alcohol
Ch. 12 - 51
Reaction with esters●3o alcohol
O
R OR'
1. Et2O
2. H3O++ R"MgX
OH
RR"
R"
+ R'OH
Ch. 12 - 52
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 - 53
Examples
O
H H(1)
MgBr
+Et2O
H
OMgBr
H
OH
H3O+
(1o alcohol)
Ch. 12 - 54
Examples
O
H3C H(2)
MgI
+Et2O
CH3
OMgI
H
OH
H3O+
(2o alcohol)
CH3
Ch. 12 - 55
Examples
O
Ph Ph(3) +
Et2O
OMgBr
PhH3O
+
(3o alcohol)
MgBr
Ph
OH
Ph
Ph
Ch. 12 - 56
Examples
O
Ph OMe(4) +
Et2O
H3O+
(3o alcohol)
OMgI
Ph
MgI
O
PhOMe
MgI
O
Ph
OH
Ph
MgI
Ch. 12 - 57
8A.How to Plan a Grignard Synthesis
OH
MeMe
Synthesis of
Ch. 12 - 58
OH
MeMe
disconnection
MgBr
+O
Me Me
Method 1●Retrosynthetic analysis
●Synthesis OH
MeMeMgBr
+O
Me Me
1. Et2O
2. H3O+
Ch. 12 - 59
OH
MeMe
disconnection
+MeMgBrMe
O
Method 2●Retrosynthetic analysis
●SynthesisOH
MeMe
+MeMgBrMe
O
1. Et2O
2. H3O+
Ch. 12 - 60
OH
MeMe
disconnection
+ 2 MeMgBrOEt
Odisconnection
Method 3●Retrosynthetic analysis
●SynthesisOH
MeMe1. Et2O
2. H3O+
+ 2 MeMgBr
OEt
O
Ch. 12 - 61
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 - 62
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 - 63
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 - 64
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 - 65
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 - 66
9. Protecting Groups
HOI
HO
OHHow?
Ch. 12 - 67
Retrosynthetic analysis
HO
OH O
HOMgBr +
disconnection
HOBr
However
HOBr
Mg
Et2O OMgBr
H
BrMg OHacidic proton powerful
base
Ch. 12 - 68
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 - 69
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)
Ch. 12 - 70
END OF CHAPTER 12
