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Modified from sides of William Tam & Phillis ChangCh. 16 - 1
Chapter 16Chapter 16
Aldehydes & Ketones:Aldehydes & Ketones:Nucleophilic AdditionNucleophilic Additionto the Carbonyl Groupto the Carbonyl Group
Ch. 16 - 2
About The AuthorsAbout 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. 16 - 3
1. Introduction
Carbonyl compounds
O
R R'ketone
O
R Haldehyde
O
R OR'ester
(R, R' = alkyl, alkenyl, alkynyl or aryl groups)
Ch. 16 - 4
2. Nomenclature of Aldehydes &Ketones
Rules● Aldehyde as parent (suffix)
Ending with “al”;● Ketone as parent (suffix)
Ending with “one”● Number the longest carbon chain
containing the carbonyl carbon and starting at the carbonyl carbon
Ch. 16 - 5
ExamplesCl
H
O
4-Chloro-2,2-dimethylpentanal
12345
O
Br
12 3 4 5 6
7
6-Bromo-4-ethyl-3-heptanone
Ch. 16 - 6
group as a prefix: methanoyl or
formyl group
O
H
group as a prefix: ethanoyl or
acetyl group (Ac)
O
groups as a prefix: alkanoyl or
acyl groups
O
R
Ch. 16 - 7
2-Methanoylbenzoic acid(o-formylbenzoic acid)
CO2H
H
O
4-Ethanoylbenzenesulfonic acid(p-acetylbenzenesulfonic acid)
SO3H
O
Ch. 16 - 8
3. Physical Properties
Butane
bp -0.5oC
(MW = 58)
H
O O
OH
Propanal
bp 49oC
(MW = 58)
Butane
bp 56.1oC
(MW = 58)
1-Propanol
bp 97.2oC
(MW = 60)
Ch. 16 - 9
4. Synthesis of Aldehydes
4A.4A. Aldehydes by Oxidation of 1Aldehydes by Oxidation of 1oo AlcoholsAlcohols
R OHR H
OPCC
Ch. 16 - 10
OH O
H
PCC
CH2Cl2(90%)
PCC
CH2Cl2
OH O
H(89%)
e.g.
Ch. 16 - 11
4B.4B. Aldehydes by Ozonolysis ofAldehydes by Ozonolysis ofAlkenesAlkenes
R'
R
H
R"
O
R'
R
O
H
R"1. O3
2. Me2S+
Ch. 16 - 12
O
O
H
1. O3, CH2Cl2, -78oC
2. Me2S
+
e.g.
H3C
1. O3, CH2Cl2, -78oC
2. Me2S
O
H3C
H
+
O
H H
Ch. 16 - 13
4C.4C. Aldehydes by Reduction of AcylAldehydes by Reduction of AcylChlorides, Esters, and NitrilesChlorides, Esters, and Nitriles
LiAlH4R OH
O
R HLiAlH4
O
R OH
O
R OR'
O
R Cl
R C N
or
or
or
Ch. 16 - 14
LiAlH4 is a very powerful reducing agent, and aldehydes are easily reduced● Usually reduced all the way to the
corresponding 1o alcohol● Difficult to stop at the aldehyde
stage Not a good method to
synthesize aldehydes using LiAlH4
Ch. 16 - 15
Two derivatives of aluminum hydride that are less reactive than LAH
Lithium tri-tert-butoxyaluminum hydride
AlR
OtBu
AlLi+ H OtBu
OtBu
−
Diisobutylaluminum hydride(abbreviated i-Bu2AlH or DIBAL-H)
Ch. 16 - 16
1. LiAlH(OtBu)3, -78oC
2. H2O
O
R Cl
O
R OR'
R C N
O
R H
1. DIBAL-H, hexane, -78oC
2. H2O
1. DIBAL-H, hexane
2. H2O
Acyl chloride
Ester
Nitrile
Ch. 16 - 17
Aldehydes from acyl chlorides: RCOCl RCHO
1.
2.
O
R Cl
O
R OH
O
R H
SOCl2
LiAlH(OtBu)3,
Et2O, -78oC
H2O
e.g.
1. LiAlH(OtBu)3, Et2O, -78oC
2. H2O
Cl
O
CH3
H
O
CH3
Ch. 16 - 18
Reduction of an Acyl Chloride to an Aldehyde
LiAlH(OtBu)3R C
Cl
O
R C
Cl
O Li+ Al(OtBu)3
H
R C
Cl
O
H
Li
Al(OtBu)3R C
Cl
O
H
Al(OtBu)3
Li
R C
H
O Al(OtBu)3-LiCl
R C
H
OH2O
Ch. 16 - 19
Aldehydes from esters and nitriles: RCO2R’ RCHO
RC≡N RCHO● Both esters and nitriles can be
reduced to aldehydes by DIBAL-H
Ch. 16 - 20
Reduction of an ester to an aldehyde
R C
OR'
O
H
Al(i-Bu)2 R C
OR'
O Al(i-Bu)2
H
R C
OR'
O
H
Al(i-Bu)2
R C
H
O H2O
Ch. 16 - 21
Reduction of a nitrile to an aldehyde
R C N
H
Al(i-Bu)2 Al(i-Bu)2
H
NCR
R C
N
H
Al(i-Bu)2R C
H
O H2O
Ch. 16 - 22
Examples
1. DIBAL-H, hexane, -78oC
2. H2O(1)
O
O
OH
H
O
1. DIBAL-H, hexane, -78oC
2. H2O
(2) C
H
O
N
Ch. 16 - 23
5. Synthesis of Ketones
5A.5A. Ketones from Alkenes, Arenes,Ketones from Alkenes, Arenes,and 2and 2oo Alcohols Alcohols
Ketones (and aldehydes) by ozonolysis of alkenes
R'
R
H
R"
O
R'
R
O
H
R"1. O3
2. Me2S+
Ch. 16 - 24
Examples
1. O3
2. Me2S
O
O
(i)
OO
H
+
(ii)1. O3
2. Me2S
Ch. 16 - 25
Ketones from arenes by Friedel–Crafts acylations
O
R Cl
AlCl3 R
O
+ HCl+
an alkyl arylketone
Ch. 16 - 26
Ketones from secondary alcohols by oxidation
OH
R R'
O
R R'
H2CrO4
or PCC
Ch. 16 - 27
5B.5B. Ketones from NitrilesKetones from Nitriles
R C N1. R'−M, Et2O
N M
R'R
2. H3O+
Ch. 16 - 28
Examples
C N
O
Me1. MeLi, Et2O
2. H3O+
C N1. , Et2O
2. H3O+
MgBr
O
Ch. 16 - 29
Suggest synthesis of
O
from andBr
HO
Ch. 16 - 30
Retrosynthetic analysis
O
HO
need to add one carbon
5 carbons here 4 carbons here
Ch. 16 - 31
Retrosynthetic analysisO
C
MgBr
N+
NC
Br
+
HO
disconnection
disconnection
Ch. 16 - 32
Synthesis
O
HO Br
CN
PBr3
NaCNDMSO
1.
2. H3O+
Et2O
MgBr
Ch. 16 - 33
Suggest synthesis of
O
from andBr
HO
Ch. 16 - 34
Retrosynthetic analysis
O
HO
no need to add carbon
5 carbons here
5 carbons here
Ch. 16 - 35
Retrosynthetic analysis
O
MgBr
+H
O
disconnection
Ch. 16 - 36
Synthesis
O
PCC
2. H3O+
1. , Et 2O
MgBr
HO O
OH
PCC
Ch. 16 - 37
6. Nucleophilic Addition to theCarbon–Oxygen Double Bond
StructureO
C
~ 120o
~ 120o
~ 120o
δ−
● Carbonyl carbon: sp2 hybridized● Trigonal planar structure
Nu⊖
Ch. 16 - 38
Polarization and resonance structure
C
O
δ+
O
C
δ−
● Nucleophiles will attack the nucleophilic carbonyl carbon
● Note: nucleophiles usually do not attack non-polarized C=C bond
Ch. 16 - 39
With a strong nucleophile:
δ+ δ−C O
R
R'
Nu: C O:
R
R'
Nu
H Nu
C O
R
R'
Nu
HNu: +
Ch. 16 - 40
Also would expect nucleophilic addition reactions of carbonyl compounds to be catalyzed by acid (or Lewis acid)
O
C H+O
C
HO
C
H
(protonated carbonyl group)
+
● Note: full positive charge on the carbonyl carbon in one of the resonance forms Nucleophiles readily attack
Ch. 16 - 41
+ A:C OH
R
R'
C OH
R
R'
Mechanism
δ+ δ−C O
R
R'
H A+
(or a Lewis acid)
Ch. 16 - 42
+ A:C O
R
R'
Nu
H
H
C OH
R
R'
:Nu H
Mechanism
C O
R
R'
:Nu
H
H A+
Ch. 16 - 43
6A.6A. Reversibility of NucleophilicReversibility of NucleophilicAdditions to the CarbonAdditions to the Carbon––OxygenOxygenDouble BondDouble Bond
Many nucleophilic additions to carbon–oxygen double bonds are reversible; the overall results of these reactions depend, therefore, on the position of an equilibrium
Ch. 16 - 44
6B.6B. Relative Reactivity: AldehydesRelative Reactivity: Aldehydesvs. Ketonesvs. Ketones
O
R H
O
R R'
O
R OR'> >
Ch. 16 - 45
large
small
O
R H
O
RNu
H
Nu
O
R R'
O
RNu
R'
Nu
Steric factors
Ch. 16 - 46
O
CR H
O
CR R'
δ−
δ+
δ−
δ+> >< <
Electronic factors
(positive inductive effect from only one R group)
(positive inductive effect from both R & R' groups) carbonyl carbon less δ+ (less nucleophilic)
Ch. 16 - 47
7. The Addition of Alcohols:Hemiacetals and Acetals
Acetal & Ketal Formation: Addition of Alcohols to Aldehydes
R R'
O
R R'
R"O OHH+
R R'
R"O OR"
+ R"OH
H+
R"OH
hemi-acetal (R' = H)hemi-ketal (R' = alkyl)
acetal (R' = H)ketal (R' = alkyl)
Catalyzed by acid
Ch. 16 - 48
O
CR R'
H+
+ R"OH
Mechanism
RC
R'
O:H
OR"
H
+
RC
R'
OH
+ R"OH
OH
R O
R' R"
H
Ch. 16 - 49
Mechanism (Cont’d)
OH
R O
R' R"
H R"OHOH
R OR"
R'
R"O
HH
hemi-acetal (R' = H) or
hemi-ketal (R' = alkyl)
+
OH2
R OR"
R'RC
R'
OR"
H2O +
Ch. 16 - 50
RC
R'
OR"
R"OH
Mechanism (Cont’d)
OR"
R O
R' R"
H
R"OH
OR"
R OR"
R'
acetal (R' = H) orketal (R' = alkyl)
Ch. 16 - 51
Note: All steps are reversible. In the presence of a large excess of anhydrous alcohol and catalytic amount of acid, the equilibrium strongly favors the formation of acetal (from aldehyde) or ketal (from ketone)
On the other hand, in the presence of a large excess of H2O and a catalytic amount of acid, acetal or ketal will hydrolyze back to aldehyde or ketone. This process is called hydrolysis
Ch. 16 - 52
Acetals and ketals are stable in neutral or basic solution, but are readily hydrolyzed in aqueous acid
H+OR"
R OR"
R'
H2OO
R R'+ + 2 R"OH
Ch. 16 - 53
Aldehyde hydrates: gem-diols
H2O+O
H
H3C
H
H3C O
O
H
H
Acetaldehyde Hydrate(a gem-diol)
Ch. 16 - 54
δ+ δ−C O
H
H3C OH2
Mechanism
OH2H3C
O:H
OHH3C
OHH
OHHO
HR
O
R H+ H2O
distillation
Ch. 16 - 55
HO
O
O
O
O
OH
H
Butanal-4-ol
A cyclichemiacetal
Hemiacetal: OH & OR groups bonded to the same carbon
7A.7A. HemiacetalsHemiacetals
Ch. 16 - 56
(+)-Glucose(A cyclic hemiacetal)
OHO
HO OH
OH
OH Hemiacetal: OH & OR groups bonded to the same carbon
Ch. 16 - 57
Sucrose(table sugar)
O
O
OHO
OH
HOHO
OHHO
OH
OHAn acetal
A ketal
7B.7B. AcetalsAcetals
Ch. 16 - 58
+O
R R'
HOOH
H3O+
O O
R R'
+ H2O
Ketone (excess) Cyclic acetal
Cyclic acetal formation is favored when a ketone or an aldehyde is treated with an excess of a 1,2-diol and a trace of acid
Ch. 16 - 59
+
O
R R'
HOOH
H3O+
O O
R R'
+ H2O
This reaction, too, can be reversed by treating the acetal with aqueous acid
Ch. 16 - 60
7C.7C. Acetals Are Used as Protecting GroupsAcetals Are Used as Protecting Groups Although acetals are hydrolyzed to
aldehydes and ketones in aqueous acid, acetals are stable in basic solutions
R'O OR"
R H H2O
OH−
No Reaction
O O
R R'H2O
OH−
No Reaction
Acetals are used to protect aldehydes and ketones from undesired reactions in basic solutions
Ch. 16 - 61
O
OH
Br
O
Attempt to synthesize:
from:
Example
Ch. 16 - 62
O
O
OH
BrMg
O
+
● Synthetic plan
This route will not work
Ch. 16 - 63
BrMg
O
δ+ δ−
Reason:
(a) Intramolecular nucleophilic addition
(b) Homodimerization or polymerization
BrMg
O
BrMg
O
BrMg
O
Ch. 16 - 64
Br
O O
HO
Thus, need to “protect” carbonyl group first
Br
O O
HOOH
, H+
(ketal)
BrMg
O O
MgEt2O δ+
δ− O
OMgBr
O O
aqueous H+
Ch. 16 - 65
7D.7D. ThioacetalsThioacetals
Aldehydes & ketones react with thiols to form thioacetals
EtS SEt
R H
O
R H
2 EtSH
HA+ H2O
Thioacetal
O
R R' BF3
+ H2OS S
R R'
HSSH
Cyclicthioacetal
Ch. 16 - 66
Thioacetal formation with subsequent “desulfurization” with hydrogen and Raney nickel gives us an additional method for converting carbonyl groups of aldehydes and ketones to –CH2– groups
H2, Raney Ni
+ NiS
S S
R R'HS
SH
R R'
H H+
Ch. 16 - 67
8. The Addition of Primary andSecondary Amines
Aldehydes & ketones react with 1o amines to form imines and with 2o amines to form enamines
From a 1o amine From a 2o amine
N
R1 R2
R3
Imine
R1
NR5
R2
R3
R4
Enamine
R1, R2, R3 = C or H;R4, R5 = C
Ch. 16 - 68
8A.8A. IminesImines
Addition of 1o amines to aldehydes & ketones
R
R'
O H2N R"
R
R'
NR"
H++
(1o amines) (imines)
[(E) & (Z) isomers]
+ H2O
Ch. 16 - 69
H2NR"
Mechanism
R R'
O H3O+
R R'
OH O
RR'
H
N R"
H
H
-H+
O
RR'
H
NHR"
(amino alcohol)
H+OH2
RR'
NHR"N
R'
R
R"
H
H2O
N
R'
R
R"
Ch. 16 - 70
Similar to the formation of acetals and ketals, all the steps in the formation of imine are reversible. Using a large excess of the amine will drive the equilibrium to the imine side
Hydrolysis of imines is also possible by adding excess water in the presence of catalytic amount of acid
N
R'
R
R"H2O
H+
O
R'
R
+ + H2NR"
Ch. 16 - 71
8B.8B. Oximes and HydrazonesOximes and Hydrazones Imine formation – reaction with a 1o amine
C O H2N R C N+
R
+ H2O
a 1o amine an imine
[(E) & (Z) isomers]aldehydeor ketone
C O H2N OH C N+
OH
+ H2O
hydroxylamine
an oxime
[(E) & (Z) isomers]
aldehydeor ketone
Oxime formation – reaction with hydroxylamine
Ch. 16 - 72
Hydrazone formation – reaction with hydrazine
C O H2NNH2 C N+NH2
+ H2O
hydrazine a hydrazonealdehydeor ketone
N R C C+
N
+ H2O
2o amine
cat. HA
O
CC
H R
H
RR
enamine
Enamine formation – reaction with a 2o amine
Ch. 16 - 73
8C.8C. EnaminesEnamines
N R5+
N
+ H2O
2o amine
cat. HAO
C R3
R2H
R1
R4
H
R4 R5
enamine
R3R1
R2
Ch. 16 - 74
N R+
O
CC
H R
H
Mechanism
C C
H
O
N
R
R
H
aminoalcoholintermediate
C C
H
O
N R
R
H
Ch. 16 - 75
C C
H
O
N R
R
H
A H +
Mechanism (Cont’d)
C C
H
O
N R
R
HH
iminium ionintermediate
C
H
C
N
R
R:A + H2O +
Ch. 16 - 76
C
H
C
N
R
R
A:
Mechanism (Cont’d)
enamine
C
H
CN
R
R
+ H A
Ch. 16 - 77
9. The Addition of HydrogenCyanide: Cyanohydrins
Addition of HCN to aldehydes & ketones
R R'
OHCN
OH
RR'
CN
O
RR'
CN
H+CN
(cyanohydrin)
Ch. 16 - 78
R R'
OCN
Mechanism
O
RR'
CN(slow)
NC H
OH
RR'
CN
Ch. 16 - 79
Slow reaction using HCN since HCN is a weak acid and a poor source of nucleophile
Can accelerate reaction by using NaCN or KCN and slow addition of H2SO4
R R'
O
NaCN
O Na
RCN
R'
OH
RR'
CNH2SO4
Ch. 16 - 80
R'
OHCN
RR'
RHO CN
R'R
COOH95% H2SO4
heat
HCl, H2O
heat R'R
HO COOH
1. LiAlH4
2. H2O R'R
HO NH2
(α-hydroxy acid)
(α,β-unsaturated acid)
(β-aminoalcohol)
Synthetic applications
Ch. 16 - 81
10. The Addition of Ylides: TheWittig Reaction
R
R'
O
aldehydeor ketone
+ (C6H5)3P C
R"
R"
C C
R'
R
R"
R"
O P(C6H5)3
+
phosphorus ylide(or phosphorane)
alkene[(E) & (Z) isomers]
triphenyl-phosphine
oxide
Ch. 16 - 82
Phosphorus ylides
(C6H5)3P C
R"
R"
(C6H5)3P C
R"
R"
(C6H5)3P CH
R"'
R"
(C6H5)3P: XXCH
R"'
R"
+
triphenyl-phosphine
an alkyltriphenylphos-phonium halide
(C6H5)3P C
R"'
R"
H :B + H:B(C6H5)3P C
R"'
R"
a phosphorusylide
Ch. 16 - 83
Example
(C6H5)3P CH3(C6H5)3P: Br+
Methyltriphenylphos-phonium bromide
(89%)
CH3BrC6H6
(C6H5)3P CH3
Br
+ C6H5Li (C6H5)3P CH2:
+ + LiBrC6H6
Ch. 16 - 84
Mechanism of the Wittig reaction
+C
O
R R'R"
:C R"'
P(C6H5)3: :
aldehydeor ketone
ylide
R'
C CR
:O
R"
R"'
P(C6H5)3
oxaphosphetane
:
C C
R
R'
R"
R"
O P(C6H5)3 +
alkene(+ diastereomer)
triphenylphosphineoxide
::
Ch. 16 - 85
10A. 10A. How to Plan a Witting SynthesisHow to Plan a Witting Synthesis
Synthesis of
using a Wittig reaction
Ch. 16 - 86
Retrosynthetic analysis
disconnection
O
Ph3P+route 1
BrPh3P: +route 2
PPh3
O+
Br
+ :PPh3
Ch. 16 - 87
Synthesis – Route 1
O
Ph3PBr:PPh3
Br
nBuLi
Ph3P
Ch. 16 - 88
Synthesis – Route 2
PPh3 Br
O
:PPh3
nBuLi
Br
PPh3
Ch. 16 - 89
10B. 10B. The HornerThe Horner––WadsworthWadsworth––EmmonsEmmons ReactionReaction
P OEt
O
OEt
NaH
+ H2
P OEt
O
OEt
a phosphonateester
Ch. 16 - 90
+P OEt
O
OEt
H
O
EtO P O
O
EtONa+
84%
Ch. 16 - 91
P OEt
O
OEt
X
OEt
PEtO OEt
+
EtX +
Triethyl phosphite
The phosphonate ester is prepared by reaction of a trialkyl phosphite [(RO)3P] with an appropriate halide (a process called the Arbuzov reaction)
Ch. 16 - 92
11. Oxidation of Aldehydes
R H
O O
R O−
O
R OH
H3O+
KMnO4, OH−
or Ag2O, OH−
Ch. 16 - 93
12. Chemical Analyses for Aldehydes and Ketones
R
R'
O + NO2
O2N
N
H
H2N
R
R'
N
N
H
NO2
O2N
H+
hydrazine
hydrazone(orange ppt.)
12A. 12A. Derivatives of Aldehydes & KetonesDerivatives of Aldehydes & Ketones
Ch. 16 - 94
R H
O O
R O−
Ag(NH3)2+
H2O+ Ag
silvermirror
12B. 12B. TollensTollens’’ Test (Silver Mirror Test) Test (Silver Mirror Test)
Ch. 16 - 95
13. Spectroscopic Properties of Aldehydes and Ketones
13A. 13A. IR Spectra of Aldehydes and KetonesIR Spectra of Aldehydes and Ketones
Range (cm−1)
R CHO
Ar CHO
C C
CHO
C C
COR
RCOR
ArCOR
Compound Range (cm−1)Compound
Cyclohexanone
Cyclopentanone
Cyclobutanone
1715
1751
1785
1720 - 1740
1695 - 1715
1680 - 1690
1705 - 1720
1680 - 1700
1665 - 1680
C=O Stretching Frequencies
Ch. 16 - 96
Conjugation of the carbonyl group with a double bond or a benzene ring shifts the C=O absorption to lower frequencies by about 40 cm-1
O Osingle bond
Ch. 16 - 97
Ch. 16 - 98
13B. 13B. NMR Spectra of Aldehydes andNMR Spectra of Aldehydes and KetonesKetones
13C NMR spectra● The carbonyl carbon of an aldehyde
or ketone gives characteristic NMR signals in the δ 180–220 ppm region of 13C spectra
Ch. 16 - 99
1H NMR spectra● An aldehyde proton gives a distinct 1H
NMR signal downfield in the δ 9–12 ppm region where almost no other protons absorb; therefore, it is easily identified
● Protons on the α carbon are deshielded by the carbonyl group, and their signals generally appear in the δ 2.0–2.3 ppm region
● Methyl ketones show a characteristic (3H) singlet near δ 2.1 ppm
Ch. 16 - 100
Ch. 16 - 101
Ch. 16 - 102
14. Summary of Aldehyde and Ketone Addition Reactions
O
OH
R1. RM
2. H3O+
OH
H1. LiAlH4 or NaBH4
2. H3O+
OH
CN
1. NaCN
2. H3O+
RR PPh3
RO OR
2 ROH, H+
NR
R-NH2, H+
R2NH
H+
NR2
Ch. 16 - 103
END OF CHAPTER 16
Recommended