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Created byProfessor William Tam & Dr. Phillis
Chang Ch. 16 - 1
Chapter 16Chapter 16
Aldehydes & Ketones:Aldehydes & Ketones:Nucleophilic AdditionNucleophilic Additionto the Carbonyl Groupto the Carbonyl Group
Ch. 16 - 2
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 - 3
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 - 4
Examples:Cl
H
O
4-Chloro-2,2-dimethylpentanal
12345
O
Br
12 3 4 5 6
7
6-Bromo-4-ethyl-3-heptanone
Ch. 16 - 5
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 - 6
2-Methanoylbenzoic acid(o-formylbenzoic acid)
CO2H
H
O
4-Ethanoylbenzenesulfonic acid(p-acetylbenzenesulfonic acid)
SO3H
O
Ch. 16 - 7
3. Physical Properties
Butanebp -0.5oC
(MW = 58)
H
O O
OH
Propanalbp 49oC
(MW = 58)
Propanonebp 56.1oC(MW = 58)
1-Propanolbp 97.2oC(MW = 60)
Comparison:
Ch. 16 - 8
4. Synthesis of Aldehydes
4A.4A. Aldehydes by Oxidation of 1Aldehydes by Oxidation of 1oo Alcohols:Alcohols:
R OHR H
OPCC
Ch. 16 - 9
OH O
H
PCC
CH2Cl2(90%)
PCC
CH2Cl2
OH O
H(89%)
e.g.
Ch. 16 - 10
4B.4B. Aldehydes by Ozonolysis ofAldehydes by Ozonolysis ofAlkenes:Alkenes:
R'
R
H
R"
O
R'
R
O
H
R"1. O3
2. Me2S+
Ch. 16 - 11
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 - 12
4C.4C. Aldehydes by Reduction of AcylAldehydes by Reduction of AcylChlorides, Esters, and Nitriles:Chlorides, Esters, and Nitriles:
LiAlH4R OH
O
R HLiAlH4
O
R OH
O
R OR'
O
R Cl
R C N
or
or
or
Not a good method for aldehydes.LiAlH4 is to reactive.
Ch. 16 - 13
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. Using LiAlH4 is not a good
method to synthesize aldehydes.
Ch. 16 - 14
Two derivatives of aluminum hydride that are less reactive than LiAlH4.
These are effective where LiAlH4 is not.
Lithium tri-tert-butoxyaluminum hydride
AlH
OtBu
AlLi+ H OtBu
OtBu
Diisobutylaluminum hydride(abbreviated i-Bu2AlH or DIBAL-H)
For acid chlorides For esters and nitriles
Ch. 16 - 15
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 - 16
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 - 17
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 - 18
Aldehydes from esters and nitriles:
RCO2R’ RCHORC≡N RCHO
●Both esters and nitriles can be reduced to aldehydes by DIBAL-H.
Ch. 16 - 19
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 - 20
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 - 21
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 - 22
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 - 23
Examples:
1. O3
2. Me2S
O
O
(i)
OO
H
+
(ii)1. O3
2. Me2S
Ch. 16 - 24
Ketones from arenes by Friedel–Crafts acylations.
O
R Cl
AlCl3 R
O
+ HCl+
an alkyl arylketone
Ch. 16 - 25
Ketones from secondary alcohols by oxidation.
OH
R R'
O
R R'
H2CrO4
or PCC
Ch. 16 - 26
5B.5B. Ketones from Nitriles:Ketones from Nitriles:
R C N1. R' M, Et2O
N M
R'R
2. H3O+
O
R'R
Ch. 16 - 27
Examples:
C N
O
Me1. MeLi, Et2O
2. H3O+
C N1. , Et2O
2. H3O+
MgBr
O
Ch. 16 - 28
Suggest synthesis of:
O
from andBr
HO
Ch. 16 - 29
Retrosynthetic analysis:
O
HO
need to add one carbon
5 carbons here 4 carbons here
Ch. 16 - 30
Retrosynthetic analysis:O
C
MgBr
N+
NC
Br
+
HO
disconnection
disconnection
Ch. 16 - 31
Synthesis:
O
HO Br
CN
PBr3
NaCNDMSO
1.
2. H3O+
Et2O
MgBr
Ch. 16 - 32
Suggest synthesis of:
O
from andBr
HO
Ch. 16 - 33
Retrosynthetic analysis:
O
HO
no need to add carbon
5 carbons here
5 carbons here
Ch. 16 - 34
Retrosynthetic analysis:
O
MgBr
+H
O
HO
disconnection
Ch. 16 - 35
Synthesis
O
PCC
2. H3O+
1. , Et 2O
MgBr
HO O
OH
PCC
Ch. 16 - 36
6. Nucleophilic Addition to theCarbon–Oxygen Double Bond
Structure:O
C
~ 120o
~ 120o
~ 120o
●Carbonyl carbon: sp2 hybridized
●Trigonal planar structure
Nu⊖
Ch. 16 - 37
Polarization and resonance structure:
C
O
O
C
●Nucleophiles will attack the nucleophilic carbonyl carbon.
●Note: nucleophiles usually do not attack non-polarized C=C bond.
Ch. 16 - 38
With a strong nucleophile:
C O
R
R'
Nu: C O:
R
R'
Nu
H Nu
C O
R
R'
Nu
HNu: +
Ch. 16 - 39
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 - 40
+ A:C OH
R
R'
C OH
R
R'
Mechanism:
C O
R
R'
H A+
(or a Lewis acid)
Ch. 16 - 41
+ 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 - 42
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 - 43
6B.6B. Relative Reactivity: AldehydesRelative Reactivity: Aldehydesvs. Ketonesvs. Ketones
O
R H
O
R R'
O
R OR'> >
Ch. 16 - 44
large
small
O
R H
O
RNu
H
Nu
O
R R'
O
RNu
R'
Nu
Steric factors:
Ch. 16 - 45
O
CR H
O
CR R'
Electronic factors:
(positive inductive effect from only one R group)
(positive inductive effect from both R & R' groups) carbonyl carbon less + (less nucleophilic)
Ch. 16 - 46
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 - 47
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 - 48
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 - 49
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 - 50
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 - 51
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 - 52
Aldehyde hydrates: gem-diols
H2O+O
H
H3C
H
H3C O
O
H
H
Acetaldehyde Hydrate(a gem-diol)
Ch. 16 - 53
C O
H
H3C OH2
Mechanism:
OH2H3C
O:H
OHH3C
OHH
OHHO
HR
O
R H+ H2O
distillation
Ch. 16 - 54
HO
O
O
O
O
OH
H
Butanal-4-ol
A cyclichemiacetal
Hemiacetal: OH & OR groups bonded to the same carbon
7A.7A. Hemiacetals:Hemiacetals:
Ch. 16 - 55
(+)-Glucose(A cyclic hemiacetal)
OHO
HO OH
OH
OH Hemiacetal: OH & OR groups bonded to the same carbon
Example:
Ch. 16 - 56
Sucrose(table sugar)
O
O
OHO
OH
HOHO
OHHO
OH
OHAn acetal
A ketal
7B.7B. Acetals:Acetals:
Ch. 16 - 57
+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.
Protective group for aldehydes and ketones.
Ch. 16 - 58
+
O
R R'
HOOH
H3O+
O O
R R'
+ H2O
This reaction, too, can be reversed by treating the acetal with aqueous acid.
Cyclic acetals and thioacetalsare good protecting groups foraldehydes and ketones.
Ch. 16 - 59
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 - 60
O
OH
Br
O
Attempt to synthesize:
from:
Example:
Ch. 16 - 61
O
O
OH
BrMg
O
+
●Synthetic plan:
This route will not work
Ch. 16 - 62
BrMg
O
Reason:(a) Intramolecular nucleophilic
addition.
(b) Homodimerization or polymerization.
BrMg
O
BrMg
O
BrMg
O
Ch. 16 - 63
Br
O O
HO
Thus, need to “protect” carbonyl group first:
Br
O O
HOOH
, H+
(ketal)
BrMg
O O
MgEt2O
O
OMgBr
O O
aqueous H+
Ch. 16 - 64
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 - 65
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 - 66
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 - 67
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 - 68
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 - 69
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 - 70
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 - 71
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 - 72
8C.8C. EnaminesEnamines
N R5+
N
+ H2O
2o amine
cat. HAO
C R3
R2H
R1
R4
H
R4 R5
enamine
R3R1
R2
Ch. 16 - 73
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 - 74
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 - 75
C
H
C
N
R
R
A:
Mechanism (Cont’d):
enamine
C
H
CN
R
R
+ H A
Ch. 16 - 76
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 - 77
R R'
OCN
Mechanism:
O
RR'
CN(slow)
NC H
OH
RR'
CN
Ch. 16 - 78
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 - 79
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
(-hydroxy acid)
(,-unsaturated acid)
(-aminoalcohol)
Synthetic applications of cyanaohydrin:
Ch. 16 - 80
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 - 81
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
Ylide preparation:
Ch. 16 - 82
Example:
(C6H5)3P CH3(C6H5)3P: Br+
Methyltriphenylphos-phonium bromide
(89%)
CH3BrC6H6
(C6H5)3P CH3
Br
+ C6H5Li (C6H5)3P CH2:
+ + LiBrC6H6
Ch. 16 - 83
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 - 84
10A. 10A. How to Plan a Witting SynthesisHow to Plan a Witting Synthesis
Synthesis of
using a Wittig reaction.
Ch. 16 - 85
Retrosynthetic analysis:
disconnection
O
Ph3P+route 1
BrPh3P: +route 2
PPh3
O+
Br
+ :PPh3
Ch. 16 - 86
Synthesis – Route 1:
O
Ph3PBr:PPh3
Br
nBuLi
Ph3P
Ch. 16 - 87
Synthesis – Route 2:
PPh3 Br
O
:PPh3
nBuLi
Br
PPh3
Ch. 16 - 88
11.Oxidation of Aldehydes
R H
O O
R O
O
R OH
H3O+
KMnO4, OH
or Ag2O, OH
Ch. 16 - 89
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 & Ketones:Derivatives of Aldehydes & Ketones:
Ch. 16 - 90
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 - 91
R H
O O
R O
Cu tartarate
NaOH, H2O+ Cu2O
red ppt.
12C. Fehlings12C. Fehlings’’ Test (Red precipitate) Test (Red precipitate)
Ch. 16 - 92
13.Spectroscopic Properties of Aldehydes and Ketones
13A. 13A. IR Spectra of Aldehydes and KetonesIR Spectra of Aldehydes and Ketones
Range (cm )
R CHO
Ar CHO
C C
CHO
C C
COR
RCOR
ArCOR
Compound Range (cm )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 - 93
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 - 94
Infra-red:
Ch. 16 - 95
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 180–220 ppm region of 13C spectra.
Ch. 16 - 96
1H NMR spectra:● An aldehyde proton gives a distinct
1H NMR signal downfield in the 9–12 ppm region where almost no other protons absorb; therefore, it is easily identified.
● Protons on the carbon are deshielded by the carbonyl group, and their signals generally appear in the 2.0–2.3 ppm region.
● Methyl ketones show a characteristic (3H) singlet near 2.1 ppm.
Ch. 16 - 97
Proton (H1) NMR:
Ch. 16 - 98
Broadband C13 NMR:
Ch. 16 - 99
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 - 100
END OF CHAPTER 16
