Chapter 19.

Aldehydes and
Ketones: Nucleophilic
Addition Reactions
醛 與 酮 : 親核加成反應

Based on McMurry’s Organic Chemistry, 9th edition

 Aldehydes and Ketones
 Aldehydes (RCHO) and ketones (R2CO) are characterized
by the the carbonyl functional group (C=O)
 The compounds occur widely in nature as intermediates in
metabolism and biosynthesis

coenzyme steroid hormone

2
Why this Chapter?
 Much of organic chemistry involves the
chemistry of carbonyl compounds

 Aldehydes/ketones are intermediates in

synthesis of pharmaceutical agents, biological
pathways, numerous industrial processes

 An understanding of their properties is

essential

3
Kinds of Carbonyl Compounds
CH 19

 Nucleophilic Addition
Reaction

CH 20 , CH 21 ,

 Nucleophilic Substitution
Reaction

4
5
 Nature of Carbonyl Group
 Carbon is sp2 hybridized.
 C=O bond is shorter, stronger, and more
polar than C=C bond in alkenes.

C ＝ C 雙鍵是非極性
的，而 C ＝ O 是極性
雙鍵。

6
* Structure of Carbonyl Group

•The double bond of the carbonyl group has a large

dipole moment because oxygen is more electronegative
than carbon, and the bonding electrons are not shared
equally. 由於氧原子的電負度較大，使電子雲偏向電負度較大的氧，羰基化合
物都具有偶極矩。
 Structure of Acetaldehyde

8
*
Reactivity of Carbonyl Group
•The polarization ( 極化 ) of carbonyl group contribute to
the reactivity of aldehyde and ketone
•Carbonyl carbon carries a partial positive charge

• Is an electrophilic site, and react with nucleophiles

• Carbonyl oxygen carries a partial negative charge

• Is an nucleophilic site, and react with electrophiles

+ –
C O
C act as electrophile O act as nucleophile
(Lewis acid) (Lewis base)

(nucleophilic addition)
9
19.1 Naming Aldehydes and Ketones
 Aldehydes are named by replacing the terminal -e
of the corresponding alkane name with –al
 The parent chain must contain the CHO group
 The CHO carbon is numbered as C1

(Acet-ic acid) (Propion-ic acid)

10
 Naming Aldehydes and Ketones
• If the CHO group is attached to a ring, use the
suffix carbaldehyde

11
 Common Names of Aldehyde
• Use the common name of the acid.
• Drop -ic acid and add -aldehyde
• 1 C: formic acid, formaldehyde
• 2 C’s: acetic acid, acetaldehyde
• 3 C’s: propionic acid, propionaldehyde
• 4 C’s: butyric acid, butyraldehyde

甲醛
乙醛
丙烯醛

β- 甲基丙烯醛

苯甲醛

12
Naming Ketones
 Replace the terminal -e of the alkane name with –one
 Parent chain is the longest one that contains the
ketone group
 Numbering begins at the end nearer the carbonyl
carbon

13
 Ketones with Common Names
 IUPAC retains well-used but unsystematic names for
a few ketones

丙酮 苯乙酮 二苯基酮

14
 Ketones and Aldehydes as Substituents
 The R–C=O as a substituent is an acyl group, used with the
suffix -yl from the root of the carboxylic acid
 CH3CO: acetyl; CHO: formyl; C6H5CO: benzoyl

(Acet-ic acid) (Form-ic acid) (Benzo-ic acid)

醯基 乙醯基 甲醯基 苯甲醯基
• The prefix oxo- is used if other functional groups are
present and the doubly bonded oxygen is labeled as a
substituent on a parent chain

15
 醛酮的製備
水合
1 HgSO4, H2O , H2SO4
2 Hydroboration-Oxidiation Friedel-Crafts
Ozonolysis acylation

烯 炔 ( 末端 ) 芳香族化合

醇 醛 酮 羧酸衍生物
Reduction
Oxidation

organometallic reagent
16
19.2 Preparation of Aldehydes and Ketones
Preparing Aldehydes
 Oxidize primary alcohols using Dess-Martin periodinane (Section 17.7)
 Alkenes with a vinylic hydrogen can undergo oxidative cleavage when
treated with ozone, yielding aldehydes (Section 8.8)
 Ester can be partially reduced with mild reducing agent
diisobutylaluminum hydride (DIBAH or DIBAL) to yield
aldehydes(Section 21.6)

DMP
10 alcohol
17
Preparation of Aldehydes

DIBAL

diisobutylaluminum hydride
18
 Preparing Ketones
 Oxidization of a secondary alcohol
(Section 17.7)
 Choice of oxidant is based on factors such as:
 Scale
 Cost
 Acid/base sensitivity of the alcohol
 Dess–Martin periodinane or a Cr(VI) reagent
are a common choice

20 alcohol
 Ketones from Ozonolysis
 Ozonolysis of alkenes yields ketones if one of the
unsaturated carbon atoms is disubstituted (Section
8.8)

20
Aryl Ketones by Acylation
3. Friedel–Crafts acylation of an aromatic ring with an
acid chloride in the presence of AlCl3 catalyst.
(Section 16.3)

21
 Preparing Ketones

• Acid chloride with organocupper reagent

(Gilman reagent , Section 21..4)

 Methyl Ketones can be prepared with hydration of terminal

alkynes in the presence of Hg2+ (catalyst: Section 8.4)

22
 19.3 Oxidation of Aldehydes and Ketones

 Aldehyde are easily oxidized to carboxylic acids

 ketones are generally inert toward oxidation

23
 Oxidation of Aldehydes
 Aldehydes oxidize to yield carboxylic acids
 CrO3 in aqueous acid oxidizes aldehydes to
carboxylic acids efficiently

 Aldehyde oxidations occur through

intermediate 1,1-diols, or hydrates
 Ketones Oxidize with Difficulty
 ketones Inert to most oxidizing agents
 ketones Undergo slow cleavage with hot, alkaline KMnO4
 C–C bond next to C=O is broken to give carboxylic acids
 Reaction is practical for cleaving symmetrical ketones

O OH O
HN O 3 HO
OH
O
Cyclohexanone Cyclohexanone Hexanedioic acid
(keto form) (enol form) (Adipic acid)
25
 Reaction of Aldehydes and Ketones
• There are three regions of reactivity in
aldehydes and ketones (2) attack by electrophile
(H+)
O

α C
C
H
R (1) attack by nucleotrophile
(NaBH4, RMgX) (CH 19)
(3) α-carbon with acidic H
, enolate (CH 22, CH 23)

醛、酮的三大類主要化學反應 :
親核加成反應、 α － H 的反應、氧化還原反應
26
 醛酮的化學性質
 醛酮的結構對化學性質的影響

 
C O C O
 在羰基中，由於 π 鍵的極化，使得氧原子上帶部分負電荷，碳原子上帶部分
正電荷。因此反應中心是羰基中帶正電荷的碳。所以羰基碳易受帶負電荷的
或具有未共用電子對的中性分子的進攻，這類進攻試劑具有親正電性，即對
帶正電荷的中心碳具有親合力，因此，稱作親核試劑（ Nucleophile) 。而
由親核試劑進攻而引發的加成反應，在有機化學中稱做親核加成反應
（ Nucleophilic addition ）。

27
19.4 Nucleophilic Addition Reactions of
Aldehydes and Ketones
Nucleophilic Addition Reactions 親核加成反應 :
A nucleophile ,Nu-, adds to the electrophilic carbon of the
carbonyl group

28
 Nucleophilic Addition Reactions of
Aldehydes and Ketones
 Two general reaction pathways following addition of
a nucleophile to an aldehyde or ketone.
 Alcohol product : a direct result of the tetrahedral

intermediate being protonated by water or acid

 C=Nu product: carbonyl oxygen atom is protonated
and eliminated as HO- or H2O to give a product with
a C=Nu double bond
Formation of Alcohol

30
 Formation of C=Nu
Formation of Imine 亞胺 , R2C=NR’, by reaction of an amine
with an aldehyde or a ketone

31
 Nucleophilic Addition Reactions 親核加成反應 of
Aldehydes and Ketones
Mechanism:
 Nu- approaches 75° to the plane of C=O and adds to C
 A tetrahedral alkoxide ion intermediate is produced

32
 Nucleophiles
 Nucleophiles can be negatively charged ( : Nu) or
neutral ( : Nu) at the reaction site

Strong
: Nu

Weak
: Nu

Strong
: Nu

33
 Relative Reactivity of Aldehydes and Ketones
 Aldehydes are generally more reactive than ketones in
nucleophilic addition reactions
 steric effect and electronic effect

 The transition state for addition is less crowded and

lower in energy for an aldehyde than for a ketone
 Aldehydes have one large substituent bonded to the
C=O: ketones have two
•steric effect
Aldehydes less sterically hindered than ketones

aldehyde
ketones 34
 Electrophilicity of Aldehydes and Ketones
 Aldehyde C=O is more polarized than ketone C=O
 As in carbocations, more alkyl groups stabilize + character
 Ketone has more alkyl groups, stabilizing the C=O carbon
inductively
 electronic effect
C=O of aldehyde less stabilized than C=O of ketone

35
 Reactivity of Aromatic Aldehydes
 Less reactive in nucleophilic addition reactions than
aliphatic aldehydes
 Electron-donating resonance effect of aromatic ring
makes C=O less reactive electrophile than the
carbonyl group of an aliphatic aldehyde

36
19.5 Nucleophilic Addition of H2O: Hydration 水合
 Aldehydes and ketones react with water to yield 1,1-diols (geminal
(gem) diols)( hydrate 水合物 )
 Hyrdation is reversible: a gem diol can eliminate water
 Position of the equilibrium depends on structure of carbonyl
compound

K= 0.002

K= 40

O - O - O -
Reactivity: C  < C 
< C 
R R R H H H
ketone Aldehyde formaldehyde
two alkyl groups less stable relatively unstable
more stable more reactive very reative
Less reactive 37
 Base-Catalyzed Addition of Water
 Addition of water is catalyzed by both acid and base
 The base-catalyzed hydration, nucleophile is the
hydroxide ion,
 a much stronger nucleophile than water
In base,
Mechanism: hydroxide is
the nucleophile
Strong
: Nu

38
Acid-Catalyzed Addition of Water
 Protonation of C=O makes it more electrophilic
 nucleophile is H2O

Mechanism:

In acid, water is
the nucleophile
Weak
: Nu

39
 Addition of H-Y to C=O
 Reaction of C=O with nucleophile H-Y gives an addition product
 Y is electronegative, and can stabilize a negative charge

 Formation is readily reversible

 Alcohol addition product is not stable

nucleophile

addition product

40
 19.6 Nucleophilic Addition of HCN: Cyanohydrin 氰醇
Formation
 Cyanohydrins: Product of nucleophilic reaction between aldehydes and unhindered ketones with HCN, RCH(OH)CN
 Addition of hydrogen cyanide HCN ( 氰化氫 )is reversible and base-catalyzed, generating nucleophilic cyanide ion, CN-
 Addition of CN ( 氰化物 ) to C=O yields a tetrahedral intermediate, which is then protonated
 Equilibrium favors adduct

41
 Uses of Cyanohydrins 氰醇
 The nitrile group 腈基 (CN) can be reduced with
LiAlH4 to yield a primary amine (RCH2NH2)
 Can be hydrolyzed by hot acid to yield a carboxylic acid

(CH20.7)

(CH20.7)

42
 19.7 Nucleophilic Addition of Hydride Reagents and
Grignard Reagents : Alcohol Formation
 Addition of hydride reagents: Reduction
 Alcohols can be prepared by reduction of carbonyl

compounds (Section 17.4)

 Aldehydes reduced using NaBH yields 1° alcohols
4
Ketones are reduced in using similar methods to
give 2° alcohols
 Carbonyl reduction occurs by typical nucleophilic
addition mechanism under basic conditions
Nucleophilic Addition of Hydride Reagents : Alcohol
Formation

 LiAlH4 and NaBH4 react as donors of hydride ion

 Protonation after addition yields the alcohol
 Reaction is effectively irreversible
19.7 Nucleophilic Addition of and Grignard Reagents :
Alcohol Formation
 Treatment of aldehydes or ketones with Grignard
reagents yields an alcohol (Section 17.5)
 Nucleophilic addition of the equivalent of a carbon
anion, or carbanion. A carbon–magnesium bond is
strongly polarized, so a Grignard reagent reacts for all
practical purposes as R :  MgX +.

45
 Mechanism of Addition of Grignard Reagents
 Complexation of C=O by MgX+, Nucleophilic addition of
R : , protonation by dilute acid yields the neutral alcohol
 Grignard additions are irreversible because a carbanion
is not a leaving group

46
 19.8 Nucleophilic Addition of Amines: Imine
and Enamine Formation
 1o amine, RNH2,, adds to C=O to form imines 亞胺 , R2C=NR
(after loss of HOH)
 2o amine, R2NH, yields enamines 烯胺 , R2NCR=CR2 (after
loss of HOH) (ene + amine = unsaturated amine)

1o amine 2o amine

• Imines are common as intermediates in biological pathways,

and are called Schiff bases
47
 Mechanism of Formation of Imines
 1o amine adds to C=O
 Proton is lost from N and adds to O to yield a neutral amino alcohol
(carbinolamine)
 Protonation of OH converts into water as the leaving group
 Result is iminium ion, which loses proton

pH Dependence of imine formation, an acid catalyst is
required in step 3 to protonate the intermediate
carbinolamine
 If enough acid is not present, the reaction is slow
 If too much acid is present, the basic amine nucleophile is
completely protonated
 Optimum pH is around 4.5
控制適當的 pH 值，使 OH H2O 離去。而 amine 不會質子化，
維 持親核性

48
Mechanism of Formation of Imines

1o amine

The key step is

nucleophilic addition to
yield a carbinolamine
intermediate, which then
loses water to give the
imine.
Mechanism of Formation of Imines
 Imine Derivatives 亞胺衍生物
 Addition of amines with an atom containing a lone pair of
electrons on the adjacent atom(N or O) occurs very readily,
giving useful, stable imines
 hydroxylamine 羥胺 forms oximes 肟
 2,4-dinitrophenylhydrazine 聯胺 readily forms 2,4-
dinitrophenylhydrazones 腙 (DNP)
 These are usually solids and help in purifying and characterizing
liquid ketones or aldehydes by melting points (mp)

亞胺衍生物應用： 1. 醛酮鑑定 2. 醛酮純化

51
 Imine Derivatives

(solid)
• DNP test for carbonyl compounds
(DNP)

腙
DNP (solid) 52
 Enamine Formation

 Identical to imine formation up to the iminium

ion stage
 After addition of 2o amine R2NH and loss of
water, proton is lost from adjacent carbon

Yields an enamine 烯胺
Enamine Formation

2o amine
Enamine Formation
1o amine

2o amine
 19.9 Nucleophilic Addition of Hydrazine: The
Wolff–Kishner Reduction Reaction

Treatment of an aldehyde or ketone with hydrazine, H2NNH2
and KOH converts the compound to an alkane

Reduction of R2C=O to R2CH2
 More useful than catalytic hydrogenation

57
Mechanism
Mechanism
 19.10 Nucleophilic Addition of Alcohols:
Acetal Formation
 Aldehydes and ketones react reversibly with 2 equivalents
of an alcohol in the presence of an acid catalyst to yield
acetals, R2C(OR’)2 縮醛
 Called ketals if derived from a ketone

 Under acidic conditions reactivity of the carbonyl group is

increased by protonation, so addition of an alcohol occurs
rapidly
 Nucleophilic Addition of
Alcohols: Acetal Formation

 Nucleophilic addition of 1 equivalents of an

alcohol to the carbonyl group initially yields a
hydroxy ether called a hemiacetal 半縮醛
 Formed reversibly
 Reaction can be driven either forward or
backward depending on the conditions
 Addition of Alcohols- Acetal

Acetal 縮醛 : a molecule containing two -OR

or -OAr groups bonded to the same carbon
 Addition of Alcohols-Hemiacetal

Hemiacetal 半縮醛 : a molecule containing

an -OH and an -OR or -OAr bonded to the
same carbon
 Mechanism
 Must be acid-catalyzed.
 Adding H+ to carbonyl makes it more reactive with
weak nucleophile, ROH.
 Hemiacetal( 半縮醛 ) forms first, then acid-catalyzed
loss of water, then addition of second molecule of
ROH forms acetal( 縮醛 ).
 All steps are reversible.

醛酮與一分子醇反應得到的産物叫半縮醛（ hemiacetal ）
醛酮與兩分子醇反應得到的産物叫縮醛（ acetal ）
縮醛反應是親核加成反應，為可逆反應
醇的親核能力較弱，需要在酸催化下才能與醛酮反應。
64
 ROH  Weak :Nu

 中度 electrophile 強 electrophile

65
 Mechanism for Hemiacetal
• addition of first molecule of ROH forms hemiacetal (reversible)

O + OH OH

H+ +

H
OH HO OCH3
HO OCH3
+
+ HOCH3 HOCH3 +
+ H2OCH3

hemiacetal 66
 Hemiacetal to Acetal
•acid-catalyzed loss of water, then addition of second molecule
of ROH forms acetal (reversible)
H
+ OCH3
HO OCH3 HO OCH3
+
H+ + HOH

(OH- poor (H2O good

leaving group) leaving group)
HOCH3
H
OCH3 +
CH3O OCH3 CH3O OCH3
+
HOCH3

acetal
67
68
 Cyclic Acetals
 Addition of a diol produces a cyclic acetal.
 The reaction is reversible.
 This reaction is used in synthesis to protect carbonyls
from reaction.

(a cyclic acetal)

69
 Uses of Acetals
 Acetals can serve as protecting groups for aldehydes
and ketones
 It is convenient to use a diol, to form a cyclic acetal

縮醛的應用：保護醛酮

70
 19.11 Nucleophilic Addition of Phosphorus Ylides:
The Wittig Reaction
 Conversion of aldehydes and ketones into alkenes
by means nucleophilic addition
 The Wittig reaction is a very useful synthetic
method for the synthesis of alkenes(C=C) from
aldehydes and ketones (C=O).
 Phosphorus Ylides 磷偶極體
 The phosphorus stabilized carbanion is an ylide - a molecule
that bears no overall charge but has a negatively charged
carbon atom bonded to a positively charged heteroatom (P or
S).
ylide 亞烷基化物或偶極體 : 相鄰原子上有相反電荷的中性分子。一種電荷中性
的分子 , 此分子含有一負電性碳相鄰於一正電性異原子上 。在 phosphorus
ylide 中碳負離子被正電荷的磷穩定。

• Formation of phosphorus ylide is shown below

pKa = 22.4
三苯磷
72
 Nucleophilic Addition of Phosphorus Ylides: The
Wittig Reaction
 Triphenylphosphorus ylide adds to an aldehyde or
ketone to yield a dipolar intermediate, betaine , and
futher form a four-membered cyclic intermediate called
an oxaphosphetane
 The oxaphosphetane intermediate spontaneously
decomposes to give an alkene plus triphenylphosphine
oxide 氧化三苯磷 , (Ph)3P=O
 Mechanism for Wittig Reaction
Driving force of wittig reaction: Ph3PPh3PO
triphenylphosphine oxide(Ph3PO) is very stable,

74
 Uses of the Wittig Reaction
 For comparison, addition of CH3MgBr to cyclohexanone
and dehydration with, yields a mixture of two alkenes

75
 Wittig Reaction
+ -
O + Ph3P CH2 CH2
85%

反應特點：合成特定結構的烯烴 , 雙鍵的位置由 C=O 和 phosphorus ylide 決定

Synthesis target retroanalysis:

CH3 CH2CH3 CH3
CH2CH3
C C (A) C O + + -C
Ph3P
CH3 H H
CH3
Synthesis: CH3
CH2CH3
1. Ph3P
CH3CH2CH2Br
+ - C O
Ph3P C CH3
2. BuLi H
1o RX

CH3 CH2CH3
C C (A)
CH3 H
76
77
 19.12 Biological Reductions
 Cannizzaro reaction: Exception reaction
 Nucleophilic addition of OH- to an aldehyde to give a
tetrahedral intermediate, which expels hydride ion as a
leaving group and is thereby oxidized
 A second aldehyde molecule accepts the hydride ion in

another nucleophilic addition step and is thereby reduced

 resulting in a simultaneous oxidation and reduction

(disproportionation)
 Mechanism of Biological Aldehyde and Ketone
Reductions
• Cannizzaro reaction is rarely used, except in biological reducing agents
NADH.
 19.13 Conjugate Nucleophilic Addition to
-Unsaturated Aldehydes and Ketones
 1,2-addition: Addition of a nucleophile directly to the
carbonyl group
 Conjugate addition (1,4-addition): Addition of a
nucleophile to the C=C double bond of an -
unsaturated aldehyde or ketone
 1,2-Addition and 1,4-Addition
,-unsaturated
carbonyl
compound

 When attack occurs at the carbonyl group, protonation of the oxygen

leads to a 1,2-addition.

• When attack occurs at the  position, the oxygen atom is the

fourth atom counting from the nucleophile, and the addition
is called a 1,4-addition.
• Activated doubled bond act as electrophile,
• nucleophilic addition can occur

• Unactivated doubled bond act as nucleophile,

• nucleophilic addition reaction would not occur .
 1,2-Addition or 1,4-Addition

• -Unsaturated aldehyde or ketone

• Nucleophile for 1,4-addition(conjugate addition )
• amine ,H2O, R2CuLi
• Nucleophile for 1,2-addition
• RMgX, RLi

83
 Conjugate Addition of Amines
 Primary and secondary amines add to , -
unsaturated aldehydes and ketones to yield -amino
aldehydes and ketones

84
 Conjugate Addition of Water
 Conjugate addition of water
 Yields -hydroxy aldehydes and ketones, by adding reversibly to
-unsaturated aldehydes and ketones

• Citric acid cycle 檸檬酸循環 of metabolism

85
 Conjugate Addition of Alkyl Groups:
Organocopper Reactions
 Reaction of an , -unsaturated ketone with a lithium
diorganocopper reagent, R2CuLi
 Diorganocopper (Gilman) reagents form by reaction of 1

equivalent of cuprous iodide and 2 equivalents of

organolithium

-
R2CuLi

organocuprate

86
 Conjugate Addition of Alkyl Groups:
Organocopper Reactions

R2CuLi, 1, 2, 3 alkyl, aryl and alkenyl groups react but not
alkynyl groups

R2CuLi  conjugate addition (1,4-addition)
 RMgX, RLi  1,2-addition

1,2-addition

1,4-addition

87
Mechanism of Alkyl Conjugate Addition
 Conjugate nucleophilic addition of a diorganocopper anion,
R2Cu, to an enone
 Transfer of an R group and elimination of a neutral
organocopper species, RCu

oxidative reductive
addition elimination

88
 19.14 Spectroscopy of Aldehydes and Ketones
 Infrared Spectroscopy
 Aldehydes and ketones show a strong C=O
peak from 1660 to 1770 cm-1
 Aldehydes show two characteristic C–H
absorptions in the 2720 to 2820 cm-1 range
 The bond’s force constant is lowered as a
result of delocalization of vinyl/aryl groups
 Lowers vibrational frequency
 Angle strain in the carbonyl group raises the
absorption position
Infrared spectra of (a) benzaldehyde
and (b) cyclohexanone
Infrared Absorptions of Some
Aldehydes and Ketones
 NMR Spectra of Aldehydes
 Aldehyde proton signals are at  10 in 1H NMR
 distinctive spin–spin coupling with protons on the

neighboring carbon, J  3 Hz

92
13
C NMR of C=O
 Carbonyl-group carbon atoms of aldehydes and
ketones signal is at 190  to 215 
 No other kinds of carbons absorb in this range

93
Mass Spectrometry – McLafferty
Rearrangement
 Aliphatic aldehydes and ketones that have hydrogens
on their gamma () carbon atoms rearrange as shown

94
Mass Spectroscopy: -Cleavage
 Cleavage of the bond between the carbonyl group
and the  carbon
 Yields a neutral radical and an oxygen-containing
cation

95
Mass spectrum of 5-methyl-2-hexanone
 Summary

 Most common general reaction type for aldehydes

and ketones is nucleophilic addition reaction
 Addition of HCN to aldehydes and ketones yields
cyanohydrins
 Primary amines add to carbonyl compounds
yielding imines, or Schiff bases, and secondary
amines yield enamines
 Wolff-Kishner reaction is the reaction of an
aldehyde or a ketone with hydrazine and base to
give an alkane
 Summary

 Acetals, valuable protecting groups, are

produced by adding alcohols to carbonyl
groups
 Phosphorus ylides add to aldehydes and
ketones in the Wittig reaction to give alkenes
 -unsaturated aldehydes and ketones react
with nucleophiles to give product of conjugate
addition, or 1,4-addition