ACETALDEHYDE

1

Acetaldehyde

O

H

[75-07-0]

C

2

H

4

O

(MW 44.05)

InChI = 1/C2H4O/c1-2-3/h2H,1H3
InChIKey = IKHGUXGNUITLKF-UHFFFAOYAB

(reagent used as two-carbon electrophilic component in a wide

array of reactions)

Physical Data:

mp −123.5

◦

C; bp 21

◦

C; d 0.788 g cm

−3

.

Solubility:

sol H

2

O, alcohol, ether, and most organic solvents.

Form Supplied in:

colorless liquid; widely available.

Purification:

shaken with powdered NaHCO

3

for 30 min; dried

over CaSO

4

, and fractionally distilled at 760 mmHg through a

70 mm Vigreux column.

Handling, Storage, and Precautions:

bottles may develop pres-

sure and should be cooled before opening. To help prevent poly-
merization and autoxidation, store under nitrogen atmosphere
and refrigerate. Acetaldehyde is a cancer suspect agent and
should be used only in a well-ventilated fume hood. Toxicity
(oral) rat LD

50

: 661 mg kg

−1

. Incompatible with strong acids,

strong bases, oxidizing and reducing agents. Decomposes on
prolonged exposure to air.

1,2-Additions. Acetaldehyde reacts with a myriad of nucleo-

philic reagents, generally providing excellent yields of the two-
carbon extended secondary alcohols. Aryl-,

1

alkynyl-,

2

and

alkyllithiums

3

react rapidly with acetaldehyde even at low

temperature. A chiral vinyllithium reagent at low temperature
reacts stereoselectively to afford a 10:1 mixture of diastere-
omeric alcohols (eq 1).

4

Aryl

5

or alkyl

6

Grignard reagents behave

in an analogous manner with acetaldehyde to give the secondary
alcohols or the methyl ketones

7

upon subsequent oxidation.

Allyl organometallics react with varying degrees of stereocontrol
depending on the metal and conditions to give the correspond-
ing homoallylic alcohols.

8

Chiral allylboronates also react with

acetaldehyde at −78

◦

C to afford the homoallylic alcohols with

high enantioselectivity.

9

trans

-Epoxides are produced selectively

through the Darzens reaction of acetaldehyde with halomethyl
sulfones under basic phase transfer conditions.

10

Classical Wittig

reagents

11

and Horner–Emmons phosphonate

12

ylides react with

acetaldehyde to give the alkene.

Aldol Additions. Acetaldehyde serves as an electrophilic part-

ner in the aldol condensation with a wide array of enolates.

13

Knoevenagel condensation of acetaldehyde with active methylene
compounds in the presence of base provides good yields of the
ethylidene substituted compounds.

14

Addition of two equivalents

of an active methylene compound to acetaldehyde results in a
Michael addition of the second equivalent to the initially formed
ethylidene.

15

Tollens reaction of acetaldehyde with formalde-

hyde gives pentaerythritol.

16

The addition of acetaldehyde in

a Baylis–Hillman condensation with Ethyl Acrylate using 1,4-
Diazabicyclo[2.2.2]octane (DABCO) as catalyst gives a 90%

yield of the allylic alcohol.

17

The stereoselective aldol reaction

of acetaldehyde with achiral

18

and chiral

19

imide enolates has

received much attention and is a proven method for control-
ling acyclic relative and absolute stereochemistry.

13

For example,

the boron enolate of a norephedrine-derived propionyloxazoli-
dine reacts with acetaldehyde to afford in 90% yield and >98%
de the syn aldol product (eq 2).

19a

Acetaldehyde also smoothly

undergoes nitro-aldol condensation to the corresponding nitro
alcohols.

20

The lithium enolates of a variety of heterocycles react

with acetaldehyde to give good yields of product alcohols.

21

In

addition, the zinc,

22

copper,

23

and boron

24

enolates of esters and

ketones provide aldol products with acetaldehyde.

H

MEMO

Br

Br

H

MEMO

Br

HO

H

MEMO

Br

HO

10:1

+

(1)

n

-BuLi, THF

MeCHO

–105 °C

86%

N

O

O

Ph

O

O

OH

N

O

O

Ph

Bu

2

BOTf, Et

3

N

CH

2

Cl

2

, –78 °C

98% de

(2)

MeCHO

93%

Mannich and Mannich-type Reactions.

Although not as

commonly used as Formaldehyde, acetaldehyde undergoes many
synthetically useful Mannich reactions. Intramolecular Mannich
reaction of acetaldehyde has been utilized to produce the natural
product myrtine (eq 3).

25

The intramolecular Mannich reaction

has also been used in the synthesis of proline derivatives.

26

Nu-

cleophiles as diverse as dialkyl phosphites

27

and amines

28

or aryl

radicals

29

may also add to the intermediate imine of acetaldehyde

in Mannich-type reactions. A historically significant reaction of
acetaldehyde in this mode is the Strecker synthesis of alanine,
whereby cyanide is added to the adduct of ammonia and acetalde-
hyde followed by hydrolysis of the intermediate α-aminonitrile.

30

The Pictet–Spengler reaction utilizing acetaldehyde is an impor-
tant ring-forming reaction. Acetaldehyde has been extensively
used in the synthesis of the biolog ically active β-carbolines from
tryptophan derivatives through this cyclization.

31

Other ring sys-

tems such as tetrahydroisoquinolines

32

and dihydrooxazines

33

have also been formed employing Pictet–Spengler cyclization
with acetaldehyde.

NH

O

MeCHO

N

O

H

(3)

(+)-Myrtine

MeCO

2

H

Metal and Other Promoted Condensations. In the mixed

Tishchenko reaction using Aluminum Isopropoxide as promoter,
acetaldehyde is predominately the oxidized partner. Thus when
condensed with benzaldehyde, benzyl acetate is the major
product.

34

Recently an interesting and synthetically useful stere-

oselective intramolecular Tishchenko reduction of β-hydroxy ke-
tones using acetaldehyde and promoted by Samarium(II) Iodide,
affording anti-1,3-diol monoacetates, has been reported (eq 4).

35

The stereoselective pinacol cross-coupling of acetaldehyde with

Avoid Skin Contact with All Reagents

2

ACETALDEHYDE

other higher-order aldehydes that contain chelating functionali-
ties has been achieved using a vanadium(II) reagent.

36

The pho-

tochemical addition of acetaldehyde in the presence of molecular
oxygen to α,β-unsaturated esters and ketones provides excellent
yields of the 1,4-dicarbonyl compounds (eq 5).

37

O

OH

OH

AcO

( )

5

MeCHO

15% SmI

2

( )

5

>98 de

(4)

THF, –10 °C

96%

O

MeCHO

O

O

(5)

hν,

air

95%

Pericyclic Reactions. The thermal ene reactions of acetalde-

hyde and other aliphatic aldehydes with alkenes are generally
not very productive.

38

However, acetaldehyde can be induced

to undergo ene reactions with a variety of alkenes under Lewis
acid activation. Dimethylaluminum Chloride has been used to
promote the ene reaction between the relatively reactive 1,1-di-,
tri-, and tetrasubstituted alkenes (eq 6).

39

With the more unre-

active monosubstituted terminal alkenes, the more Lewis acidic
Ethylaluminum Dichloride must be employed to obtain reason-
able yields of ene products with acetaldehyde.

40

Acetaldehyde

is a relatively unreactive dieneophile towards dienes. The hetero-
Diels–Alder reaction of acetaldehyde has been reported under high
pressure acceleration with 1-alkoxydienes to afford good yields
of dihydropyrans with modest endo selectivity.

41

OH

Me

2

AlCl (1.5 equiv)

(6)

CH

2

Cl

2

, rt

65%

Paraldehyde and Other Acetaldehyde Derivatives. Paral-

dehyde has historically been used as a stabile and less volatile
form of acetaldehyde in a wide array of chemical reactions.

42

However, since its classification as a controlled substance, its re-
stricted availability has led to its limited use in modern synthetic
organic chemistry. Acetaldehyde can be generated from paralde-
hyde through acid catalyzed degradation of the trimer and iso-
lated by distillation.

43

The diethyl acetal of acetaldehyde, com-

monly known as acetal, may be generated from acetaldehyde or
paraldehyde, ethanol, and calcium chloride.

44

Acetaldehyde and

paraldehyde have also been used for the protection of diols as their
ethylidene acetals.

45

Related Reagents. Acetaldehyde N-t-Butylimine; Acetal-

doxime; Crotonaldehyde; Dimethylaluminum Chloride; Ethyl
Vinyl Ether; Formaldehyde; Formaldehyde–Dimethylamine;
Vinyl Acetate.

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A list of General Abbreviations appears on the front Endpapers

ACETALDEHYDE

3

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Thomas J. Sowin & Laura M. Melcher

Abbott Laboratories, Abbott Park, IL, USA

Avoid Skin Contact with All Reagents