Acetaldehyde
[75-07-0] · C2H4O
· Acetaldehyde · (MW 44.05)
(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 H2O,
alcohol, ether, and most organic solvents.
Form Supplied in: colorless liquid; widely available.
Purification: shaken with powdered NaHCO3
for 30 min; dried over CaSO4,
and fractionally distilled at 760 mmHg through a 70 mm Vigreux
column.
Handling, Storage, and Precautions: bottles may
develop pressure and should be cooled before opening. To help
prevent polymerization 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 LD50:
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 nucleophilic reagents,
generally providing excellent yields of the two-carbon extended
secondary alcohols. Aryl-,1
alkynyl-,2 and alkyllithiums3
react rapidly with acetaldehyde even at low temperature. A
chiral vinyllithium reagent at low temperature
reacts stereoselectively to afford a 10:1 mixture of diastereomeric
alcohols (eq 1).4 Aryl5
or alkyl6 Grignard
reagents behave in an analogous manner with acetaldehyde to
give the secondary alcohols or the methyl ketones7
upon subsequent oxidation. Allyl organometallics react with
varying degrees of stereocontrol depending on the metal and
conditions to give the corresponding 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 reagents11 and
Horner-Emmons phosphonate12 ylides
react with acetaldehyde to give the alkene.
Aldol Additions.
Acetaldehyde serves as an electrophilic partner 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 formaldehyde 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 achiral18
and chiral19 imide enolates has
received much attention and is a proven method for controlling
acyclic relative and absolute stereochemistry.13
For example, the boron enolate of a norephedrine-derived propionyloxazolidine
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 boron24 enolates of esters
and ketones provide aldol products with acetaldehyde.
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
Nucleophiles as diverse as dialkyl phosphites27
and amines28 or aryl radicals29
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 acetaldehyde followed by hydrolysis of the intermediate
a-aminonitrile.30
The Pictet-Spengler reaction utilizing acetaldehyde is an
important ring-forming reaction. Acetaldehyde has been
extensively used in the synthesis of the biologically active
b-carbolines from tryptophan derivatives
through this cyclization.31 Other
ring systems such as tetrahydroisoquinolines32
and dihydrooxazines33 have also
been formed employing Pictet-Spengler cyclization with acetaldehyde.
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 stereoselective intramolecular
Tishchenko reduction of b-hydroxy
ketones 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
other higher-order aldehydes that contain chelating functionalities
has been achieved using a vanadium(II) reagent.36
The photochemical addition of acetaldehyde in the presence
of molecular oxygen to a,b-unsaturated
esters and ketones provides excellent yields of the 1,4-dicarbonyl
compounds (eq 5).37
Pericyclic Reactions.
The thermal ene reactions of acetaldehyde 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
unreactive monosubstituted terminal alkenes, the more Lewis
acidic Ethylaluminum Dichloride must be employed
to obtain reasonable 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
Paraldehyde and Other Acetaldehyde Derivatives.
Paraldehyde 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 restricted availability
has led to its limited use in modern synthetic organic chemistry.
Acetaldehyde can be generated from paraldehyde through acid
catalyzed degradation of the trimer and isolated by distillation.43
The diethyl acetal of acetaldehyde, commonly 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;
Acetaldoxime; Crotonaldehyde;
Dimethylaluminum Chloride; Ethyl
Vinyl Ether; Formaldehyde; Formaldehyde-Dimethylamine;
Vinyl Acetate.
- 1. (a) Trécourt, F.; Marsais, F.;
Güngör, T.; Quéguiner, G. JCS(P1)
1990, 2409. (b) Devys, M.; Barbier, M.; Parsiot,
D. H 1990, 31, 1485.
- 2. Marshall, J. A.; Wang, X.-J. JOC
1991, 56, 960.
- 3. (a) Walter, L. A. OSC 1955,
3, 757. (b) Oppolzer, W.; Snowden, R. L. TL
1976, 4187. (c) Bailey, W. F.; Khanolkar, A. D. JOC
1990, 55, 6058.
- 4. Mahler, H.; Braun, M. CB 1991,
124, 1379.
- 5. (a) Overberger, C. G.; Saunders, J.
H.; Allen, R. E.; Gander, R. OSC 1955, 3,
200. (b) Bertini, V.; De Munno, A.; Pocci, M. JCS(P1)
1976, 570.
- 6. Drake, N. L.; Cooke, G. B. OSC
1943, 2, 406.
- 7. Sugai, T.; Kakeya, H.; Ohta, H. JOC
1990, 55, 4643.
- 8. (a) Hoffman, R. W. AG(E) 1982,
21, 555. (b) Coxon, J. M.; van Eyk, S. J.; Steel,
P. J. TL 1985, 26, 6121. (c) Doxsee,
K. M.; Mouser, J. K. M. TL 1991, 32,
1687.
- 9. (a) Roush, W. R.; Grover, P. T.; Lin,
X. TL 1990, 31, 7563. (b) Stürmer,
R.; Hoffman, R. W. SL 1990, 759.
- 10. Hewkin, C. T.; Jackson, R. F. W.
TL 1990, 31, 1877.
- 11. Speziale, A. J.; Ratts, K. W. JACS
1962, 84, 854.
- 12. (a) Motoyoshiya, J.; Yazaki, T.;
Hayashi, S. JOC 1991, 56, 735. (b)
Craig, D.; Daniels, K.; Marsh, A.; Rainford, D.; Smith,
A. M. SL 1990, 531.
- 13. Heathcock, C. H. In Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic: New York,
1984; Vol. 3, pp 111-212.
- 14. Fones, W. S. OSC 1963,
4, 293.
- 15. (a) Kent, R. E.; McElvain, S. M.
OSC 1955, 3, 591. (b) Horning, E. C.;
Denekas, M. O.; Field, R. E. OSC 1955, 3,
317. (c) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. TL
1978, 1759.
- 16. Schurink, H. B. J. OSC 1932,
1, 425.
- 17. Yadav, J. S.; Ravishankar, R. TL
1991, 32, 2629.
- 18. Kishikawa, K.; Sankhavasi, W.; Yamamoto,
M.; Kohmoto, S.; Yamada, K. SC 1990, 20,
2339.
- 19. (a) Evans, D. A.; Dow, R. L.; Shih,
T. L.; Takacs, J. M.; Zahler, R. JACS 1990,
112, 5290. (b) Sankhavasi, W.; Yamamoto, M.; Kohmoto,
S.; Yamada, K. BCJ 1991, 64, 1425.
(c) Ma, C.; Miller, M. J. TL 1991, 32,
2577.
- 20. (a) Ballini, R. JCS(P1) 1991,
1419. (b) Ono, N.; Kawamura, H.; Bougauchi, M.; Maruyama,
K. T 1990, 46, 7483.
- 21. (a) Amberg, W.; Seebach, D. CB
1990, 123, 2413. (b) Reissig, H.-U., Hippeli,
C. CB 1991, 124, 115. (c) West, F.
G.; Fisher, P. V.; Willoughby, C. A. JOC 1990,
55, 5936.
- 22. Lambert, F.; Kirschleger, B.; Villiéras,
J. JOM 1991, 406, 71.
- 23. (a) Ito, T.; Okamoto, S.; Sato, F.
TL 1990, 31, 6399. (b) Heng, K. K.;
Smith, R. A. J. TL 1975, 589.
- 24. Boldnini, G. P.; Mancini, F.; Tagliavini,
E.; Trombini, C.; Umani-Ronchi, A. JCS(C) 1990,
1680.
- 25. Slosse, P.; Hootelé, C. TL
1978, 397.
- 26. Capasso, R.; Randazzo, G.; Pecci,
L. CJC 1983, 61, 2657.
- 27. Courtois, G.; Miginiac, L. SC
1991, 21, 201.
- 28. Katritzky, A. R.; Latif, M.; Urogdi,
L. JCS(P1) 1990, 667.
- 29. Clerici, A.; Porta, O. TL
1990, 31, 2069.
- 30. Kendall, E. C.; McKenzie, B. F. OSC
1932, 1, 21.
- 31. (a) Shiqi, P.; Min, G.; Winterfeldt,
E. LA 1993, 137. (b) Leete, E. CC 1979,
821. (c) Czerwinski, K. M.; Deng, L.; Cook, J. M. TL
1992, 33, 4721. (d) Zhang, F.; Goyal, R. N.;
Blank, C. L.; Dryhurst, G. JMC 1992, 35,
82. (e) Behforouz, M.; West, S. J.; Chakrabarty, C.; Rusk,
D. A.; Zarrinmayeh, H. H 1992, 34,
483. (f) Hermkens, P. H. H.; van Maarseveen, J. H.; Cobben,
P. L. H. M.; Ottenheijm, H. C. J.; Kruse, C. G.; Scheeren,
H. W. T 1990, 46, 833. (g) Bates, H.
A.; Bagheri, K.; Vertino, P. M. JOC 1986,
51, 3061.
- 32. (a) Kametani, T.; Ujiie, A.; Ihara,
M.; Fukumoto, K. JCS(P1) 1976, 1218. (b) Dominguez,
E.; Leete, E.; Badia, M. D.; Villa, M. J.; Castedo, L.;
Dominguez, D. T 1987, 43, 1943.
- 33. Sabie, R.; Fillion, H.; Pinatel,
H.; Fenet, B. JHC 1990, 27, 1893.
- 34. Lin, I.; Day, A. R. JACS 1952,
74, 5133.
- 35. Evans, D. A.; Hoveyda, A. H. JACS
1990, 112, 6447.
- 36. (a) Konradi, A. W.; Pedersen, S.
F. JOC 1990, 55, 4506. (b) Park, J.;
Pedersen, S. F. JOC 1990, 55, 5924.
- 37. Macias, F. A.; Molinillo, J. M. G.;
Collado, I. G.; Massanet, G. M.; Rodriguez-Luis, F. TL
1990, 31, 3063.
- 38. Mikami, K.; Shimizu, M. CRV
1992, 92, 1021.
- 39. (a) Snider, B. B.; Rodini, D. J.
TL 1980, 21, 1815. (b) Cartaya-Marin,
C. P.; Jackson, A. C.; Snider, B. B. JOC 1984,
49, 2443.
- 40. Snider, B. B.; Phillips, G. B. JOC
1983, 48, 464.
- 41. (a) Makin, S. M.; Él'yanov,
B. S.; Raifel'd, Y. E. IZV 1974, 2654. (b)
Jurczak, J.; Chmielewski, M.; Flipek, S. S 1979,
41. (c) Raifel'd, Y. E.; Él'yanov, B. S.; Makin S.
M. IZV 1976, 1090.
- 42. (a) Emerson, W. S.; Patrick, T. M.,
Jr. OSC 1963, 4, 980. (b) Fones, W.
S. OS 1952, 32, 54. (c) Dolder, M.;
Xie, S.; Tamm, C. HCA 1990, 73, 63.
(d) Long, F. A.; Howard, J. W. OSC 1943, 2,
87. (e) Ronzio, A. R.; Waugh, T. D. OSC 1955,
3, 438. (f) Frank, R. L.; Pilgrim, F. J.; Riener,
E. F. OSC 1963, 4, 451. (g) Spivey,
A. M.; Curd, F. H. S. JCS 1949, 2656. (h)
Wong, O.; Huntington, J.; Konishi, R.; Rytting, J. H.; Higuchi,
T. JPS 1988, 77, 967.
- 43. Drake, N. L.; Cooke, G. B. OSC
1943, 2, 407.
- 44. Adkins, H.; Nissen, B. H. OSC
1932, 1, 1.
- 45. Greene, T. W.; Wuts, P. G. M. Protective
Groups in Organic Synthesis, 2nd ed.; Wiley: New York,
1991; p 120.
Thomas J. Sowin & Laura M. Melcher
Abbott Laboratories, Abbott Park, IL, USA
|