Acetic Formic Anhydride1

[2258-42-6]  · C3H4O3  · Acetic Formic Anhydride  · (MW 88.06)

(useful formylating agent for the hydroxyl,2 phenol,3 and amine groups4 as well as other heteroatoms;5 useful for the synthesis of aldehydes from aromatic Grignard reagents,6 for the preparation of formyl fluoride,7 and for the preparation of diazoacetaldehyde8)

Alternate Name: AFA.

Physical Data: bp 27-28 °C/10 mmHg.

Analysis of Reagent Purity: IR, NMR, MS.1

Preparative Methods: acetic formic anhydride is not comercially available. The easiest method of preparation is by the reaction of sodium formate and Acetyl Chloride in dry ether as reported by Krimen.9 Alternatively, Ketene and Formic Acid form the title compound at room temperature or below.10 Acetic formic anhydride can be prepared rapidly in situ by stirring formic acid, acetyl chloride, and Triethylamine in THF at -70 °C for 10 min.11 AFA is found in a mixture of formic acid (excess) with Acetic Anhydride.1 The mixture is more accurately described as formic acid-acetic anhydride mixture (FAM) and is also used as a formylating agent.

Purification: by fractional distillation at low pressure.

Handling, Storage, and Precautions: acetic formic anhydride decomposes slowly at room temperature and faster at elevated temperatures, giving acetic acid and carbon monoxide. Due to gas evolution, AFA is best stored at 4 °C in a flask fitted with a polyethylene stopper since sealed samples can explode. The compound is an eye and skin irritant and should be handled in a fume hood.

O-Formylations.

Acetic formic anhydride (AFA) as well as formic acid-acetic anhydride mixture (FAM) can be used to formylate alcohols and phenols.2,3 While the yields of formates are high, the reaction takes from 50 to 80 days (eq 1).

An improved method for formation of aryl formates uses pure AFA with the addition of tertiary amine bases or sodium formate.12 The reaction takes place at 20 °C, is complete in 24-48 h, and gives excellent yields of formate. The procedure is general and is an easy method of preparation of pure aryl formates in high yield with no acetate byproducts. The reaction can be applied to aryl groups with electron donating or electron withdrawing substituents.

Phenolic ketones cyclize to isoflavones with AFA catalyzed by sodium formate or Triethylamine (eq 2).13

Salicylamide is formylated in 53% yield using AFA with Pyridine at 0 °C (eq 3).14 Interestingly, no rearrangement to N-formylsalicylamide occurs under these reaction conditions. This protocol is superior to formic acid or ethyl formate which give the N-formyl compound exclusively.

Aliphatic alcohols can be converted to their formates using FAM.2 Tertiary alcohols yield formate esters exclusively, while secondary and primary alcohols yield mixtures of formate and acetate. Formylation of primary and secondary alcohols can be enhanced by the addition of tertiary nitrogen bases or sodium formate.

Tertiary alcohols that are typically dehydrated upon acetylation yield formates under these reaction conditions. O12a-Formyltetracycline (1) can be prepared in high yield using AFA.15

Complex hydroxy acids such as gibberellin A3 react with acetic formic anhydride in pyridine to give the 3-O-monoformyl derivative (2) and the O-diformyl derivative in 85% and 13% yields, respectively.16

Acetic formic anhydride formylates the sugar moiety of some nucleosides such as uridine and others.17 Polyformylation occurs on all free hydroxyl groups. The 5-hydroxyl of nucleosides can be formylated efficiently to give a 5-O-formyl derivative (3).18 The selective hydrolysis of formate esters in hot methanol compared with acetates makes formylation an attractive protecting group for some nucleosides.

N-Oxides of tertiary amines are deoxygenated in nearly quantitative yield using AFA (eq 4).19 The reaction is general for trialkylamine N-oxides and N,N-dialkylarylamine N-oxides. Heteroaromatic N-oxides and sulfoxides are unchanged under these reaction conditions.20

N-Formylations.

Ammonia can be monoformylated using AFA at 0 °C in dry ether as shown in eq 5.21 No polyformylated products were detected in the reaction.

Many aliphatic and aromatic amines (primary and secondary) have been formylated successfully using AFA or FAM.4 Primary amines can be monomethylated in a one-pot procedure using excess FAM which gives a monoformylated intermediate (eq 6).22 Weakly basic and sterically hindered amines are also reactive.

Heterocyclic compounds have been N-formylated at the side chain or ring nitrogen using AFA or FAM. Some examples, (4),23 (5),24 (6),25 and (7),26 are shown.

N-Formylation of amino acids has been achieved using FAM without racemization. An excess of FAM is required; however, AFA can be used in a 2-3 molar excess. Most amino acids have been formylated in 70-94% yields without formation of the acetate.27

The formyl group is very useful as a blocking group in peptide synthesis. The formyl group can be introduced without racemization and is selectively removed by mild acid hydrolysis without affecting the peptide linkage. Since the N-formyl group is stable toward basic hydrolysis, saponification of esters in amino acids can be achieved. Thus the peptide chain can be extended at the amino or carboxyl ends.

C-Formylations.

A few examples of C-formylation reactions have been reported in the literature. The first involves formylation of indole derivatives in the 3-position when this position is free.28

Aromatic Grignard reagents react with AFA to give good yields of aldehydes as the only carbonyl product formed without formation of alcohol.6 However, aliphatic Grignard reagents and AFA lead to substantial amounts of methyl ketone and alcohol formation.

C-Formylation of diazomethane with AFA leads to Diazoacetaldehyde (eq 7).8 Diazoacetaldehyde is a precursor of formylcarbene. It has also been used for ethanalation of alkenes.

Formyl Fluoride.

Anhydrous HF reacts with AFA to yield Formyl Fluoride in 68% yield. A small amount of acetyl fluoride was also formed.7 Formyl fluoride is the only known stable halide of formic acid. It has been used in a Friedel-Crafts type reaction to produce aromatic aldehydes (eq 8).


1. Strazzolini, P.; Giumanini, Angelo G.; Cauci, S. T 1990, 46, 1081.
2. Van Es, A.; Stevens, W. RTC 1965, 84, 704.
3. (a) Van Es, A.; Stevens, W. RTC 1964, 83, 1294. (b) Sofuku, S.; Muramatsu, I.; Hagitani, A. BCJ 1967, 40, 2942.
4. Barta-Szalai, G.; Fetter, J.; Lempert, K.; Moller, J. Acta Chim. Acad. Sci. Hung. 1980, 104, 253.
5. (a) Treppendahl, S.; Jakobsen, P. ACS 1978, 36, 697. (b) Bartmess, J. E.; Hays, R. L.; Caldwell, G. JACS 1981, 103, 1338. (c) Vasella, A.; Voeffray, R. HCA 1982, 65, 1953.
6. Edwards, W. R., Jr.; Kammann, K. P., Jr. JOC 1964, 29, 913.
7. Olah, G. A.; Kuhn, S. J. JACS 1960, 82, 2380.
8. Hooz, J.; Morrison, G. F. OPP 1971, 3, 227.
9. Krimen, L. I. OS 1970, 50, 1.
10. (a) Hurd, C. D.; Drake, S. S.; Fancher, O. JACS 1946, 68, 789. (b) Hurd, C. D.; Roe, A. S. JACS 1939, 61, 3355.
11. Baltzer, B.; Lund, F.; Rastrup-Andersen, N. JPS 1979, 68, 1207.
12. Van Es, A.; Stevens, W. RTC 1965, 84, 1247.
13. Pivovarenko, V. G.; Khilya, V. P.; Babichev, F. S. DOK 1985, 56.
14. Treppendahl, S.; Jakobsen, P. ACS 1983, 37, 953.
15. Blackwood, R. K.; Rennhard, H. H.; Stephens, C. R. JACS 1960, 82, 5194.
16. Serebryakov, E. P. IJS(B) 1980, 2596.
17. Zemlicka, J.; Beranek, J.; Smrt, J. CCC 1962, 27, 2784.
18. Fromageot, H. P. M.; Griffin, B. E.; Reese, C. B.; Sulston, J. E. T 1967, 23, 2315.
19. (a) Polonovski, M.; Polonovski, M. BSF(2) 1927, 41, 1190. (b) Tokitoh, N.; Okazaki, R. CL 1985, 1517.
20. Tokitoh, N.; Okazaki, R. CL 1985, 1517.
21. (a) Allenstein, E.; Beryl, V. CB 1967, 100, 3551. (b) Allenstein, E.; Beryl, V.; Eitel, W. CB 1969, 102, 4089. (c) Steinmetz, W. E. JACS 1973, 95, 2777.
22. Krishnamurthy, S. TL 1982, 23, 3315.
23. Hannig, E.; Kollmorgen, C.; Dressel, M. Pharmazie 1974, 29, 685.
24. Perrone, E.; Alpegiani, M.; Giudici, F.; Bedeschi, A.; Pellizzato, R.; Nannini, G. JHC 1984, 21, 1097.
25. Tamura, Y.; Miyamoto, T.; Shimooka, K.; Masui, T. CPB 1971, 19, 119.
26. Bergman, J.; Bergman, S. JOC 1985, 50, 1246.
27. Muramatsu, I.; Murakami, M.; Yoneda, T.; Hagitani, A. BCJ 1965, 38, 244.
28. Bergman, J. JHC 1971, 8, 329.

Regina Zibuck

Wayne State University, Detroit, MI, USA



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