Phosphorus Oxychloride

POCl3

[10025-87-3]  · Cl3OP  · Phosphorus Oxychloride  · (MW 153.32)

(formylation of aromatic rings1,2 (Vilsmeier-Haack reaction); phosphorylating agent;3 dehydrating agent for amides; halogenation of alcohols, phenols, and heterocycles)

Alternate Name: phosphoryl chloride.

Physical Data: mp 1 °C; bp 106 °C; d 1.675 g cm-3; n 1.461.

Solubility: sol THF, MeCN, CH2Cl2, many other solvents.

Form Supplied in: colorless, fuming liquid; commercially available.

Purification: by distillation in vacuo.4

Handling, Storage, and Precautions: toxic and corrosive; reacts vigorously with alcohols and water, liberating HCl, phosphoric acid, and heat. Protect from water. Use in a fume hood.

Chloromethyleneiminium Ions.5-8

Phosphorus oxychloride (1) is a strong Lewis acid that is widely used in synthesis. Of particular importance are reactions of (1) with substituted amides, most often N,N-Dimethylformamide or dimethylacetamide (DMA). These reactions lead to the formation of chloromethyleneiminium salts (2) (eq 1). These salts (Vilsmeier reagents, see Dimethylchloromethyleneammonium Chloride) are highly versatile intermediates6 and are involved in numerous important reactions, including the Vilsmeier-Haack2,6 and Bischler-Napieralski9 reactions. Formation of (2) can be achieved using Thionyl Chloride or Phosgene, although there have been reports of differences in reactivity between POCl3/DMF, SOCl2/DMF, and COCl2/DMF systems.7,10,11

Formylation of Aromatic Rings.2,5,6,8,11

The Vilsmeier reagent attacks electron-rich aromatic systems to form arylmethyleneiminium ions which liberate a formylated aromatic compound upon hydrolysis (eq 2). Thio- and selenoaldehydes can be prepared by hydrolysis in the presence of Sodium Hydrogen Sulfide6,12 or Sodium Hydrogen Selenide.13 A wide range of aromatic systems6,11 can be formylated in this fashion, including benzene derivatives, polyaromatic hydrocarbons (eq 3), and azulene.11 Substitution occurs at relatively electron-rich positions.

Formylation of Heterocycles.6,11,14

Many heterocycles are readily formylated by POCl3/DMF, including pyrroles, thiophenes, furans, indoles, quinolines, pteridines, and purines.6 Reaction at the 2- and 5-positions of pyrroles, furans, and thiophenes is preferred, and indoles undergo attack at the 3-position (eq 4).6

Formylation of Alkenes.10,11

Both activated and unactivated alkenes undergo electrophilic attack by (2).5 Reaction at terminal positions is preferred.6 Styrene derivatives give cinnamaldehydes; enamines6 and aryl polyenes15,16 react at terminal positions (eq 5).

Bischler-Napieralski Reaction.

A widely used method for cyclization of N-b-phenylethyl amides to form dihydroisoquinolines and isoquinolines (eq 6)17-19 is the Bischler-Napieralski reaction.9 A nitrilium ion intermediate has been implicated in this reaction.20,21

Fragmentation of the nitrilium ion interferes with the cyclization20,21 of 1,2-diphenylethane derivatives, leading to formation of stilbenes rather than cyclization products. This problem has been overcome by using Oxalyl Chloride instead of (1).22 Fragmentation (von Braun reaction or retro-Ritter reaction) occurs whenever a highly stable cation can be formed, such as benzyl20 or t-butyl (eq 7).21,23,24

Treatment of tertiary amides with POCl3/DMF (2) results in formation of b-dimethylamino a,b-unsaturated amides. The highly electrophilic iminium ion (3) is formed in this reaction, and in the presence of an alkene this undergoes cyclization (eq 8).14,25

Excess POCl3 and DMF can lead to formylation of the initial heterocycle (eq 9). A series of a-substituted acrylonitriles has been prepared by dehydration of a,b-unsaturated amides (eq 10). POCl3/DMF and SOCl2/DMF give comparable results.26

Chloroaldehydes from Carbonyl Compounds.7

The enol tautomers of ketones react with POCl3/DMF to form b-chloroacrolein derivatives (eq 11). The regiochemistry is determined both by the stability of the enol as well as by steric factors. Nonsymmetrical ketones often give a mixture of regioisomers, and most ketones produce a mixture of (E) and (Z) isomers of the product.27 Aldehydes will undergo this type of reaction, although there are relatively few reports.

Reaction of POCl3/DMF with carboxylic acids results in vinamidinium ions (eq 12).28,29 These ions react with a variety of nucleophiles to produce pyrazoles, oxazoles, pyrimidines, diazepines, quinolines, quinolizines, and vinylogous sulfonamides.30

The Vilsmeier reagent (2) reacts with Grignard reagents as well as with alkylzinc and alkylaluminum reagents to form tertiary amines.31 It also reacts with heteroatom nucleophiles, including thiols,32 alcohols, and amines,8 as well as with nucleophilic amines containing other functional groups.5,33,34 Aromatic alcohols react with POCl3/DMF to form aryl formates in 50-80% yield,35 but aliphatic alcohols are more efficiently formylated with Benzoyl Chloride/DMF.36 Homoallylic alcohols such as (4) produce biphenyls in 30-98% yield16 through initial dehydration6 (eq 13) followed by electrophilic attack on the resulting aryl diene.

Halogenation of Alcohols.

The combination of POCl3 and DMF can be used to halogenate primary, secondary, and tertiary aliphatic alcohols (eq 14),37 whereas the reaction of primary alcohols and POCl3 without DMF or DMA will generally lead to the formation of trialkyl phosphates.

A comparison of POCl3 with SO2Cl2, PCl3, MsCl, and SOCl2 indicated that optimum conditions for the conversion of (5) to (6) (eq 15) are 1.1 equiv POCl3 in DMF at 0 °C.38

Halogenation of Heterocycles.

Phosphorus oxychloride is widely used in the chlorination of heterocycles. In general, heterocyclic ketones (eq 16) or alcohols (eq 17) react readily with (1), including pteridines,39 purines,40,41 and others.

In the chlorination of the isoxazole (7), it was noted that freshly distilled POCl3 is ineffective but that an older sample leads to the formation of the chloride (8). Further investigation showed that a mixture of POCl3, acid (H3PO4), and an additional chloride source (pyridinium chloride) leads to reliable conversion of (7) to (8) (eq 18).42

Phosphorylation.3,43

Phosphorus oxychloride reacts with alcohols, amines, and thiols, resulting in phosphorylation of these functional groups. Trimethyl phosphate is a particularly effective solvent,44 and tertiary amine bases are generally used as well. Treatment of primary alcohols with POCl3 results in the formation of phosphonyl dichloride intermediates which, in the presence of excess alcohol, convert to symmetrical trialkyl phosphates.10 It is generally possible to isolate aryl phosphorodichloridates when a two-fold excess of (1) is used and AlCl3, KCl, or pyridine is used as a catalyst.45,46 Secondary and tertiary alcohols tend to form alkyl chlorides and phosphoric acid.

Phosphorus oxychloride is very useful in the preparation of nucleoside 5-phosphates (eq 19) given appropriate mixtures of POCl3, pyridine, and water.44,47 The primary hydroxy (5) is sufficiently reactive for there to be minimal formation of cyclic phosphates at the 2,3-positions of nucleosides. The intermediate phosphorodichloridate can be converted to the corresponding triphosphate by treatment with inorganic phosphate in a convenient one-pot fashion.

Under anhydrous conditions, POCl3 can be used to produce cyclic dialkyl phosphonyl chlorides from diols, and these can be hydrolyzed with water to the cyclic phosphates or with an alcohol to trialkyl phosphates. Treatment of forskolin (9) with POCl3 leads to the formation of the cyclic phosphoryl chloride (10) in 55% yield as a mixture of two stereoisomers at phosphorus (eq 20).48 A comparison of several phosphorylating agents showed that POCl3, (MeOC6H4)2POCl, and 2-chloro-2-oxo-1,3,2-dioxaphospholane all give the analogous products in virtually identical yield.48

Similar results can be obtained with primary amines,49 although it is possible to obtain diamidophosphorochloridates by reaction of POCl3 with substoichiometric amounts of amine.50 Phosphorus oxychloride reacts more readily with primary amines than with primary alcohols, so that it is possible to prepare phosphoramides.51 Alkoxides, however, react more rapidly than amines so it is possible to phosphorylate hydroxyls in the presence of amines. Again, like the reaction of POCl3 with diols, diamines react with POCl3 to form diazaphospholidines (eq 21).52

Carboxylic anhydrides can be prepared by treatment of carboxylic acids with POCl3,32 allowing the formation of both esters32 and amides, although other methods are more common.53 Dichloroacetyl chloride produces dichloroketene when treated with POCl3 and Zinc/Copper Couple.54

Dehydration of Amides.

Unsubstituted amides undergo dehydration upon treatment with POCl3. This reaction can also be performed with P2O5, SOCl2, or other reagents, and in a study of racemization at the a-position it was determined that dehydration with POCl3 leads to more (albeit little) epimerization than dehydration with P2O5 or SOCl2 (eq 22).55

Dehydration of alkyl and aryl N-formyl compounds with POCl3 is one of the more general routes to alkyl and aryl isocyanides (eq 23).56-59 A base, typically an amine base or Potassium t-Butoxide, is also required. The method is simple and effective, although less useful for small, volatile isocyanides than other techniques.60 The Bischler-Napieralski reaction can occur preferentially to isocyanide formation.17

Dehydration of Alcohols.

The combination of POCl3 and Pyridine is an effective dehydrating agent for alcohols (eq 24)61 and cyanohydrins.62 The stereochemistry of elimination is anti, although the regioselectivity is often not high, particularly for tertiary alcohols.63

The combination of phosphorus oxychloride and Tin(II) Chloride reduces halohydrins to alkenes (eq 25). The elimination proceeds in an anti fashion.64

Beckmann Rearrangement.

Treatment of ketoximes with POCl3 induces Beckmann rearrangement to form amides (eq 26).65 Numerous other Lewis acids can be used for this transformation.66,67

Related Reagents.

Bis(trichloromethyl) Carbonate; Phosphorus(V) Oxide; Phosphorus Oxychloride-Zinc(II) Chloride; Thionyl Chloride; p-Tolyl Vinyl Sulfoxide; Trichloromethyl Chloroformate.


1. FF 1967, 1, 876.
2. Seshadri, S. J. Sci. Ind. Res. 1973, 32, 128.
3. Hayakawa, H. COS 1991, 6, 601.
4. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: Oxford, 1988.
5. Meth-Cohn, O.; Stanforth, S. P. COS 1991, 2, 777.
6. Jutz, C. In Iminium Salts in Organic Chemistry; Böhme, H.; Viehe, H. G.; Eds.; Wiley: New York, 1976; Vol. 9, pp 225-342.
7. Marson, C. M. T 1992, 48, 3659.
8. Kantlenher, W. COS 1991, 6, 485.
9. Hilger, C. S.; Fugmann, B.; Steglich, W. TL 1985, 26, 5975.
10. Burn, D. CI(L) 1973, 870.
11. Khimii, U. RCR 1960, 29, 599.
12. Lin, Y.; Lang, S. A. JOC 1980, 45, 4857.
13. Reid, D. H.; Webster, R. G.; McKenzie, S. JCS(P1) 1979, 2334.
14. Meth-Cohn, O. H 1993, 35, 539.
15. Jutz, C.; Heinicke, R. CB 1969, 103, 623.
16. Suresh Chandler Rao, M. S. C.; Krishna Rao, G. S. K. S 1987, 231.
17. Badia, D.; Carrillo, L.; Dominguez, E.; Cameno, A. G.; Martinez de Marigorta, E.; Vincente, T. JHC 1990, 27, 1287.
18. Kametani, T.; Fukumoto, K. In Isoquinolines; G. Grethe, Ed.; Wiley: New York, 1981; Vol. 31, Part 1, pp 142-160.
19. Knabe, J.; Krause, W.; Powilleit, H.; Sierocks, K. Pharmazie 1970, 25, 313.
20. Fodor, G.; Gal, J.; Phillips, B. A. AG(E) 1972, 11, 919.
21. Fodor, G.; Nagubandi, S. T 1980, 36, 1279.
22. Larsen, R. D.; Reamer, R. A.; Corley, E. G.; Davis, P.; Grabowski, E. J. J.; Reider, P. J.; Shinkai, I. JOC 1991, 56, 6034.
23. Ketcha, D. M.; Gribble, G. W. JOC 1985, 50, 5451.
24. Perni, R. B.; Gribble, G. W. OPP 1983, 15, 297.
25. Meth-Cohn, O.; Tarnowski, B. Adv. Heterocycl. Chem. 1982, 31, 207.
26. Bargar, T. M.; Riley, C. M. SC 1980, 10, 479.
27. Schellhorn, H.; Hauptmann, S.; Frischleder, H. ZC 1973, 13, 97.
28. Gupton, J. T.; Riesinger, S. W.; Shah, A. S.; Bevirt, K. M. JOC 1991, 56, 976.
29. Gupton, J. T.; Gall, J. E.; Riesinger, S. W.; Smith, S. Q.; Bevirt, K. M.; Sikorski, J. A.; Dahl, M. L.; Arnold, Z. JHC 1991, 28, 1281.
30. McNab, H.; Lloyd, D. AG(E) 1976, 15, 459.
31. Mesnard, D.; Miginiac, L. JOM 1989, 373, 1.
32. Arrieta, A.; Garcia, T.; Lago, J. M.; Palomo, C. SC 1983, 13, 471.
33. Harris, L. N. S 1981, 907.
34. Zelenin, K. N.; Khrustalev, V. A.; Sergutina, V. P. CA 1980, 93, 70 910.
35. Morimura, S.; Horiuchi, H.; Muruyama, K. BCJ 1977, 50, 2189.
36. Barluenga, J.; Campos, P. J.; Gonzalez-Nuñez, E.; Asensio, G. S 1985, 426.
37. Yoshihara, M.; Eda, T.; Sakaki, K.; Maeshima, T. S 1980, 746.
38. Sanda, K.; Rigal, L.; Delmas, M.; Gaset, A. S 1992, 6, 541.
39. Albert, A.; Clark, J. JCS 1964, 1666.
40. Golovchinskaya, E. S. RCR 1974, 43, 1089.
41. Robins, R. K.; Revankar, G. R.; O'Brien, D. E.; Springer, R. H.; Novinson, T.; Albert, A.; Senga, K.; Miller, J. P.; Streeter, D. G. JHC 1985, 22, 601.
42. Andersen, K.; Begtrup, M. ACS 1992, 46, 1130.
43. Edmunson, R. S. In Comprehensive Organic Chemistry; Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol. 2, pp 1262-1263.
44. Yoshikawa, M.; Kato, T.; Takenishi, T. BCJ 1969, 42, 3505.
45. Owen, G. R.; Rees, C. B.; Ransom, C. J.; van Boom, J. H.; Herscheid, J. D. H. S 1974, 704.
46. Taguchi, Y.; Mushika, Y. TL 1975, 1913.
47. Sowa, T.; Ouchi, S. BCJ 1975, 2084.
48. Lal, B.; Gangopadhyay, A. K. JCS(P1) 1992, 15, 1993.
49. Edmunson, R. S. In Comprehensive Organic Chemistry; Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol. 2, pp 1262-1265.
50. Ireland, R. E.; O'Neil, T. H.; Tolman, G. L. OS 1983, 61, 116.
51. Crans, D. C.; Whitesides, G. M. JACS 1985, 107, 7008.
52. Alexakis, A.; Mutti, S.; Mangeney, P. JOC 1992, 57, 1224.
53. Mulzer, J. COS 1991, 6, 323.
54. Hassner, A.; Dillon, J. S 1979, 689.
55. Rickborn, B.; Jensen, F. R. JOC 1962, 27, 4608.
56. Sandler, S. R.; Karo, W. In Organic Functional Group Preparations, 2nd ed.; Academic: San Diego, 1989; Vol. 3, pp 207-238.
57. Ugi, I.; Meyr, R.; Lipinski, M.; Bodesheim, F.; Rosendahl, F. OSC 1973, 5, 300.
58. van Leusen, D.; van Leusen, A. M. RTC 1992, 47, 1249.
59. van Leusen, A. M.; Boerma, G. J. M.; Helmholdt, R. B.; Siderius, H.; Strating, J. TL 1972, 2367.
60. Höfle, G.; Lange, B. OS 1983, 61, 14.
61. Mehta, G.; Murthy, A. N.; Reddy, D. S.; Reddy, A. V. JACS 1986, 108, 3443.
62. Oda, M.; Yamauro, A.; Watabe, T. CL 1979, 1427.
63. Giner, J.-L.; Margot, C.; Djerassi, C. JOC 1989, 54, 369.
64. Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. JCS 1959, 2539.
65. Fujita, S.; Kotauna, K.; Inagaki, Y. S 1982, 68.
66. Gawley, R. E. OR 1988, 35, 1.
67. Donaruma, L. G.; Heldt, W. Z. OR 1960, 11, 1.

Mark S. Meier

University of Kentucky, Lexington, KY, USA

Suzanne M. Ruder

Virginia Commonwealth University, Richmond, VA, USA



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