Polyphosphoric Acid1

[8017-16-1]

(moderately strong mineral acid with powerful dehydrating properties; used for intramolecular and intermolecular acylations, heterocyclic synthesis, and acid-catalyzed rearrangements)

Alternate Name: PPA.

Physical Data: hygroscopic, highly viscous, clear, colorless, or light amber; specific gravity 2.060 at 83% phosphorus pentoxide content.

Solubility: dissolution in any protic solvent will result in solvolysis of the reagent; dissolution in polar aprotic solvents could result in dehydration or destruction of the solvent; polyphosphoric acid is neither soluble in nor reacts with nonpolar organics such as toluene or hexane.

Form Supplied in: inexpensive and commercially available from most major suppliers.

Preparative Methods: by mixing x mL of Phosphoric Acid (85%, d 1.7 g mL-1) with 2.2 x g of Phosphorus(V) Oxide (P2O5) followed by heating to 200 °C for 30 min.

Handling, Storage, and Precautions: normally used as the solvent so that a 10-50 fold excess is routinely employed. Due to high viscosity, PPA is difficult to pour and stir at rt, but is much easier to work with at temperatures above 60 °C. Addition of cosolvents, such as xylene, has facilitated the difficult workup usually associated with PPA.2 Eaton's reagent (see Phosphorus(V) Oxide-Methanesulfonic Acid) has been found to perform similar chemistry at lower temperatures without the viscosity problems. When diluting PPA or working up a reaction, ice is normally used to moderate the exothermic reaction that occurs with water. PPA has the ability to burn mucous membranes immediately and unprotected skin with time. Other than the corrosive nature of this reagent it has low inherent toxicity. Use in a fume hood.

Description.

Polyphosphoric acid is a mixture of orthophosphoric acid and linear phosphoric acids. In order to simplify discussion of this reagent, the complex mixture is described empirically as a wt % of P2O5 in water. The distribution of phosphoric acids that are found in PPA is dependent upon the wt % of P2O5. Commercially available PPA contains 82-85% P2O5, with 83% P2O5 considered to be the standard. At this concentration there is no free water and the distribution of phosphoric acids is approximately 6% orthophosphoric acid, 19% pyrophosphoric acid, and 11% triphosphoric acid, while the remaining material is linear phosphoric acids up to a chain length of approximately 14 phosphoric acid units.3 Only at wt % of P2O5 over 84% do appreciable high weight polymeric species occur. Neutralization of the most acidic protons in PPA is accomplished at pH 3.8-4.2 and corresponds to one strongly acidic proton for each phosphorus atom.

The powerful dehydrating properties of PPA, low nucleophilicity of the phosphoric acid media, and moderate acidity explain why this reagent is so widely used. Unlike Sulfuric Acid, PPA has a low propensity to cause oxidation of the substrate and is also able to dissolve organic compounds. PPA has demonstrated rates of dehydration equal to that of 100% sulfuric acid even though it is a much weaker acid.

Cyclization of Acids, Esters, Ketones, Aldehydes, Acetals, Alcohols, and Alkenes onto Aromatic Rings.

Polyphosphoric acid is the reagent of choice to cyclize aromatic carboxylic acids to indanones (eq 1),4 tetralones (eq 2),5 and benzosuberones (eq 3).6 Anomalous results for the cyclization of 3-(2-methoxyphenyl)propionic acid led researchers to discover a method for synthesis of metacyclophanes (eq 4).7 Another interesting reaction that demonstrates the utility of PPA in forming cyclic aromatic ketones is the double cyclization of biscarboxylic acids (eq 5).8 Carboxylic esters often demonstrate the ability to be cyclized as readily as the acids (eq 6).9

Methoxy or alkyl substitution of the aromatic ring has also been found to allow shorter reaction times and lower reaction temperatures.10 Cyclization of ketones (eq 7),11 aldehydes (eq 8),12 and acetals (eq 9)13 occurs with dehydration to give cyclic alkenes. Tertiary or benzylic alcohols are usually the only alcohols which give straightforward cyclization products (eq 10).14 Secondary and primary alcohols usually rearrange (Wagner-Meerwein rearrangements) before cyclization can occur. Just as in alcohols, alkenes are also prone to rearrangement unless the carbonium ion formed upon protonation is tertiary or benzylic. Low to moderate yields have been reported for cyclization of alkenes onto aromatic rings (eq 11).15

Cyclization onto Nonaromatic Moieties.

Cyclopentenones have been synthesized from carboxylic acids in good yield (eqs 12-14).16 Compared with other protic acids, PPA has demonstrated the ability to favor carbon-carbon bond formation over lactone formation.17

Synthesis of cyclohexenones from alkenyl acids has been demonstrated (eq 15);18 however, formation of methylcyclopentenones and lactones may occur when possible (eq 16).19

Cyclization Reactions which Form Heterocycles.

Use of PPA as an acid catalyst to form heterocyclic compounds has been exhaustively reviewed in the literature.1 The ability of PPA to be used in place of more acidic or more nucleophilic reagents has led to applications in a variety of heterocyclic systems.

Nitrogen Heterocycles.

Although Zinc Chloride is normally used as catalyst, indoles substituted in the 2-position can be obtained from hydrazones by ring closure with PPA (Fisher indole synthesis) (eq 17).20

Use of PPA in the Bischler-Napieralski reaction has shown superior results to other reagents for construction of the isoquinoline ring system.21 For example, dihydroisoquinolines are obtained from phenethylformamides in yields superior to phosphorus pentoxide (eq 18).22 In the first report which popularized the use of PPA in organic synthesis, treatment of N-acetyl-b-phenethylamine with PPA gave the 1-methyl-3,4-dihydroisoquinoline in 23% yield (eq 19).23 Synthesis of isoquinolines using a PPA-catalyzed Pomeranz-Fritsch reaction has been reported (eq 20),24 but the low yields and poor reproducibility of this reaction have been overcome by the use of Hydrogen Chloride/dioxane to cyclize the N-tosyl derivative.25

The quinoline carbon framework can be assembled by ring closure of an aromatic acid to give a keto quinoline (eq 21).26 Using PPA as catalyst, phenylquinolinones can be prepared from 3-aryl-3-hydroxypropionanilides (eq 22),27 or from amido ketones (eq 23).28

When attempting to effect a Beckmann rearrangement it was found that the oxime of a hexahydrobenzindolizine did not give the expected amide but instead dehydrated. This was followed by ring opening then ring closure to give a dihydrobenzonaphthyridinone (eq 24). When the hexahydrobenzindolizine itself was treated with PPA the compound simply dehydrated without rearrangement to give the dihydrobenzindolizone (eq 25). Sulfuric acid completely failed to effect this dehydration and Eaton's reagent was reported to give lower yields of product.29

Alkyl- or chloro-substituted isatins were obtained more conveniently with PPA than with sulfuric acid (eq 26).30 Synthesis of the bacterial coenzyme methoxatin was facilitated by use of PPA to synthesize the pivotal isatin intermediate (eq 27).31

Complex lactams were stereoselectively assembled in a beautifully simple reaction between 3-alkenamides and benzaldehyde (eq 28).32 Oxazolinones can be made utilizing the Erlenmeyer azlactone synthesis. Use of PPA cleanly affords the (E) isomer whereas other methods provide only the (Z) isomers or mixtures of (E) and (Z) isomers (eq 29).33 Other nitrogen-containing heterocyclic systems which can be obtained using PPA include benzimidazoles (eq 30)34 and triazoles (eq 31).35

Oxygen and Sulfur Heterocycles.

Diphenylfurans are formed in higher yields with PPA than with sulfuric acid, Acetic Anhydride, or phosphorus pentoxide as the dehydrating/cyclization agent (eq 32).36 Similar to cyclization of aromatic acids to form aromatic cyclic ketones, the replacement of the benzylic methylene group with an oxygen affords chromanones in good yield (eq 33).37 The structurally related flavones can be prepared by an intramolecular 1,4-addition catalyzed by PPA (eq 34).38 Seven-membered rings which contain oxygen, such as benzoxepinones, can be made in good yield from 4-phenoxybutyric acids (eq 35).39 Benzofurans are formed in good yield by cyclization of a-phenoxy ketones (eq 36).40 Thienopyrroles are obtained by ring closure of a pyrrolecarboxylic acid (eq 37).41

Rearrangements and Isomerizations.

The same characteristics which facilitate cyclizations, such as media with low nucleophilicity, good solvation power, relatively mild acidity, and low oxidation potential, are also conducive to clean, high-yielding acid-catalyzed rearrangements. PPA has been considered to be an effective reagent to carry out conversion of oximes into amides (Beckmann rearrangement) (eq 38).42 Rearrangement of a decalin oxime could be carried out with p-Toluenesulfonyl Chloride/Pyridine to maintain the original cis-decalin stereochemistry or PPA could be used to allow formation of the trans-decalin system through an alternative mechanism (eq 39).43

Treatment of aromatic carboxylic acids with Nitromethane and PPA (Lossen rearrangement) gives high yields of anilines (eq 40).44 Although PPA can be used to catalyze the reaction of Hydrazoic Acid with carboxylic acids, ketones, and aldehydes (Schmidt rearrangement), sulfuric acid is usually the reagent of choice. One example of PPA being equivalent to sulfuric acid in the Schmidt rearrangement is when it is applied to acetophenone (eq 41).45

Wagner-Meerwein rearrangements and, more generally, carbonium ion-mediated carbon skeleton rearrangements can be effected with PPA. Lewis acids are generally preferred due to the ease of use and workup. An example of a high yield PPA induced Wagner-Meerwein rearrangement is formation of the phenanthrene skeleton from substituted fluorenes (eq 42).46 Ring contraction was found to occur when a thiochromene was treated with PPA (eq 43).47

Acid-catalyzed isomerizations which can be affected with PPA include conversion of trans-cinnamic acid to cis-cinnamic acid (eq 44), trans,trans-diene conversion to trans,cis-dienes (eq 45),48 and azlactone isomerizations (eq 46).33

Intermolecular Reactions.

PPA is generally used as an intramolecular catalyst but has demonstrated limited utility for intermolecular alkylations. Due to the elevated temperatures necessary to achieve catalysis (and reduce PPA viscosity), most reactions give mixtures of products favoring multiple substitution. Consequently, most Friedel-Crafts alkylations are carried out with Aluminum Chloride or another Lewis acid which can be more readily controlled. In the case of activated aromatics, such as phenol, alkylation can proceed under moderate conditions (eq 47).49

Acylations with PPA are much more prevalent. In the seven years between the first popularized use of PPA in 195023 and the Popp and McEwen review,1b over 200 intermolecular acylations were reported. One of the first acylations was the reaction between cyclohexene and Acetic Acid (eq 48).50 Acylation of activated aromatics proceeds in high yield (eq 49).51 Acylation of phenols is problematic due to competing ester formation (eq 50).52

Miscellaneous Uses of Polyphosphoric Acid.

Nitrile hydrolysis to amides is commonly carried out using PPA. At 100-110 °C, nitriles are routinely converted to amides (eq 51).53

When the temperature is raised to 200 °C, decyanation of aromatic nitriles often results.54 Reagents with unique abilities have been developed by mixing PPA with other agents. The reduced acidity of PPA compared to other mineral acids proved beneficial when a PPA/Ethanethiol mixture was used to open one epoxide selectively in a bis-epoxy steroid (eq 52).55 PPA/POCl3 affords a medium which is used to convert tertiary alcohols into chlorides (eq 53).56

In an attempt to generate HCl in situ during cyclization of a tetraamine, a PPA/NaCl mixture was superior to PPA alone (eq 54).57 PPA/Acetic Acid was used to synthesize nonenolizable b-diketones (eq 55).58 Although Wagner-Meerwein rearrangements predominate when primary carbonium ions are formed with PPA, a mixture of PPA/Potassium Iodide allowed conversion of a primary methyl ether to a primary alkyl iodide in high yield (eq 56).59 It has been reported that nitrations carried out using PPA/Nitric Acid are less hazardous than Ac2O/HNO3 mixtures (eq 57).60


1. The most recent (literature up to 1981) comprehensive synthetic review is: (a) Pizey, J. S. Synthetic Reagents; Ellis Horwood: Chichester, 1985; Vol. 6. Two very useful comprehensive reviews which cover the synthetic applications of PPA up to 1960 are: (b) Popp, F. D.; McEwen, W. E. CRV 1958, 58, 321; and (c) Uhlig, F.; Snyder, H. R. In Advances in Organic Chemistry: Methods and Results; Raphael, R. A.; Taylor, E. C.; Wynberg, H., Eds.; Interscience: New York, 1960; Vol. 1, p 35. Additional reviews: (d) Marthe, J.- P.; Munavalli, S. BSF 1963, 2679. (e) Krongauz, E. S.; Rusanov, A. L.; Renard, T. L. RCR 1970, 39, 747. (f) Verhe, R.; Schamp, N. Ind. Chim. Belg. 1973, 38, 945.
2. Guy, A.; Guetté, J. P. S 1980, 222.
3. Jameson, R. F. JCS 1959, 752.
4. Gilmore, Jr., J. C. JACS 1951, 73, 5879.
5. Koo, J. JACS 1953, 75, 1891.
6. Horton, W. J.; Walker, F. E. JACS 1952, 74, 758.
7. Zhang, J.; Hertzler, R. L.; Holt, E. M.; Vickstrom, T.; Eisenbraun, E. J. JOC 1993, 58, 556.
8. Allen, J. M.; Johnston, K. M.; Shotter, R. G. CI(L) 1976, 108.
9. Horii, Z.; Ninomiya, K.; Tamura, Y. YZ 1956, 76, 163.
10. Pizey, J. S. Synthetic Reagents; Ellis Horwood: Chichester, 1985; Vol. 6, p 245.
11. Birch, A. J.; Smith, H. JCS 1951, 1882.
12. Newman, M. S.; Seshadri, S. JOC 1962, 27, 76.
13. Kotchetkov, N. K.; Nifant'ev, E. J.; Nesmeyanov, A. N. DOK 1955, 104, 422.
14. Nasipuri, D.; De Dalal, I. IJC 1973, 11, 823.
15. Nasipuri, D.; Chaundhury, S. R. R.; Mitra, A.; Ghosh, C. K. IJC 1972, 10, 136.
16. Dorsch, M.; Jager, V.; Sponlein, W. AG(E) 1984, 23, 798.
17. Ansell, M. F.; Palmer, M. H. QR 1964, 18, 211.
18. Rae, I. D.; Umbrasas, B. N. AJC 1975, 28, 2669.
19. Ansell, M. F.; Emmett, J. C.; Coombs, R. V. JCS 1968, 217.
20. Kissman, H. M.; Farnsworth, D. W.; Witkop, B. JACS 1952, 74, 3948.
21. Cannon, J. G.; Webster, G. L. J. Am. Pharm. Assoc. 1958, 47, 353.
22. Pratt, E. F.; Rice, R. G.; Luckenbaugh, R. W. JACS 1957, 79, 1212.
23. Snyder, H. R.; Werber, F. X. JACS 1950, 72, 2962.
24. Djerassi, C.; Markley, F. X.; Ehrlich, R. JOC 1956, 21, 975.
25. Boger, D. L.; Brotherton, C. E.; Kelley, M. D. T 1981, 37, 3977.
26. (a) Koo, J. JOC 1961, 26, 2440. (b) Koo, J. JOC 1963, 28, 1134.
27. Hazai, L.; Deak, G.; Sohar, P.; Toth, G.; Tamas, J. JHC 1991, 28, 919.
28. Stephenson, E. F. M. JCS 1956, 2557.
29. Barbry, D.; Couturier, D. JHC 1990, 27, 1383.
30. Grimshaw, J.; Begley, W. J. S 1974, 496.
31. Gainor, J. A.; Weinreb, S. M. JOC 1982, 47, 2833.
32. Marson, C. M.; Grabowska, U.; Walsgrove, T.; Eggleston, D. S.; Baures, P. W. JOC 1991, 56, 2603.
33. Rao, Y. S. JOC 1976, 41, 722.
34. Hein, D. W.; Alheim, R. J.; Leavitt, J. J. JACS 1957, 79, 427.
35. Arcus, C. L.; Prydal, B. S. JCS 1957, 1091.
36. Nowlin, G. JACS 1950, 72, 5754.
37. Loudon, J. D.; Razdan, R. K. JCS 1954, 4299.
38. Nakazawa, K.; Matsuura, S. YZ 1955, 75, 469.
39. Freedman, J.; Stewart, K. T. JHC 1989, 26, 1547.
40. Trippett, S. JCS 1957, 419.
41. Matteson, D. S.; Snyder, H. R. JACS 1957, 79, 3610.
42. Horning, E. C.; Stromberg, V. L. JACS 1952, 74, 2680.
43. Hill, R. K.; Chortyk, O. T. JACS 1962, 84, 1064.
44. Bachman, G. B.; Goldwater, J. E. JOC 1964, 29, 2576.
45. Conley, R. T. JOC 1958, 23, 1330.
46. Bavin, P. M. G.; Dewar, M. J. S. JCS 1955, 4477.
47. MacNicol, D. D.; McKendrick, J. J. TL 1973, 2593.
48. Rao, Y. S.; Filler, R. CC 1976, 471.
49. Gardner, P. D. JACS 1954, 76, 4550.
50. Dev, S. JIC 1956, 33, 703.
51. Barrio, J. R.; Barrio, M. D. C. G.; Vernengo, M. J. JMC 1971, 14, 898.
52. Nakazawa, K.; Baba, S. YZ 1955, 75, 378.
53. Snyder, H. R.; Elston, C. T. JACS 1954, 76, 3039.
54. Ceder, O.; Vernmark, K. ACS 1973, 27, 3259.
55. Tomoeda, M.; Furuta, T.; Koga, T. CPB 1967, 15, 887.
56. Kopecky, J.; Smejkal, J. TL 1967, 1931.
57. Snyder, H. R.; Konecky, M. S. JACS 1958, 80, 4388.
58. Gerlach, H.; Muller, W. AG(E) 1972, 11, 1030.
59. (a) Cope, A. C.; Burrows, E. P.; Derieg, M. E.; Moon, S.; Wirth, W. D. JACS 1965, 87, 5452. (b) Stone, H.; Shechter, H. JOC 1950, 15, 491.
60. Kispersky, J. P.; Klager, K. JACS 1955, 77, 5433.

John H. Dodd

The R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA



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