Polyphosphoric Acid
1[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 pento-xide content.
Solubility: dissolution in any protic solvent will result in
solvo-lysis of the reagent; dissolution in polar aprotic solvents could result in dehydration or destruction of the solvent; polyphos-phoric 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
sol-vent 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.2Eaton’s reagent (see Phospho-rus(V) Oxide–Methanesulfonic Acid) has been found to per-form similar chemistry at lower temperatures without the vis-cosity 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 mem-branes 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 orthophos-phoric acid and linear phosorthophos-phoric acids. In order to simplify discussion of this reagent, the complex mixture is described empirically as a wt % of P2O5in water. The distribution of phos-phoric acids that are found in PPA is dependent upon the wt % of P2O5. Commercially available PPA contains 82–85% P2O5, with 83% P2O5considered to be the standard. At this concentra-tion there is no free water and the distribuconcentra-tion 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 nucleophilic-ity of the phosphoric acid media, and moderate acidnucleophilic-ity 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),4tetralones (eq 2),5and benzosuberones (eq 3).6
Anomalous results for the cyclization of 3-(2-methoxyphenyl)-propionic acid led researchers to discover a method for synthe-sis of metacyclophanes (eq 4).7Another 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
CO2H (1) O PPA 100 °C, 2 h 93% (2) CO2H PPA 70 °C, 40 min O 93% (3) CO2H O PPA 95 °C, 2 h 84% OMe CO2H O O OMe MeO (4) PPA 70–80 °C, 30 min 46% (5) PPA 130 °C CO2H HO2C O O 18% (6) 100 °C, 2–3 h CO2R O R = H, 74% R = Et, 72% PPA
Methoxy or alkyl substitution of the aromatic ring has also been found to allow shorter reaction times and lower reac-tion temperatures.10Cyclization 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 rearrange-ment 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
(7) PPA 160 °C, 45 min O O O 95% (8) PPA 100 °C, 15 min F CHO F >56% OMe OH OMe (9) PPA 60 °C 24% PPA (10) OH 90% PPA 70–80 °C H (11) 57%
Cyclization onto Nonaromatic Moieties. Cyclopentenones have been synthesized from carboxylic acids in good yield (eqs 12–14).16Compared with other protic acids, PPA has
demon-strated the ability to favor carbon–carbon bond formation over lactone formation.17 (12) PPA CO2H O 96% (13) PPA 70–80 °C, 3 h O CO2H 82% CO2H Pr O Et (14) 60% PPA
Synthesis of cyclohexenones from alkenyl acids has been demonstrated (eq 15);18however, formation of methylcyclopen-tenones and lactones may occur when possible (eq 16).19
(15) PPA 110 °C, 4 h CO2H O 59% CO2H PPA O O O O (16) + + 90 °C 120 °C 140 °C 2% 22% 29% 5% 13% 3% 47% 34% 3%
Cyclization Reactions That Form Heterocycles. Use of PPA as an acid catalyst to form heterocyclic compounds has been ex-haustively 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 in-dole synthesis) (eq 17).20
N H N Ph N H Ph (17) PPA 120 °C 76%
Use of PPA in the Bischler–Napieralski reaction has shown superior results to other reagents for construction of the iso-quinoline ring system.21For example, dihydroisoquinolines are obtained from phenethylformamides in yields superior to phosphorus pentoxide (eq 18).22In the first report which popular-ized the use of PPA in organic synthesis, treatment of
N-acetyl-β-phenethylamine with PPA gave the 1-methyl-3,4-dihydro-isoquinoline in 23% yield (eq 19).23Synthesis 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
N HN CHO (18) PPA 160–180 °C, 2 h 79% N HN COMe (19) PPA 160 °C, 1.5 h isolated as picrate 23%
N N OMe MeO OMe MeO
EtO OEt PPA
100 °C, 14 h
(20) 15%
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),27or from amido ketones (eq 23).28 (21) PPA 110 °C, 2 h N H CO2H Cl N H Cl O 66% (22) PPA 80 °C, 10 h N H O OH N H NH2 NH2 O 87% PPA 143 °C, 30 min N H O O Ph N H Ph O (23) 69%
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 dihydrobenzonaph-thyridinone (eq 24). When the hexahydrobenzindolizine itself was treated with PPA the compound simply dehydrated with-out 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
N N O OH N N
yield not reported
(24) 100 °C H O PPA N O O N O (25) PPA 140 °C, 1 h 70%
Alkyl- or chloro-substituted isatins were obtained more conve-niently with PPA than with sulfuric acid (eq 26).30Synthesis of
the bacterial coenzyme methoxatin was facilitated by use of PPA to synthesize the pivotal isatin intermediate (eq 27).31
+ 60 °C, 6 h 26% N H N O OH (26) N H N H O O O O 43% PPA (27) N H N OH MeO PPA 100 °C, 20 min N H O O MeO OMe O OMe 70%
Complex lactams were stereoselectively assembled in a beau-tifully 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 mix-tures of (E) and (Z) isomers (eq 29).33Other nitrogen-containing heterocyclic systems which can be obtained using PPA include benzimidazoles (eq 30)34and triazoles (eq 31).35
NH2 O H O N H H H (28) O PPA 35 °C, 72 h + 74% Ph HN O CO2H N O Ph O Ph Ph CHO (29) PPA 80–95 °C, 1.5 h + 90% NH2 NH2 N H N Ph (30) PPA 250 °C, 4 h PhCO2H 75% Ph O N H O NH NH Ph Ph N N N Ph OH (31) PPA 65 °C, 45 min 76%
Oxygen and Sulfur Heterocycles. Diphenylfurans are formed in higher yields with PPA than with sulfuric acid, Acetic
Anhydride, or phosphorus pentoxide as the dehydrating/cycli-zation 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).37The 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 benzox-epinones, can be made in good yield from 4-phenoxybutyric acids (eq 35).39 Benzofurans are formed in good yield by cyclization
of α-phenoxy ketones (eq 36).40Thienopyrroles are obtained by ring closure of a pyrrolecarboxylic acid (eq 37).41
O Ph Ph (32) PPA 130 °C, 1.5 h Ph Ph O O 95% (33) O CO2H O O PPA 87% OMe O OMe OMe MeO OH OMe MeO O O (34) PPA 80% O O O F (35) F CO2H PPA 65 °C, 1 h 75% (36) PPA 100 °C, 3 h O O O 93% (37) PPA 125 °C N H CO2H S N H S O 36%
Rearrangements and Isomerizations. The same characteri-stics which facilitate cyclizations, such as media with low nucleo-philicity, 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 Chlo-ride/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
Ph Ph N OH Ph N Ph O H (38) PPA 100 °C 99% (39)
yield not specified N H O NOH rt, 16 h PPA
Treatment of aromatic carboxylic acids with Nitromethane and PPA (Lossen rearrangement) gives high yields of anilines (eq 40).44Although 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 (40) CO2H PPA NH2 115 °C, 1.5 h Cl Cl + MeNO2 60% (41) Ph O Ph H N O PPA 50 °C, 7 h NaN3 98% +
Wagner–Meerwein rearrangements and, more generally, car-bonium 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).46Ring
contraction was found to occur when a thiochromene was treated with PPA (eq 43).47
(42) PPA 160 °C, 0.5 h CH2OAc NO2 NO2 89% (43) PPA 100 °C, 3 h S S i-Pr moderate yield
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
(44) Ph CO2H Ph HO2C PPA 80–95 °C, 1.5 h 100%
yield not specified Ph CO2H Ph CO2H (45) 80–95 °C, 1.5 h PPA N O Ph O N O Ph O MeO OMe (46) PPA 100 °C, 1.5 h 90%
Intermolecular Reactions. PPA is generally used as an tramolecular catalyst but has demonstrated limited utility for in-termolecular alkylations. Due to the elevated temperatures nec-essary to achieve catalysis (and reduce PPA viscosity), most re-actions 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 phe-nol, alkylation can proceed under moderate conditions (eq 47).49
(47) PPA 85 °C, 40 min OH OH OH OH + + 58% combined yield
Acylations with PPA are much more prevalent. In the seven years between the first popularized use of PPA in 195023and the Popp and McEwen review,1bover 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).51Acylation of phenols is problematic due to competing ester formation (eq 50).52
(48) PPA 55 °C, 45 min O MeCO2H 60% + (49) CO2H OMe O PPA 75 °C, 5 h OMe + 85% OH Ph CO2H OH O O Ph Ph O (50) 100 °C, 20 min + + 16% 68% PPA
Miscellaneous Uses of Polyphosphoric Acid. Nitrile hydrol-ysis to amides is commonly carried out using PPA. At 100–110◦C, nitriles are routinely converted to amides (eq 51).53
(51)
Ph CN Ph CONH2
PPA 110 °C, 1 h
96%
When the temperature is raised to 200◦C, decyanation of aro-matic nitriles often results.54Reagents 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).55PPA/POCl3affords a medium which is used to convert tertiary alcohols into chlorides (eq 53).56 (52) PPA, EtSH O O O H H O O O H H O SEt 90 °C (53) PPA, POCl3 ∆ OH Cl 75–80%
In an attempt to generate HCl in situ during cyclization of a tetraamine, a PPA/NaCl mixture was superior to PPA alone (eq 54).57PPA/Acetic Acid was used to synthesize nonenolizable
β-diketones (eq 55).58 Although Wagner–Meerwein rearrange-ments 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 (54) PPA, NaCl 165 °C, 4 h H2N NH2 NH2 NH2 N H2N NH2 33%
(55) CO2H O O O PPA, AcOH 100 °C, 7 h 75% (56) PPA, KI 135–140 °C, 5 h MeO I 99% i-Pr CO2Et CO2Et i-Pr (57) PPA, HNO3 60 °C, 1 h NO2 CO2Et CO2Et 78%
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Chem. Rev. 1958, 58, 321; and (c) Uhlig, F.; Snyder, H. R. In Advances in Organic Chemistry: Methods and Results; Raphael, R. A.; Taylor,
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John H. Dodd
The R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA
