SULFURIC ACID 1

Sulfuric Acid1

H2SO4

[7664-93-9] H2O4S (MW 98.09)InChI = 1/H2O4S/c1-5(2,3)4/h(H2,1,2,3,4)/f/h1-2HInChIKey = QAOWNCQODCNURD-KRMADWITCT

(widely used protic acid solvent and catalyst;1 can oxidize ali-phatic and aromatic hydrocarbons;1d can sulfonate aromatic

rings1b)

Physical Data: mp 3 ◦C (98% sulfuric acid); bp 290+ ◦C; d 1.841g cm−3 (96–98% sulfuric acid).

Solubility: sol water.Form Supplied in: liquid sold in aqueous solutions of concen-

trations 78, 93, 95–98, 99, 100 wt %. Sulfuric acid (fuming)contains 18–24% free Sulfur Trioxide.

Preparative Methods: 100% sulfuric acid can be prepared byadding 95–98% sulfuric acid (concentrated sulfuric acid) tofuming sulfuric acid.2

Protic Acid Solvent and Catalyst.3 Sulfuric acid is aninexpensive, easily handled protic acid, solvent, and catalyst.Typical workup procedures for reactions in H2SO4 involveaqueous dilution prior to product separation.

Hydrolyses. Nitroalkanes are readily available and theirhydrolysis is an important synthetic tool. Hydrolysis of primarynitroalkanes with H2SO4, the most effective catalyst, gives car-boxylic acids.4 The salts of primary or secondary nitroalkanes,when hydrolyzed with H2SO4, form aldehydes or ketones (alsosee Titanium(III) Chloride).5 This reaction has been applied toβ,γ-unsaturated nitroalkenes as a mild route to α,β-unsaturatedaldehydes.5c An improved two-layer method treats the nitronateanion with H2SO4 in pentane; the product aldehyde dissolves inpentane and avoids contact with acid.5d

Vinyl halides are hydrolyzed by H2SO4 in the Wichterle reac-tion, a route to 1,5-diketones in which 1,3-dichloro-cis-2-buteneserves as a methyl vinyl ketone equivalent.6 The hydrolysis canbe controlled to avoid acid-catalyzed aldol condensation (seecondensations, below).7

Sulfuric acid is a useful catalyst for cleavage of protectinggroups,8 and has been used to cleave TBDMS protecting groupsin the presence of TBDPS groups.9 A useful method for resolu-tion of chiral ketones involves formation and separation of chiralhydrazones followed by hydrolysis with 10% H2SO4.10

Hydrations. Alkyne hydration generally involves mercury(II)ion catalysts.1b However, H2SO4 hydrates the alkyne (1) and alsocatalyzes a subsequent regio- and stereoselective cyclopentanoneannulation via the Nazarov cyclization (eq 1).11 Nitriles can beselectively hydrated to amides using strong H2SO4.12

Additions.1a,b The Ritter reaction, in which nitriles add toalkenes in conc H2SO4, is a useful procedure for preparationof amides of t-alkylcarbinamines.1b As applied to the threo α-halo alcohol (2), retention of stereochemistry is observed (eq 2).13

H2SO4 catalyzes carbonylation of α,β-unsaturated aldehydes ina general synthesis of 3,4-dialkyl-2(5H)-furanones (eq 3).14

Michael additions to conjugated ketones are catalyzed by H2SO4

(see condensations, below).7

i-Pr

OH

OH

i-Pr

O

i-Pr

O

(1)

(1)

64% 10%

+

H2SO4

MeOH

+ MeCNHO Br AcHN Br

(2)H2SO4

(2)

81%

O

O

Et (3)Et O96% H2SO4

+ CO (6–9 MPa)44%

Sulfuric acid catalyzes the regioselective methoxy-bromination of α,β-unsaturated carbonyl compounds withN-Bromosuccinimide (eq 4); Boron Trifluoride, Acetic Acid,and Phosphoric Acid were unsatisfactory catalysts.15 Sensitivityto acid catalyst was also noted in the intramolecular diazo ketonecyclization of β,γ-unsaturated diazomethyl ketone (3) (eq 5);H2SO4 gave a rearrangement product (4).16

Ph

O

MeO Ph

Br

O

(4)

conc H2SO4 (cat)NBS, MeOH

91%

OMe

COCHN2

OMe

O

OMe

O98% H2SO4

MeNO2, 25 °C

BF3 etherateMeNO2, 25 °C(3)

(5)

OH

(4)

70%

79%

Dehydrations and β-Eliminations.1b Useful stereospecificH2SO4-catalyzed anti elimination of threo-β-hydroxyalkylsilanesis stereoselective for the cis-alkene, while Potassium Hydride

Avoid Skin Contact with All Reagents

2 SULFURIC ACID

mediated syn elimination affords selectively trans-alkenes(eq 6).17

Pr

Pr+

H2SO4, THFKH, THF

Pr

92%96%

Pr

100: 0 5:95

Pr

TMS OH

Pr(6)

Electrophilic Substitutions.1a Sulfuric acid catalyzes nitra-tion of aromatic carbocycles1a,b and heterocycles.18 Benzeneswith meta-directing groups can be alkylated by primary andsecondary alcohols in H2SO4, Polyphosphoric Acid, or 85%phosphoric acid; even nitrobenzene can be alkylated byethanol.19 H2SO4 catalyzes the α-amidoalkylation reaction20 andis especially useful for Friedel–Craft ketone synthesis using anhy-drides.1a For acylations with acids, PPA avoids charring, sul-fonation, and ester cleavage and is generally a preferred reagent(Hydrogen Fluoride and Trifluoromethanesulfonic Acid).21

Keto acids and phenol react selectively to give phenolic esterswith PPA, but ring substitution products with H2SO4.22

The utility of H2SO4 as a catalyst for the substitution ofalkanes is evidenced in the formation of carboxylic acids bytrans carboxylation (eq 7);23 the hydrocarbon must have atertiary hydrogen and the acid source for CO must be a tertiaryalkyl acid.

CO2H

98% H2SO430 °C

(7)+ Et2(Me)CCO2H84%

Carbonyl Reactions.1a,b H2SO4 is considerably more effec-tive than p-Toluenesulfonic Acid for conversion of anthrone to9-alkoxyanthracenes.24 A practical procedure for regioselectiveformation of pyridoxine dimethyl acetal which replaces anhydrousTsOH utilizes 96% H2SO4 (eq 8).25

N N

O

O (8)

MeCOMeH2SO4 (10 equiv)

OH

HO

HOOH74%

H2SO4 catalyzes esterification of highly hindered aromaticacids,1b and it catalyzes the formation of N-acylamides fromacid anhydrides and amides.26 A rapid esterification procedureinvolves reaction of primary, secondary, or tertiary alcohols withacids in H2SO4 using ultrasound.27

Condensations. Sulfuric acid is a useful reagent for thesynthesis of heterocycles by dehydrative cyclization.18,28 Yieldsin the Skraup quinoline synthesis, which utilizes sulfuric acid asthe condensing agent, are remarkably sensitive to H2SO4

concentration.29

Sulfuric acid-catalyzed aldol condensations of 1,5-diketones inH2SO4 are under thermodynamical control30 and products maydiffer from those of base-catalyzed reactions (eqs 9 and 10).7–32

O

Oconc H2SO4

benzene

NaOEt, EtOHheat

(9)

OO

+major

87%

heat

O O

Et

PrPr

O

O

(10)+

3N H2SO4; 81%LDA, ether; 82%

95: 521:79

Rearrangements. The choice of acid catalyst can influenceskeletal rearrangements; for example, H2SO4 and H3PO4 can af-ford different products in polyene cyclizations (eq 11).33 The re-ductive rearrangement of alcohol (5) gave different products inH2SO4 and H3PO4 (eq 12).34

O

O

O (11)

95% H2SO425 °C

85% H3PO4100 °C

97%

72%

conc H2SO4C5H12

85% H3PO4C7H16

(12)

HO

(5) 72%

97%

For functional group isomerizations, H2SO4 is useful in theBeckmann rearrangement of oximes and the Hofmann–Loffler–Freytag reaction of N-haloamines and amides.1b H2SO4 issuperior to BF3 in the isomerization of α-epoxycyclopentanonesto α-hydroxycyclopentenones (eq 13).35 The formation of 2-oxoadamantane from bicyclo[3.3.1]nonane-2,6-diol is highlysensitive to acid concentration and requires 95% H2SO4 foroptimum yield.36

O O

Bn

O

OH

Bn

(13)

AcOH, 2% H2SO455 °C, 1 h

65%

Choice and strength of acid catalyst can have regiochemi-cal consequences. H2SO4-catalyzed Wallach rearrangement of

A list of General Abbreviations appears on the front Endpapers

SULFURIC ACID 3

azoxybenzenes provides mainly p-hydroxyazobenzenes, whileAntimony(V) Chloride gives mainly ortho products.37 Regio-chemistry in the Schmidt reaction of ketones can be dependentupon H2SO4 concentration (eq 14).38

O

NHMe

O

NHCOMe (14)+

89% H2SO450% H2SO4

27:7390:10

NaN3

H2SO4 can catalyze stereochemical isomerizations (eq 15);thermodynamic conditions afforded cis-lactone (6); the diastere-omeric cis-lactone is formed under kinetic control with FormicAcid or Tin(IV) Chloride.39 If a chiral center is present, enan-tioselective allylic alcohol rearrangement40 and enantioselectivealkene cyclization can be catalyzed by H2SO4 (eq 16).41

OO

98% H2SO42 h

CO2HMeO MeO H

(15)

(6)

100%

AcOH, H2SO4heat, 6–8 h

(16)

H

OAc

80%

Catalyzed Oxidations.1b Sulfuric acid is the catalyst ofchoice for m-Chloroperbenzoic Acid oxidation of unreactive 11-keto steroids,42 and it catalyzes the NaBO3 oxidation of alkenesin Ac2O to trans-diols.43

Dehydrogenation. H2SO4 acts as solvent, catalyst, and selec-tive oxidizing agent in the formation of 2-pyridones from cycliccyano ketones (eq 17).44 Aromatization of unsaturated carbo-cyclic rings can be effected using H2SO4 and heat,1d and α-alkylcyclohexanones can be converted to o-alkylphenyl acetatesby reaction using H2SO4 (eq 18).45 Intermolecular dehydrogena-tion of an aminonaphthalene to a biphenyl occurs with 66% H2SO4

(eq 19).46

96% H2SO425 °C, 3 h

O

CN

NH

O

(17)77%

conc H2SO4, AcOH, Ac2Oheat

O

R R

OAc

(18)60–90%

66% H2SO4heat, 50 h

(19)H2N NH2NH2

74%

Hydroxylation. Hydroxylation of nitro and hydroxyl-substituted fused aromatic rings can be effected with sulfuricacid under forcing conditions.1d Adamantanone has been preparedfrom adamantane using 98% H2SO4 as oxidant.47

Sulfonation. Sulfonation of β-carbolines occurs in concen-trated H2SO4; pyrrole, indole, and carbazole do not sulfonate un-der the conditions.48

Formation of Reducing Agents. An easily scaled-up methodto convert amino acids to amino alcohols without affecting N-tosyl or N-Cbz groups uses H2SO4/Sodium Borohydride (see alsoAluminum Hydride).49

1. (a) Olah, G. A. Friedel-Craft and Related Reactions; Interscience: NewYork, 1963–65; Vols. I–IV. (b) March, J. Advanced Organic Chemistry,4th ed.; Wiley: New York, 1992. (c) Kirk-Othmer Encyclopedia ofChemical Technology, 3rd ed.; Wiley: New York, 1983; Vol. 22, p 190.(d) Methoden Org. Chem. (Houben-Weyl) 1981, IV/1a, 323.

2. Fieser & Fieser 1981, 9, 441.

3. Cox, R. A., Acc. Chem. Res. 1987, 20, 27.

4. Crandall, R. B., Locke, A. W., J. Chem. Soc. (B) 1968, 98.

5. (a) Noland, W. E., Chem. Rev. 1955, 55, 137. (b) Pinnick, H. W., Org.React. 1990, 38, 655. (c) Lou, J.-D.; Lou, W.-X., Synthesis 1987, 179.(d) Chikashita, H.; Morita, Y.; Itoh, K., Synth. Commun. 1987, 17, 677.

6. House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: New York,1972; p 611.

7. Steen, R. v. d.; Biescheuvel, P. L.; Erkelens, C.; Mathies, R. A.;Lugtenburg, J., Recl. Trav. Chim. Pays-Bas 1989, 108, 83.

8. (a) Kunz, H.; Waldmann, H., Comprehensive Organic Synthesis 1991,6, Chapter 3.1. (b) Greene, T. W.; Wuts, P. G. M. Protective Groups inOrganic Synthesis, 2nd ed.; Wiley: New York, 1991.

9. Franke, F.; Guthrie, R. D., Aust. J. Chem. 1978, 31, 1285.

10. Fernandez, F.; Perez, C., Heterocycles 1987, 26, 2411.

11. Hiyama, T.; Shinoda, M.; Nozaki, H., J. Am. Chem. Soc. 1979, 101, 1599.

12. Zabricky, J. The Chemistry of Amides; Interscience: New York, 1970; p119.

13. Wohl, R. A., J. Org. Chem. 1973, 38, 3099.

14. Woo, E. P.; Cheng, F. C. W., J. Org. Chem. 1986, 51, 3706.

15. Heasley, V. L.; Wade, K. E.; Aucoin, T. G.; Gipe, D. E.; Shellhamer, D.F., J. Org. Chem. 1983, 48, 1377.

16. Satyanarayana, G. O. S. V.; Roy, S. C.; Ghatak, U. R., J. Org. Chem.1982, 47, 5353.

17. Hudrlik, P. F.; Peterson, D., J. Am. Chem. Soc. 1975, 97, 1464.

18. Newkome, G. R.; Paudler, W. W. Contemporary Heterocyclic Chemistry;Wiley: New York, 1982, p 104.

19. Shen, Y.-S.; Liu, H.-X.; Wu, M.; Du, W.-Q., Chen, Y.-Q.; Li, N.-P., J.Org. Chem. 1991, 56, 7160.

20. Zaugg, H. E.; Martin, W. B., Org. React. 1965, 14, 52.

21. Popp, F. D.; McEwen, W. E., Chem. Rev. 1958, 58, 321.

22. Bader, A. R.; Kontowicz, A. D., J. Am. Chem. Soc. 1954, 76, 4465.

23. Lazzeri, V.; Jalal, R.; Poinas, R.; Gallo, R., Nouv. J. Chim. 1992, 16, 521.

24. Pirkle, W. H.; Finn, J. M., J. Org. Chem. 1983, 48, 2779.

25. Wu, Y., Ahlberg, P., Acta Chem. Scand. 1989, 43, 1009.

26. Challis, B. C.; Challis, J. A. In Comprehensive Organic Chemistry;Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol. 2, p982.

27. Khurana, J. M.; Sahoo, P. K.; Maikap, G. C., Synth. Commun. 1990, 20,2267.

Avoid Skin Contact with All Reagents

4 SULFURIC ACID

28. Paquette, L. A. Principles of Modern Heterocyclic Chemistry; Benjamin:New York, 1968.

29. Manske, R. H. F.; Kulka, M., Org. React. 1953, 7, 59.

30. Nielsen, A. T.; Houlihan, W. J., Org. React. 1968, 16, 1.

31. Larcheveque, M.; Valette, G.; Cuvigny, T., Synthesis 1977, 424.

32. Still, W. C.; Middlesworth, F. L. v., J. Org. Chem. 1977, 42, 1258.

33. Johnson, W. S., Acc. Chem. Res. 1968, 1, 1.

34. Takaishi, N.; Inamoto, Y.; Tsuchihashi, K.; Aigami, K.; Fujikura, Y., J.Org. Chem. 1976, 41, 771.

35. Barco, A.; Benetti, S.; Pollini, G. P.; Taddia, R., Synthesis 1975, 104.

36. Averina, N. V.; Zefirov, N. S., J. Chem. Soc., Chem. Commun. 1973, 197.

37. Yamamoto, J.; Nishigaki, Y.; Imagawa, M.; Umezu, M.; Matsuura, T.,Chem. Lett. 1976, 261.

38. Fikes, L. E.; Shechter, H., J. Org. Chem. 1979, 44, 741.

39. Rouessac, F.; Zamarlik, H., Tetrahedron Lett. 1979, 20, 3421.

40. Fehr, T.; Stadler, P. A., Helv. Chim. Acta 1975, 58, 2484.

41. Ansari, H. R., Tetrahedron 1973, 29, 1559.

42. Suginome, H.; Yamada, S.; Wang, J. B., J. Org. Chem. 1990, 55,2170.

43. Xie, G.; Xu, L.; Hu, J.; Ma, S.; Hou, W.; Tao, F., Tetrahedron Lett. 1988,29, 2967.

44. Meyers, A. I.; Garcia-Munoz, G., J. Org. Chem. 1964, 29, 1435.

45. Kablaoui, M. S., J. Org. Chem. 1974, 39, 2126.

46. Fierz-David, H. E.; Blangey, L.; Dubendorfer, H., Helv. Chim. Acta 1946,29, 1661.

47. Geluk, H. W.; Keiser, V. G., Org. Synth., Coll. Vol. 1988, 6, 48.

48. Munoz, M. A.; Balon, M.; Carmona, C.; Hidalgo, J.; Poveda, M. L.,Heterocycles 1988, 27, 2067.

49. Abiko, A.; Masamune, S., Tetrahedron Lett. 1992, 33, 5517.

Grant R. KrowTemple University, Philadelphia, PA, USA

A list of General Abbreviations appears on the front Endpapers