Sulfuric Acid1

H2SO4

[7664-93-9]  · H2O4S  · Sulfuric Acid  · (MW 98.09)

(widely used protic acid solvent and catalyst;1 can oxidize aliphatic and aromatic hydrocarbons;1d can sulfonate aromatic rings1b)

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

Solubility: sol water.

Form Supplied in: liquid sold in aqueous solutions of concentrations 78, 93, 95-98, 99, 100 wt %. Sulfuric acid (fuming) contains 18-24% free Sulfur Trioxide.

Preparative Method: 100% sulfuric acid can be prepared by adding 95-98% sulfuric acid (concentrated sulfuric acid) to fuming sulfuric acid.2

Protic Acid Solvent and Catalyst.3

Sulfuric acid is an inexpensive, easily handled protic acid, solvent, and catalyst. Typical workup procedures for reactions in H2SO4 involve aqueous dilution prior to product separation.

Hydrolyses.

Nitroalkanes are readily available and their hydrolysis is an important synthetic tool. Hydrolysis of primary nitroalkanes with H2SO4, the most effective catalyst, gives carboxylic acids.4 The salts of primary or secondary nitroalkanes, when hydrolyzed with H2SO4, form aldehydes or ketones (also see Titanium(III) Chloride).5 This reaction has been applied to b,g-unsaturated nitroalkenes as a mild route to a,b-unsaturated aldehydes.5c An improved two-layer method treats the nitronate anion with H2SO4 in pentane; the product aldehyde dissolves in pentane and avoids contact with acid.5d

Vinyl halides are hydrolyzed by H2SO4 in the Wichterle reaction, a route to 1,5-diketones in which 1,3-dichloro-cis-2-butene serves as a methyl vinyl ketone equivalent.6 The hydrolysis can be controlled to avoid acid-catalyzed aldol condensation (see condensations, below).7

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

Hydrations.

Alkyne hydration generally involves mercury(II) ion catalysts.1b However, H2SO4 hydrates the alkyne (1) and also catalyzes a subsequent regio- and stereoselective cyclopentanone annulation via the Nazarov cyclization (eq 1).11 Nitriles can be selectively hydrated to amides using strong H2SO4.12

Additions.1a,b

The Ritter reaction, in which nitriles add to alkenes in conc H2SO4, is a useful procedure for preparation of amides of t-alkylcarbinamines.1b As applied to the threo a-halo alcohol (2), retention of stereochemistry is observed (eq 2).13 H2SO4 catalyzes carbonylation of a,b-unsaturated aldehydes in a 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

Sulfuric acid catalyzes the regioselective methoxybromination of a,b-unsaturated carbonyl compounds with N-Bromosuccinimide (eq 4); Boron Trifluoride, Acetic Acid, and Phosphoric Acid were unsatisfactory catalysts.15 Sensitivity to acid catalyst was also noted in the intramolecular diazo ketone cyclization of b,g-unsaturated diazomethyl ketone (3) (eq 5); H2SO4 gave a rearrangement product (4).16

Dehydrations and b-Eliminations.1b

Useful stereospecific H2SO4-catalyzed anti elimination of threo-b-hydroxyalkylsilanes is stereoselective for the cis-alkene, while Potassium Hydride mediated syn elimination affords selectively trans-alkenes (eq 6).17

Electrophilic Substitutions.1a

Sulfuric acid catalyzes nitration of aromatic carbocycles1a,b and heterocycles.18 Benzenes with meta-directing groups can be alkylated by primary and secondary alcohols in H2SO4, Polyphosphoric Acid, or 85% phosphoric acid; even nitrobenzene can be alkylated by ethanol.19 H2SO4 catalyzes the a-amidoalkylation reaction20 and is especially useful for Friedel-Craft ketone synthesis using anhydrides.1a For acylations with acids, PPA avoids charring, sulfonation, and ester cleavage and is generally a preferred reagent (Hydrogen Fluoride and Trifluoromethanesulfonic Acid).21 Keto acids and phenol react selectively to give phenolic esters with PPA, but ring substitution products with H2SO4.22

The utility of H2SO4 as a catalyst for the substitution of alkanes is evidenced in the formation of carboxylic acids by trans carboxylation (eq 7);23 the hydrocarbon must have a tertiary hydrogen and the acid source for CO must be a tertiary alkyl acid.

Carbonyl Reactions.1a,b

H2SO4 is considerably more effective than p-Toluenesulfonic Acid for conversion of anthrone to 9-alkoxyanthracenes.24 A practical procedure for regioselective formation of pyridoxine dimethyl acetal which replaces anhydrous TsOH utilizes 96% H2SO4 (eq 8).25

H2SO4 catalyzes esterification of highly hindered aromatic acids,1b and it catalyzes the formation of N-acylamides from acid anhydrides and amides.26 A rapid esterification procedure involves reaction of primary, secondary, or tertiary alcohols with acids in H2SO4 using ultrasound.27

Condensations.

Sulfuric acid is a useful reagent for the synthesis of heterocycles by dehydrative cyclization.18,28 Yields in the Skraup quinoline synthesis, which utilizes sulfuric acid as the condensing agent, are remarkably sensitive to H2SO4 concentration.29

Sulfuric acid-catalyzed aldol condensations of 1,5-diketones in H2SO4 are under thermodynamical control30 and products may differ from those of base-catalyzed reactions (eqs 9 and 10).7,31,32

Rearrangements.

The choice of acid catalyst can influence skeletal rearrangements; for example, H2SO4 and H3PO4 can afford different products in polyene cyclizations (eq 11).33 The reductive rearrangement of alcohol (5) gave different products in H2SO4 and H3PO4 (eq 12).34

For functional group isomerizations, H2SO4 is useful in the Beckmann rearrangement of oximes and the Hofmann-Loffler-Freytag reaction of N-haloamines and amides.1b H2SO4 is superior to BF3 in the isomerization of a-epoxycyclopentanones to a-hydroxycyclopentenones (eq 13).35 The formation of 2-oxoadamantane from bicyclo[3.3.1]nonane-2,6-diol is highly sensitive to acid concentration and requires 95% H2SO4 for optimum yield.36

Choice and strength of acid catalyst can have regiochemical consequences. H2SO4-catalyzed Wallach rearrangement of azoxybenzenes provides mainly p-hydroxyazobenzenes, while Antimony(V) Chloride gives mainly ortho products.37 Regiochemistry in the Schmidt reaction of ketones can be dependent upon H2SO4 concentration (eq 14).38

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

Catalyzed Oxidations.1b

Sulfuric acid is the catalyst of choice for m-Chloroperbenzoic Acid oxidation of unreactive 11-keto steroids,42 and it catalyzes the NaBO3 oxidation of alkenes in Ac2O to trans-diols.43

Dehydrogenation.

H2SO4 acts as solvent, catalyst, and selective oxidizing agent in the formation of 2-pyridones from cyclic cyano ketones (eq 17).44 Aromatization of unsaturated carbocyclic rings can be effected using H2SO4 and heat,1d and a-alkylcyclohexanones can be converted to o-alkylphenyl acetates by reaction using H2SO4 (eq 18).45 Intermolecular dehydrogenation of an aminonaphthalene to a biphenyl occurs with 66% H2SO4 (eq 19).46

Hydroxylation.

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

Sulfonation.

Sulfonation of b-carbolines occurs in concentrated H2SO4; pyrrole, indole, and carbazole do not sulfonate under the conditions.48

Formation of Reducing Agents.

An easily scaled-up method to convert amino acids to amino alcohols without affecting N-tosyl or N-Cbz groups uses H2SO4/Sodium Borohydride (see also Aluminum Hydride).49


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Grant R. Krow

Temple University, Philadelphia, PA, USA



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