Nitromethane

MeNO2

[75-52-5]  · CH3NO2  · Nitromethane  · (MW 61.05)

(building block in synthesis; polar solvent)

Physical Data: mp -28.5 °C; bp 101 °C; d 1.13 g cm-3; dipole moment 3.5 D.

Solubility: completely misc most organic solvents; slightly sol petroleum ether, water; sol alkaline solution.

Form Supplied in: colorless liquid, widely available.

Purification: purified by drying over MgSO4 and distilling; a small acidic forerun is discarded.

Handling, Storage, and Precautions: stable compound. It is advised not to distill large quantities at reduced pressure. Flammable; toxic. Gives shock- and heat-sensitive alkali and heavy metal salts. Do not dry the sodium salt.

Introduction.

Nitromethane is a common starting material for the synthesis of aliphatic nitro compounds, which serve as valuable building blocks, providing access to a variety of other functionalized products such as 2-nitro alcohols, nitroalkanes, nitroalkenes, hydrocarbons, amines, oximes, carbonyl compounds, and heterocycles.1 Nitromethane reacts with alkali metal hydroxides and alkoxides to form the metal nitronates which are used as in situ generated reagents. The alkali metal nitronates are unstable and it is advisable not to isolate them. The sodium salt of nitromethane undergoes violent decomposition or detonation on heating and drying.

The Nitroaldol Reaction (Henry Reaction).2

Reactions with Aldehydes.

In the presence of base, nitromethane reacts with aliphatic aldehydes in an aldol-type reaction with formation of 2-nitro alcohols (nitroaldols). Due to its reversibility, the reaction is normally carried out in the presence of only catalytic quantities of base, although in certain cases stoichiometric amounts are used to precipitate the product.3 The reaction of nitromethane with aldehydes in the presence of one equivalent of base gives the salt of the aci-nitro tautomer of the product, which must be carefully acidified to avoid the Nef reaction. Alkali metal hydroxides, alkoxides or carbonates, and tertiary amines are effective catalysts.2a Elimination of water, the aldol reaction, and the Cannizzaro reaction are competing side reactions.2a,b 2-Nitro alcohols are unstable compounds and care has to be exercised during workup (decomposition during distillation). Fluoride ion catalysts often give higher yields.4 The reaction has been carried out in the absence of solvent using powdered NaOH,5 Al2O3,6 and Al2O3-supported KF7 as catalysts. The 2-nitro alcohols are readily converted into a variety of functionalities (eq 1).1b,4,5,7-13,16-21

Aromatic aldehydes react smoothly with nitromethane under the same conditions.14 Elimination of water to give b-nitrostyrenes takes place on acidification.2a Synthesis of b-nitrostyrenes can be accomplished in one step by heating aromatic aldehydes in acetic acid and with NH4OAc as catalyst.15 Dehydration of 2-nitro alcohols to nitroalkenes has been accomplished with Methanesulfonyl Chloride,16 phthalic anhydride,17 1,3-Dicyclohexylcarbodiimide,18 pivaloyl chloride,19 Trifluoroacetic Anhydride,20 and Acetic Anhydride.20 Heating 2-nitro alcohols in dichloromethane in the presence of basic aluminium oxide is another mild method for the synthesis of nitro alkenes.21 Nitroalkenes can be converted into a variety of functionalities (eq 2)2,5,22,24-30 and have found utility as heterodienes in hetero Diels-Alder reactions and as reactants in Lewis acid promoted tandem [4 + 2]/[3 + 2] cycloadditions.23

A catalytic asymmetric nitroaldol reaction has been developed.31 The catalyst is formed from Lanthanum(III) Chloride, the dilithium salt of (R)-1,1-Bi-2,2-naphthol, NaOH, and H2O in a 1:1:1:10 molar ratio in THF. Nitromethane reacts with various aldehydes in the presence of 10% of the catalyst to give 2-nitro alcohols in high yields and with an ee as high as 93% (eq 3). Chiral binaphthol complexes of other rare earth metal trichlorides show similar catalytic effects. The optical purities of nitroaldols obtained using these rare earth metal complexes as asymmetric catalysts are highly dependent on the amount of water present and on the relation between substrate and radius of the rare earth metals.

Nitromethane can react with two mol equiv of an aldehyde.2a The reaction with the second aldehyde molecule proceeds slower than that with the first due to the lower acidity of the a-proton in 2-nitro alcohols and enhanced steric hindrance. With sterically hindered aldehydes, the reaction with the second aldehyde is difficult.2b,d Seebach et al.32 synthesized the multiple coupling reagent 2-nitro-2-propenyl 2,2-dimethylpropanoate (NNP) from nitromethane. In the initial step, nitromethane reacts with two moles of formaldehyde to give 1,3-dihydroxy-2-nitropropane in 95% yield. Subsequent acylation with two mol equiv of pivaloyl chloride and elimination of pivalic acid gives NNP. The reaction may be run on a 40 to 200 g scale without problems (eq 4). NNP allows succesive introduction of two different nucleophiles Nu1 and Nu2 (eq 5).

With dialdehydes, nitromethane forms cyclic nitro compounds.33 Nitromethane reacts with glyoxal at pH 10 to give a mixture of isomeric inositol derivatives from which neo-inositol, one of 14 possible diastereomers, precipitates (72% yield) (eq 6).

Tartaraldehyde gives a mixture of stereomeric nitro-2,3,4,5-cyclopentanetetraols.33 With o-phthalaldehydes, nitromethane reacts in alcoholic alkali to give, after acidification, 2-nitro-3-hydroxyindenes.33 Dialdehydes derived from periodate cleavage of sugars react with nitromethane in a one-pot cyclization reaction to give, frequently, one predominant stereoisomer (eq 7).33,34

meso-1,5-Dialdehydes react with nitromethane in methanol and a catalytic amount of NaOH to give a crude mixture of 2,6-dihydroxynitrocyclohexanes from with the major trans,trans-isomer precipitates (eq 8).35 The diacetates of carbocyclic and heterocyclic six-membered compounds formed by this reaction can be saponified enantioselectively with pig liver esterase (PLE) to give monoacetates of >95% ee.35

In the presence of primary or secondary amines, aldehydes react with nitromethane in a Mannich-type reaction.2d

Reactions with Ketones.

Unlike other nitroalkanes, nitromethane often gives satisfactory yields in the reaction with ketones.2b The reaction is complex and depends on the ratio of reactants, base, temperature, and time (eq 9).2a

With alkali metal hydroxides or alkoxides, quaternary ammonium hydroxides, primary or tertiary amines, or Tetra-n-butylammonium Fluoride under pressure36 it is usually possible to stop the reaction at the nitro alcohol stage.2d When the reaction is catalyzed by secondary amines, nitroalkenes are isolated.37 From 3b-hydroxyandrost-5-en-17-one, nitromethane, and 1% 1,2-Diaminoethane as catalyst, an exocyclic nitroalkene is obtained (eq 10),38 although exocyclic nitroalkenes often rearrange to the endocyclic b,g-nitroalkenes. With N,N-dimethylethylenediamine as base, it is possible to selectively synthesize allylic nitro compounds from both acyclic and alicyclic ketones (eq 11).39

Nitromethane has been used in the Tiffeneau-Demjanov ring expansion of cyclic ketones by reduction of the nitro alcohol to the b-hydroxy amine and diazotization (eq 12).40

Michael Reactions.

Conjugate addition of nitromethane to activated double bonds is another important C-C bond forming reaction (eq 13). Unsaturated aldehydes give rise to competing 1,2-addition (Henry reaction), which can be controlled to some extent by the choice of catalyst.2a Michael additions with nitromethane are catalyzed in homogeneous solution with catalysts such as alkali metal hydroxides in alcohol,41 organic nitrogen bases,42 and fluoride ions.43 The reaction is also catalyzed in heterogeneous systems with alumina44 or Al2O3-supported KF or CsF.45 Nitromethane reacts smoothly with two moles of Michael acceptors to give a variety of coupling products (eq 13).43,44

Nitromethane has been employed in cyclopropanation.46 The product is formed by Michael addition of nitromethane to a double bond with two geminal electron withdrawing groups followed by elimination of the nitro group (eq 14).

Acylation of Nitromethane.

With few exceptions, acylation of sodium methanenitronate with acyl halides or anhydrides occurs on oxygen. The unstable products rearrange into hydroxamic acid derivatives. C-Acylation can be accomplished with acylimidazoles,47 acyl cyanide,48 and phenyl benzoates49 and from benzoic acids by the action of Diethyl Phosphorocyanidate (eq 15).50

Carboxylation can be accomplished by reaction with methoxymagnesium methyl carbonate (Stiles reagent).51 Another method for the preparation of methyl 2-nitroacetate is by heating nitromethane at 160 °C in the presence of KOH, followed by acidification of the nitronate salt at -15 °C in the methanolic solution (eq 16).52

The dilithium salt of nitromethane reacts with carboxylic esters at -30 °C to form the b-oxo nitronate, which must be carefully acidified at -90 °C with acetic acid (eq 17).53 The dilithium salt of nitromethane is formed by treatment of nitromethane with n-Butyllithium in THF/HMPA at -65 °C.53 The dilithium salt is a much harder carbon nucleophile than the sodium nitronate.

Alkylation of Nitromethane.

The ambident methanenitronate ion reacts with alkyl iodides to give a mixture of C-alkylated and primarily O-alkylated compounds. The alkyl nitronates of nitromethane are very unstable and decompose to carbonyl compounds and formaldoxime.54 The sodium salt of nitromethane can be selectively C-benzylated with 1-benzyl-2,4,6-triphenylpyridinium tetrafluoroborate in good to moderate yields.55 The pyridinium cations are readily available from 2,4,6-Triphenylpyrylium Tetrafluoroborate and the corresponding benzylamines.55

The dilithium salt of nitromethane is C-alkylated with 1-iodohexane in moderate yield.56 Kornblum et al. has reported on a general high yielding method for the C-alkylation of nitromethane with tertiary nitro compounds (eq 18).57 The tertiary nitro group is substituted with nitromethane in a radical chain process. The reaction is carried out at 25 °C in DMSO with exposure to fluorescent light and the molar ratio of tertiary nitro compound, nitromethane, and NaH is 1:4:8.

1,3-Dipolar Cycloadditions of Nitromethane.

Nitromethane can be O-silylated with Chlorotrimethylsilane in the presence of Triethylamine.58a The trimethylsilyl methanenitronate is unstable and dimerizes, but it can be trapped with an activated alkene in a 1,3-dipolar cycloaddition to give isoxazolidines which, upon acid treatment, give isoxazolines (eq 19).58

In contrast to other primary nitro compounds, the corresponding nitrile oxide (fulminic acid) of nitromethane is not formed in the Mukaiyama reaction.59 When nitromethane is treated with Phenyl Isocyanate, a-nitroacetanilide is formed first and is subsequently transformed to the nitrile oxide with a second mol equiv of phenyl isocyanate (eq 20). The nitrile oxide reacts with terminal double bonds in a regioselective manner to give 3,5-substituted isoxazolines.59

Related Reagents.

t-Butyldimethylsilyl Ethylnitronate; Lithium a-Lithiomethanenitronate; O,O-Dilithio-1-nitropropene; Nitroethane; 1-Nitropropane; 1-Nitro-1-propene.


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Kurt B. G. Torssell & Kurt. V. Gothelf

Aarhus University, Denmark



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