Sodium nitrite, with alkyl halides

Reaction time is extremely important in avoiding the side reaction illustrated in Eq. (1.1), where the nitroalkane product reacts with nitrite anion and any nitrite ester, formed as byproduct, to give a pseudonitrole. The reaction of sodium nitrite with alkyl halides is much faster than this competing nitrosation side reaction, even so, prompt work-up on reaction completion is essential for obtaining good yields. 

The reaction of alkyl halides with metal nitrites is one of the most important methods for the preparation of nitroalkanes. As a metal nitrite, silver nitrite (Victor-Meyer reaction), potassium nitrite, or sodium nitrite (Kornblum reaction) have been frequently used. The products are usually a mixture of nitroalkanes and alkyl nitrites, which are readily separated by distillation (Eq. 2.47). The synthesis of nitro compounds by this process is well documented in the reviews, and some typical cases are listed in Table 2.3.92a Primary and secondary alkyl iodides and bromides as well as sulfonate esters give the corresponding nitro compounds in 50-70% yields on treatment with NaN02 in DMF or DMSO. Some of them are described precisely in vol 4 of Organic Synthesis. For example, 1,4-dinitrobutane is prepared in 41 -46% yield by the reaction of 1,4-diiodobutane with silver nitrite in diethyl ether.92b 1-Nitrooctane is prepared by the reaction with silver nitrite in 75-80% yield. The reaction of silver nitrite with secondary halides gives yields of nitroalkanes of about 15%, whereas with tertiary halides the yields are 0-5%.92c Ethyl a-nitrobutyrate is prepared by the reaction of ethyl a-bromobutyrate in 68-75% yield with sodium nitrite in DMF.92d Sodium nitrite is considerably more soluble in DMSO than in DMF as a consequence, with DMSO, much more concentrated solutions can be employed and this makes shorter reaction times possible.926... 

A. number of rutro compounds used m ndturdl product synthesis have been prepared by the n of alkyl halides Some recent examples are summarized m Table 2 4 fi-Nitro carbonyl compounds are important for synthesis of natural products The reaction of alkyl vinyl ketones with sodium nitrite and acetic acid in THF gives thecorrespondmgfi-nitro carbonyl compounds in42-82% ""rhis method is better for the preparation of fi-nitro carbonyl compounds than the nitration of the corresponclmg halides... 

Sodium nitrite can be used to form nitro compounds with primary or secondary alkyl bromides or iodides, though the method is of limited scope. Silver nitrite gives nitro compounds only when RX is a primary bromide or iodide. Nitrite esters are an important side product in all these cases (10-33) and become the major product (by an SnI mechanism) when secondary or tertiary halides are treated with silver nitrite. 

Thus, the reaction of alkyl halides and a-halo esters with sodium nitrite provides a very useful synthetic method for nitroalkanes and a-nitro esters. However, ethyl bromoacetate is exceptional in that it fails to give ethyl nitroacetate on treatment with sodium nitrite.93 This is due to the acidic hydrogen of the ethyl nitroacetate, which undergoes a further reaction with sodium nitrite to give the oxidized products (see Section 6.1, which discusses the Nef reaction). In a similar way, the reaction of benzyl bromide with sodium nitrite at 25 °C gives benzoic acid predominantly. To get phenylnitromethane, the reaction must be carried out at low temperature (-16 °C) (Eq. 2.48).93... 

Schneider and Busch have showed thattetraaza[8.1.8.1]paracyclophane catalyzes the nitration of alkyl bromides with sodium nitrite. In dioxane-water (1 1) at 30 °C, the reaction of 2-bromomethylnaphthalene with sodium nitrite is accelerated by a factor of 20 in the presence of the catalyst.106 Concomitantly, the product ratio of [R-ONO] [RN02] changes from 0.50 1 to 0.16 1. Thus, an accumulation of nitrite ions at the positively charged cyclophanes or IRA-900-nitrite form provides a new method for selective nitration of alkyl halides. 

The synthesis of aliphatic nitro compounds from the reaction of alkyl halides with alkali metal nitrites was discovered by Kornblum and co-workers and is known as the modified Victor Meyer reaction or the Kornblum modification. The choice of solvent in these reactions is crucial when sodium nitrite is used as the nitrite soiuce. Both alkyl halide and nitrite anion must be in solution to react, and the higher the concentration of nitrite anion, the faster the reaction. For this reason, both DMF and DMSO are widely used as solvents, with both able to dissolve appreciable amounts of sodium nitrite. Although sodium nitrite is more soluble in DMSO than DMF the former can react with some halide substrates.Urea is occasionally added to DMF solutions of sodium nitrite to increase the solubility of this salt and hence increase reaction rates. Other alkali metal nitrites can be used in these reactions, like lithium nitrite,which is more soluble in DMF than sodium nitrite but is also less widely available. 

Silver nitrite gives significantly higher yields of nitro compounds from primary alkyl halides, and consequently, the synthesis of Q, ty-dinitroalkanes from the reaction of o, )-dihaloalkanes with sodium nitrite is inferior to the same reaction with silver nitrite (Table 1.2). However, the use of a solvent system composed of DMSO and MEK is reported to considerably improve the yields of Q , y-dinitroalkane when using sodium nitrite. ... 

Synthesis of nitroalkanes and their derivatives from the reaction of alkyl halides with sodium nitrite under the modified Victor Meyer conditions... 

The reaction of a -halocarboxylic acids with sodium nitrite has been used to synthesize ni-tromethane, nitroethane and nitropropane, although the reaction fails for higher nitroalkanes. " A number of other reactions have been reported which use nitrite anion as a nucleophile, including (1) reaction of alkyl halides with potassium nitrite in the presence of 18-crown-6, (2) reaction of alkyl halides with nitrite anion bound to amberlite resins, (3) synthesis of 2-nitroethanol from the acid-catalyzed ring opening of ethylene oxide with sodium nitrite, and (4) reaction of primary alkyl chlorides with sodium nitrite in the presence of sodium iodide. ... 

This method is clearly expensive, and nowadays the cheaper sodium nitrite is employed with the alkyl halide in dimethyl sulphoxide or dimethylformamide as solvent.197 Although the yields are a little lower than in the silver nitrite method, a further feature is that secondary halides may be converted into secondary nitroalkanes, although even this modification fails with tertiary halides. The reaction is illustrated by the preparation of 2-nitrooctane (Expt 5.189). 

In experimental work indirect methods of introducing nitro groups find wide application as, for example, the substitution of a halogen (iodine or bromine in an alkyl iodide or bromide) by the Nitro group, by means of silver nitrite (the Victor Meyer reaction), and the new modification of this method described recently by Komblum et al. [4, 4a], in which alkyl halides are reacted with sodium nitrite. 

Reaction of alkyl halides with sodium nitrite Nitromercuration of alkcncs Formation of nitroalkancs from nitrate esters Chemical properties of nitroalkancs Nitronic acids... 

Recently, however, Kornblum et al.651 showed that alkali nitrites, in particular sodium nitrite, can replace silver nitrite in the preparation of nitro compounds if dimethylformamide is used as solvent. The method has the additional advantage that not merely primary but also secondary alkyl iodides and bromides react readily in this solvent. Yields are around 60% in both cases. It usually suffices to stir the halide with an excess of sodium nitrite in dimethylformamide for some hours at room temperature primary iodides need about 2.5 hours, primary bromides about 6 hours for complete reaction. With secondary halides it is advisable to add urea as this raises the solubility... 

The silver and sodium nitrites may exist in tautomeric forms as shown in the formula and outlined in Chapter II. There is no evidence at hand at present to show which form predominates under any given conditions. When the nitrite is treated with the alkyl halide RX, in all probability an addition compound is formed which is not given in the equations, and this addition compound is in equilibrium with the two sets of products represented by equations (a) and (6).. There is no oxidation or reduction involved in either of these equations. Unquestionably both sets of products are obtained with any metallic nitrite. Which... 

Among the indirect methods of preparing aliphatic nitro compounds are the reaction of various alkyl halides with silver nitrite or sodium nitrite, the oxidation of oximes and amines with peroxy-trifluoroacetic acid, and the potassium permanganate oxidation of tertiary amines. 

The reaction of alkyl halides or dialkyl sulfates with both silver nitrite and sodium nitrite has been extensively studied by Komblum and... 

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