Nitration of alkyl halides

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 

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 

Several improved methods for the nitration of alkyl halides have been reported. For example, the use of KN02 in the presence of lS-crown-694 or nitrite ion bounded to macroporous quaternary ammonium amberlite resin (amberlite IRA 900) improves the yield of nitro compounds (Eq. 2.49) 95 

Mosher and coworkers have prepared 2-(2-nitroethy 1)-1,3-dioxolane from the corresponding 2-bromo compounds by various procedures (Eq. 2.50).96 They found that IRA-900-N02 is best for this conversion. 

A number of nitro compounds used in natural product synthesis have been prepared by the nitration of alkyl halides. Some recent examples are summarized in Table 2.4. 

Mosher and co workers have prepared 2-f2-nitroethyl -l,3-dioxo lane from thecorrespondmg 2-bromo compoimds by various procedures OEq. 2.50. They foimd thal IRA-900-NOj is besl 

DMSD DMSD-oiea DMSD lS-ctQwn-6 DMSD 

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 

Schneider and Busch have showed that tetraazafS 1 8 l paracyclophane catalyzes the nitration of alkyl bromides with sodiiun nitrite In dioxane-water d l at 30 C, the reaction of 2-bromomethylnaphthalene with sodiiun nitrite is accelerated by a factor of 20 in the presence of the catalyst Concomitantly, the product ratio of [R-ONO [RNO-, changes from 0 50 1 to 016 1 Thus, an acciuruiladon of nitrite ions at the positively charged cyclophanes or IRA-900-nitrite form provides a new method for selective nitration of alkyl halides 

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For a review of formation of nitrates from alkyl halides, see Boguslavskaya, L.S. ... 

The formation of S-alkyl thiosulfate (Bunte salt) by the reaction of alkyl halide and sodium thiosulfate has been well known. Whereas a patent claimed the formation of Bunte salt from PECH and sodium thiosulfate (23), the reaction hardly proceeded in DMF owing to low solubility of sodium salt. On the other hand, both ammonium thiosulfate and PECH were soluble in HMPA-H20 (7 1 vol/vol) and the reaction proceeded homogeneously. Water soluble Bunte salt (j2, v(S0), 1200, 1020 cm-1) was isolated by pouring the reaction mixture into water and salting out with ammonium chloride. The DS based on the mercuric nitrate titration was in nearly accord with that on elemental analysis. The DS values depended on the thiosulfate concentration were shown below. 

The reaction of alkyl halides with silver nitrate constitutes an extremely useful method for the synthesis of high purity nitrate esters on a laboratory scale. ° The driving force for these reactions is the formation of the insoluble silver halide. Reactions have been conducted under homogenous and heterogeneous conditions. For the latter a solution of the alkyl halide in an inert solvent like benzene or ether is stirred with finely powdered silver nitrate. However, this method has been outdated and reactions are now commonly conducted under homogeneous conditions using acetonitrile as solvent. 

Synthesis of nitrate esters from the reaction of alkyl halides with silver nitrate... 

Alkyl halides are often used as substrates instead of alcohols. In such cases the salt of the inorganic acid is usually used and the mechanism is nucleophilic substitution at the carbon atom. An important example is the treatment of alkyl halides with silver nitrate to form alkyl nitrates. This is used as a test for alkyl halides. In some cases there is competition from the central atom. Thus nitrite ion is an ambident nucleophile that can give nitrites or nitro compounds (see 0-60).731 Dialkyl or aryl alkyl ethers can be cleaved with anhydrous sulfonic acids.732... 

In some cases, in the laboratory a method of indirect introduction of 0N02 group through the action of silver nitrate upon alkyl halides can be used. 

Heavy-metal salts, particularly those of silver, mercury, and copper, catalyze SX1 reactions of alkyl halides in much the same way that acids catalyze the SN reactions of alcohols. A heavy-metal ion functions by com-plexing with the unshared electrons of the halide, thereby making the leaving group a metal halide rather than a halide ion. This acceleration of the rates of halide reactions is the basis for a qualitative test for alkyl halides with silver nitrate in ethanol solution ... 

The interaction of alkyl halides with silver nitrite produces a mixture of the alkyl nitrite and the isomeric nitro compound in addition, alkyl nitrates may be formed. Straight-chain primary halides, preferably the bromides, give better yields than branched-chain primary, secondary, and tertiary halides. For the most part, the yields are low. In a similar manner, polynitroparaffins are obtained from polyhalides. 

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

The in situ synthesis of organoboranes via reaction of alkyl halides with magnesium in the presence of diborane can also be used to prepare coupled products (equations 20 and 21). Oxidation of the reaction mixture with alkaline silver nitrate leads to good yields of dimeric products. The reaction is successful for primary and secondary halides. A related reaction is the coupling of secondary alkyl halides in the presence of catalytic quantities of thallium salts. This procedure fails for primary alkyl halides and gives modest yields for secondary alkyl halides (equation 22). 

Uses. Tetramethylene sulfone has high solvent power for aromatics and has been used extensively by Olah and co-workers for Friedel-Crafts type nitrations and for studies of the mechanism of nitronium tetrafluoroborate nitration of alkyl-benzenes and halobenzenes in homogeneous solution. It is a superior solvent for quaternization of tertiary amines with alkyl halides, since it has a high dielectric constant and does not enter into side reactions observed with nitrobenzene and dimethylformamide. For example in the synthesis of the acridizinium salt (3), Bradsher and Parham effected quaternization of (1) with benzyl bromide in tetramethylene sulfone at room temperature in excellent yield. Several other salts analagous to (2) were obtained in good yield and in crystalline form with use of tetramethylene sulfone, whereas with other solvents the products were colored... 

Another method for the aliphatic nitration is the reaction of alkyl halide with silver nitrite, in which considerable nitro compound is formed. With alkali nitrite on the other hand, very little nitro compound is formed. This difference... 

The nitrate esters are formed with retention of configuration in contrast to the reaction of silver nitrate with alkyl halides. Furthermore, the reac-tion of benzyl alcohol shows that 0-nitration of alkylary] alcohols in transfer nitration is preferred to aromatic Onitration. 

Boon et al. have reported the alkylation of benzene with a wide number of alkyl halides in acidic chloroaluminate(lll) ionic liquids and general organic reactions in low melting chloroaluminate ionic liquids have also been described, which include chlorinations and nitrations in acidic ionic liquids. ... 

Qualitative tests for alkyl halides are useful in deciding whether the compound in question is a primary, secondary, or tertiary halide. In general, it is quite difficult to prepare solid derivatives of alkyl halides, so this discussion is limited to two qualitative tests (a) reaction with alcoholic silver nitrate solution, and (b) reaction with sodium iodide in acetone. 

Silver Nitrate Test. Alkyl halides that undergo the S l substitution reaction react with alcoholic silver nitrate (AgNOs) to form a precipitate of the corresponding silver halide. 

It will be recalled that methane (CH4) can be converted to nitromethane (H3CNO2) by the action of nitric acid on methane at high temperature (Chapter 6, Equation 6.10). The nitration of other alkanes by the same process can also be effected, but separation of the multitude of isomers that can be formed (from all but the simplest alkanes) can be difficult. Nitroalkanes, R-NO2 (sometimes accompanied by their corresponding nitrite isomers, R-ONO), can also be prepared (as shown in Chapter 7, Table 7.5e) by treatment of alkyl halides with nitrite anion (ONO ). Reduction of nitroalkanes (R-NO2) with hydrogen (H2) in the presence of a platinum (Pt) catalyst or lithium aluminum hydride (LiAIlT,) in ether produces the corresponding amine (Equation 10.18). 

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