Sodium Nitrite1

NaNO2

[7632-00-0]  · NNaO2  · Sodium Nitrite  · (MW 69.00)

(diazotization of primary aliphatic and aromatic amines;1 N- and C-nitrosating agent;2,3 reacts with alkyl halides to form aliphatic nitro compounds4)

Physical Data: mp 271 °C; dec. above 320 °C; d 2.17 g cm-3.

Solubility: very sol water (0.815 g mL-1, 15 °C); sol DMSO, DMF; slightly sol Et2O, MeOH, EtOH.

Form Supplied in: white crystalline, hygroscopic solid; reagent grade 97%+; widely available.

Handling, Storage, and Precautions: should be kept dry in tightly closed containers. Nitrites undergo slow oxidation to the nitrate in air. Aqueous solutions of NaNO2, which are alkaline (ca. pH 9), are unstable on prolonged storage and should be made up fresh prior to use. NaNO2 decomposes in the presence of weak acids with the evolution of brown fumes of N2O3. Since NaNO2 is classified as toxic, oral ingestion should be avoided.

Introduction.

In many synthetic applications, NaNO2 is used as a convenient precursor of the unstable nitrous acid HONO which is generated in situ on treatment with a variety of mineral and carboxylic acids. Reactions involving HONO are complex because, in solution, it exists in equilibrium with a variety of other reactive species, including N2O3, nitrosyl halides, and the nitrosonium ion ON+. Although LiNO2 and KNO2 will also react in a similar fashion to the sodium salt, the latter is preferred on the basis of price and availability. Diazotization and nitrosation reactions can also be carried out using a variety of reagents including Nitrosyl Chloride and alkyl nitrites.

Reactions with Amines and Related Compounds.

In such reactions, a solution or suspension of the amine in dilute hydrochloric acid (2.5 molar equiv per mole of amine) is treated with a molar equiv of NaNO2 solution at 0-10 °C. Reactions are normally rapid and in many cases quantitative.1 The reaction outcome depends markedly on the nature of the amine. With primary aliphatic amines, the reaction (usually described as diazotization) produces the corresponding diazonium ion (1) as the first significant intermediate. This can subsequently eliminate either a molecule of nitrogen to generate a carbocation, or H+ to give a diazoalkane (eq 1).5 In the diazotization of simple primary aliphatic amines with sodium nitrite in dilute mineral acid, the former process predominates resulting in rapid evolution of N2, an observation which forms the basis for the characteristic chemical test for primary aliphatic amines.

Cycloalkylamines (ring sizes C4 and C6-C8) can undergo ring contraction on diazotization (eq 2); conversely, cycloalkylmethylamines (ring sizes C3-C8) undergo ring expansion under similar conditions (Demjanov rearrangement) (eq 3).6 Ring expansions of certain alkanolamines (ring sizes C4-C8) also occur on diazotization, affording cyclic ketones (Tiffeneau-Demjanov rearrangement) (eq 4).7 Product yields from the latter reaction are generally superior to those from the corresponding simple Demjanov rearrangements.

Diazotization of amino acids using NaNO2 in HCl affords the corresponding a-chloro carboxylic acids in moderate yield and with almost complete retention of configuration (95-98% ee) (eq 5).8 Analogous deamination/halogenation transformations have also been effected on 6b-aminopenicillanic acid (2) with inversion of configuration.9 In the presence of Bromine, the corresponding geminal dibromide (ca. 30%) is obtained;10 yields can be increased to 80% if a two-phase solvent system is used (eq 6).11 The S,S-dioxide derivative of (2) affords the corresponding geminal dibromide in good yield and high purity with methanol, rather than water, as solvent.12

When primary aliphatic amines with strongly electron-withdrawing substituents attached to the amino carbon atom are diazotized, the corresponding diazoalkanes can be isolated.5,13 Diazotization of 2,2,2-trifluoroethylamine affords the corresponding diazoalkane in 70% yield.14 Treatment of glycine ethyl ester hydrochloride with sodium nitrite in dilute sulfuric acid affords the important synthetic intermediate Ethyl Diazoacetate (eq 7).15 The benzyl ester of acid (2) has also been transformed into the corresponding a-diazo derivative using sodium nitrite in aqueous acetone.16 Attempted diazotization of 2-aminocyclohexanone results in deamination and rearrangement to cyclopentanecarboxylic acid (57%).17

Primary aromatic amines readily undergo diazotization to give the corresponding diazonium salts, which are generally stable in solution at temperatures below 0 °C.1 These are important intermediates in electrophilic aromatic substitution reactions, e.g. the formation of azo dyes, and a variety of coupling/displacement reactions including the Sandmeyer, Balz-Schiemann, and Gomberg reactions. Amines with strongly acidic groups are best diazotized by the slow addition of a solution of the amine and NaNO2 in dilute alkali to the acid with vigorous stirring.1a To avoid hydrolysis of the diazonium salt, amines with strongly electron-withdrawing groups should be diazotized in concentrated acid.1a,18 The transformation of aromatic 1,2-diamines to bis-diazonium salts should also be carried out in concentrated acid. In dilute or weak acid, the mono-diazonium ions derived from 1,2-phenylenediamines cyclize to give 1,2,3-benzotriazoles (eq 8).1a,b,19 By analogy, diazotization of p-nitro-o-toluidine affords 5-nitroindazole under similar conditions.20

Treatment of diazonium salts, preferably the tetrafluoroborates, with NaNO2 in the presence of a CuI catalyst at pH > 7 results in the formation of the corresponding aromatic nitro compounds (cf. the Sandmeyer reaction).21 For analogous reactions involving amines with strongly electron-withdrawing groups, a CuI catalyst is not required.22

Heteroaromatic amines also undergo diazotization on treatment with sodium nitrite in acid; for example, 3-aminopyridines give isolable diazonium salts whereas the 2- and 4-derivatives afford either the corresponding pyridones in dilute acid23 or halopyridines in concentrated HCl or HBr (eq 9).24 Diazotization of 2-aminopyrimidine in concentrated HCl produces 2-chloropyrimidine.25

Treatment of secondary dialkyl-, diaryl-, and alkylarylamines with sodium nitrite in mineral acid with gentle heating usually results in the formation of the corresponding N-nitrosamines which, being unable to lose a proton, are comparatively stable to further reaction (eq 10).2,26 Secondary amides will also undergo N-nitrosation.27

Although erroneously considered to be inert towards nitrosation,28 tertiary amines do undergo nitrosative dealkylation when treated with NaNO2 in aqueous acetic acid at 90 °C to give mixtures of products including dialkyl-N-nitrosamines, carbonyl compounds, and nitrous oxide (eq 11).29 A diterpenylalkanolamine was found to lose a terpenyl substituent selectively on nitrosation with NaNO2 in acetic acid.30

Nitrosation of hydrazine derivatives using NaNO2 in acid solution provides a convenient method of preparing the corresponding azide derivatives.31 For example, phenyl azide can be prepared by treating a suspension of phenylhydrazine hydrochloride in dilute HCl with NaNO2 at 0 °C in a two-phase water/ether system (eq 12).32 Highly substituted hydrazines undergo nitrosative dealkylation in an analogous fashion to give tertiary amines.33 Hydrazinium salts, derived from N,N-dimethylhydrazine and an alkyl halide, are deaminated on treatment with NaNO2 in HCl (4 M) to yield tertiary amines (eq 13).34 Like simple hydrazines, hydrazides can be converted into the corresponding acyl azides by reaction with NaNO2 in dilute HCl at low temperature.31,35

C-Nitrosation Reactions.

Aliphatic carbon centers in alkanes do not readily undergo C-nitrosation with nitrous acid unless activated by an electron-withdrawing substituent such as acyl, aroyl, carbonyl, carboxyl, nitro, cyano, imino, or aryl.3 The usual products are C-nitrosamines or oximes, depending on the degree of substitution at the carbon center in question (eq 14). Detailed procedures have been reported for the preparation of the oximes derived from the active methylene compounds Ethyl Acetoacetate and Diethyl Malonate.36,37 The unstable b-chloro- and bromopyruvaldoximes have been obtained by treatment of the appropriate g-haloacetoacetyl chlorides with NaNO2 in ether-water via a reaction sequence which involves hydrolysis and nitrosation of the resulting b-keto acid followed by decarboxylation.38

Although gaseous NOCl is generally the reagent of choice for the direct nitrosation of alkenes, the simultaneous addition of concentrated solutions of NaNO2 and hydrochloric acid to limonene in isopropanol (t < 10 °C) affords the corresponding chloro oxime in good yield (eq 15).39 The rate of nitrosation of alkenes using NaNO2 and aqueous hydrochloric acid can be accelerated to a significant extent by bromide and chloride ions.40 Tetracyclone undergoes cis-dihydroxylation on treatment with NaNO2 in acetic acid; the reaction is thought to proceed via a cycloaddition of N2O3 to one of the double bonds (eq 16).41a Under similar conditions, methyl methacrylate and tricyclone are nitrated at unsubstituted sp2 carbon centers, and 2,5-disubstituted furans ring open to unsaturated diketones.41b Isopropylidene and terpene alkenes undergo dehydromethylation to give alkynes in moderate to good yield on reaction with NaNO2 in acetic acid; the reaction is complex and the Me group is lost as CO2 (eq 17).42 Mucobromic acid in ethanol is transformed to the sodium salt of nitromalonaldehyde, a useful building block for the synthesis of pyrimidines, by the action of aqueous NaNO2.43

Nitrosation of phenols using NaNO2 in hydrochloric acid generally results in formation of the corresponding nitroso compound.44 Thus, for example, phenol yields 4-nitrosophenol, together with a small quantity of the 2-isomer (ca. 10%) (eq 18),44 and 2-naphthol produces 1-nitroso-2-naphthol.45 Treatment of phenols with buffered nitrous acid (NaNO2 in large excess compared to HCl) in aqueous acetone results in the formation of diazonium salts.46

Although anisole and diphenyl ether are readily nitrosated, they both give rise to 4-nitrosophenol.47 4-Nitrosoanisole is, however, obtained in 57% yield from anisole if the nitrosation reaction is carried out in CH2Cl2/CF3CO2H under argon at 0 °C.48 Nitration of simple aromatic compounds is reported to be readily achieved by reaction with NaNO2 in Trifluoroacetic Acid at 25 °C; isomer ratios are similar to those expected from electrophilic aromatic substitution reactions.49 Hydroquinones are conveniently oxidized to quinones by excess NaNO2 in acetic acid.50 Reaction of 2,3,5-trisubstituted pyrroles and 3,5-disubstituted pyrazoles with buffered nitrous acid gives rise to diazo compounds.51

Oxidation Reactions.

NaNO2 in various acidic media, including dilute HCl, acetic acid, and CF3CO2H, oxidatively cleaves C=N bonds in oximes,52 semicarbazones,53 and hydrazones,54,55 thereby regenerating the carbonyl group under mild reaction conditions (eq 19). 2,4-Dinitrophenylhydrazones, which are normally resistant to hydrolysis, are transformed to carbonyl compounds in ca. 80% yield.55 Reaction of secondary or tertiary thioamides with NaNO2 in HCl (4 M) affords the corresponding amides in good yield (70-90%).56

a-Nitro esters57 and sulfones58 are readily converted into their respective a-oximino derivatives on reaction with NaNO2 in aqueous ethanol and DMF, respectively. Reactions between secondary aliphatic nitro compounds and mixtures of NaNO2 and alkyl nitrites give ketones in good yield;59 with primary aliphatic nitro compounds, carboxylic acids are obtained in low yield.60 Carboxylic acids can undergo oxidative decarboxylation with concomitant formation of cyano compounds (50-70%) on treatment with a mixture of NaNO2 and Trifluoroacetic Anhydride (1:3) in CF3CO2H.61 Benzylic alcohols can be oxidized to aldehydes with NaNO2 in aqueous CF3CO2H.62 Diazotization of benzylamine with NaNO2/CF3CO2H in dry DMSO at 100 °C results in the formation of benzaldehyde (60-80%); poorer yields are obtained from the analogous isoamyl nitrite reaction.63

Nitroalkanes and Nitrite Esters.

Since the nitrite ion is bidentate, nucleophilic displacement reactions with alkyl halides can take place through either nitrogen or oxygen to give nitro compounds or nitrite esters respectively (eq 20). NaNO2 in either DMF or DMSO reacts readily with primary and secondary alkyl bromides or iodides to yield the corresponding nitro compounds; Silver(I) Nitrite gives better yields with primary alkyl halides.64 It is important that significant quantities of both the nitrite and the halide are in solution or the reaction does not take place. Secondary nitrosation reactions can be minimized by the addition of a nitrite scavenger such as phloroglucinol.

Simple alkyl nitrites can be prepared by direct esterification of the appropriate alcohol with aqueous NaNO2 in sulfuric acid at 0 °C. The preparations of methyl,65 ethyl,66 and butyl nitrites67 have been described in detail. Isopentyl Nitrite is obtained in high yield by treatment of a mixture of the alcohol and NaNO2 with aluminum sulfate.68 Propargyl bromides have been transformed into 3-nitroisoxazoles (20-60%) using NaNO2 in DMF (eq 21).69

Fremy's Salt.

Potassium Nitrosodisulfonate, a useful reagent for the selective oxidation of phenols and aromatic amines to quinones (Teuber reaction), has been prepared by the reaction of NaNO2 with NaHSO3 and SO3 followed by electrolysis using a stainless steel anode in alkaline solution.70 Fremy's salt has also been generated in situ as a marker in ESR spectroscopy by bubbling O2 through an equimolar mixture of NaNO2 and NaHSO3 in alkaline solution (pH 9).71


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Kevin J. McCullough

Heriot-Watt University, Edinburgh, UK



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