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Author: Subject: 2,6-dinitrosobenzene-1,4-diol prep ?

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[*] posted on 21-7-2007 at 09:01
2,6-dinitrosobenzene-1,4-diol prep ?

Hello again

Pleased to anounce that I still have fingers. Anyway more to the topic, I have made several searches (without success) and attempted several methods (of my own design also without success) to find a procedure which would produce 2,6-dinitrosobenzene-1,4-diol. To summerise I dissolved 1mol eq hydroquinone in a solution containing 2mol eq NaOH and 2mol eq NaNO2.Keeping the temperature 5deg C I added dropwise 50% H2SO4 While stirring until the solution was neutral. I vacuumed off the water, then dissolved the solid immediately in ethanol. The ethanolic solution was then added to an ethanolic solution containing 1mol eq aminoaniline and 2mol eq HCl at a temp of 20 deg c. The expected polymer never formed. I expect that my 2,6-dinitrosobenzene-1,4-diol prep was riddled with errors. Please supply your thoughts on where my error may lie.
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International Hazard

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[*] posted on 21-7-2007 at 09:10

I hope you have good safety equipment because nitrosobenzene is a carcinogen and so I would expect 2,6-dinitrosobenzene-1,4-diol if you can make it to be the same.

does the corresponding dinotrobenzene-diol (a nitrated hydroquinone) exist?

IIRC you get to mononitrosobenzene from nitrobenzene.

So if you nitrate the 1,4-diphenol, hydroquinone, the 2,6-dinitro isomer ought to be main product of conditions for dinitration, because 2 and 6 are the only positions available that are ortho to a phenol and meta to each other.

Then perhaps you can proceed with the partial reduction to the d-nitroso you want in the usual manner if you are lucky.

[Edited on 22-7-2007 by Sauron]
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[*] posted on 23-7-2007 at 04:16

Thanks Sauron

These links are also useful
For nitration

for reduction

The method I initially used was
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[*] posted on 23-7-2007 at 23:33

Here's some more information but I don't see any mention of a dinitrosation,

Preparations of C-Nitroso Compounds
Brian G. Gowenlock*† and George B. Richter-Addo*‡
Department of Chemistry, University of Exeter, Exeter EX4 4QD, U.K., and Department of Chemistry and Biochemistry, University of Oklahoma, 620 Parrington Oval, Norman, Oklahoma 73019
†University of Exeter.
‡University of Oklahoma.
The publisher's final edited version of this article is available at Chem Rev.
See other articles in PMC that cite the published article.
Abbreviations: AcO acetate, Am amyl, BSA N, O-bis(trimethylsilyl)acetamide, Bu butyl, Cp η5-cyclopentadienyl, DDQ dichlorodicyanobenzoquinone, DMF dimethylformamide, EDTA ethylenediaminetetraacetic acid, Et ethyl, hmpa hexamethylphosphoramide, MCPBA m-chloroperoxybenzoic acid, Me methyl, Ph phenyl, Pr propyl, THF tetrahydrofuran
1. Introduction
2. Synthetic Methods
3. Epilogue
1. Introduction
The discovery of important roles of C-nitroso compounds in various biological metabolic processes has generated a renewed interest in the general chemical properties of nitrosoalkanes (R–N=O; R =alkyl) and nitrosoarenes (ArNO; Ar =aryl), two important subsets of this general class of compounds. For example, the identification of the nitrosobenzene adduct of hemoglobin as a product of nitrobenzene poisoning1,2 and the realization that some amine-containing drugs may be metabolized to nitroso derivatives3–6 led to an increased desire to study the fundamental biochemical properties of this fascinating class of C-nitroso compounds. To this end, many studies have been reported on the fundamental chemistry of C-nitroso compounds under conditions that either stabilize the C-nitroso functionality or enhance their reactivity toward isomerization or reactivity with substrates.
A major difficulty in C-nitroso chemistry, however, is that the high reactivity of these compounds necessarily imposes constraints upon the methods employed for their preparation, particularly with regard to the yield of the desired product. For example, the ease of oxidation of the desired nitroso compound (if oxidation of a suitable precursor is the chosen synthetic route) to its nitro derivative can significantly reduce the yield of the nitroso product. Similarly, the ease of isomerization of R2C(H)NO compounds to the corresponding oximes R2C=NOH can restrict the choice of solvent for the preparation of primary and secondary nitrosoalkanes. A further consideration to be borne in mind is the possibility of reaction of the C-nitroso compound with the starting material and/or preparative reagents. There is, however, a considerable variety of synthetic routes available for the high-yield preparations of C-nitroso compounds (monomers or dimers; Figure 1), some of which have been in regular use for well over 100 years.
Some earlier reviews of this area have been published. Book chapters by Sandler and Karo (in 1986)7 and by Williams (in 1988)8 present the most detail to date on the experimental techniques for preparations of C-nitroso compounds. Other useful earlier reviews are those by Touster,9 Boyer,10 Metzger and Meier,11 Seidenfaden,12 and Katritzky et al.13
Given the renewed interest in the study of the biological and environmental consequences of C-nitroso compound formation, it is not surprising that many new and/or improved procedures for the preparations of these compounds have been developed over the last two decades. In this review, we present a comprehensive review of the synthetic procedures for the preparation of C-nitroso compounds and place these procedures in proper historical context. We also include a small number of routes to the production of C-nitroso compounds that may have preparative possibilities or which require improved workup methods. We indicate, when known, whether the method of preparation is applicable to all types of C-nitroso compounds or only to separate classes such as nitrosoarenes, nitrosoalkanes, nitrosohomocycles, or nitrosoheterocycles. Nitrosoalkenes are considered in a separate section. The coordination chemistry of C-nitroso compounds with metals has been reviewed recently.6,14

1. Introduction
2. Synthetic Methods
3. Epilogue
2. Synthetic Methods
2.1. Direct Substitution of –H by –NO
2.1.1. Hydrocarbons. A very successful direct nitrosation of some poly-methyl-substituted benzenes was reported by Bosch and Kochi.15 The nitrosations of the arenes were achieved using solutions of nitrosonium tetrafluoroborate in acetonitrile under argon; the arenes employed included 1,3-dimethylbenzene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, 1,3,5-trimethylbenzene, and 1,2,3,4-tetramethylbenzene (eq 1).

Atherton et al.16 extended this electrophilic nitrosation reaction to other arenes such as toluene, 1,2-dimethylbenzene, and 1,3-dimethylbenzene using degassed trifluoroacetic acid under a nitric oxide atmosphere. The nitrosoarenes produced under the latter conditions are unstable, but the method ensures reaction with the nitrosonium ion.
For the nitrosations of alkanes and cycloalkanes, the preparative method employed is a radical trapping reaction with nitric oxide and as such is discussed in section 2.7.
2.1.2. Compounds with Activated CH Groups. The nitrosation of aliphatic compounds requires that electron-withdrawing groups be situated adjacent to the carbon atom to be nitrosated; for preparative purposes it is important for this carbon to be a 3° carbon atom, as the nitrosation of 1° or 2° carbon atoms frequently leads to the production of the isomeric oximes. The activating groups include the carbonyl, alkoxycarbonyl, nitro, cyano, and aryl moieties. The nitrosating agent used in the nitrosation of ketones is an alkyl nitrite in the presence of acetyl chloride or HCl. The preparation of dimeric 3-methyl-3-nitroso-2-butanone (Scheme 1) from 3-methyl-2-butanone by Aston et al.17,18 is a good example of this approach.

Scheme 1
Other examples are provided by Pritzkow and Rösler.19 An early preparation20 of dimeric 4-nitrosomenthon employed pentyl nitrite and HCl as the nitrosating agent, and such nitrosations have been extended using pentyl nitrite and acetyl chloride.21 An extension of this synthetic route is provided by the direct nitrosation of the diketone, dipivaloyl-methane, by nitrosyl chloride in ether or acetic acid to give a 50% yield of the dimeric 4-nitroso-2,2,6,6-tetramethylheptane-3,5-dione product (Scheme 2).22

Scheme 2
A further example is provided by the reaction of 3-methylbutyl nitrite (isoamyl nitrite) in glacial acetic acid under reflux with 3-ethoxycarbonyl-5,5-dimethyl-2-phenyl-1-pyrroline-1-oxide to give dimeric 3-ethoxycarbonyl-5,5-dimethyl-3-nitroso-2-phenyl-1-pyrroline-1-oxide (eq 2).23


A variation is provided by the nitrosation of cyclo-hexanone in acetic anhydride by dinitrogen tetraoxide to give a high yield of dimeric 2-nitroso-2-nitrocyclohexanone.24
Nitrosation of secondary nitro compounds such as 2-nitropropane to give 2-nitro-2-nitrosopropane is noteworthy in that the first aliphatic nitroso compound was prepared by this method by Meyer and Locher in 1874.25
2.1.3. Phenols and Aromatic Ethers. The nitrosation of phenol by nitrous acid was first studied by Baeyer and Caro in 1874,26 the product being p-quinone monoxime, a tautomer of p-nitrosophenol. Substituted phenols and naphthols with para H-atoms behave similarly. The direct nitrosation of anisole was realized well over a century later using sodium nitrite in dichloromethane/trifluoro-acetic acid27 and then extended15 by using nitrosonium tetrafluoroborate in acetonitrile under argon. Nitrosation of anisole has also been accomplished using acetic acid/nitrosyl sulfuric acid/sulfuric acid mixtures under a stream of nitric oxide.28 Bosch and Kochi’s synthetic route has been applied successfully to substituted anisoles with 2-methyl, 3-methyl, 2,6-dimethyl, 3,5-dimethyl, 2-bromo, 3-bromo, and 2-mesityl substituents.15,29 The 4-nitrosoanisole was obtained in very high yield, whereas very little or no nitroso products were obtained when 4-substituted anisoles were used in the nitrosation reactions.15
Interestingly, nitrosation of anisole by nitrosonium ethyl sulfate (EtOSO2O−NO+) is reported to result in the generation of both 4-nitrosoanisole (major) and 4-EtOC6H4NO (minor).30
2.1.4. Aromatic Amines. The direct nitrosation by nitrous acid of tertiary aromatic amines is a long established method for the preparation of para-nitroso-N,N-disubstituted anilines,31 and a standard detailed method is available.32 The nitrosation of secondary aromatic amines occurs at the nitrogen, giving an N-nitrosoamine. In the presence of hydrochloric or hydrobromic acid, a Fischer–Hepp rearrangement occurs to give the para-nitroso-monosubstituted amine.33 An example of this is the nitrosation of N-(2-cyanoethyl)aniline in methanolic sodium nitrite/HCl yielding the para-nitroso-N-(2-cyanoethyl)aniline (eq 3).34


Willenz35 extended this to the preparation of a number of N-alkyl- and N,N-dialkyl-p-nitroso-anilines, although poor yields were obtained from N-n-hexylaniline, and no C-nitroso compound resulted from N-n-octadecylaniline. Morgan and Evens36 nitrosated 2-methylaminonaphthalene to give the N-nitroso product; stirring this product in cold ethanolic hydrochloric acid produced 1-nitroso-2-methylaminonaphthalene in good yields. Nitrosation of N,N-dialkylanilines by nitrosonium ethyl sulfate yielded the 4-nitroso-N,N-dialkylaniline products; the ionic (protonated) nitroso intermediates could be isolated as well, since they precipitated out of solution.30
An interesting ring nitrosation of a secondary aromatic amine without the apparent formation of an intermediary N-nitroso compound is provided by the formation of 2,4,6-tris(phenylamino)nitrosobenzene when 1,3,5-tris(phenylamino)benzene is reacted with nitrous acid (eq 4),37 although the reported NO bond length in the product (1.13 Å) is unusually short.


2.1.5. Heteroaromatic Compounds. Only electron-rich heterocyclic ring systems are subject to electrophilic attack by nitrosating agents: examples include pyrroles,38,39 pyrazoles,40 antipyrine (2,3-dimethyl-1-phenylpyrazol-5-one),41 imidazoles,42 fused benzimidazoles,43–45 1H-pyrrolo[1,2-a]imidazoles,46,47 imidazo[2,1-b]thiazoles,48–51 indolizines,52,53 indoles,54–57 8-thia-1,4-diazacycl[3,3,2]azines,58 and thiazoles.59 Nitrosation of four 3,5-diamino-2H-1,2,6-thiadiazine 1,1-dioxides with sodium nitrite and acetic acid in a DMF/water solution at 0–5 °C gives good yields of the corresponding 4-nitroso derivatives (eq 5; R =CH2Ph, CH2CH2Ph, Bu, Ph).60


2.2. Substitution of a Functional Group by the Nitroso Group
2.2.1. Nitrosation of Organometallic Compounds. The use of nitroso demetalation reactions for the generation of C-nitroso compounds has a long history. In 1874, Baeyer61 prepared nitrosobenzene from the reaction of nitrosyl bromide with diphenylmercury. A similar reaction by Oddo using phenylmagnesium bromide and nitrosyl chloride also produced nitrosobenzene,62 but Waters and Marsh,63 in attempting to repeat this work, reported that the predominant product was diphenylamine. A range of methyl-substituted nitrosobenzenes was obtained from the reaction of the arylmercuriacetate with nitrosyl chloride generated in situ from a mixture of ethyl nitrite and hydrochloric/acetic acids.64 Beginning in the 1960s, the use of nitrosative demetalation has been considerably extended both with and beyond the use of organomercury and organomagnesium compounds. Robson et al.65 prepared two nitrosoalkynes by reaction of bis(tert-butylethynyl)- and bis(n-butyl-ethynyl)mercury with nitrosyl chloride at −40 °C, the yields being better with the mercury compounds than with the magnesium or lithium analogues. Motte and Viehe66 also prepared tert-butylnitrosoacetylene from reaction of tert-butyltrimethylstannylacetylene with dinitrogen tetroxide at −60 °C (eq 6).

Prickett67 prepared nitrosocyclopropane from di-cyclopropylmercury and nitrosyl chloride. This method has also been used for halogenated nitroso compounds by Tarrant and O’Connor68 in the preparation of CF3CFClNO, CF3CCl2NO, and (CF3)2CFNO from reaction of the corresponding difluoroalkylmercury with nitrosyl chloride in DMF. Near-quantitative yields of the nitrosoperfluoroalkanes CnF2n+1NO (n =1, 2, 3, 6) are realized from the reaction of nitrosyl chloride with the corresponding Cd(CnF2n+1)2glyme reagent.69
The successful use of organolithium compounds in C-nitroso compound syntheses is illustrated by the preparation of 1-nitroso-ortho-carborane and 1-methyl-2-nitroso-ortho-carborane (eq 7) from reaction of the corresponding lithium compounds with excess nitrosyl chloride in ether–hexane at low temperatures (−70/−125 °C).70,71


Extension to the preparation of 1-nitroso-m-carborane, 1-methyl-7-nitroso-m-carborane, and 1-nitroso-p-carborane has been reported by Zakharkin.72
Other preparations using organotin compounds have been reported.73 Several monosubstituted phenyltrimethylstannanes give good yields of the corresponding substituted nitrosobenzenes (eq 8) when the reactions with nitrosyl chloride in anhydrous dichloromethane are performed at −20 °C; when a halogen substituent is present, the reaction is much slower even at the higher reaction temperature of 0 °C.


Preparation of various arylnitroso compounds in good yields using organothallium precursors has been reported (e.g., eq 9).74


In a similar vein, 4-nitrosopyrazole has been prepared from the reaction of both 4-trimethylsilylpyrazole and 3,4-bis(trimethylsilyl)pyrazole with sodium nitrite/trifluoroacetic acid at 0 °C (eq 10).75


The method has been extended to prepare 3(5)-nitroso-4-trimethylsilylpyrazole and 3(5)-nitrosopyrazole. The reaction between tridodecylaluminum and nitrosyl chloride in THF under nitrogen at −10 °C gives trans-dimeric 1-nitrosododecane (eq 11).76

All of these preparations are based upon the observation that the leaving group that results is a relatively stabilized metal cation. In view of the considerable number of organolithium and organo-mercury compounds that can be synthesized in good yields, it seems likely that the preparation of a wide range of nitroso compounds should prove possible by the increased use of nitrosative demetalations.
The synthesis of nitrosoferrocene from ferrocenyl-lithium (FcLi) has been reported using the reaction sequence shown in Scheme 3.77 FcLi reacted with CpCr(NO)2Cl by nucleophilic addition of the ferrocenyl moiety to the nitrogen atom of a nitrosyl group. The resulting intermediate, on reaction with tert-butyl isocyanide, formed a nitrosoferrocene complex, which on controlled oxidative degradation with hydrogen peroxide in dichloromethane gave nitrosoferrocene.

Scheme 3
The insertion of the nitrosonium cation into the chromium–carbon bond of CpCr(NO)2Ph gives the cationic nitrosobenzene complex [CpCr(NO)2{N(O)-Ph}]+, which upon further reaction with chloride ion releases PhNO in fair yields.78 Stoichiometric carbon–nitrogen bond formation mediated by metal complexes, in which the C-nitroso compounds remain coordinated to the metal centers, has been reviewed.6,14
2.2.2. Nitrosation by Replacement of Other Functional Groups. There are a number of examples of such replacements in which nitrosyl chloride is used as the source of nitric oxide. Sutcliffe79,80 used the reaction between nitrosyl chloride and sodium trichloromethylsulfinate to prepare trichloronitrosomethane, for which the reaction pathway in Scheme 4 is suggested.

Scheme 4
Tattershall81 used the mercury arc photolysis of equimolar quantities of chloroform and nitrosyl chloride to prepare solutions of trichloronitrosomethane in chloroform. The reaction between nitrosyl chloride and peroxyphenylacetic acid in petroleum ether at 0 °C produces dimeric ω-nitroso-toluene (Scheme 5).82

Scheme 5
2.3. Addition Reactions to C=C Double Bonds
2.3.1. Addition of Nitrosyl Halides. The addition of nitrosyl halides to alkenes is a very useful approach to the synthesis of C-nitroso compounds (eq 12).


The addition of nitrosyl chloride to the C=C double bond of various terpenes played an important role in the early studies of the structure of terpenes.83 An early review84 of the chemistry of nitrosyl chloride includes a summary of reactions with compounds containing C=C bonds. A later review by Kadzyauskas and Zefirov85 on the nitrosochlorination of alkenes was published in 1968. A series of papers by Ogloblin and co-workers gives details of the reactions with alkenes and cycloalkenes,86,87 ketene acetals,88 vinyl ethers,89 α,β-unsaturated ketones containing a substituted vinyl group,90 acyclic α,β-unsaturated ketones,91 chloroalkenes,92 cyclopropene derivatives,93 and enamines.94 In some cases the nitroso compounds formed are unstable (e.g., from some vinyl ethers89 and some α,β-unsaturated ketones90), but even where the majority of products formed are the result of disproportionation of the resulting nitroso chlorides, in the case of 1-acetoxy-1-chloro-2-nitroso-2-methyl-propane a crystalline dimer was formed.95 The papers by Ogloblin and co-workers describe the use of IR spectroscopy to distinguish between the E- and Z-dimers; however, questions concerning the stereochemistry of the nitrosyl chloride addition to the C=C bonds and the nature of the chirality of the compounds produced were not addressed. Rogic and co-workers96 considered these in detail and demonstrated that as the addition of nitrosyl chloride to cyclohexene can occur both cis and trans with respect to the ring, there is the possibility that three different Z-dimers and three different E-dimers can form (Figure 2).
Similar considerations have been applied to the reaction products of nitrosyl chloride and 1,5-cyclooctadiene and trans, trans, trans-cyclododecatriene.97 Ponder and Wheat98 studied the dimeric nitrosochloride products of the addition to the strained bicyclic olefins norbornene, norbornadiene, 5-methylene-2-norbornene, 5-ethylidene-2-norbornene, and bicyclo[2,2,2]octene-2. Other authors have given careful consideration to the stereochemistry of nitrosyl chloride addition products to various terpenes, e.g., γ-terpinene,99 sylvestrene,100p-menth-1-ene, limonene and α-pinene,101 (±)-α-terpinyl acetate,102 (+)-car-3-ene,103 and trans-β-terpineol.104
Tkachev and Vorobjev105 have shown that nitrosyl chloride reacts with the diterpenoid cembreme at −50 °C in dichloromethane to give a blue solution, whereas at −5 °C a tar-like product forms within 1 s. Subsequent reaction of the blue solution with morpholine confirms the formation of the nitrosochloride. Mark-ova and Tkachev106 isolated a crystalline dimeric nitrosochloride of the acyclic monoterpenoid linalyl-acetate from the interaction of a gaseous stream of nitrosyl chloride in nitrogen slowly passed over a dichloromethane solution of the terpenoid at −15/−5 °C, the product being a 1:1 mixture of diastereomers.
Nitrosyl chloride has been shown to react readily and with a high degree of stereospecificity with three acetylated glycals at −40/−80 °C in either ethyl acetate or dichloromethane to produce trans-dimeric acetylated 1,2-cis-2-deoxy-2-nitroso-α-D-aldopyrano-syl chlorides (Figure 3).107
Similar reactions of glycals have also been reported,108,109 and further examples of the preparation of such dimeric nitrosochloride derivatives are provided by Heyns and Hohlweg (Scheme 6).110

Scheme 6
The rates of addition of nitrosyl chloride to C=C double bonds are subject to wide variation depending upon the structure of the alkene, cycloalkene, or substituted styrene concerned,111,112 and these studies are obviously relevant to the successful use of this addition reaction for synthetic purposes. The patent literature113 gives details of the production of dimeric nitroso chlorides of propene and ethene from the metal-catalyzed reaction in a chlorinated hydrocarbon solvent within the temperature range −25/40 °C.
Although nitrosyl bromide has been less frequently employed than nitrosyl chloride in these addition reactions, it has been shown that the ethyl nitrite/phosphorus tribromide system is a good source of nitrosyl bromide and gives high yields of dimeric nitrosobromides from norbornene and benzonor-bornene, the addition occurring as a syn-exo process.114
The reaction of nitrosyl fluoride with C=C double bonds has received some attention. The review by Knunyants et al.115 gives the major references to the Russian preparative work. Andreades116 obtained 2-nitrosoheptafluoropropane and tert-nitrosononafluorobutane from reaction of nitrosyl fluoride with hexafluoropropene and octafluoroisobutene, respectively. He also prepared heptafluorocyclobutyl nitrite from reaction of nitrosyl fluoride with hexafluorocyclobutanone; thermal decomposition of this product yielded γ-nitrosohexafluorobutyryl fluoride together with the corresponding nitro compound.117
2.3.2. Addition of Oxides of Nitrogen. These addition reactions can be carried out with nitric oxide or dinitrogen trioxide or dinitrogen tetraoxide. An early study by Bunge118 showed that the reaction of a terpene once ascribed to nitric oxide addition was, in fact, due to dinitrogen trioxide addition. Almost a century later, Brown119 showed that when highly purified nitric oxide was used in an attempted reaction with 2-methylpropene, no addition occurred; the reaction occurred when trace quantities of nitrogen dioxide were present (e.g., Scheme 7).

Scheme 7
Park and Walton120 used EPR spectroscopy to demonstrate that small amounts of nitrogen dioxide were necessary to produce β-nitroalkyl radicals, which can react further with nitric oxide.
The reaction of nitric oxide with α-tocopherol (vitamin E) in air-equilibrated cyclohexane gave a variety of products including a colorless oil in ~10% yield for which the structure 2,3-dimethyl-4-acetyl-4-hydroxy-5-nitroso-2-cyclopentenone is proposed (eq 13) based on UV–vis, IR, and 1H NMR spectroscopic evidence.121


The absence of any blue color is, however, surprising. It is not clear what, if any, inferences can be drawn regarding the biological relevance of this NO–vitamin E reaction. However, vitamin E has antioxidant properties, and it will be interesting to determine the in vivo relevance of vitamin E in protection against NO-induced cell damage.
Dimeric 1-nitro-2-nitroso-4-phenylbutane (eq 14) has been identified as the reaction product from the room-temperature reaction of 4-phenyl-1-butene, dissolved in 1,2-dichloroethane, with nitric oxide at atmospheric pressure.122


The reaction of nitric oxide with benzene solutions of chloroprene and 2,3-dichlorobutadiene yields dimeric 2-chloro-1-nitro-4-nitrosobut-2-ene and 2,3-dichloro-1-nitro-4-nitrosobut-2-ene, respectively.123
Ketene O-alkyl-O′-silyl acetals react with nitric oxide or 3-methylpentyl nitrite in the presence of titanium(IV) chloride to give good yields (>65%) of α-nitroso esters (Scheme 8).124 When R2 =H in Scheme 8, the isomeric oximes are the final products.

Scheme 8
The study of the addition of dinitrogen trioxide to alkenes is over a century old, examples being the addition to styrene125 and 2-methylbut-2-ene.126,127 The product was named ‘trimethylethylene nitrosite’ and shown to exist as a blue monomer in solution or as a colorless dimer in the solid state. The term nitrosite is a shortened form of nitrosonitrite, whereas the term pseudonitrosite is used for the isomeric nitronitroso addition compound. Preparative details for addition of dinitrogen trioxide to C=C compounds to give dimeric nitronitroso (pseudonitrosite) derivatives are given for but-2-ene, dimethylbutadiene, styrene, 4-methoxypropenylbenzene (anethole), 4-propenyl-1,2-methylenedioxybenzene (isosafrole), stilbene, cyclohexene, cyclooctene, and cycloocta-1,5-diene.127–129 Details are also given for nitronitroso derivatives from L-α-phellandrene130 and for cinnamyl acetate131 and for initial nitrosonitrites from propene, 2-methylpropene, 3-chloropropene, and 2,3-dimethylbut-2-ene.132 Pfab133 showed that the addition of dinitrogen trioxide to 2-methyl-propene produced the trans-dimer of 1-nitro-2-methyl-2-nitrosopropane together with other products from oxidation of the monomeric nitroso compound.
It should be noted that there are considerable differences in the melting point values recorded for dimeric 1-nitroso-2-nitro-1-phenylethane, and these may be accounted for in terms of the geometric isomerism of the azodioxy group together with conformational isomerism. The crystal structure134 identifies a trans-dimer of melting point 108.4 °C, but other preparations using different solvents and recrystallization procedures give values of 112,127 122,129 129,135 130,131 and 158 °C.135 Detailed studies of these wide divergences have not been carried out.
Other preparations of dimeric nitronitroso compounds by dinitrogen trioxide addition include the products resulting from the addition to seven silanes containing an ethylenic bond (e.g., eq 15),136 seven indenes (e.g., eq 16),137 and nine α,β-unsaturated ketones of the chalcone class (eq 17).138




Preparative details are available for two distinct conformers of blue crystalline humulene nitrosite139,140 and caryophyllene nitrosite.141
2.3.3. Addition of N-Nitroso Compounds. The photoaddition of N-nitroso compounds to compounds containing C=C bonds in acidified solvents such as methanol has been reviewed by Chow,142 who proposed that formation of an aminium radical was followed by its addition to (by electrophilic radical attack at) a π bond and subsequent capture of the resultant radical by nitric oxide (e.g., Scheme 9). The resultant 1:1 adduct isomerizes to the oxime if there is an α-H atom present, and only in the absence of this α-H atom can the nitroso compound be isolated. In a series of published reports it was shown that the majority of products were oximes; however, preparative details for C-nitroso compounds from photolysis of nitrosamines using 0.05 mol of nitrosamine and 1–3 mol equiv of alkene in methanol and concentrated HCl have been described.143 Interestingly, the photolysis of N-nitroso-N-hexylacetamide or N-nitroso-N-methylhexanamide in cyclohexane yielded small quantities of dimeric nitrosocyclohexane.144Trans-dimeric nitroso compounds are obtained from the reaction of N-nitrosopiperidine with 3,3-dimethylbut-1-ene and 1-hexene145 and cyclohexene.146 Similarly, dimethylnitrosamine undergoes photoaddition to norbornene (eq 18).147


Scheme 9
An interesting analogous synthesis is provided by the photoaddition of N-nitrosopiperidine to phenyl-acetylene followed by hydrolysis to form phenylglyoxal ketoxime, which tautomerizes to give the dimer of 1-nitroso-2-hydroxystyrene (Scheme 10),148 a compound which merits a full structural study.

Scheme 10
2.3.4. Addition of O-Nitroso Compounds. The addition of 1-methoxycyclohexene to a solution of methyl nitrite in liquid sulfur dioxide at −40 °C in the presence of a catalytic amount of sulfur trioxide, sulfuric acid, or boron trifluoride etherate yields the trans-dimer of 1,1-dimethoxy-2-nitrosocy-clohexane quantitatively (eq 19).149 The method has been extended (using methyl or ethyl nitrite) to produce eight other α-nitroso ketone acetal dimers in yields of >70%.


2.3.5. Addition of S-Nitroso Compounds. The photolysis of tritylthionitrite and tert-butylthionitrite in the presence of styrene produces diastereomeric dimeric nitroso compounds (eq 20).150


2.3.6. Addition of Other Nitrosyl Compounds. Hamann and Swern151 showed that nitrosyl formate, prepared in situ from isoamyl nitrite and formic acid, added readily to a number of acyclic-, alicyclic-, and aryl-substituted unsaturated compounds yielding formoxy nitroso compounds. Dimeric crystalline products were obtained from cyclohexene, norbornene, styrene, and α- and trans-β-methylsty-rene, whereas 2,3-dimethylbut-2-ene and 9-octalin yielded blue monomeric oils; upon purification, the latter product gave blue needles of cis- and trans-9-formoxy-10-nitrosodecalin. The addition of nitrosyl acetate and of nitrosyl benzoate to 2,3-dimethylbut-2-ene was also shown to give high yields of 2,3-dimethyl-2-acetoxy-3-nitrosobutane and 2,3-dimethyl-2-benzoyloxy-3-nitrosobutane, respectively. In a similar study, Sharpe152 showed that nitrosyl benzoate and dinitrosyl terephthalate added to 2,3-dimethylbut-2-ene and that nitrosyl benzoate added to 9-octalin giving high yields of the nitroso product.
The presumed 3-carene nitrosate studied by Simonsen153 has been shown to be an unsymmetrical trans-dimeric nitroso compound formed by a reaction of isoamyl nitrite and nitric acid in acetic acid with the (+)-3-carene, in which the double bond is left intact and the cyclopropane ring is cleaved.154 The two identical units of the compound give rise to separate 1H NMR spectroscopic signals due to the dissymmetry of the molecule which is named as (3R,3′R,4R,4′R)-(E)-di(8-nitrooxy-6-menthen-3-yl)dia-zene N,N′-dioxide (eq 21).


Heterolytic addition of dinitrogen tetraoxide to tetramethylethylene in the absence of oxygen at −20 °C using deuteriochloroform as solvent has been shown to produce the unstable blue nitrosonitrate (eq 22).155


Perrotti and De Malde156 isolated a dimeric nitrosonitrate in quantitative yield from reaction of dinitrogen tetraoxide with 2-methylpropene in the presence of concentrated nitric acid and suggested an ionic mechanism for the addition reaction.
2.4. Oxidation of Other Nitrogen-Containing Functional Groups
2.4.1. Primary Amines. A wide variety of oxidizing agents is available for the oxidation of 1° amines to nitroso derivatives. The period from 1970 onward was marked by an increase in the number of possible synthetic routes for high-yield preparations of aromatic, aliphatic, and homo-cyclic nitroso compounds.
(1) Caro’s Acid. There are a number of suitable oxidizing agents for the syntheses of nitrosoarenes, nitrosoalkanes, and nitrosocycloalkanes, of which the first to be employed was Caro’s acid (peroxomono-sulfuric acid, H2SO5).157 Experimental details for the preparations using Caro’s acid are to be found in the paper by Mijs et al.158 for nitrosobenzenes with the following substituents: 2,6-dimethyl, 2,6-dimethyl-4-iodo, 2-methyl-4-iodo, 4-methoxy, 2,6-dimethyl-4-methoxy, 2,6-dimethyl-4-bromo, and 2-nitro. Mijs159 extended the syntheses to nitrosobenzene itself and to nitrosobenzenes with the following substituents: 4-nitro, 2-methoxy, 3-methoxy, 2-methyl-4-bromo, and 2,4,5-trimethyl. In an earlier study by Schors et al.,160 the syntheses of the following substituted nitrosobenzenes by Caro’s acid oxidation were reported: 3-chloro-4-nitrosoanisole, 2,4-diethoxynitroso-benzene, 4-chloronitrosobenzene, 4-bromonitrosoben-zene, 4-iodonitrosobenzene, 3-nitroso-ethylbenzoate, 4-nitroso-ethylbenzoate, and nitrosomesitylene. Other substituted nitrosobenzenes have been obtained by this method.161,162 Many of the preparations by Bam-berger and co-workers in the 1898–1910 period made use of Caro’s acid as the oxidant for reaction with aromatic amines.163 Langley164,165 gives preparative details for 2-methyl-4-nitro-nitrosobenzene. Hirota and Otano166 also used Caro’s acid oxidation to prepare nitrosobenzenes with the following substituents: 2-isopropyl, 2-tert-butyl, 2-fluoro, 2,6-diisopropyl, 3,4-dibromo, 4-ethyl, 4-n-propyl, 4-isopropyl, and 4-tert-butyl.
Caro’s acid oxidation of primary aminoalkanes to give dimeric nitrosoalkanes was first achieved by Bamberger and Seligman167 for the cases of Me2C-(CH2X)NH2 (X = H, Me, COMe). Caro’s acid oxidation of amines has been used to prepare the trans-dimers of 1-methyl-1-nitrosocyclohexane and 2-nitroso-2-phenylpropane.128 Commercially available Oxone (with acetone as solvent in a biphasic oxidation process) has been used to prepare the trans-dimers of nitrosocyclohexane, 1-nitrosobutane, and 1-nitrosodecane.168 In these cases, the isomeric oximes were also formed.
(2) Peracetic Acid. Holmes and Bayer169 used 30% hydrogen peroxide/acetic acid to prepare several disubstituted and trisubstituted nitrosobenzenes with the following substituents: 2,6-dichloro, 2,6-dibromo, 2,4,6-trichloro, 2,4,6-tribromo, 2,3,6-trichloro-4-methyl, 2,6-dibromo-4-chloro, 2,6-dichloro-4-bromo, 2,6-dichloro-4-methyl, 2,6-dibromo-4-methyl, 2,6-dibromo-4-COOEt, 2,6-dichloro-4-COOEt, 2,6-dichloro-4-cyano, and 2,6-dibromo-4-cyano. Gorrod170 used this method to prepare nitrosobenzene, 2-nitrosobiphenyl, 4-nitrosobiphenyl, 1-nitrosonaphthalene, 2-nitrosonaphthalene, and 2-nitrosofluorene.
There are further examples of the use of peracetic acid as the oxidizing agent in the preparation of 2-nitrosobenzamide171 and 2-nitrosoaniline172 from the corresponding amino compounds. Dimeric 4-nitrosotetrafluoropyridine has been prepared by oxidation of the amine using a mixture of trifluoroacetic anhydride and 85% hydrogen peroxide in methylene chloride.173
Emmons174 prepared several dimeric nitrosoalkanes (alkyl =propyl, tolyl, octadecyl, tert-butyl, cyclohexyl) by oxidation of the amines using peroxy-acetic acid (prepared from 90% hydrogen peroxide and acetic anhydride in dichloromethane). Similarly, Meister175 prepared nitrosocyclododecane using a 20% solution of peroxyacetic acid in ethyl acetate, and Corey and Gross176 prepared three tert-alkylnitroso compounds by this method (tert-alkyl =tert-butyl, tert-octyl, and 1-adamantyl).
(3) Potassium Permanganate. Bamberger and Tschirner177 used potassium permanganate together with formaldehyde in sulfuric acid for the oxidation of aniline to nitrosobenzene. 2,4,6-Tri-tert-butylnitrosobenzene was isolated from the products obtained by potassium permanganate oxidation of the corresponding amine in a chloroform/water mixture at 20 °C.178 Similarly, nitrosocyclohexane was prepared from cyclohexylamine using potassium permanganate and formaldehyde in sulfuric acid.179
(4) 3-Chloroperoxybenzoic Acid (MCPBA) and Peroxybenzoic Acid. From the late 1960s onward, there have been many reports of the use of 3-chlo-roperoxybenzoic acid for the synthesis of nitroso compounds. A particular example is the oxidation of 3-aminobenzamide by 3-chloroperoxybenzoic acid in DMF at 0–5 °C to give 3-nitrosobenzamide.180 Preparation of 6-nitroso-1,2-benzopyrone, 5- nitroso-1(2H)-isoquinolinone, 7-nitroso-1(2H)-isoquinolinone, and 8-nitroso-1(2H)-isoquinolinone was also reported. These aryl nitroso compounds were prepared to test their suitability as specific inactivators of retroviral zinc fingers and as antitumor agents.180 The preparation of 2,6-dimethyl- and 2,6-diethylnitrosobenzene and 2-ethyl-6-methylnitrosobenzene using dichloromethane as solvent has been reported181 and extended using acetonitrile-d3 as solvent to prepare the same products and 2-methyl-6-tert-butylnitrosoben-zene (very low yields of <5% were obtained upon oxidation of the 2-chloro-4-methylaniline and 2,4-dimethylaniline precursors).182 Okazaki183 used per-oxybenzoic acid oxidation to produce five sterically encumbered tert-butyl-substituted nitrosobenzenes (eq 23); these nitrosobenzenes were proposed to exist as monomers even in the solid state due to the presence of bulky tert-butyl substituents in the 2-positions.


Peroxybenzoic acid was also used to produce nitrosobenzenes with 2,6-di-fluoro, 2,6-dichloro, 2,6-dibromo, 2,6-dibromo-4-methyl, and 2-nitro-4-methyl substituents.184
The reaction of 3-chloroperoxybenzoic acid with aliphatic primary amines (2-butylamine, 1-hexylamine, 1-propylamine, 2-phenylethylamine, and cy-clohexylamine) in dichloromethane at room temperature has been shown to give excellent yields of the dimeric nitroso compounds.185 Baer and Chiu186 prepared a number of dimeric nitroso sugars, the chloroform or chloroform–methanol solution of the amino sugar being added dropwise to a refluxing solution of 3-chloroperoxybenzoic acid in chloroform; trans-dimeric 2-nitrosocyclohexanol was also prepared by the same method. Several C-nitroso compounds such as nitrosomesitylene, 2-nitrosotoluene, nitrosocyclohexane, 1-alkyl-1-nitrosocyclohexane (alkyl =Me, Et, cyclohexyl), 1-ethyl-1-nitrosocyclopentane, nitroso-tert-butane, 2-nitrosoisocamphane, and 2,2,4-trim-ethyl-4-nitrosopentane have been prepared using 3-chloroperoxybenzoic acid as the oxidant.187 Eleven trans-dimeric aralkyl C-nitroso compounds have been prepared by addition of the oxidant to a chloroform solution of the amine at 0–5 °C.188 An interesting variant189 is provided by passing a stream of tert-butylamine in dry nitrogen through a tube packed with 3-chloroperoxybenzoic acid in sodium chloride maintained at 4 °C, the effluent gas being passed through a trap at −80 °C where a blue liquid condensed. Slow conversion to the colorless dimer in the presence of unreacted amine took place at −30 °C. Another synthesis by this method is that of nitrosocyclopropane; commercial cyclopropylamine is slowly distilled through a plug of 3-chloroperbenzoic acid suspended on sodium chloride, the blue product being condensed out with subsequent dimerization.190
(5) Hydrogen Peroxide in the Presence of a Catalyst. Sakaue et al.191 used 35% hydrogen peroxide in the presence of peroxotungstophosphate (H3-PW12O40) to oxidize aromatic amines such as aniline, 4-methylaniline, and 4-chloro-aniline to give the respective nitroso compounds. Another catalyst for the hydrogen peroxide oxidation of 1° aromatic amines is [Mo(O)(O2)2(H2O)(hmpa)];192 high yields for a wide range of substituted nitrosobenzenes RC6H4-NO (R =H, 4-Me, 4-Et, 4-tert-Bu, 4-OMe, 4-CO2Me, 4-NHCOMe, 4-F, 4-Cl, 4-Br, 3-Me, 3-Cl, 3-OMe, 2-Me, 2-Et, 2-OMe) were obtained. In a later development,193 14 substituted anilines RC6H4NH2 (R =2-Me, 2-Et, 2-Cl, 2-Br, 3-Me, 3-Cl, 3-Br, 4-Me, 4-Et, 4-isopropyl, 4-tert-butyl, 4-F, 4-Cl, and 4-Br) were oxidized by hydrogen peroxide in the presence of cis-Mo(O)2(acac)2 (acacH =MeC(O)CH2C(O)Me) to give, in most cases, high yields of the nitroso products. Another example of the catalytic oxidation of substituted anilines 4-RC6H4NH2 (R =H, Me, OMe, CO2-Et, COMe, F, Cl, Br, CF3, and CN) to give the corresponding nitroso derivatives is provided by the catalyst oxoperoxo(pyridine-2,6-dicarboxylato)(hmpa)molybdenum(VI).194 Methylrhenium trioxide has also been used as a catalyst for the hydrogen peroxide oxidation of some anilines RC6H4NH2 (R =H, 2-Me, 3-Me, 4-Me, 4-cyclohexyl, 4-Cl).195
(6) Peroxyformic Acid. Peroxyformic acid has been used in the oxidation of precursor substituted anilines in refluxing dichloromethane to give C6F5-NO,196,197 4-BrC6F4NO,198 4-(HOOC)C6F4NO,198 and 4-CF3C6F4NO.199
(7) Other Peroxy Compounds. Dimeric nitrosocyclohexane was prepared from oxidation of the amine by a sodium tungstate–hydrogen peroxide mixture.200 Burckard and co-workers201 reported the use of the same reagents in the oxidation of aromatic amines to their nitroso derivatives. Stowell202 similarly prepared the trans-dimers of 2-methyl-2-nitrosopropane (nitroso-tert-butane) and 2,4,4-trimethyl-2-nitrosopentane (nitroso-tert-octane). Baldwin et al.187 also reported the preparation of nitroso-tert-octane from octylamine using a mixture of sodium tungstate, the sodium salt of EDTA, and 15% hydrogen peroxide. Details of this methodology for the preparation of nitroso-tert-octane are given by Corey and Gross.203 Stowell and Lau204 prepared dimeric 2,6-dimethylnitrosobenzene by the sodium tungstate-30% hydrogen peroxide oxidation of the precursor amine.
Zajac and co-workers used two different peracid salts as the source of oxidants to prepare nitrosoalkanes and nitrosocycloalkanes from the corresponding amines in high yields. Both of these synthetic pathways avoid the use of added hydrogen peroxide solutions. The first example205 used sodium percarbonate (as the source of hydrogen peroxide), sodium bicarbonate, and N,N,N′,N′-tetraacetylethylenedi-amine in a biphasic system of ethyl acetate or dichloromethane and water to prepare the dimers of 1-nitrosododecane, 1-nitroso-2-phenylethane, 2-nitrosomethyl-endo-norbornane, nitrosocyclohexane, 1-nitrosoadamantane, 2-nitrosoadamantane, 3-nitrosonoradamantane, 2-nitroso-endo-norbornane, and 2-nitroso-exo-norbornane. Following the success of the above syntheses, Zajac206 used sodium perborate in place of sodium percarbonate and obtained good yields of 1-nitrosododecane, 1-nitroso-2-phenylethane, nitrosocyclohexane, 2-nitroso-endo-norbornane, 1-nitrosoadamantane, 2-nitrosoadamantane, and 3-nitrosonoradamantane.
Crandall and Reix168 used dimethyldioxirane to oxidize aliphatic primary amines, the products including not only dimeric nitrososalkanes but also oximes, nitroalkanes, nitrones, and oxaziridines. Good yields of the nitroso dimers could be isolated from the initial reaction mixture in the cases of nitrosocyclohexane, 1-nitrosobutane, and 1-nitrosodecane, but benzylamine gave only the benzaldoxime.
(8) Oxaziridines and Oxaziridinium Salts. The synthesis of dimeric nitroso compounds in low yields from the reaction of 2-(phenylsulfonyl)-3-oxaziridine (Davis’ reagent) with benzylamine, endo-2-norbornyl-methylamine, cyclohexylamine, endo- and exo-2-norbornylamine, tert-butylamine, 1-adamantylamine, 2-adamantylamine, and 3-noradamantylamine has been reported.207 Hanquet and Lusinchi208 prepared dimeric nitroso compounds from n-butylamine, tert-butylamine, benzylamine, and 1-phenyl-2-propylamine using the oxaziridinium tetrafluoroborate derived from dihydroisoquinoline.
(9) Oxygen Difluoride. Oxygen difluoride oxidation of tert-butylamine, tert-octylamine, and cyclo-propylamine at temperatures below −42 °C to obtain the corresponding dimeric nitroso compounds has been reported.209 The production of two different dimers of nitroso-tert-butane and nitrosocyclopropane was claimed; however, no other reports of the cis dimers of these have appeared to date in the literature.
(10) Nitrous Acid. An unusual oxidation of an amino group by an equivalent of nitrous acid to form the corresponding nitroso compound is provided by the formation of dimeric tris(nitromethyl)nitrosomethane from tris(nitromethyl)methylamine at 0–5 °C (eq 24).210

2.4.2. Hydroxylamines. The controlled oxidation of N-aryl- and N-alkylhydroxylamines (RNHOH) is a common method for the production of nitroso compounds, there being a wide variety of oxidizing agents available for this purpose. The N-substituted hydroxylamines are usually obtained by partial reduction of the nitro precursors RNO2; in most cases, the favored reagents for this step are powdered zinc together with ammonium chloride as in the case of the formation of N-1-adamantylhydroxylamine from 1-nitroadamantane.211 Preparative details are given for the reduction of nitrobenzene to N-phenylhydroxylamine followed by acidified dichromate oxidation to nitrosobenzene.212 Oxidizing agents used are listed below.
(1) Ferric Chloride. The oxidation of aromatic hydroxylamines has been used in the preparation of substituted nitrosobenzenes for over 100 years, and Table 1 lists the major references for the preparation of many monosubstituted, disubstituted, and trisubstituted nitrosobenzenes using ferric chloride.
A related ferric ion oxidation reaction is provided by the oxidation of 2-hydroxylaminofluorene by ferric ammonium sulfate (eq 25).224


(2) Sodium or Potassium Dichromate and Sulfuric Acid. The use of acidified dichromates as an alternative to ferric chloride to prepare substituted nitrosobenzenes has been employed for many years, and many examples are available.225–230 This method has been extended to the syntheses of dimeric 3-nitrosopyridine231 and to trans-dimeric 2-methyl-2-nitrosobutane and 2-methyl-2-nitroso-1-acetoxypropane from the N-alkylhydroxylamines.232 A related method uses chromium trioxide in the attempted oxidation of 1,3-dihydroxylamino-4,6-dinitrobenzene to the corresponding dinitroso compound.233 The presence of a bright green color suggests that some of the desired product was obtained, but the reported further oxidation to the 1,3,4,6-tetranitrobenzene product suggests that a milder oxidant might be needed for the preparation of high yields the desired nitroso compound.
(3) Potassium Ferricyanide in Sodium Hydroxide. The preparation of trans-dimeric α-alkyl-substituted 2-nitroso-1-phenylethanes (PhCH2CH-(R)NO)2 (R =H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, and tert-Bu) by this method has been described.234,235
(4) Periodates and Periodic Acid. In 1960, Emery and Neilands236 discovered that periodic acid oxidation of N-methylhydroxylamine and of N-methylacethydroxamic acid produced cis-dimeric nitrosomethane in high yield. Although they did not attempt to extend this method to other N-alkylhydroxylamines, they suggested that such an extension was likely to succeed. In 1964, Sklarz and coworkers237,238 introduced the use of tetraethylammonium periodate as an oxidant for hydroxylamines, and this was developed from 1973 onward by Kirby and co-workers239 for the oxidation of a range of hydroxylamines to produce short-lived nitroso compounds, which were then trapped by dienes to produce dihydrooxazines. Later studies240–242 added the compounds ROC(O)NHOH, RR′NC(O)NHOH and RCH(OR′;)C(O)NHOH (R and R′ =alkyl or aryl) to the list of hydroxylamines used to produce short-lived C-nitroso compounds. A further development took place in the use of tetraethylammonium periodate for the oxidation of chloroform solutions of sugar hydroxylamines of the general structure R3CNHOH to the corresponding monomeric R3CNO. The same product can also be obtained using the oxidant dichlorodicyanobenzoquinone (DDQ). The use of periodate for the oxidation of sugar hydroxylamines RCH2NHOH and R2CHNHOH gives only the isomeric oximes. In contrast, the use of DDQ with RCH2-NHOH gives both the oxime and the dimeric nitroso compound, whereas only the dimeric nitroso compound is produced when R2CHNHOH is used.243,244
(5) Halogens and Hypohalites. Oxidation of tert-butylhydroxylamine by bromine in sodium hydroxide (as a source of NaOBr) at 0 °C gives good yields of the corresponding nitrosoalkane.174,245 This has been extended to prepare dimeric 1-nitroso-1-carboxylic acid-tert-butyl ester-cyclohexane (Scheme 11).246
Oxidation using bromine water together with a solution of the hydroxylamine in 2 M HCl gave good yields of dimeric nitroso compounds (RNO)2 (R =cyclohexyl, 4-heptyl, cycloheptyl, cyclooctyl, 2-methylcyclohexyl).247,248 Further extension to the trans-dimers of 1-nitroso-trans-decalin, 2-nitroso-trans-decalin, and 2-nitroso-cis-decalin followed.249 Oxidation of 1-cyano-1-hydroxylaminocyclohexane by chlorine yields the corresponding nitroso compound,250 and an ethanol solution of 3-chloro-4-methyl-phenylhydroxy-lamine was oxidized to the dimeric nitroso compound by stirring with iodine, sodium iodide, and sodium acetate in water.251

Scheme 11
(6) Silver Carbonate. Maassen and de Boer252 showed that when silver carbonate, precipitated on Celite, was added to a dichloromethane solution of RNHOH (R =Ph, 4-ClC6H4, cyclohexyl, isopropyl, cyclo-C3H5CHMe, and 2-adamantyl) at room temperature, 84–95% yields of the dimeric nitroso compounds were obtained within a few minutes, thereby avoiding the danger of coupling between the nitroso compound and the unreacted hydroxylamine to form azoxy derivatives. Lower yields (57–66%) were obtained for R =tert-butyl (in dry CFCl3) and benzyl (in dry CH2Cl2 at 0 °C). With the exception of nitrosobenzene, the dimers obtained were the trans-dimers, and the 1-cyclopropyl-1-nitrosoethane was a mixture of the racemic and meso forms of the dimer. Further details are given by Maassen.253
(7) Lead Dioxide. The oxidation of five N-hy-droxycarbamates (ROC(O)NHOH; R =Me, Et, i-Pr, Ph, CH2Ph) with freshly prepared lead dioxide in dichloromethane at −10 °C showed the presence of the corresponding nitrosoformates ROC(O)NO, as judged by the further reaction with alcohols to yield carbonate products.254
(8) Other Oxidizing Agents. tert-Butylhydro-peroxide oxidizes N-alkylhydroxylamines R(Me)2-CNHOH (R =Me, Et, CH2OCOMe) and the nitroso compounds were detected by visible absorption spectroscopy.255 Good yields of C-nitroso compounds result from the rapid oxidation of both phenyl- and tert-butylhydroxylamine by phenylseleninic anhydride ((PhSeO)2O) in dry THF at room temperature.256 Oxidation of 4-hydroxylaminopyridine-1-oxide by potassium permanganate is an easy route to the nitroso derivative.257 Other oxidizing agents employed in such oxidations include phenyliodine ditrifluoroac-etate,258 diethyl azodicarboxylate,259 2,6-dichloro-3,5-dicyanobenzoquinone (DDQ),244 peroxyformic acid,260 MCPBA,261 and pyridinium chlorochromate with arylhydroxylamines in THF.262 Diethyl azodicarboxy-late oxidizes cyclopropylhydroxylamine to give the trans-dimer of nitrosocyclopropane at −24 °C, the hydroxylamine having been obtained by controlled reduction of nitrocyclopropane.263 Potassium ferrate-(VI) has recently been reported to oxidize N-phenyl-hydroxylamine to nitrosobenzene.264
2.4.3. Oximes. Rheinboldt and Dewald265,266 showed that nitrosyl chloride reacted with both ketoximes and aldoximes to give geminal chloronitroso compounds (eq 26).


A further study267 showed that only some oximes yielded chloronitroso compounds when treated with nitrosyl chloride (nitrimines and ketones were produced in some cases). The successful cases included camphor oxime and pinacolone oxime: the statement that the IR spectra of both monomeric and dimeric 2-chloro-2-nitroso-3,3-dimethylbutane are identical is obviously incorrect. The preferred method for the preparation of chloro- and bromo-nitroso compounds is the reaction of halogen or alkylhypohalite with oxime. This method, based upon the early work of Piloty and Schmidt, has been reviewed by Kosinski268 and Kresze et al.269 and was employed by several groups in the 1950s.248,250,270–272 Diekman and Lüt-tke273 used tert-butylhypochlorite as the chlorinating agent for oximes (RR′C=NOH) to give geminal chloronitroso compounds in high yield (>90%) and purity (R/R′ =H/Me, H/Ph, Me/Me, Me/t-Bu, Me/n-Bu, Me/CH2Ph, and (CH2)5). The same reagent was used to oxidize five para-substituted phenylhydroxylamines to their nitroso derivatives.216 High yields (>70%) of chloronitroso compounds were obtained from the reaction of chlorine with five different ketoximes in ether.248 The bromination of acetaldoxime was shown by Piloty and Stock274 to give 1-bromo-1-nitrosoethane, which could be isolated as the dimer; chlorination of some oximes yielded the 1-chloro-1-nitrosoal-kanes.275 The further reactions giving 1,1-dichloro-1-nitrosoethane are shown in Scheme 12.

Scheme 12
Chiang276 reported similar results on chlorination of various benzaldoximes. The chlorination of al-doximes to aldehydo–sugar oximes has been studied by Tronchet et al.;277 the white solid dimer of RCH-ClNO dissociates in solution to form the monomer, which subsequently isomerizes to the oxime (Scheme 13).
It has been reported278 that hexafluoroacetoxime (CF3)2C=NOH reacts with chlorine at –78 °C to give (CF3)2C(Cl)NO; 2-nitrosoheptafluoropropane has been prepared from the same oxime by reaction with hydrogen fluoride/chromium trioxide.279 Bromination of 2-pentanone oxime by N-bromosuccinimide in sodium carbonate yields the bromonitroso product.270

Scheme 13
Lead tetraacetate reacts with ketoximes to give geminal nitrosoacetates.280 Extension of these studies281 showed that geminally substituted nitroso compounds resulted from the reaction of aliphatic and alicyclic ketoximes with lead tetraacetate and lead tetrabenzoate in inert solvents such as ether, benzene, dichloromethane, and tetrachloroethylene (Scheme 14).

Scheme 14
It was also shown that when cyclohexanone oxime reacted with lead tetraacetate in ethereal 4-nitroben-zoic acid, pale blue crystals of 1-nitroso-1-(4-nitroben-zoxy)cyclohexane were formed (eq 27).


Extension to reaction of lead tetraacetate with aldoximes resulted in the isolation of four different trans-dimeric nitroso acetoxyalkanes (RCH(OAc)NO)2 (R =propyl, pentyl, heptyl, and benzyl). Similarly, Lown282 showed that geminal nitroso acetoxy derivatives were obtained in 23–72% yields from the reactions of lead tetraacetate with the ketoximes of acetone, cyclopentanone, cyclohexanone, 4-tert-bu-tylcyclohexanone, heptan-2-one, and heptan-4-one. Dimeric 1-equatorial-1-acetoxy-1-nitroso-4-tert-butyl-cyclohexane and monomeric 1-axial-1-acetoxy-1-nitroso-4-tert-butylcyclohexane were obtained. White and Considine283 were the first to study the reaction between lead tetrabenzoate and both aliphatic and alicyclic ketoximes. Dimeric 2-nitroso-2-benzoyloxy-propane was isolated from the reaction with acetoxime (Scheme 15).
The reaction of lead tetraacetate with aliphatic anti-aldoximes284 and steroid ketoximes285 yielded geminal nitrosoacetates. Isolation of the colorless trans-dimer of 1-acetoxy-1-nitrosoheptane was achieved from reaction with anti-heptanaldoxime, whereas the colorless reaction product (with a blue tinge) from syn-trimethylacetaldoxime did not yield a pure sample of the spectroscopically indicated dimeric 1-acetoxy-1-nitroso-2,2-dimethylpropane. The light blue color of the solid 3β,6β-diacetoxy-6α-nitroso-5α-cholestane suggested the presence of both monomeric and dimeric forms. Two short reviews of the reactions of lead tetraacetate with oximes have appeared.286,287

Scheme 15
Extension to the oxidation of the dioximes of aliphatic and alicyclic diketones has been made;288,289 pyrazoline1,2-dioxides are formed, and geminal ac-etoxynitroso compounds are probable precursors. The reaction of mesityl oxide oxime with nitrite ester in acetic acid produces 3,5,5-trimethyl-3-pyrazoline N,N′-dioxide (eq 28).290


Ozonolysis of N-phenylbenzaldoxime and N-tert-butylbenzaldoxime produced nitrosobenzene and 2-methyl-2-nitrosopropane intermediates, respectively, which were further oxidized to their nitro derivatives.291
2.4.4. Other N-Containing Functional Groups. Lee and Keana261 showed that oxidation of an oxazoline with 3-chloroperoxybenzoic acid gave the oxaziridine (Scheme 16), which upon further manipulation gave the nitroso ester as the final product.
Similar oxidation of a dihydrooxazine with 2 equiv of 3-chloroperoxybenzoic acid produced 2-nitroso-2-methyl-4-acetoxypentane as a blue oil which crystallized as the colorless dimer at −20 °C (eq 29).


The ozonation of two nitrones using 1 mol equiv of ozone produced their nitroso products; nitro compounds were the final products of ozonation.291 The oxidation of the amines N-pentachlorophenylpiperidine and N-pentachlorophenylpyrrolidine with peroxyformic acid gave pentachloronitrosobenzene.260 The intermediate N-pentachlorophenyl-2-formoxypiperidine similarly gave pentachloronitrosobenzene. In a similar manner, tetrachloro-4-nitrosopyridine was obtained from tetrachloro-4-methylaminopyridine on reaction with peroxytrifluoroacetic acid.292

Scheme 16
2.5. Preparation from Nitro Compounds
2.5.1. Direct Reduction. The direct reduction of nitrobenzene to give nitrosobenzene has attracted the attention of chemists for about 100 years. Early examples are provided on the reduction of nitrobenzene by barium oxide293 and by sodium, potassium, calcium, strontium, barium, magnesium, zinc, and aluminum amalgams in dry organic solvents.294 A related reduction of m-dinitrobenzene by zinc to give m-nitro-nitrosobenzene was reported in 1905.295 The more recent studies by Ponec and co-workers have provided essential insight into the conditions necessary for selective surface-catalyzed deoxygenation of nitrobenzene. The catalysts used were carefully characterized,296,297 and by using various oxides of manganese it has been shown298 that the steady-state catalyst for the reduction is the spinel Mn3O4 in a slightly reduced form, the mechanism for this selective reduction being that proposed by Mars and Van Krevelen for vanadium oxide catalysts.299 Further studies have investigated the role of Li+, Na+, and K+ ions on the activity and selectivity of Mn3O4 and similarly of the mixed oxide catalyst PbO–Mn3O4.296,300–302 The deoxygenation reaction is carried out at 573 K using an open-flow system with a fixed bed reactor and using helium as the carrier gas. A further variation of the catalyst is shown in the use of a series of mixed cobalt aluminum oxides with spinel structures, the rate of production of nitrosobenzene increasing almost linearly with increasing concentration of cobalt in the surface.303 The importance of these studies lies in the potential for producing nitrosobenzene from nitrobenzene on an industrial scale without the formation of the waste products that result from the batch process involving reduction to the hydroxylamine and subsequent oxidation.
In a series of papers, Moinet reported the development of direct synthetic methods for the high-yield production of substituted 2-nitrosobenzoic acids and other substituted nitrosobenzenes from their nitrobenzene precursors using a “redox” cell. In general, the solution was allowed to flow through two consecutive porous electrodes of opposite polarity; at the first porous cathode the nitro compound was reduced to the hydroxylamine, and at the second porous anode this was oxidized to the nitroso compound.304–307 High-yield syntheses of ortho-substituted nitrosobenzenes RC6H4NO (R =CO2H, CO2Me, CONH2, CON-HMe, CONEt2, CON(Me)Ph, CH2CO2H, CHOHCO2H, NHCO2Me) were achieved by this method.305
An efficient electrochemical synthesis of nitrosobenzene from nitrobenzene has been reported;308 a THF–0.2 M tetrabutylammonium perchlorate solution in the presence of 6 equiv of benzoic acid was used. When the oxidation step (after the four-electron reduction of PhNO2 to PhNHOH) was carried out at −30 °C, the isolated yield of nitrosobenzene was 90%.
Optimum conditions for the electrosyntheses of meta- and para-substituted nitrosobenzenes from nitrobenzenes RC6H4NO2 with the electron-withdrawing substituents (R =CN, COO−, COOMe, CHO, COMe) have been described.309 Extension of this technique to nitroheterocyclic compounds has yet to be attempted.
It has been shown that photoreduction (by irradiation with a medium-pressure mercury lamp with a Pyrex filter) of the ternary complexes of β-cyclodextrin, some nitrophenyl ethers, and 1-phenylethylamine in the solid state gave >95% yields of the corresponding nitroso compounds (eq 30).310


The reaction of mononitroarenes with alkyl Grig-nard reagents has been investigated extensively;311 it has been shown that conjugate addition of the alkyl RMgX system occurs and that nitroso compounds can be obtained from a number of bicyclic aromatic systems such as naphthalenes, quinolines, indoles, benzothiophenes, benzoxazoles, and benzothiazoles (e.g., eq 31).312


2.5.2. Redox Reactions. Light-catalyzed intramolecular rearrangements of nitroaromatic compounds containing an ortho substituent in which a C–H bond is attached to the ortho ring carbon have long been known. Ciamician and Silber313 found that o-nitrobenzaldehyde rearranged photolytically to o-nitrosobenzoic acid (Scheme 17), and Sachs and Hilpert314 suggested that “all aromatics which have a hydrogen ortho to a nitro group will be light sensitive”.

Scheme 17
These rearrangements occur for the nitroaromatics containing the ortho groups CH=NPh,315 C(CN)H-(OH),314 CH(OEt)2,316 CH2OH,316,317 and CHPh2.318 The quantum yield of the o-nitrobenzaldehyde intramolecular rearrangement in acetone is 0.5,319 which was found to be in good agreement with the unweighted value of 0.46 for the isomerization reaction in the solid state.320 This photolytic oxygen-transfer rearrangement321 has been employed as a chemical actinometer using a dispersion of o-nitrobenzaldehyde in a thin film of poly(methyl methacrylate).322 γ-Irradiation of solid o-nitrobenzaldehyde results in the formation of o-nitrosobenzoic acid in >90% yield.323 In all these examples the products are the trans-dimeric nitroso compounds.
Other developments of the photoredox reaction are shown in the production of o-4-pyridylnitrosobenzenes from the light-sensitive o-4-(1,4-dihydropy-ridyl)nitrobenzene precursors,324 in the production of o-nitrosophenols from o-nitrophenoxyacetic acids,325 and in the formation of o-nitrosoanilines from o-nitro-N-alkylanilines (eq 32).326


In addition to these photochemical reactions, thermal rearrangements have been observed; o-nitrocy-clopropylbenzene in the presence of concentrated sulfuric acid at low temperatures gives o-nitrosopropiophenone, and o-nitrostyrene similarly produces o-nitrosoacetophenone (eq 33).327


The rearrangement of o-cyclopropylnitrobenzene in trifluoromethane sulfonic acid gives o-nitroso-propiophenone in 79% yield (eq 34).328


Some o-nitrobenzene derivatives are of pharmaceutical importance and can form nitroso compounds on irradiation of their solutions by sunlight or by ultraviolet light. Examples are provided by the irradiation of nifedipine, an antihypertensive drug and calcium channel blocker, which gives high yields of an apparently monomeric nitroso compound (eq 35),324,329,330 and by the irradiation of the structurally similar nisoldipine, also a calcium channel blocker, which gives a monomeric and two dimeric nitroso compounds (eq 36).331



Three o-nitrobenzyl ethers of choline, when subjected to laser flash photolysis at 351 nm, give ortho-substituted nitrosobenzenes with release of choline (Scheme 18).332

Scheme 18
Photolysis of o-nitrobenzyl alcohol has been shown to generate o-nitrosobenzaldehyde.317 Hydrolysis of o-nitrobenzyl tosylate in 1:1 acetonitrile/water gives o-nitrobenzyl alcohol and o-nitrosobenzaldehyde by an intramolecular nucleophilic substitution reaction (Scheme 19).333

Scheme 19
2.5.3. Photochemical Synthesis from Nitroalkanes in Solution. Reid and Wilcox334 found that the trans-dimer of nitrosocyclohexane was the major product from the irradiation (at 254 nm) of nitroethane in degassed cyclohexane (eq 37); the same product was obtained from photolysis of nitromethane in degassed cyclo-hexane.335


Co-60 γ-irradiation of liquid nitromethane resulted in the formation of cis-dimeric nitrosomethane.336
2.6. Preparation from Other Nitroso Compounds
Ingold337 prepared the para-substituted nitrosobenzenes 4-RC6H4NO (R =Cl, Br, NO2) by reaction of the elemental halogens (reaction temperature of ~5 °C) or concentrated nitric acid (reaction temperature of 0 °C) with nitrosobenzene in carbon disulfide. Hammick and Illingworth338 showed that the production of 4-bromonitrosobenzene did not occur when glacial acetic acid was the solvent. 4-Nitrosophenyl ethers can be aminated with primary aromatic amines to give 4-nitrosodiphenylamines (Scheme 20).339

Scheme 20
2.7. Reaction of Free Radicals with Nitric Oxide
The formation of a nitroso compound by the reaction described in eq 38 was first proposed in 1911 to explain the blue coloration obtained when nitric oxide (itself a radical) was passed into a solution of the equilibrium mixture of the trityl dimer (at the time believed to be “hexaphenylethane”, but now known to have an unsymmetrical quinoid structure)340 and triphenylmethyl.341


Staveley and Hinshelwood342–344 found that addition of small quantities of nitric oxide to the reaction vessel during the pyrolytic decomposition of diethyl ether brought about a considerable reduction of the decomposition reaction rate (by trapping of radicals with NO) and ascribed this to the reactions in Scheme 21, although no experimental detection of nitrosomethane or formaldoxime was presented.

Scheme 21
It is, however, possible that the unidentified white solid obtained from the photolysis of gaseous dim-ethylmercury in the presence of nitric oxide was (or contained) a dimer of nitrosomethane.345
Dimeric nitrosomethane was first isolated in 1948 by Coe and Doumani346 from the photolysis of gaseous tert-butyl nitrite, the overall reaction (eq 39) being followed by deposition of the dimeric nitrosomethane at the unirra
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