Nitrenes

Nitrenes, the nitrogen analogs of carbenes have been introduced as a reactive group in photoaffinity labels for antibodies by Fleet et al. (1969). Nitrenes tend to be more selective in their reactions and possibly will provide fewer products than carbenes (but see also 6.2.3). The types of reaction that they can undergo (eq. 6.2, Knowles 1972) include insertions into C-H bonds to yield secondary amines, cycloadditions to double bonds to form cyclic 3-member imines and 

Nitrenes ([NH]) are the neutral nitrogen analogs of carbenes, while nitrenium ions ([NH2]+) are isoelectronic to carbenes. Many of the reactions which are observed for carbenes have parallels in nitrene and nitrenium ion chemistry. Like carbenes, nitrenes and nitrenium ions can exist in both singlet and triplet states. There are some interesting divergences in chemical properties and in the effects of substituents, however, which are readily understood on the basis of orbital interaction diagrams. 

The singlet state, Si, is the first state reached when a nitrene is generated by most methods, including photolysis of the corresponding azide, R—N3. The reactions of 

Nitrenes.—The importance of nitrenes is well known,128 and the prototype NH has been extensively studied in the past,129 but until recently no ab initio work has appeared on other nitrenes. The simplest alkylnitrene, MeN, has not been studied spectroscopically but three recent papers have investigated the ground state and some excited states.11 130 131 

Harrison and Shalhoub131 have recently investigated the related carbonylnitrenes HCON, FCON, MeCON, and MeOCON, finding a triplet ground state in all cases. Geometry optimizations were carried out using an STO-3G basis set. 

More recently two complementary studies on the dissociation [reaction (6)] have 

Ab initio Calculations on Molecules containing Five or Six Atoms 

Diazomethane.— This molecule is of considerable importance as a source of methylene, and there have been several detailed studies recently. Following earlier work on the ground state by Snyder and Basch, Hart, in 1973, carried out calculations using a Gaussian lobe basis set on CHaNj and several of its isomers. A similar study by Leroy and Sana in 1974 also employed an essentially minimal basis set (73/3) and also Pople s 4-31G basis. The bonding and charge distribution were discussed and the enthalpy of formation computed. 

Nitrenes (R—N) are hypovalent species that are commonly formed by thermal or photochemical denitrogenation of azides (R—N3), which are readily synthesized and isolated, especially acyl and aryl azides. Simple alkyl azides do not in general produce alkyl nitrenes as detectable or trappable reactive intermediates upon direct irradiation (254 nm) due to rapid 1,2-migration to form the corresponding imines. Trifluoromethylnitrene is, however, formed by irradiation of CF3N3.408 

Organic azides are used for photoaffinity labelling (see Special Topic 6.16) because the azide group is small and, when attached to enzyme inhibitors, they often retain their activity as inhibitors. Azides are readily synthesized and the light-induced denitrogenation 

Co-ordinated Nitrenes.— The complex rm -[RuCl(Ng)(diars)2] reacts in hydrochloric acid to produce approximately equal numbers of molecules of [RuCl(NH3)(diars)g]+ and [RuCl(N2)(diars)a]+. When this reaction is carried out with N-labelled complex containing specifically Ru( N N N), the dinitrogen complex produced contains exclusively Ru( N N). This result is consistent with a co-ordinated nitrene (Ru N) intermediate, similar to those previously reported for reactions of ruthenium(m)-azide complexes. However, product and product-distribution comparisons between the ruthenium(ii)-and ruthenium(m)-azide plus hydrochloric acid reactions suggest that there must be some difference in mechanism between the complexes of the two different oxidation states. It is therefore proposed that for the rra j-[RuCl(N3 (diars)a] reaction the first step is protonation of the co-ordinated azide, which may occur at either end, followed by a split into Ng plus NH, which gives an ammonia ligand one way and a dinitrogen ligand the other  

The reaction of [Ru(NH3)s(OHa)] + with hydrazoic acid has as its first step an easy substitution at ruthenium to give [Ru(NH3)5(N3H)] +. This decomposes to [Ru(NH3)6(NH)] + plus dinitrogen. The main interest here, and in other similar cases, is whether this species behaves as an imido (19) or a nitrene (20) derivative. The chemical characteristics of the present intermediate indicate that it acts as an imido-complex.  

Photochemical reactions of the iridium(m) and rhodium(m) complexes [M(NH3)6(N3)] + result in the production of a co-ordinated nitrene intermediate. In concentrated hydrochloric add the iridium(m) product is [Ir(NH3)6(NH2Cl)] +, as in the equivalent thermal reaction. These iridium(ra) and rhodium(m) complexes thus behave photochemically in a similar mmmer to hydrazoic acid and to organic azides. Their behaviour contrasts with that of some other transition-metal azide complexes, e.g. those of ruthenium(n), where an azido-radical is the photochemical intermediate. One can indeed group transition-metal azide complexes into three groups, with their thermal and photochemical reactions depending on the relative ease of oxidation or reduction (or neither) of the transition-metal centre.  

Despite their limited reactivity aryl nitrenes have proved exceedingly useful as photogenerated reagents and this is documented in later chapters. Reviews on nitrene chemistry include those of Lwowski (1970), Moss and Jones (1978), Wentrup (1979), Iddon et al. (1979), Colman et al. (1981), and Scriven (1983). 

For an excellent summary of the potential of different classes of nitrenes as photogenerated reagents the reader should consult Lwowski (1980). 

In the literature of photoaffinity labeling, much ado is made about the half-lifes of carbenes, nitrenes and other reactive intermediates. It is often implied that the half-life has a fixed value for each intermediate, but it is of course a function of the temperature and environment. 

Most of the situations considered in this book approximate to pseudo first-order reactions. Iffc is the second-order rate constant for the reaction in 

Triplet diphenylcarbene has a Tl/2 of 2 ps in the presence of 1.0 M isoprene (Eisenthal et al., 1980). The lifetime of singlet phenylchlorocar-bene ranges from 5 to 500 ns in the presence of 1.0 M alkenes with various substituents (Turroetal., 1980). In 1.0M methanol singlet fluorenylidene and singlet diphenylcarbene have half-lives of 0.77 ns and 0.02 ns respectively (Zupancic and Schuster, 1980 Eisenthal et al., 1980). Triplet carbenes react very rapidly with 02. 

The nitrogen analogs of carbenes are called nitrenes. As with the carbenes, both singlet and triplet electronic states are possible. The triplet state is usually the ground state, but either species can be involved in reactions. There are many similarities between nitrene and carbene chemistry, but of course there are also significant differences. 

By far the most commonly applied means of generating a nitrene is photolysis or thermolysis of an azide. This method is clearly analogous to formation of a carbene from a diazo compound. The types of azides in which the decomposition has been 

Studied extensively are those where R = alkyl, aryl, acyl, and sulfonyl. The characteristic reaction of alkyl nitrenes is migration of one of the substituents to nitrogen, giving an imine  

Intermolecular insertion and addition reactions are almost unknown for alkyl nitrenes. In fact, it is not clear that the nitrenes exist as discrete species. The conformation of the azide group seems to determine which substituent migrates in the decomposition of alkyl azides. This observation implies that migration begins before the nitrogen molecule has become completely detached from the incipient 

At present, the chemistry of aryl nitreUes defies simple systematic description. In general terms, the course of reactions seems to be governed by transformations characteristic of the nitrene and a cyclic azirine isomer. The dominant species seems to depend on the nature of the substituents on the benzene ring. Aryl nitrenes are. 

Matrix generation has allowed us to study dinitrenes. Conjugated derivatives are strongly ferromagnetic in nature. However, interaction is reduced when nonconjugated, and such intermediates are only weakly antiferromagnetic [56]. 

Aryl nitrenes also generally rearrange rather than undergo addition or insertion reactions. A few intramolecular insertion reactions in aromatic systems go in good yield.  

The nitrenes which most consistently give addition and insertion reactions analogous to carbenes are the carboalkoxynitrenes generated from alkyl azidofor- 

This nitrene is somewhat more selective than simple carbenes, showing selectivities of roughly 1 10 40 for the primary, secondary, and tertiary positions in 2-methyl-butane in insertion reactions. The relationship between nitrene multiplicity and stereospecificity in addition to alkenes is analogous to that described for carbenes. The singlet gives stereospecific addition, while the triplet gives nonstereospecific addition products. 

Acyl azides are well-known compounds. Their role in the thermal Curtius rearrangement, a reaction that apparently does not involve a nitrene, will be discussed in Section 9.3. Photochemical decomposition of acyl azides elicits nitrene reactivity. In particular, intramolecular C-H insertion reactions have been observed, but not usually in high yield. 

2 Photoaddition to Enones and other Unsaturated Systems 3.2.2.1 Nitrenes 

Our knowledge about supramolecular nitrene chemistry and the reactivity of these intermediates in a constrained system is still in its infancy even though nitrenes are widely used for photoaffinity labelling. However, the exact structures of the products formed after reaction with the active sites are often unknown. Therefore, a better understanding of the binding properties of a nitrene precursor within the host molecule is necessary. Moreover, it is essential to learn which reactions still do occur inside a supramolecular structure. 

Our group has investigated the behavior of nitrenes enclosed in host molecules. For this purpose, we have obtained initial results with adamantyl nitrenes which can be generated either thermally or photochemically from readily available adamantane azides.  

Two main reasons guided this choice. On one hand, the reactions of these compounds under classical conditions are already known. This facilitates to find out, how nitrene reactivity has been modified by inclusion. On the other hand, as has been shown earlier in this chapter, the adamantane skeleton is a good fit for the cavity of a- and j8-cyclodextrins leading to high association constants upon complexation. 

Reactive Intermediates in Organic Chemistry Structure, Mechanism, and Reactions, First Edition. 

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The two-bond disconnection (re/ro-cycloaddition) approach also often works very well if the target molecule contains three-, four-, or five-membered rings (see section 1.13 and 2.5). The following tricyclic aziridine can be transformed by one step into a monocyclic amine (W. Nagata, 1968). In synthesis one would have to convert the amine into a nitrene, which-would add spontcaneously to a C—C double bond in the vicinity. 

Reductive carbonylation of nitro compounds is catalyzed by various Pd catalysts. Phenyl isocyanate (93) is produced by the PdCl2-catalyzed reductive carbonylation (deoxygenation) of nitrobenzene with CO, probably via nitrene formation. Extensive studies have been carried out to develop the phosgene-free commercial process for phenyl isocyanate production from nitroben-zene[76]. Effects of various additives such as phenanthroline have been stu-died[77-79]. The co-catalysts of montmorillonite-bipyridylpalladium acetate and Ru3(CO) 2 are used for the reductive carbonylation oLnitroarenes[80,81]. Extensive studies on the reaction in alcohol to form the A -phenylurethane 94 have also been carried out[82-87]. Reaction of nitrobenzene with CO in the presence of aniline affords diphenylurea (95)[88]. 

As another example of nitrene formation, the reaction of o-nitrostilbene (96) with CO in the presence of SnCU affords 2-phenylindole (97). The reaction is explained by nitrene formation by deoxygenation of the nitro group with CO, followed by the addition of the nitrene to alkene. Similarly, the 2//-indazole derivative 99 was prepared by reductive cyclization of the A-(2-nitrobenzyli-dene)amine 98[89]. 

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

Fig. 5. Chemistry of cyclized mbbei—bis-a2ide negative acting resist, (a) Preparation of cyclized mbber resin from polyisoprene (b) photochemistry of aromatic bis-a2ide sensiti2ers. The primary photoproduct is a highly reactive nitrene which may combine with molecular oxygen to form oxygenated products, or may react with the resin matrix by addition or insertion to form polymer—polymer linkages.

The preparation and properties of these tertiary aminimides, as weU as suggested uses as adhesives (qv), antistatic agents (qv), photographic products, surface coatings, and pharmaceuticals, have been reviewed (76). Thermolysis of aminimides causes N—N bond mpture foUowed by a Curtius rearrangement of the transient nitrene (17) intermediate to the corresponding isocyanate ... 

Sulfonic acid hydrazides, RSO2NHNH2, are prepared by the reaction of hydraziae and sulfonyl haUdes, generally the chloride RSO2CI. Some of these have commercial appHcations as blowiag agents. As is typical of hydrazides generally, these compounds react with nitrous acid to form azides (26), which decompose thermally to the very reactive, electron-deficient nitrenes (27). The chemistry of sulfonic acid hydrazides and their azides has been reviewed (87). 

Irradiation of ethyleneimine (341,342) with light of short wavelength ia the gas phase has been carried out direcdy and with sensitization (343—349). Photolysis products found were hydrogen, nitrogen, ethylene, ammonium, saturated hydrocarbons (methane, ethane, propane, / -butane), and the dimer of the ethyleneimino radical. The nature and the amount of the reaction products is highly dependent on the conditions used. For example, the photoproducts identified ia a fast flow photoreactor iacluded hydrocyanic acid and acetonitrile (345), ia addition to those found ia a steady state system. The reaction of hydrogen radicals with ethyleneimine results ia the formation of hydrocyanic acid ia addition to methane (350). Important processes ia the photolysis of ethyleneimine are nitrene extmsion and homolysis of the N—H bond, as suggested and simulated by ab initio SCF calculations (351). The occurrence of ethyleneimine as an iatermediate ia the photolytic formation of hydrocyanic acid from acetylene and ammonia ia the atmosphere of the planet Jupiter has been postulated (352), but is disputed (353). 

The porphyrin ligand can support oxidation states of iron other than II and III. [Fe(I)Por] complexes are obtained by electrochemical or chemical reduction of iron(II) or iron(III) porphyrins. The anionic complexes react with alkyl hahdes to afford alkyl—iron (III) porphyrin complexes. Iron(IV) porphyrins are formally present in the carbene, RR C—Fe(IV)Por p.-carbido, PorFe(IV)—Fe(IV)Por nitrene, RN—Fe(IV)Por and p.-nittido, PorFe(IV)... 

Preparation from Nitrene Intermediates. A convenient, small-scale method for the conversion of carboxyhc acid derivatives into isocyanates involves electron sextet rearrangements, such as the ones described by Hofmann and Curtius (12). For example, treatment of ben2amide [55-21-0] with halogens leads to an A/-haloamide (2) which, in the presence of base, forms a nitrene intermediate (3). The nitrene intermediate undergoes rapid rearrangement to yield an isocyanate. Ureas can also be formed in the process if water is present (18,19). 

A process for the commercial synthesis of -phenylene diisocyanate using terephthalamide [3010-82-0] as a precursor and involving N-halo intermediates has been studied extensively (21). The synthesis of 1,4-diisocyanatocyclohexane from terephthaUc acid [100-21-0] also involves a nitrene intermediate (22). 

Fig. 6. Coupling of polymer chains via (a) photoinduced hydrogen abstraction free-radical reactions and (b) nitrene insertion/addition reactions.

Iminoboianes have been suggested as intermediates in the formation of compounds derived from the pyrolysis of azidoboranes (77). The intermediate is presumed to be a boryl-substituted nitrene, RR BN, which then rearranges to the amino iminoborane, neither of which has been isolated (78). Another approach to the synthesis of amino iminoboranes involves the dehydrohalogenation of mono- and bis(amino)halobotanes as shown in equation 21. Bulky alkah-metal amides, MNR, have been utilized successfully as the strong base,, in such a reaction scheme. Use of hthium-/i /f-butyl(ttimethylsilyl)amide yields an amine, DH, which is relatively volatile (76,79). 

An early synthesis of pyrido[3,4-6]quinoxalines involved cyclization by strong heating of o-aminoanilinopyridinamine derivatives, e.g. (418) to give (419) (49JCS2540). In a related reaction, o-nitroanilinopyridines (420) were cyclized to pyrido-[2,3-6]- or -[3,4-6]-quinoxa-lines (421) by reduction with iron(II) oxalate, probably via a nitrene intermediate (74JCS(P1)1965). 

Reactions with Radicals and Electron-deficient Species Reactions at Surfaces 4.02.1.8.1 Carbenes and nitrenes... 

However, in some cases carboxylic acid-derived groups can participate in ring fission-reclosure reactions. Thus photolysis of 1,5-disubstituted tetrazole (399) gives nitrogen and appears to involve the amino-nitrene intermediate (400), which reacts further to give (401) (77AHC(21)323). 

The most important chemistry of azidoazoles is the fragmentation of derived nitrenes of which the prototypes are (453) (454) and (455) (456). Thus 5-azido-l,4-diphenyltriazole (457) evolves nitrogen at 50 °C (70JOC2215). 4-Azido-pyrazoles and -1,2,3-triazoles (458) undergo fragmentation with formation of unsaturated nitriles (8lAHC(28)23l). 

Photochemical elimination of carbon dioxide from suitable precursors has given a variety of reactive intermediates at low temperatures where they are often stable and can be studied further. This approach has been utilized in attempts to generate new 1,3-dipolar species, and photolysis of (515) gave an azomethine nitrene intermediate (516) (see Section 4.03.6)... 

Nitrenes have enjoyed appreciable application in the synthesis of a wide variety of heterocyclic systems, and the majority of the methods used for generating nitrenes have been utilized in these syntheses. 

The synthetic potential of nitrenes is more readily apparent in the synthesis of ring-fused systems (81AHC(28)309), which can be accomplished by cyclization onto a heteroatom or onto an adjacent ring, the latter having the possibility of reaction at carbon or at a heteroatom. 

Triethyl phosphite is an effective reagent for the deoxygenation of appropriate nitro (or nitroso) aromatic systems. Free nitrenes or some nitrenoid-like species may be involved, and the use of this reagent is illustrated by the examples below. It has the advantage over the azide approach in that two steps in the synthesis can be avoided. 

Thermolysis of 4- and 5-azidopyrazoles has been studied by Smith (B-70MI40402, 81AHC(28)232). These compounds undergo fragmentation with formation of unsaturated nitriles via the nitrenes (474a) and (474b Scheme 42). 

Another example of the analogy between pyrazole and chlorine is provided by the alkaline cleavage of l-(2,4-dinitrophenyl)pyrazoles. As occurs with l-chloro-2,4-dinitrobenzene, the phenyl substituent bond is broken with concomitant formation of 2,4-dinitrophenol and chlorine or pyrazole anions, respectively (66AHC(6)347). Heterocyclization of iV-arylpyrazoles involving a nitrene has already been discussed (Section 4.04.2.1.8(i)). Another example, related to the Pschorr reaction, is the photochemical cyclization of (515) to (516) (80CJC1880). An unusual transfer of chlorine to the side-chain of a pyrazole derivative was observed when the amine (517 X = H, Y = NH2) was diazotized in hydrochloric acid and subsequently treated with copper powder (72TL3637). The product (517 X = Cl, Y = H) was isolated. 

In the attempted thermolytic preparation of pyrroloisoxazole (32) from azidoisoxazole (31a), only cinnamoyl cyanide was isolated. The assumed intermediate nitrene (33) did not insert into the styryl bond, but rather ring rupture and loss of acetonitrile produced the product. Similar products were obtained from the homolog (31b) (Scheme 7) (79TL4685). The stabilized nitrene intermediate is similar to that postulated for diazofuryl- and diazoisoxazolyl-methanes (78JA7927, 79TL2961). 

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