Protonated aminyl radical

The electronic nature of a nitrogen centered radical, dictated by reaction conditions and/or the radical precursor employed, is crucial to the mode of reaction, to the ability to undergo efficient intramolecular cyclizations or intermolecular additions, and to the products isolated from the radical reaction. The types of radicals discussed in this review include neutral aminyl radicals, protonated aminyl radicals (aminium cation radicals), metal complexed aminyl radicals, and amidyl radicals. Sulfonamidyl and urethanyl radicals are known (71S1 78T3241), but they are not within the scope of this chapter. 

Neutral aminyl radicals bearing electron-withdrawing tV-substituents (for example, amidyl radicals), or aminium radicals (protonated aminyl radicals) and metal ion complexed aminyl radicals are more reactive due to the lower nonbonding electron density on nitrogen, and consequently the diminished repulsive interaction with the it electrons of the alkene4,6. 

Other methods, among which thermolysis or photolysis of tetrazene [59], photolysis of nitrosoamines in acidic solution [60], photolysis of nitrosoamides in neutral medium [61], anodic oxidation of lithium amides [62], tributylstannane-mediated homolysis of O-benzoyl hydroxamic derivatives [63, 64], and spontaneous homolysis of a transient hydroxamic acid sulfinate ester [65] could have specific advantages. The redox reaction of hydroxylamine with titanium trichloride in aqueous acidic solution results in the formation of the simplest protonated aminyl radical [66] similarly, oxaziridines react with various metals, notably iron and copper, to generate a nitrogen-centered radical/oxygen-centered anion pair [67, 68]. The development of thiocarbazone derivatives by Zard [5, 69] has provided complementary useful method able to sustain, under favorable conditions, a chain reaction where stannyl radicals act simply as initiators and allow transfer of a sulfur-containing... 

The reductive couphng of imines can follow different pathways, depending on the nature of the one-electron reducing agent (cathode, metal, low-valent metal salt), the presence of a protic or electrophihc reagent, and the experimental conditions (Scheme 2). Starting from the imine 7, the one-electron reduction is facihtated by the preliminary formation of the iminiiim ion 8 by protonation or reaction with an electrophile, e.g., trimethylsilyl (TMS) chloride. Alternatively, the radical anion 9 is first formed by direct reduction of the imine 7, followed by protonation or reaction with the electrophile, so giving the same intermediate a-amino radical 10. The 1,2-diamine 11 can be formed from the radical 10 by dimerization (and subsequent removal of the electrophile) or addition to the iminium ion 8, followed by one-electron reduction of the so formed aminyl radical. In certain cases/conditions the radical 9 can be further reduced to the carbanion 12, which then attacks the... 

In solution photochemistry in the presence of acids, the primary process is also the same except that both NND and the aminyl radical are protonated the recombination of the aminium radical and NO to give 295A is too slow to compete with bond scissions174 (Scheme 11). The failure of oxygen to quench nitrosamine photoreactions in either solution (see below) or gas phases under various conditions must also mean a very short lifetime of singlet excited nitrosamines, in agreement with the fast dissociation159,160. 

Nitramines are known to photodissociate from their jt,jt state to give aminyl and nitric oxide radicals in the presence of an acid the aminyl radicals are protonated to give aminium radicals, which can initiate addition to olefins. As a synthetic reaction, photolysis of nitramines in the presence of acids can be conveniently run under oxygen to give oxidative addition similar to those shown in equation 145 indeed TV-nitrodimethylamine is photolysed with triene 299 under such conditions to give a mixture of 301 and 302, similar to results observed in the oxidative nitrosamine photoaddition169. To simplify the isolation, the crude products are reduced with LAH to form the open-chain amino alcohol 303. Some other oxidative photoadditions of N-nitro dimethylamine to other olefins are reported. As the photoreaction has to use a Corex filter and product yields are no better than those shown by nitrosamines, further investigations were scarcely carried out. 

A similar procedure has successfiiUy generated aminyl radicals by treating the iV-carbamates of Ar-hydroxyl-2-thiopyridones (40) with radical initiators such as RS- and RsSi-. The aminyl radical generated abstracts a proton or adds intramolecularly to the double bond to result in the cycli-zation products shown in Scheme 26 (87JA3163). 

A similar pattern of reactivity has been observed by Burrows and coworkers for the reaction between A -acetyllysine methyl ester (Lys) and dG. This reaction was studied in order to gain an understanding of structural aspects of DNA-protein cross-links (DPCs). These cross-links are regarded as a common lesion of oxidative damage to cells, but remain, from a chemical point, a poorly understood DNA lesion. As pointed out by Burrows, oxidation of protein-DNA complexes should occur preferentially at the primary amines since these sites have a lower oxidation potential (1.1 V vs. NHE, pH 10) than G. While protonation of the primary amine inhibits the oxidative process, transient deprotonation of a lysine residue would give rise to a lysine aminyl radical (or aminium radical cation). Using... 

To facilitate the cyclizations of nitrogen-centered radicals, one need only increase the electronegativity at nitrogen. This makes the radical more electrophilic (which accelerates the cyclization), and strengthens the forming bonds (which shifts the equilibrium to the cyclic product). Amminium radical cations are more well-behaved in cyclizations than aminyl radicals, and these radical cations can either be formed directly from ammonium salts, or by protonation of aminyl radicals (which are relatively weak bases and require strong acids for protonation). Metal-complexed aminyl radicals are highly reactive, and amidyl radicals are also useful.178... 

Neutral aminyl radicals (I), also referred to as amino radicals, can be considered to be nucleophilic species whereas aminium cation radicals (II), metal complexed aminyl radicals (III), and amidyl radicals (IV) are electrophilic in nature. Greater utility has been observed with electrophilic nitrogen radicals than with neutral aminyl radicals (71 SI). Aminyl radicals are easily protonated with Br0nsted acids to give aminium cation radicals and readily complex with Lewis acids to form radicals III therefore, control of the reaction conditions is critical to ensure that reactions of interest are occurring from only one species. 

Aminyl radicals can be protonated with Br0nsted acids or complexed by Lewis acids to generate an electrophilic nitrogen radical. The pKa of an aminium cation radical in water is =7 as determined from a titrametric... 

One of the best methods for the controlled generation of alkenaminyl radicals is via PTOC carbamates (Section II,E). These precursors react in efficient radical chain reactions with hydrogen atom donors to form amines and pyrrolidines. They are stable to anhydrous acids and, therefore, are suitable precursors for aminium radicals produced by protonation of the first-formed neutral aminyl radical. 

The acid is also a critical factor. Acetic acid does not appear to protonate an aminyl radical completely even in acetonitrile. Under highly acidic conditions, the PTOC carbamate may be protonated as was indicated in a study of the simple (V,/V-dipropyl PTOC carbamate. In neat trifluoroace-tic acid (TFA), the long wavelength absorbance responsible for the yellow color of the precursor completely disappeared, presumably from protonation at the thione sulfur to form the thiol cation 68 (Scheme 19). The yellow PTOC carbamate was recovered upon neutralization of the TFA... 

In intermolecular reactions, neutral aminyl radicals, R2N", react with n systems preferably by HAT. N-protonation increases the electrophUicity of the radical center, and successful addition of aminium radicals, R2NH, to 7t systems, usually alkenes, has been reported in the hterature." Compared to aminium radicals, amidyl and imidyl radicals, for example, RN C(0)R and [RC(0)]2N , are less electrophilic. Although they are delocahzed 7t-allyl radicals, they react exclusively at nitrogen." Only very few examples for radical cascades that are initiated by addition of A-centered radicals to alkynes have been reported. 

A radical chain reaction initiated by visible light irradiation occurs with l,2-dihydro-2-thioxo-1-pyridinyl 4-alkenylcarbamates (PTOC carbamates) 1 in the presence of a carboxylic acid and a hydrogen-atom donor, preferably tert-butyl mercaptan after homolytic cleavage of the weak N—O bond and a decarboxylation step, the aminyl radical is protonated by the carboxylic acid and cyclizes to give a carbon radical. After reaction with tert-butyl mercaptan and a base the pyrrolidine 2 is obtained. In competition with trapping by tert-butyl mercaptan, or in the absence of this, the carbon radical can react with the PTOC carbamate 1 in a chain-propagating step to give the sulfide 3 (Section 7.2.5.9.)127. 

Photoinduced oxidation of amines leads to the formation of amine radical cations. These intermediates display both radical and cationic character with the N-H protons of the primary and secondary amine cation radicals being acidic. As a result, an efficient deprotonation occurs at the carbon a to the nitrogen radical cation giving aminyl radicals (Eq. (3)) [100]. 

ROOH] > 10 mole.l. This is attributed to a radical-cation InH, which may be formed by protonation of aminyl radical ... 

Aminyl radicals have also been detected indirectly during the reaction of hydroxyl radicals (HO ) or their conjugated base ( 0 ) with the free amino group of amino acids (Reactions (3.9) and (3.10)) [40-43], and identified by time-resolved EPR experiments [44]. Similar reactions may be expected for peptides. While Reactions (3.9) and (3.10) show a net hydrogen transfer, they likely proceed via a stepwise electron-transfer and proton-transfer (Reaction (3.11)), a reaction commonly referred to as proton-coupled electron transfer (PCET). Proton transfer from the ami-nium radical cation to the base (OH ) will likely occur within the solvent cage. 

Cyclization of the aminyl radical 22 is slow and reversible [53], and the kinetics of related cyclizations and ff-fragmentations were measured directly by LFP [54]. Protonation of the dialkylaminyl radicals gives dialkylaminium cation radicals such as 24 that react much more rapidly [55], and Lewis acid complexes of aminyl radicals such as 23 are intermediate in reactivity [56]. Clocks such as 23 and 24 are in equilibrium with the neutral aminyl radicals, and the concentrations of the proto-nated or complexed forms are necessary if one is to use these clocks equilibrium constants for protonations and Lewis acid complexations in some solvents were determined in the initial kinetic calibration studies. 

Thus, the types of reactions favored by amino radicals depend to a significant degree upon the extent with which the lone electron pair is associated with a proton, with a Lewis acid, or with an electron-withdrawing group. Clearly, aminium radical cations 2 (Scheme 1), metal-complexed aminyl radicals 3, amidyl radicals 4, sulfo-namidyl radicals 5 and cyanamidyl radicals 6 are electrophilic in nature. On the other hand, dialkylaminyl radicals 1 have been shown to display nucleophilic character... 

The iV-hydroxypyridine-2(///)thione derivatives (PTOC carbamates and PTOC imidates) permit facile generation of neutral, protonated, Lewis acid-complexed aminyl radicals and amidyl radicals. For cyclization reactions, the PTOC protocol was comparable or superior in yield to those involving Af-chloro or Al-thioaryl compounds. The thioxothiazolyloxycarbonyl (TTOC) carbamates containing a primary amine group would appear to be the most useful precursors now available for generating monoalkylaminium cation radicals [55]. Some representative examples are collected in Table 6. 

Experimental data have been evaluated for the reactions of the aminyl radicals from glycine (R = H,H), alanine (R = H,CH3) and a-methylalanine (R = CH3,CH3) with BH" " = H2P04, HP04 and the respective unoxidized zwitterions of the amino acids, AA-. Rate constants (in the 10 - lO s bracket) increase in the order of the three amino acids as listed, are naturally the highest for H2P04 as proton donor, and lower and almost equal for HP04 and AA . ... 

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