N-centered radicals

Scheme 14.—Proposed Fragmentation Reactions of the N-Centered Radical from 2-Amino-2-deoxy-D-glucose.34...

Interestingly, the catalytic reaction yielded predominantly the threo-4-(chloro-methyl)oxazolidinones, whereas under thermal conditions in 1,1,2,2-tetrachlo-roethane (TCE) the eryth.ro isomer was formed exclusively. If the reaction proceeded via aziridine formation followed by nucleophilic ring opening, the product stereochemistry would be erythro. As this was not the case, the involvement of an N-centered radical species was suggested (Figure 3.8). 

Figure 3.8 N centered radical species in aminochlorination reactions.

In the case of amines, protonation that withdraws electron density from the center of reaction lowers the rate of reaction by a factor of 30 (Das and von Sonntag 1986). Besides H-abstraction from carbon [reactions (18) and (21)], the formation of N-centered radical cations is observed [reactions (19)/(22) and (20) for amino acids see, e.g Bonifacic et al. 1998 Hobel and von Sonntag 1998]. Reaction (20) is also an H-abstraction reaction. The ET reaction (19)/(22) may proceed via a (bona-fide, very short-lived) adduct (Chap. 7). 

In DNA free-radical chemistry, N-centered radicals are generated from some nucleobases upon one-electron oxidation (followed by II+ loss). They are also considered as important intermediates in the purine free-radical chemistry. It is, therefore, worthwhile to address very briefly some of the chemistry of N- centered radicals that were encountered in amines and amino acids. 

Tryptophan and its derivatives such as the Hoechst compounds (Adhikary et al. 2000) have reduction potentials below that of G (tryptophan E7 = 1.0 V Jovanovic and Simic 1985) and thus are capable of repairing some of the DNA damage (for a review on indol free-radical chemistry see Candeias 1998 for the thermochemistry of N-centered radicals see Armstrong 1998). In these reactions, radical cations and N-centered radicals are formed. Similar to phenoxyl radicals, these radical react with 02- mainly by addition despite the large difference in the redox potential which would allow an ET as well (Fang et al. 1998). 

Pyrimidines. Photoexcited anthraquinone-2,6-disulfonate undergoes ET with Thy and its methyl derivatives as indicated by Fourier transform EPR (Geimer et al. 1997). These pyrimidine radical cations deprotonate at N( 1) thereby giving rise to the corresponding N-centered radicals [reaction (6)]. 

Upon electrochemical oxidation, dimers resulting from a recombination at C(5) are formed as well. Whether this route is mediated by the electrode surface or due to a recombination of a radical cation with an N- centered radical (note that there is a high radical density at the electrode surface and that the radical cation (pfCa = 3.2) has a lifetime of 0.5 ps), must remain speculation. To a smaller extent, a further dimer is also observed. It may arise by an addition/oxidation... 

The menadione-sensitized oxidation of dCyd leads to the formation of the four cis and trans diasteroisomers of (OH)2dUrd and to ring-opened products, and it has been concluded that the major reaction of the dCyd radical cation is its reaction with water yielding the OH-adduct radical (Decarroz et al. 1987). However, N- centered radicals could well be their precursors. The formation of Cyt and 2-dRL has also been noticed. 

Unless a non-radical mechanism accounts for the formation of 4,5-dihydro-5-hydroxy-4-(nitrosooxy)-2 -deoxyguanosine, -N02 must add to the 2 -deoxy-guanosine -OH-adduct via its O-centered mesomeric form in contrast to the nitration of tyrosine, where -N02 reacts as an N-centered radical (van der Vliet et al. 1994 Lymar et al. 1999). 

Naumov S, Beckert D (2002) Reply to the Comment on A Fourier transform EPR study of uracil and thymine radical anions in aqueous solution)/ by DM Close. Phys Chem Chem Phys 4 45 Naumov S, Barthel A, Reinhold J, Dietz F, Geimer J, Beckert D (2000) Calculation of spin densities of radicals of pyrimidine-type bases by density functional theory. Influence of solvent and comparison with EPR results. Phys Chem Chem Phys 2 4207-4211 Naumov S, Hildenbrand K, von Sonntag C (2001) Tautomers of the N-centered radical generated by reaction of SO4 - with N(1)substituted cytosines in aqueous solution. Calculation of isotropic hyperfine coupling constants by a density functional method. J Chem Soc Perkin Trans 2 1648-1653... 

Examples for frequently encountered intermediates in organic reactions are carbocations (carbenium ions, carbonium ions), carbanions, C-centered radicals, carbenes, O-centered radicals (hydroxyl, alkoxyl, peroxyl, superoxide anion radical etc.), nitrenes, N-centered radicals (aminium, iminium), arynes, to name but a few. Generally, with the exception of so-called persistent radicals which are stabilized by special steric or resonance effects, most radicals belong to the class of reactive intermediates. 

Z. B. Alfassi, The Chemistry of N-Centered Radicals, Wiley, New York, 1998. 

Generation of N-centered radicals and their cyclization to give pyrrolidines 93AHC(58)1. 

Under similar conditions, a radical-initiated [3-F2] cycloaddition of N-centered radical with benzo[.i]furan 82 was examined. A benzo[. ]furan-derived pyrrolidine 112 was obtained in good yield with again EtsB as a radical initiator (as depicted in Equation 101) <20010L2709>. 

Cascade Reactions Initiated by Addition of N-Centered Radicals to Alkynes... 

Since the computational studies support the general perception of good or poor leaving groups in self-terminating radical reactions, but clearly contradict the experimental findings, radical cyclization cascades initiated by N-centered radical addition to alkynes are not terminated by homolytic p-fragmentation. 

N-centered radicals such as iminyl radicals can also be generated from a radical cyclization step onto nitrile groups. The fate of the iminyl radical depends on the nature of the a-substituent. When this latter is an alkyl group, further cychzation can take place [45]. A combination of both processes has been achieved addition of a staimyl radical onto an azide moiety generated a N-stannylaminyl radical that cyclized onto a nitrile and underwent further cyclization, thus opening access to pyrrolopyrroles and pyrrolopyridines derivatives [46]. 

Pulse radiolysis studies using optical detection suggested the main species in equilibrium to be the ot-aminoalkyl radical (31) and the A -protonated ot-aminoalkyl radical (32) whereas results from ESR studies were indicative of protonation at the a-carbon site to form the iV-centered radical cation (30). A subsequent study showed that these results could be attributed to kinetic and thermodynamic factors [84]. Thus iV-protonation resulting in the formation of 32 is kinetically favored and is hence observed in the short time-scales involved in pulse-radiolysis systems. In the longer times involved in ESR measurements the thermodynamically more stable N-centered radical cation will be observed. The pA a of 30 and 32 were estimated as 8.0 and 3.6 by use of pulse radiolysis [84]. Using the equation for similar keto enol tautomerism of barbituric acid [97], the ratio of 30/32 was estimated to be 10 /10 = 10", indicating the N-centered radical (30) to be the predominant protonated species. 

Lind, J., Merenyi, G. Imidyl radicals. N-Centered Radicals 1998, 563-575. 

An equilibrium between 0- and N-centered radical is suggested. Complication in this simple mechanism is caused by the participation of the respective radicals in coupling, disproportionation, oxidation and recombination reactions. It is connected with the formation of products different from those in the original mixture and not involved in the regeneration cycle. A stepwise depletion of antioxidant active species depedent on both the amine and phenol structures should therefore be considered. 

A final example of an allylic C-H animation process involves a mechanism that does not fall into the classification of either a Cu-bound nitrene or N-centered radical-type process. In this case, A-Boc-hydroxylamine serves as the nitrogen source and is converted to the acylnitroso species via a disproportionation mechanism facilitated by P(OEt)3 and CuBr [50]. Such compounds will react with olefin substrates through a thermal ene-like rearrangement to give A-Boc-A-hydroxy allylic amines. The Cu catalyst is not believed to play a specific role in the actual C-H oxidation event. 

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