Aminyl radicals from amino acids

As becomes apparent from the last remarks in the above section, radiation chemistry enjoys a very fruitful interaction with life sciences. One of the important classes of compounds with biological activity are amino acids. Since real life conditions include exposure to free radicals the associated chemistry becomes, consequently, of interest. Within the amino acid molecules, the a-amino-a-carboxyl moiety is a preferred target of radical attack. Reaction with, for example, OH and other one-electron oxidants leads to appreciable yields of N-oxidation and, wherever possible, cleavage of a Ca—H bond. These primary processes are the starting point of quite complex and, in part, competitive reaction schemes. Their detailed nature depends on the respective protonation state of the two functional groups, i.e., on the pH of their environment. 15-19 

Recent radiation chemical research has mainly focused on basic solutions in which the amino nitrogen carries a free electron pair which, upon oxidation, may suffer simple loss of an electron or convert via an addition/ elimination process into the H2N -CR2-C02 radical zwitterion (R = H, alkyl). 18-19 This species is prone for fast decarboxylation and rate constant 

Decarboxylation (corresponding to eq. 5) occurs, incidentally, also quite readily from N-alkyl substituted zwitterionic radical cations. 1 An N-attached phenyl substituent, on the other hand, seems to slow down this process significantly.22 This leaves interesting questions concerning the effect of electronic resonance and, possibly, molecular structure. 

While the short lifetime of the H2N -CR2-C02 zwitterion with respect to decarboxylation practically prevents it from any engagement in bimolecular redox processes, its deprotonated form HN -CR2-C02, on the other hand, is long-lived enough to effectively act as an oxidant, e.g., towards hydroquinone (eq.7). (Although stoichiometrically representing an H-atom transfer, this reaction is most likely based on an electron transfer). 1, 23 

A representative rate constant is 7.4x10 M s for the reaction of the corresponding glycine radical HN -CH2-C02 at pH 11. (At this pH the hydroquinone is partially deprotonated, H2Q HQ Q2- = 6 71 23, and the rate constant is, accordingly, a weighted one over all three forms). 

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Bonifacic M, Schafer K, Mockel H, Asmus K-D (1975b) Primary steps in the reactions of organic disulfides with hydroxyl radicals in aqueous solution. J Phys Chem 79 1496-1502 Bonifacic M, Armstrong DA, Carmichael I, Asmus K-D (2000a) p-Fragmentation and other reactions involving aminyl radicals from amino acids. J Phys Chem B 104 643-649 Bonifacic M, Hug GL, Schoneich C (2000b) Kinetics of the reactions between sulfide radical cation complexes,[S.. S]+ and [S. N]+, and superoxide or carbon dioxide radical anions. J Phys Chem A 104 1240-1245... 

Stubbe J. A., Van der DonckW. A., Protein radicals in enzyme catalysis, Chem. Rev., 1998,98,705-762. BonifacicM., Armstrong D. A., Carmichael I., Asmus K.-D., P-Fragmentation and other reactions involving aminyl radicals from amino acids, J. Phys. Chem. B., 2000,104, 643-649,... 

In aminyl radicals from amino acids and amidyl radicals from peptides, such a... 

H-shift (Reaction (3.15)) was considered feasible based on (i) the analogy to the well-known, solvent-assisted 1,2-H-shift within alkoxy radicals [19] and (ii) the exo-thermicity based on the homolytic bond dissociation energies (BDEs) of the N-H (406 kj mol ) and the C-H bond (363 kj mol ) (representative values for the Gly anion [47]). However, both pulse radiolysis and y-radiolysis experiments concluded that the 1,2-H-shift in aminyl and amidyl radicals derived from amino acids and peptides must be rather slow (kis 1.2 x 10 s ) [37, 40]. 

The first topic to be dealt with in this article dates back to the early days of pulse radiolysis and is concerned with intermediates generated from organic nitro and nitroso compounds in some elementary redox processes. This will be followed by a presentation of some most recent results on aminyl radicals derived from amino acids, exemplifying the diversity of possible reactions of a seemingly simple type of radicals. The third example on aniline and aniline radicals aims to demonstrate the potential of time-resolved resonance Raman spectroscopy. A common message of all these studies on N-centered radicals hints at the importance of acid/base properties of radicals. The aniline system, in particular, also draws attention to spin and charge distribution, and possible implications to the chemistry of radical species. 

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 . ... 

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. 

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 and amidyl radicals are conveniently generated from the homolytic or reductive cleavage of chloramines and chloramides [32-39]. The latter form under inflammatory conditions when amino acids and/or peptides are exposed, for example, to hypochlorous acid (HOCl). In vivo, the reduction of chloramines and chloramides may proceed through the action of superoxide, eventually catalyzed by redox-active transition metals, M"+, where M may be Fe and/or Cu (Reactions... 

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. 

Radicals are also produced by manipulation of the a-carboxy and amino groups. The former usually results in decarboxylation, with the products no longer being a-amino acids [61]. Aminyl radicals have been generated from sulfenamide precursors and exploited in cyclization reactions, as illustrated in Scheme 11 [62]. Radical additions to imines [63], oximes [64], isothiocyanates [65] and isocyanides [66] of a-... 

Photoaddition of amines has also been reported and is often the result of initial electron-transfer from the amino-group. Photoadducts of triethylamine with styrene and a-methylstyrene have been obtained carbon dioxide reacts with the styrene radical anion intermediates to give carboxylic acids. In the photoreaction of arenecarbonitriles with aliphatic amines, both aminyl and... 

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