Hydrogen atom deficient radical

An interesting method for the substitution of a hydrogen atom in rr-electron deficient heterocycles was reported some years ago, in the possibility of homolytic aromatic displacement (74AHC(16)123). The nucleophilic character of radicals and the important role of polar factors in this type of substitution are the essentials for a successful reaction with six-membered nitrogen heterocycles in general. No paper has yet been published describing homolytic substitution reactions of pteridines with nucleophilic radicals such as alkyl, carbamoyl, a-oxyalkyl and a-A-alkyl radicals or with amino radical cations. 

The Homer - Emmons reagent (52) is effective in the one carbon homologation of ketones possessing acidic a-hydrogen atoms <96SL875> and electron-deficient alkenes add to 2-phenylseleno-l,3-dithiane in a photo-initiated heteroatom stabilised radical atom transfer process, giving products of considerable synthetic potential <96TL2743>. 

The relative stabilities of radicals follow the same trend as for carhoca-tions. Like carbocations, radicals are electron deficient, and are stabilized by hyperconjugation. Therefore, the most substituted radical is most stable. For example, a 3° alkyl radical is more stable than a 2° alkyl radical, which in turn is more stable than a 1° alkyl radical. Allyl and benzyl radicals are more stable than alkyl radicals, because their unpaired electrons are delocalized. Electron delocalization increases the stability of a molecule. The more stable a radical, the faster it can be formed. Therefore, a hydrogen atom, bonded to either an allylic carbon or a benzylic carbon, is substituted more selectively in the halogenation reaction. The percentage substitution at allylic and benzyhc carbons is greater in the case of bromination than in the case of chlorination, because a bromine radical is more selective. 

An alternative possible route for the formation of carbamoyl radicals may involve a hydrogen atom abstraction from formamide by the excited acetone molecule in its triplet, state (45, 57). Ketonic compounds at this state of excitation mainly if the excitation is of an n - -7r transition, are known to be hydrogen atom abstraction agents, due to the electron deficient oxygen in the excited state. Thus, the formation of carbamoyl radicals through the second route may be summarized by the following scheme ... 

Benzophenone (Amax = 340 nm, log e = 2.5, n-ir electronic transition) can be used as a photochemical reagent and eq. 4.25 shows a radical Michael-addition reaction with benzophenone. The formed benzophenone biradical (triplet state, Tx) abstracts an electron-rich a-hydrogen atom from methyl 3-hydroxypropanoate (62) to generate an electron-rich a-hydroxy carbon-centered radical [III], then its radical adds to the electron-deficient (3-carbon of a, (3-unsaturated cyclic ketone (63) through the radical Michael addition. The electrophilic oxygen-centered radical in the benzophenone biradical abstracts an electron-rich hydrogen atom from methyl 3-hydroxypropanoate (62) [70]. So, an a-hydroxy carbon-centered radical [III] is formed, and an electron-deficient a-methoxycarbonyl carbon-centered radical [III7] is not formed. 

From the practical point of view, alkylation of heteroaromatics with Barton decarboxylation of A-acyloxy-2-thiopyridones (17), prepared from carboxylic acids and Af-hydroxy-2-thiopyridone, is very useful, since it can be used for various kinds of carboxylic acids such as sugars and nucleosides [23-26]. This reaction comprises of the initial homolytic cleavage of the N-0 bond in A-acyloxy-2-thiopyridone to form an acyloxyl radical and PyS , (3-cleavage of the acyloxyl radical to generate an alkyl radical and C02, addition to the electron-deficient position of heteroaromatics by the alkyl radical to form the adduct, and finally, abstraction of a hydrogen atom from the adduct by PyS , as shown in eq. 5.10. 

Because most radicals have an odd number of electrons on an atom, the octet rule cannot be satisfied at that atom. It is no surprise, then, that most radicals are unstable species and are quite reactive. They are most often encountered, like carbocations, as transient intermediates in reactions. However, alkyl radicals tend to have longer lifetimes than carbocations because they are less electron deficient, and therefore more stable. In fact, the lifetime of a radical can be appreciable in an environment where nothing is available with which to react. For example, hydrogen atoms are the principal type of matter in interstellar space. And die methyl radical has a lifetime of about 10 min when frozen in a methanol matrix at 77 K. 

An alternative method for the substitution of a hydrogen atom in -electron deficient heterocycles is using the nucleophilic character of radicals in homolytic aromatic displacement reactions <74AHC(16)123>. Acylation with acyl radicals derived from aldehydes is an especially important approach since Friedel-Crafts-type reactions are not applicable to pteridines. 

This chapter discusses an entirely different approach to the generation and investigation of highly reactive transient intermediates. The high reactivity is usually due to an unusual electron distribution in the intermediate that was acquired in the course of the chemical reaction. This implies that for an electron rich intermediate there is a corresponding stable cation in which the electron density was lowered by ionization. Likewise, for an electron-deficient intermediate there is a corresponding stable anion in which the electron deficiency was alleviated by electron attachment. Equations (1) and (2) show simple examples of the methoxy and hydroxymethyl radicals, respectively, which are isomeric transient intermediates of hydrogen atom abstraction from methanol ... 

Thus, a 3° radical is more stable than a 2° radical, and a 2° radical is more stable than a 1 ° radical. Increasing alkyl substitution inereases radical stability in the same way it increases carboca-tion stability. Alkyl groups are more polarizable than hydrogen atoms, so they can more easily donate electron density to the electron-deficient earbon radical, thus increasing stability. 

It was found that a variety of radical precursors could be added, and that the specific electronic and steric effects exerted on the resulting radical effected the diastereoselectivity of the hydrogen atom transfer. Increasing the size of R group appeared to increase the selectivity of the trap. For instance, reaction with t-butyl radical and tributyltin hydride gave the highest selectivity, >98 2 (70% yield), for the trans product (77). Reactions with electron-deficient radicals suffered from low yields and decreased selectivity. Results also indicate that reactions with tributyltin hydride produced higher selectivities but lower yields than those per-... 

---