Competitive thiol addition

The Michael-type addition, a nucleophilic addition of an anion to the carbon-carbon double bond of an a,(3-unsaturated ketone, aldehyde, nitrile, nitro, sulphonyl, or carboxylic acid derivative, provides a powerful tool for carbon-carbon bond formation. The reaction is most successful with relatively nonbasic ( soft ) nucleophiles such as thiols, cyanide, primary and secondary amines, and P-dicarbonyl compounds. There is often a competition between direct attack on the carbonyl carbon (1,2-addition) and conjugate addition (1,4-addition) when the substrate is an a,(3-unsaturated carbonyl compound. 

One further aspect besides H-atom abstraction must, however, be considered in the reactions of thiyl radicals with PUFAs, namely, the possibility of concurrent RS additions to the double bonds. By analyzing a particular system in which the thiyl radical from mercaptoethanol had reacted with linolenic acid, Schoneich at came to the conclusion that the abstraction of bisallylic hydrogen and thiyl addition occur with comparable rates. The C-centered adduct radical formed in the addition reaction is, of course, prone for repair in the presence of thiols, i.e., will subsequently regenerate thiyl radicals via the back reaction of equilibrium 14. These, in turn, will re-enter into the abstraction / addition competition cycle and eventually all of the thiyl radicals will appear to have reacted via the abstraction route. Experimentally, overall efficiencies of up to 85 % have been measured and the difference to the limiting 100% efficiency may be accounted for by side and termination processes. But looking into the details, the situation is, in fact, even more complex. As shown by Schwinn at al., there is still another process which readily occurs within the RS -adducts to the double bonds, namely, cis-trans isomerization. Quantification of this is of imminent interest for the biological community. 

The behavior of vinyl radicals (5) generated by addition of a variety of thiyl radicals to butynedioic or propynoic acids has been studied by ESR spectroscopy The intermolecu-lar abstraction of a thiol hydrogen is in competition with l, -hydrogen shifts. An unusual 1,4-shift (equation 7) is shown to occur in cases where the resulting carbon-centered radical bears a-sulfur and a-carboxy substituents, whereas in other examples a 1,5-shift predominates (equation 3). 

MODEL STUDIES Early in this study it appeared that [2.2.1]bicyclic olefin resins added conventional crosslinking thiols in a rapid, exothermic, manner. These results appear to contradict earlier reports that internal olefins and cyclic olefins such as cyclohexene and cydopentene react only slowly with thiols. In reality, [2.2.1]bicydic olefins represent a separate dass of reactive olefins. These results are also consistent with reports (16-19) that bicyclic olefins such as norbomadiene are quite reactive to the addition of monofunctional thiols and thiyl radicals. In order to quantify the relative reactivity of norbornene resins with other "standard" ene components, a model study of the addition reaction was undertaken. A "typical" thiol (ethyl mercaptoacetate) was examined in a series of competitive reactions in which there was a defidency of olefin (Figure 4). Olefin substrates that were compared were norbornene, styrene, butyl vinyl ether, [2.2.2]bicydooctene and phenyl allyl ether. The results of that study are listed below in Table I. 

These results are probably due to a combination of several effects. The enhanced reactivity of the [2.2.1]bicyclic system is most likely due to a steric ring strain factor (16-18) which is complicated by a stereodectronic effect (19). In addition to these factors, it is probable that the kinetics of the initial addition of thiol or thiyl radical to the olefin is "less reversible" in the case of [2.2.1]bicyclic olefins This was confirmed by our model studies described above. The product distribution in the competitive reaction studies was essentially invariant with reaction temperature in the range of 10°C - 90°C There appeared to be no equilibration of the discreet olehn thiol adducts. 

The 2-isocyanostyrene derivatives have also been prepared by the Pudovik Reaction with a variety of aldehydes. In addition, a variant of the 5-exo-dig radical cyclization of 2-alkynylphenylisonitriles using thiols as both radical initiators and nucleophiles has been developed. Under these conditions, quinolines can be obtained by a potentially competitive 6-endo-dig radical cyclization. ... 

The five-membered ring products result from the normal (Markownikoff) internal addition of the thiol group to the double bond, whereas the six-membered ring products result from abnormal (anti-Markownikoff) addition, which is characteristic of a free radical process. The formation of both heterocycles thus indicates competitive thermally induced heterolytic and homolytic fissions of the thiol S—H bond (equation 7). The cyclization mechanisms were verified by a detailed examination of the thermal behaviour of 104. Product 102 was formed almost exclusively... 

In dilute solutions of a thiol, RSH, it should be possible to explain the radiation chemistry in terms of the reactions of RSH with OH, e and H at low conversions, but as the radiation products accumulate, competition between these and RSH for the radicals will occur, leading to secondary products. Thus initial yields of products are normally measured ej ri-mentally in mechanistic investigations. When a second solute is also present, e.g. O, competition for the primary products will occur, and the intermediates formed from RSH may also react with this added solute. The pH of the solution is also important because H may compete with RSH for e , and in addition the actual form, and hence the reactivity, of the thiol may change with pH in a manner depending on its add dissodation constants. 

Since SH groups react more readily with double bonds than do NH2 groups (43,44,49,54), addition of thiols should trap the residue of dehydroalanine as described below. These competitive reactions should minimize lysinoalanine formation. These expectations were realized. 

It also appears that intramolecular thiyl radical addition is a very efficient process compared to other free radical cyclizations. But competitive reactions such as polymerization are sometimes very difficult to suppress. Furthermore, other easy cyclization pathways, such as ionic ones, may complicate the interpretation of the results. Dronov s work exemplifies this possibility. Under all the experimental conditions used, l-pentene-5-thiol led to a Cy5/Cy6 mixture of products, with the (Cy5) compound being favored in sulfuric-acid-promoted cyclization and the (Cy6) compound being favored in photolysis. Thus the claim to have observed a homolytic reaction in cyclizations of ethylenic thiols generated from fatty acids, under conditions which did not avoid acid treatment, must be considered with care. 

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