March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

Chapter 10. Aliphatic Substitution, Nucleophilic and Organometallic

10.B. SET Mechanisms

In certain reactions, where nucleophilic substitutions would seem obviously indicated, there is evidence that radicals and/or radical ions are actually involved.¹⁰⁰ The first step in such a process is transfer of an electron from the nucleophile to the substrate to form a radical anion:

Mechanisms that begin this way are called SET mechanisms.¹⁰¹ Once formed, the radical ion cleaves:

The radicals formed in this way can go on to product by reacting with the Y• produced in Step 1 or with the original nucleophilic ion Y⁻, in which case an additional step is necessary:

In the latter case, the radical ion R–X^• is formed by Step 4, as well as by Step 1, so that a chain reaction (Sec. 14.A.i) can take place.

One type of evidence for an SET mechanism is the finding of some racemization. A free radical would likely result in a completely racemized product RY, but it has been suggested¹⁰² that inversion can also take place in some SET processes. The suggestion is that in Step 1 the Y⁻ still approaches from the back side, even though an ordinary S_N2 mechanism will not follow, and that the radical R^•, once formed, remains in a solvent cage with Y^• still opposite X⁻, so that Steps 1–3 can lead to inversion.

Reactions with SET mechanisms typically show predominant, although not 100%, inversion.

Other evidence cited¹⁰³ for SET mechanisms has been detection of radical or radical-ion intermediates by ESR¹⁰⁴ or CIDNP; the finding that such reactions can take place at 1-norbornyl bridgeheads;¹⁰⁵ and the formation of cyclic side products when the substrate has a double bond in the 5,6-position (such substrates are called radical probes).

Free radicals with double bonds in this position are known to cyclize readily (Sec. 15.A.iii).¹⁰⁶

The SET mechanism is chiefly found where X = I or NO₂ (see Reaction 10-67). A closely related mechanism, the S_RN1, takes place with aromatic substrates (Chap 13).¹⁰⁷ In that mechanism, the initial attack is by an electron donor, rather than a nucleophile. The S_RN1 mechanism has also been invoked for reactions of enolate anions with 2-iodobicyclo[4.1.0]heptane.¹⁰⁸ An example is the reaction of 1-iodobicyclo[2.2.1]heptane (20) with NaSnMe₃ or LiPPh₂, and some other nucleophiles, to give the substitution product.¹⁰⁹ Another is the reaction of bromo 4-bromoacetophenone (21) with Bu₄NBr in cumene.¹¹⁰ The two mechanisms, S_N2 versus SET, have been compared and contrasted.¹¹¹ There are also reactions where it is reported that radical, carbanion, and carbene pathways occur simultaneously.¹¹²

The mechanisms so far considered can, in theory at least, operate on any type of saturated (or for that matter unsaturated) substrate. There are other mechanisms that are more limited in scope.