VI. Rate Constants for Hydrogen-atom abstraction by Carbohydrate Radicals

A. Extrapolating Results From Model Radicals

Radical philicity first was encountered in this chapter in the reactions of simple organic com­pounds (Section I.B). The assumption was that infor­mation about the reac­tivity of these com­pounds could be extrapolated to more complex ones, ­specifically, carbo­hy­drates. Exper­imental data supported the validity of this assumption by providing examples of reactions of carbo­hy­drate radi­cals that qualitatively paralleled those of simpler radicals. For instance, the reactions in eq 2 showed the cyclo­hexyl radical (a carbohy­drate model) to be nucleo­philic because it added more rapidly to electron-deficient multiple bonds than to electron-rich ones.⁶ A similar, nucleophilic behavior was seen in the reac­tions of the carbohydrate radical 26 (Scheme 2). In another example, the reac­tions described in equations 4 and 5 for simple organic mole­cules showed ­that polarity matching increased the rate of hydrogen-atom abstraction. Extending polarity matching to carbo­hydrate radicals offered a rationale for the electro­philic radical 22 abstracting an electron-rich hydrogen atom more rapidly than an electron-deficient one (Scheme 1). There is, of course, a limitation to extra­polation of results obtained from simple radicals to radicals that are more complicated. Iden­tifying a limitation, as is done in the following section, can be useful and can lead to increased under­standing of the reactivity of the more complicated radical.

B. A Limitation on Extrapolating Alkyl Radical Reactivity to Carbohydrate Radicals

Extrapolating results from reactions of structurally simple intermediates sometimes provides the only information available for judging reactivity of more complex ones. Successful extrap­o­la­tion builds confidence in the models selected, but since model systems by their very nature have limitations, such extrapolation is always subject to some uncertainty. The reaction shown in eq 9 illus­trates the need for caution in projecting reactivity from a simple to a more complex radical. The data in Table 2 show that rate constants for hydrogen-atom abstraction from com­pounds with H–Sn, H–S, and H–Si bonds are essentially inde­pendent of whether the abstracting radical is primary, sec­on­dary, or tertiary. (Steric factors have little effect on rate constants for hydrogen abstract­tion.⁴¹) Extending this reactivity pattern to compounds with H–Se bonds and knowing that the rate constant for hydrogen-atom abstraction from C₆H₅SeH by the primary radical 27 is 2.1 x 10⁹ M^-1s^-1 at 25 ^oC¹⁴ leads to the prediction that the rate constant for reaction of the pyranos-1-yl radical 9 with C₆H₅SeH should have a similar value. It does not; the value is far smaller (3.6 x 10⁶ M^‑1s^-1 at 78 ^oC).¹⁵

C. An Explanation for Unsuccessful Extrapolation: Loss of Transition-State Stabilization

In attempting to understand the smaller-than-expected rate constant for hydrogen-atom abstraction by the radical 9, it is useful to recall from Chapter 6 (Section IV.A.2.c) that the conformation of pyranos-1-yl radi­cals depends on the quasi-anomeric effect, that is, on the stabilizing inter­action of the σ* orbital of the C₂–O bond with the p-type orbitals on the ring oxygen atom and C-1. This effect is sufficiently powerful to cause 9 to adopt the otherwise unstable, boat confor­mation shown in Figure 12. Since quasi-anomeric stabil­ization can only exist in structurally complex systems, simple radicals are limited in their ability to model pyranos-1-yl radicals. The quasi-anomeric effect provides a basis for understanding the smaller-than-expected value for the rate constant for hydrogen-atom abstraction by the radical 9.

As the hydrogen-atom abstraction reaction shown in eq 9 (R· = 9) moves toward the transition state, the orbital interactions (Figure 12) that cause the electron delocalization that stabilizes the radi­cal 9 are disap­pearing. (They are totally gone when the product is reached.) This loss of stabil­ization means that the energy of activation for hydrogen-atom abstraction by 9 will be greater than that for the radical 27, for which there is no comparable reduction in electron delocal­ization as the reac­tion pro­gresses.¹⁵ Hydrogen-atom abstraction, in effect, forces an electron localization that causes a loss of stabilization for the delocalized radical 9 but not for the localized one 27. This decrease in sta­bil­i­zation at the transition state for reaction of a pyranos-1-yl radical reduces its rate constant for hydrogen-atom abstraction.

The proposal that transition-state loss of quasi-anomeric stabilization in pyranos-1-yl radi­cals is responsible for their reduced hydrogen-abstracting ability carries with it the predic­tion that carbohydrate radicals that are not so stabilized should have larger rate constants for hydrogen-atom abstraction. The quantitative information needed to evaluate this prediction does not exist, but there is qualitative information that supports the basic idea. As mentioned in Section V of Chapter 6, pyranos-1-yl radicals can be generated and observed in toluene or tetrahydrofuran but radicals centered on C-2, C-3, or C-4 (with no oxygen atom attached to the radical center and, hence, no quasi-anomeric stabilization possible) cannot be observed in these solvents because such radicals rapidly abstract hydrogen atoms from the solvent. (Only α-tetra­hydro­furyl radicals are observed in reactions conducted in tetrahydro­furan and only benzyl radicals are detected in reac­tions in tol­u­ene.⁴²)

The possibility that a loss of transition-state stabilization due to dimin­ishing delocal­ization is responsible for a smaller-than-expected rate constant for hydrogen-atom abstraction by a pyranos-1-yl radical leads to the proposal that a similar loss of stabilization should have a similar effect on hydrogen-atom abstraction by other radicals. Rate constants for abstraction from C₆H₅SH have a bearing on this proposal. Simple primary, secondary, and tertiary radicals all have rate constants for hydrogen-atom abstraction from C₆H₅SH near 1 x 10⁸ M^-1s^-1 at 25 ^oC (Table 2), but the rate constant for abstrac­tion from this thiol by the benzyl radical is far smaller (3.13 x 10⁵ M^‑1s^-1 25 ^oC).¹³ Because the benzyl radical loses resonance stabilization as hydrogen-atom abstraction takes place, it would be expected to parallel the pyran­os-1-yl radical in having a smaller rate constant hydrogen-atom abstraction than the 1 x 10⁸ M^-1s^-1 observed for unsta­bil­ized radicals. The fact that the rate constant for hydrogen-atom abstraction by the benzyl radical (3.13 x 10⁵ M^‑1s^-1) is a substantially smaller than 1 x 10⁸ M^-1s^-1 strengthens the diminishing-delocalization explanation for reduced reactivity of the pyranos-1-yl radical 9.