Kinetics

The principal kinetic barrier to direct reaction of dioxygen with an organic substrate arises from the fact that the ground state of the dioxygen molecule is triplet, i.e., contains two unpaired electrons. 15,16 Typical organic molecules that are representative of biological substrates have singlet ground states, i.e., contain no unpaired electrons, and the products resulting from their oxygenation also have singlet ground states. Reactions between molecules occur in shorter times than the time required for conversions from triplet to singlet spin. Therefore the number of unpaired electrons must remain the same before and after each elementary step of a chemical reaction. For these reasons, we know that it is impossible for Reaction (5.6) to go in one fast, concerted step.

The arrows represent electron spins: ~ t represents a singlet molecule with all electron spins paired; t t represents a triplet molecule with two unpaired electrons; and t (which we will see in Reaction 5.13) represents a doublet molecule, also referred to as a free radical, with one unpaired electron. The pathways that do not violate the spin restriction are all costly in energy, resulting in high activation barriers. For example, the reaction of ground-state triplet dioxygen, i.e. ,302 , with a singlet substrate to give the excited triplet state of the oxygenated product (Reaction 5.7) is spin-allowed, and one could imagine a mechanism in which this process is followed by a slow spin conversion to a singlet product (Reaction 5.8).

But such a reaction pathway would give a high activation barrier, because themexcited triplet states of even unsaturated molecules are typically 40-70 kcallmol less stable than the ground state, and those of saturated hydrocarbons are much higherY
 

Likewise, a pathway in which O2 is excited to a singlet state that then reacts with the substrate would be spin-allowed (Reactions 5.9 and 5.10). The high reactivity of singlet dioxygen, generated by photochemical or chemical means, is well-documented. 18 ,19 However, such a pathway for a reaction of dioxygen, which is initially in its ground triplet state, would also require a high activation energy, since the lowest-energy singlet excited state of dioxygen is 22.5 kcall mol higher in energy than ground-state triplet dioxygen.

Moreover, the products of typical reactions of singlet-state dioxygen with organic substrates (Reactions 5.1I and 5.12, for example) are quite different in character from the reactions of dioxygen with organic substrates catalyzed by oxygenase enzymes (see Section V):

One pathway for a direct reaction of triplet ground-state dioxygen with a singlet ground-state organic substrate that can occur readily without a catalyst begins with the one-electron oxidation of the substrate by dioxygen. The products of such a reaction would be two doublets, i.e., superoxide and the oneelectron oxidized substrate, each having one unpaired electron (Reaction 5.13). These free radicals can diffuse apart and then recombine with their spins paired (Reaction 5. 14).

Such a mechanism has been shown to occur for the reaction of dioxygen with reduced flavins shown in Reaction (5.15).

However, this pathway requires that the substrate be able to reduce dioxygen to superoxide, a reaction that requires an unusually strong reducing agent (such as a reduced flavin), since dioxygen is not a particularly strong one-electron oxidizing agent (see Table 5.1 and discussion above). Typical organic substrates in enzymatic and nonenzymatic oxygenation reactions usually are not sufficiently strong reducing agents to reduce dioxygen to superoxide; so this pathway is not commonly observed.

The result of these kinetic barriers to dioxygen reactions with most organic molecules is that uncatalyzed reactions of this type are usually quite slow. An exception to this rule is an oxidation pathway known as free-radical autoxidation.