42035-B4
Generation, Structure, and Reactivity of Iminoxyl Radicals
Research in our group focuses on the electron transfer chemistry of the carbon-nitrogen double bond. Of particular interest are oximes and oxime ethers because of their stability (compared to imines), their use as protection groups in organic synthesis, and the increasing use of these compounds in pharmaceuticals. Photooxidation or enzymatic oxidation may result in the formation of reactive species, such as radical ions or free radicals, which can cause damage to cells and tissue in biological systems. Our goal is to investigate the oxidative chemistry of oximes and related species and to obtain a complete understanding of the involvement of reactive intermediates in these processes.
In recent years we have shown that in general oximes can be converted into their corresponding carbonyl compounds in moderate to good yields, however, the complete mechanism remained uncertain until recently. Recent studies have shown that photooxidation of ketoximes results in the formation of oxime radical cations, which are very acidic species (pKa < –10). The oxime radical cation can lose a proton to form an iminoxyl radical, which reacts further and goes through a number of intermediates with both radical and ionic character. Nucleophilic attack by water on a cationic intermediate (an a-nitroso cation, which is possibly formed via a one-electron oxidation of the intermediate iminoxyl radical) eventually leads to the formation of the carbonyl compound.
Aldoximes were previously shown to yield both aldehydes and nitriles upon one-electron oxidation. We have studied the mechanistic aspects of the photosensitized reactions of a series of benzaldehyde oximes by steady-state (product studies) and laser flash photolysis (LFP) methods. Nanosecond LFP studies have shown that the reaction of the oxime with triplet chloranil (3CA) proceeds via an electron transfer mechanism provided the oxidation potential (Ep) is 2.0 V. Oximes with Ep > 2.0 V react via a hydrogen atom transfer (HAT) pathway, which may result in the formation of an iminoxyl radical (abstraction of the hydroxyl hydrogen) or an iminoyl radical (abstraction of the iminyl hydrogen). Product studies have shown that aldoximes react to give both the corresponding aldehyde and the nitrile. The important intermediate in the aldehyde pathway is the iminoxyl radical, which is formed via an electron transfer – proton transfer (ET-PT) sequence (for oximes with low oxidation potentials) or via a hydrogen atom transfer (HAT) pathway (for oximes with larger oxidation potentials). The nitriles are proposed to result from intermediate iminoyl radicals, which are most likely formed via direct hydrogen atom abstraction of an iminyl radical.
The results from recent studies on a series of benzaldehyde oxime ethers are consistent with these observations. Nanosecond laser flash photolysis studies have shown that these sensitized reactions result in the formation of the corresponding aldoxime ether radical cations. For the substrates with a-protons, the follow-up reactions involve deprotonation at the a-position followed by b-scission to form the benziminyl radical (and an aldehyde). The benziminyl radical reacts to give benzaldehyde, the major product under these conditions. In the absence of a-hydrogens (O-t-butyl benzaldehyde oxime), the major product is benzonitrile, which is thought to occur via reaction of the excited (triplet) sensitizer with the aldoxime ether. Abstraction of the iminyl hydrogen yields an N-alkoxy iminoyl radical, which undergoes a b-scission to yield benzonitrile. An alternative pathway involving electron transfer followed by removal of the iminyl proton was not deemed viable based on charge densities obtained from DFT (B3LYP/6-31G*) calculations. Similarly, a rearrangement pathway involving an intramolecular hydrogen atom transfer process was ruled out through experiments with a deuterium-labeled benzaldehyde oxime ether.
Most recently our efforts have been on proving the involvement of iminoyl radicals in the formation of nitriles from aldoximes and aldoxime ethers. The iminoyl radicals were generated via reaction of a series of of N-alkoxybenziminoyl chlorides with tributyltin hydride in benzene (using AIBN as the initiator). The reactions of N-methoxy, N-ethoxy, N-t-butoxy, N-benzyloxy, and N-octyloxybenziminoyl chloride all result in the formation of benzonitrile as the major product. The latter two products also provided evidence for the expected alkoxy radicals formed in a b-scission pathway. Most interestingly, the expected reduction products (benzaldoxime ethers) are not formed, which suggests a very rapid b-scission reaction. In order to determine (for the first time) the rate constant for the b-scission pathway of the intermediate N-alkoxybenziminoyl radicals we needed a value for the hydrogen atom abstraction pathway. Unfortunately, the rate constant for this pathway (kH) has not yet been determined, and therefore we have looked at two similar reactions that have been studied and used an estimated rate constant of 1 x 106 M-1s-1 for the hydrogen atom abstraction process of benziminoyl radicals, and using this rate the lower limit for the rate constant for the b-scission process is estimated to be 2.5 x 107 s-1.
