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The development of novel oxidation procedures that use the most abundant (and cheapest) oxidant, molecular oxygen, under non-toxic conditions is a major goal in synthetic chemistry. This project used a combination of experimental (solution and gas phase) and computational methods to explore, whether peroxyl radicals R''XOO (2, X = S, C) can be used to transform alkynes into carbonyl compounds. According to computational predictions, addition of R''XOO to the alkyne triple bonds in 1 should give vinyl radical 3 (Scheme 1), which, should undergo homolytic gamma-fragmentation of the weak peroxyl bond in 3 to form alpha-oxo carbene 4, potentially via an intermediate oxirene (not shown).

Since R''XOO are easily accessible through reaction of the respective C- or S-centred radical R''X with oxygen, this sequence would enable generation of highly reactive and synthetically very useful alpha-oxo carbenes in a single step from simple alkynes.

In Figure 1 are shown the alkynes and peroxyl radicals studied. For the gas phase experiments in the mass spectrometer, the charged peroxyl radical 2f was used.

For the experiments in solution, peroxyl radicals 2a-e were generated in the presence of the alkyne by both photochemical and thermal methods (Scheme 2). For the gas phase experiments performed in a mass spectrometer, the charged peroxyl radical 2f was generated by reaction of aryl radical 17 with O₂ in the ion source, and subsequently mass selected into the ion trap, where it reacted with the alkyne.

Computations predicted that intermediately formed alpha-oxo carbenes 4a-d should undergo Wolff-Rearrangement, and the resulting ketenes 18a-d could be further oxidized (by peroxyl radicals) to the corresponding ketones 19a-d (Scheme 3). Their formation would provide evidence for the success of the reaction sequence.

Interestingly, only in the reaction of diphenylacetylene (1a) with peroxyl radical 2c formation of benzophenone (19a) was observed, however with only very low yield (<10%). The rate of the addition of the electrophilic peroxyl radicals was strongly influenced by the electron density at the alkyne pi system. In the reactions of 2c with alkynes 1a,b,d the corresponding 1,2-diketones 20a,b,d were unexpectedly formed. This discovery is highly relevant from a synthetic point of view, since this reaction may be considered as a very mild alternative to the existing oxidation procedures of alkynes to 1,2-diketones, which generally require harsh conditions and toxic heavy metal compounds. Most importantly, since peroxyl radicals are commonly produced by reaction of C- or S-centred radicals with oxygen, this methodology is can be regarded as an environmentally benign, radical mediated metal-free activation of oxygen.

It appeared that presence of oxygen was crucial for the transformation 1 -> 20 by peroxyl radicals: When alkyne 1a was reacted with t-BuOO (2c), which was generated by thermal decomposition of the hypervalent iodocompound 10 in the absence of oxygen (see Scheme 2), diketone 20a was not formed and no reaction occurred. For the reaction involving S-radicals the influence of oxygen was studied in detail, since the reaction pathway depended on the oxygen concentration (Scheme 4).

At low [O₂], direct addition of the S-radical 15 to the alkyne occurred, resulting in formation of the thioethers 21 and 22. When [O₂] was increased, the yield of diketone 20a increased, at the expense of 21 and 22. Under these conditions, S-radicals 15 were trapped by oxygen to give peroxyl radicals 2e, which undergo addition to the alkyne triple bond. The sequence shown in Scheme 4 is the first example for a synthetic application of thiylperoxyl radicals.

The mechanism for formation of diketones 20 has been explored with DFT computations for an exemplary model system, and the calculated potential energy surface is shown in Figure 2.

It appears that trapping of the initially formed vinyl radical by oxygen is more favourable than gamma-fragmentation of the O–O bond to give carbene, which is subsequently trapped by oxygen. The prediction that under our experimental conditions a free carbene is not formed, was supported by additional independent experimental studies (not shown).

In order to gain more fundamental experimental insight into the mechanism of peroxyl radical additions to alkynes, we have performed mass spectrometric studies to identify the primary products of these reactions in the gas phase. The reactions were performed with alkynes 1f-i and the charged peroxyl radical 2f. In Figure 3 is exemplary shown the mass spectrum of the reaction of 2f with an excess of alkyne 1f after 1 min reaction time. Although these reactions are not fast, in general, addition of the peroxyl radical to the pi system is the major pathway, whereas propargylic hydrogen abstraction is only occurring to a minor extent. According to the data, the initially formed vinyl radical undergoes a number of fragmentation reactions, which have not been fully identified so far. However, the signal at m/z 110 supports the predicted fragmentation 3 ¨ 4 (see Scheme 1), which releases an alkoxyl radical that is rapidly reduced to the respective alcohol through hydrogen transfer.

Figure 3

Apart from these exciting "snapshots" of the alkyne – peroxyl radical reactions, these gas phase studies have provided rate data for the formation of peroxyl radicals (e.g. 17 ¨ 2f) and their addition to alkynes. This is an important outcome, since rate data for intermolecular radical additions, specifically of O-radicals, to alkynes are surprisingly rare.

Although the financial support by the PRF is now expired, this project is not finished by any means. Our research during the 2 year funding period has opened up exciting new directions for our research, specifically in the area of fundamental radical kinetics and transient spectroscopy. In the future, we will further explore this novel metal-free activation of oxygen for the oxidative transformation of pi systems into carbonyl compounds. The involved PhD will soon submit his thesis, and he has already presented the results on various national and international conferences through oral and poster presentations. It is intended that at least two research papers on this work will be submitted for publications in the next months.