On The Mechanism of Gif Reactions Derek H. R. Barton Department of Chemistry, Texas A&M University College Station, TX 77843-3255, USA The foregoing review article' makes extensive reference to Gif chemistry and involves the role that oxygen and carbon radicals may play in this phenomenon. In brief, Gif chemistry permits the conversion of saturated hydrocarbons into ketones at room temper- ature under nearly neutral conditions. There is also a surprising chemoselectivity where saturated hydrocarbons are more reactive than would be expected. Thus, ketones were originally2 formed in the presence of H2S, normally much more easily oxidized. Over the years, our theory, which originally was an hypothesis, has evolved to explain all the facts that we have observed.Other suggestions about mechanism are always welcome, but they must explain all of the facts and not just a small selection of data. From the beginning it has been important to distinguish between oxygen- and carbon-radicals and mechanisms which do not involve radicals. Fortunately, great progress has been made in the last two years in distinguishing the role of radicals in Gif chemistry from that important mechanism where they are not involved. Amongst many indications which are mechanistically helpful we would underline the following techniques. (i) The coupling of carbon radicals to pyridine as pioneered by Hey3 and later by Mini~ci.~This technique has always proved reliable. (ii)The reac- tion of carbon radicals with chloride bonded to Fel" to afford R-CI and Fell.This well known reaction' has played an important role in distinguishing between Fe" and Fellr chemistry. Finally, we would emphasize the importance of distinguishing between Fell and Fell' by simple chemical titration.6 In Gif chemistry, we recognize that Fell activated by superoxide and Fe"1 activated by nucleophilic displacement by H202 afford the Professor (Sir) Derek H. R. Barton was born on September 8, I918 in Gravesend. Kent. His first academic appointments (I 945-1 949) were as Lecturer in Inorganic and then Physical Chemistry at imperial College. After a stint at Harvard (I 949-1 950), which pro- duced eventually (1969) a Nobel Prize, he was appointed Reader at Birkbeck College, then Professor, and in 1954 was elected FRS.After two years (1955-1957) as Regius Professor in Glasgow, he returned to Imperial College (I 957-1 978) as, eventually. Hofmann Professor of Organic Chemistry. His career became more interest- ing when he was appointed as 'Directeur de l'lnstitut de Chimie des Substances Naturelles ',a large CNRS Laboratory in Gif-sur-Yvette, France. in 1986, he became a European retirement refugee at Texas A&M University where he is currently very happy as Dow Professor of Chemical Invention. He was elected an Honorary member of the National Academy in 1970 and received the Priestley Award of the American Chemical Society in 1995. His experience of working in three countries spanning two continents is probably unique.As he has commented before, 'the older you are the harder you have to work because the time left to work is diminishing.' His current schedule of 3-00 a.m. to 8:00 p.m., seven days a week is probably at his limit, pending transfer to another, celestial laboratory where perhaps you can work 24 hours a day forever! Imagine what the literature must be like! 237 Fe"+ HOz-Fe"+ H202-Fe"' + H202 Fell'-OOH Fell-OOH+ + Fev=O Fe"=O+ + Fev-CHR1 R2 Few-C+HR1 R2 + O=CR'R~ Fe"' + 'CHR'R' Scheme 1 same FeI"-OOH species (Scheme 1). Postulated evolution to an FeV oxenoid species and reaction with a saturated hydrocarbon CH2RlR2 affords an Fev species with an Fev-carbon bond. Eventually this affords ketones selectively, showing preferred inser- tion into secondary C-H bonds.A second route to activation is provided by the nucleophilic dis- placement of H,O, on Fell to furnish FeII-OOH from which an FelV oxenoid species results. This shows similar reactivity towards satu- rated hydrocarbons and affords an FeIV species which rapidly breaks down to Fell1 and a carbon radical (Scheme 1). We have good evi- dence that hydroxyl radicals are not involved in Gif chemistry in pyridine? Indeed hydroxyl radical attack could not explain the selectivity for secondary attack nor the fact that all systems have the same kinetic isotope effect of 2.1 (cyclohexanevs. perdeuteriocyclo-hexane) and the same selectivity for adamantane functionalization. This is always close to 1.O for C2/C3where C2 represents the sum (in mmol) of all secondary products and C3 is the same for all tertiary products.For tert -butoxyl radicals, in pyridine, the C2/C3is 0.3.This is a new value determined with care and not a quotation from the lit- erature.x In Scheme 1 we now distinguish two manifolds: Fe1I1-FeV, the non-radical producing manifold and FeI1--FelV, the radical mani- fold.8 In principle, electron transfer between valence states could remove these differentiations. Fortunately, the chemistry of Fell + H202is completely different from that of Fe1I1 + H20,. Also, the Fell or Fell1 + equivalent H202in both manifolds can be varied widely without any change in efficiency. So electron transfer here is not a fast process.The conclusion that iron-carbon bonds were involved in Gif chemistry came from early studies9 on the oxidation of adamantane using a superoxide +Fell system (ZnO as reductant) in pyridine-acetic acid. On reducing the oxygen pressure coupling of the tertiary position to pyridine was detected, but not at the sec- ondary position. Later work showed'O that genuine secondary radi- cals from adamantane showed the same competitive reaction as did genuine tertiary radicals. Hence, there was a difference which was most easily explained (Occam's Razor) by the formation of iron-carbon bonds at both positions. In the tertiary case the bond was so weak that spontaneous fragmentation to carbon radicals took place. It has not been easy to detect iron-carbon bonds in Gif systems.They may be present in low concentrations. The best evidence comes from recent work by Newcombll who has shown that a number of hyperactive traps do show the presence of radicals in Gif oxidation If iron-carbon bond formation precedes further chem- istry, then the structural driving force for the rearrangement may well weaken the iron-carbon bond to the point where it dissociates to give radicals In the discussion of Professor Perkins as to whether cyclohexa- no1 or cyclohexyl hydroperoxide is the precursor of the ketone, we have studied the rate of oxidation of cyclohexanol It is very slow in the Fe1I-Zno-pyridine-acetic acid system, but somewhat faster with the Fe1I1-H2O2 procedure There is, however, good evidence that the main source of the ketone, as long as pyridine-acetic acid is the solvent, is the hydroperoxide Professor Perkins suggests that the hydroperoxide, by reaction with Fell, is the source of the cyclohexyloxyl radical and hence of the alcohol He has overlooked the study that we madel, to show that with FeI1Cl2 in pyridine-acetic acid cyclohexyl hydroperoxide is converted rapidly (2 min ) and quantitativelv into cyclohexanone No cyclohexanol is formed In the FeIl-Zn" system the addition of increasing amounts of tri-phenylphosphine changes formation of ketone to formation of alcohol However, the total of ketone +-alcohol is constant over a wide range of Ph,P concentration l2 This important experiment shows that alkoxyl and alkylperoxyl radicals are not present, that the activated iron species reacts faster with the hydrocarbon than with Ph,P and that the activation to give hydroperoxide, which was then reduced to alcohol, was constant Similar studies were made with quenching experiments (benzenethiol with or without oxalic acid) In the Fe111-H202 series a l3NMR experiment proved that the hydroperoxide preceded the ketone Quenching experiments with oxalic acid demonstrated that ketone came mainly from hydroper- oxide and not from alcohol After reference to this work Professor Perkins comments on some difficulty in reproducing oxidation results obtained using hydrogen peroxide In fact, there are many articles by Sawyer on the H,O,-pyridine-acetic acid system, in one of which we were co- authors l3 l4 There was no difficulty in obtaining reproducible results The same applies to the extensive work of Professor Ulf Schuchardt and his colleagues Is This work on the oxidation of cyclohexane has examined in depth the FeI1-Zno-pyridine acetic system and the Fe1"-H,02 system with various ligands The results are always as good as ours and sometimes better with respect to yield In a comparison of iron and ruthenium chemistry,16 work on the repetition of the FeJ1-Zno process gave a turnover number of 1000,similar to our own results A communication from Geletii17 using H,O,-Fe"l in pyridine-acetic acid reported that cyclohexa- none was formed by a non-radical reaction and not via cyclohexa- no1 Similar results were obtained with Cull salts An interesting study of cyclohexane oxidation to cyclohexanone using the Fe111-H,02-pyridine-acetic acid system has been reported l8 The various variables were analysed including the kinetics There was no difficulty in repeating the Gif-type chemistry by these authors We have detected one factor that can influence yield in H20, experiments Some, but not all, metal syringes catalyse the decomposition of H,02 to oxygen and water This is usually obvious from the oxygen bubbles However, it would be normal practice to carry out the blank experiment to make sure that the H202drawn into the syringe is, in fact, delivered intact into a solu- tion of the solvent actually being used The non-existence of hydroxyl radicals in pyridine has already been commented upon earlier It is suggested by Professor Perkins that hydroxylated pyridines would be oxidized by H,O,-Fe"I In pyridine as solvent all the hydroxy-pyridines are recovered intact l9 Of course, the 2- and 4-hydroxypyridines are really amides, so oxidation would not be expected With regard to the interesting reaction2" which converts saturated hydrocarbons into dimethyl phosphates by using FeI1-Zno in pyri-dine-acetic acid in the presence of trimethyl phosphite, the follow- ing comments are relevant Trimethyl phosphite is well known to react with alkylhydroperoxyl radicals to reduce them to alkoxyl rad- icals which in turn are reduced to alkyl radicals A blank experiment with trimethyl phosphite, oxygen and cyclohexyl radicals was carried out in a previously cited paper I* In the blank experiments with trimethyl phosphite, cyclohexyl hydroperoxide and Fell, CHEMICAL SOCIETY REVIEWS, 1996 approximately equal amounts of cyclohexanone, cyclohexanol and dimethylcyclohexyl phosphate were formed No cyclohexane was observed in these accurate I3C studies In order for the Scheme 5 of Professor Perkins to be operative, the Fell1 oxidation of the inter- mediate radical would have to be favourable thermodynamically It is doubtful if this can be true The product of the proposed Arbusov reaction that makes the dimethylcyclohexyl phosphate has recently been identified by I3C NMR It is methyl acetate and not an N-methylpyridinium salt In any case, the initial addition of the cyclohexyloxyl radical postulated by Professor Perkins should have lead to immediate deoxygenation to afford a cyclohexyl radical (vide supra) The proposal in the Scheme 6 of Professor Perkins is even less likely to explain the experimental facts As above, the addition of the cyclohexyloxyl radical to triphenylphosphine would lead at once to deoxygenation to the corresponding cyclohexyl radical Over a number of years we had carried out Gif Fe1I1-H,O, oxida- tion of saturated hydrocarbons to give ketones in the presence of chloride and bromide anion without seeing a trace of alkyl chloride or bromide It was, therefore, a surprise when the addition of hydro- gen peroxide to FeCI, in the presence of triphenyl phosphine in pyridine-acetic acid gave smooth formation of cyclohexyl chloride instead of the ketone which was normally produced in the Fe1I1-FeV manifold 22 Clearly the activation of the alkane was nearly as great as it was for the usual ketone formation After a helpful publication by Mini~ci,2~ we realized that alkyl chloride formation was due to production of Fell In fact, whilst triphenylphosphine reduces Fell1 to Fe" only slowly, the addition of H202 produces a fast formation of Fell and of Ph,P=O The Fel1-FelV manifold then proceeds to activate the hydrocarbon and to make carbon radicals These combine with the chloride bonded to Fell1 to make the observed chloride In principle, this reaction reforms Fell However, there is another oxidation reaction with H,O, which oxidizes Fell to Fe"' in competition with the chlorination reaction and eventually all the Fell is reconverted to Fell1 These reactions provide a valuable proof that the Fell1 + H20, reaction makes the ketone by a non-radical mechanism * If one adds H,O, portionwise to an Fell salt in pyri-dine-acetic acid containing chloride ion, alkyl chloride is first formed However, as soon as all the Fell is converted into Fell1 (titra- tion) chloride formation ceases and the Fe1I1-FeV manifold more slowly produces ketone If more Fell is added, rapid alkyl chloride formation recommences, then ceases and is replace by ketonisation when all the Fell has been converted into Fell1 Most experiments have been done with cyclohexane We have, of course, shown by suitable blank experiments that cyclohexyl chloride is inert under the Fe111-H202 oxidation conditions and is not the source of cyclo- hexanone When all the Fell has been converted to Fell1 there is still a large excess of chloride ion present, some of which is bonded to Fell1 So if the FelI1-H,O, system were producing carbon radicals it would still be making alkyl chloride Indeed the alkyl chloride reac- tion is much faster than the ketonisation process 24 The comparison of Professor Perkins of radical bromination and Gif bromination fails to mention certain important facts Citation is made of the preliminary communication,2s but not of the full paper26 In the latter, mass balances are given for all the hydro- carbons that are not too volatile These are satisfactory mass bal- ances and there is no reason to think that the very volatile hydrocarbons (cyclopentane and 2,3-dimethylbutane) would not follow the same reactions More important is the failure to mention the comparative bromination of cyclohexyl bromide Radical bromination affords I ,2-dibromides as major products, whereas in Gif bromination 1,2-dibromides are very minor and 1,4-dibrorno- cyclohexanes are the major product This bromination in the 4-posi- tion corresponds to Schuchardt's observationI5 that the ultimate oxidation product of cyclohexanone is cyclohexane- 1,4-dione As far as tert-butyl hydroperoxide (TBHP) reactions are con- cerned, these have a kinetic isotope effect of about 7, very different from the 2 1 found for Gif chemistry It is clear that these reactions are largely radical in nature The slow formation of chloride and other congeners from cy~lohexane~~ is probably due to radical chemistry produced by reduction of a small amount of Fell1 to Fell If the reaction is started using Fell then the derivative formation is ON THE MECHANISM OF GIF REACTIONS-DEREK H R BARTON fast28 and we agree involves carbon radical formation by reaction with tert-butoxyl radicals The contrast between H202 and TBHP chemistry finds a possible explanation in the importance of the ligands in Gif chemistry All the Gif reactions are only seen when the right kind of carboxylate ligand is present 2429 This chemistry probably involves an Feiii-O-O-Feiii functionality stimulated by carboxylate bridging This peroxyl function is not possible with TBHP Finally, I would point out that if you consider the whole body of evidence, carbon radicals, when present, can be detected easily In those reactions where carbon radicals cannot be detected an alter- native mechanism must be proposed Gif chemistry is a well estab- lished experimental fact But if any other theory can be advanced to explain all of the facts, we shall be happy to consider it Such a theory must explain also the Gif paradox How is it possible to generate an iron species which attacks selectively saturated hydro- carbons in the presence of PPh,, (MeO),P, H2S, even PhSeH etc , reagents which by conventional standards are much more easily oxidized’ We have offered an explanation in the as yet unappreci- ated nature of iron-hydrogen peroxide derived species References M J Perkins,Chem Soc Rev,19%,229 D H R Barton, M J Gastiger and W B Motherwell.J Chem SOC Chem Commun , 1983,41 D H Hey, C J M Stirling and G H Williams, J Chem Soc ,1955, 3963,and references there cited F Minisci and A Citterio, Adv Free Radical Chem , 1980, 6, 65, F Minisci Acc Chem Res , 1975,8, 165 J K Kochi, in Free Radicals, ed J K Kochi, Wiley, New York, 1973, pp 591-683 L J Clark, Anal Chem . 1%2,34,348 D H R Barton,S D Beviere,W Chavasiri,D Doller,W G Liuand J H Reibenspies,New J Chem ,1992,16,1019,D T Sawyer,C Kang, A Llobet and C Redman, J Am Chem SOC, 1993, 115, 5817, J P Hage, A Llobet and D T Sawyer, Bioorg Med Chem , 1995,3.1383 C Bardin, D H R Barton, B Hu, R Rojas Wahl and D K Taylor. Tetrahedron Lett , 1994,35,5805 D H R Barton, J Boivin, W B Motherwell, N Ozbalik and K M Schwartzentruber, Nouv J Chim 1986,10,387 10 D H R Barton, F Halley, N Ozbalik, M Schmitt, E Young and G Balavoine, J Am Chem Soc ,1989,111,7144 11 M Newcomb, P A Simakov and S V Park, Tetrahedron Lett ,in press 12 D H R Barton, S D Beviere, W Chavasiri, E Csuhai, D Doller and W G Liu,J Am ChemSoc, 1992,114,2147,DH R Barton,E Csuhai, D Doller and G Balavoine J Chem SOC Chem Commun ,1990, 1787 13 C Sheu, A Sobkowiak, L Zhang, N Ozbalik, D H R Barton and D T Sawyer, J Am Chem SOC ,1989,111,8030 14 C Sheu, A Sobkowiak, S Jeon and D T Sawyer, J Am Chem Soc , 1990, 112, 879, C Sheu, S A Rickert, P Cofre, B Ross, A Sobkowiak, D T Sawyer and J R Kanofsky, 1990,112,1936,C Sheu and D T Sawyer, 1990 112,8212, and later papers from the Sawyer group15 Summanzing article U Schuchardt, W A Carvalho and E V Spinace, Svnlett, 1993,713,and references there cited 16 G Powell, D T Rickens and L Khan, J Chem Res (S),1994,506 17 Y V Geletii,V V LavrushkoandG V Lubimova, J Chem Soc Chem Commun , 1988,936 18 S B Kim, K W Lee, Y J Kim and S 1 Hong, Buff Korean Chem SOC, 1994,15,424,S B Kim and K W Lee, Korean J Chem Eng , 1995,12, 188, and prior references there cited 19 D H R Barton, B Hu and R U ROjaS Wahl, unpublished observations 20 D H R Barton, S D Beviere and D Doller, Tetrahedron Lett , 1991, 32,4671 21 D H R Barton and D K Taylor unpublished observations 22 D H R Barton and S D Beviere, Tetrahedron Lett , 1993,34,5689 23 F Minisci and F Fontana, Tetrahedron Lett .1993,35, 1431 24 D H R Barton, B Hu, D K Taylor and R U Rojas Wahl, J Chem Soc Perkin Trans 2,1996,1031 25 D H R Barton, E Csuhai and D Doller, Tetrahedron Lett, 1992,33, 3413, 26 D H R Barton, E Csuhai and D Doller, Tetruhedron, 1992, 48, 9195 27 D H R Barton, S D Beviere. W Chavasiri, D Doller and B Hu, Tetrahedron Lett , 1993,34, 1871, D H R Barton and W Chavasiri, Tetrahedron. 1994,50. 19,D H R Barton. S D Beviere and W Chavasiri, Tetrahedron, 1994.50,31, D H R Barton and W Chavasiri, Tetrahedron. 1994,50,47 28 D H R Barton,B Chab0t.N C Delanghe,B Hu,V N LeGloahec and R U Rojas Wahl, Tetrahedron Lett, 1995,36,7007 29 D H R Barton,B Hu,D K Taylorand R U Rojas Wahl, Tetrahedron Lett, 1996,37,1133 30 D H R Barton and D Doller,Acc Chem Res ,1992,25,504