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Some new aspects in the chemistry of halogenated oxyl and peroxyl radicals
Radiation Physics and Chemistry 65 (2002) 299–307
Some new aspects in the chemistry of halogenated oxyl and peroxyl radicals Roman Flyunta,b,1, Oksana Makogonb, Klaus-Dieter Asmusc,* b
a Institut fur IOM e,V., Permoserstr. 15, 04318 Leipzig, Germany . Oberflachenmodifizierung . Institute of Physico-Chemistry, National Academy of Science of the Ukraine, Naukova Street 3a, UA-79053 L’viv, Ukraine c Faculty of Chemistry, Adam-Mickiewicz-University, Grunwaldzka 6, 60-780 Poznan, Poland
Abstract Some characteristic features concerning the chemical properties of halogenated aliphatic oxyl and peroxyl radicals are presented and discussed. This includes, in particular, overall two-electron oxidation initiated by peroxyl radicals, and fragmentation and rearrangement reactions of oxyl radicals. A specific example elaborated in detail deals with the CF3CHClOOd-induced oxidation of methionine. A complete mechanism and material balance is proposed on the basis of quantitative analysis of the products of this reaction. These are: F, Cl, Br, CF3CHO, CF3CO 2 , CO2 and methioninesulfoxide. r 2002 Elsevier Science Ltd. All rights reserved. Keywords: Halogenated oxyl radicals; Halogenated peroxyl radicals; Halogenated aliphatics; Oxalyl halides; Halothane; Methionine; Electron transfer; Radical induced degradation
Halogenated organic compounds are well known, if not to say infamous, as environmental hazards. Particularly their toxic action, e.g., in the liver of animals and humans, has prompted a lot of research and corresponding attempts to minimize their effects by appropriate chemical deactivation. One of the important findings along this line was that the toxic action of halocarbons, to a decisive extent, involves free radicals. In vivo, these are readily generated, for example, by reductive and/or oxidative enzymatic initiation. It could also be demonstrated in numerous experiments employing environmental clean-up methods such as electron beam treatment, photo catalysis with semiconductor materials, ozonation, ultrasound, etc., that the most effective chemical degradation mechanisms also proceed via radical intermediates. The ultimate molecular products in all cases are CO2 and halide anions. This has prompted environmental chemists and engineers to coin the catch word ‘‘mineralization’’ for the breakdown of *Corresponding author. E-mail address: [email protected] (K.-D. Asmus). 1 Previous spelling: Fliount.
the halocarbons via the various free-radical-based degradation methods. The probably most important radical intermediates in an oxygenated environment are peroxyl and oxyl radicals. They exhibit some very interesting properties with respect to their generation as well as their subsequent reactions, particularly if the radical species still carry halogen functions. In the present paper we shall highlight some of the most striking and important features.
1. Experimental All experiments described and discussed in this article have been conducted by means of radiation chemical methods. For product studies, solutions were exposed to the fields of 60Co-g-radiation sources. Kinetic data have typically been obtained by applying time-resolved pulse radiolysis. Details on all experimental procedures have been published in the relevant literature and will, therefore, not specifically be mentioned. All data refer to the radiolysis of aqueous solutions conducted at ambient temperature.
0969-806X/02/$ - see front matter r 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 9 6 9 - 8 0 6 X ( 0 2 ) 0 0 3 3 4 - 1
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
300
Yields are given in terms of G, denoting mmol/10 J absorbed radiation energy. These numbers are almost equal to the classical radiation chemical yield unit of species per 100 eV absorbed energy (to convert into SI units, i.e., mmol/J absorbed energy, just divide the numbers by 10).
2. Results and discussion 2.1. Generation of radicals Considering a halocarbon in its most general form, i.e., a carbon functionality carrying a hydrogen and a halogen (Hal=F, Cl, Br, I) atom, a primary C-centered radical may be generated reductively as well as oxidatively, as outlined in Scheme 1. Reduction is typically initiated via reaction with or transfer of an electron to the halocarbon. Free electrons are conveniently provided as, for example, solvated electrons by radiolysis of water (high-energy electron beam and g-radiation), at electrodes in electrochemical devices, or in the form of conduction band electrons at the interface of illuminated semiconductors and a surrounding solvent phase. Electron transfer, on the other hand, may occur from reducing radicals or enzymatic systems. An oxidative radical formation usually involves an H-atom abstraction, e.g., by dOH radicals. A combined loss of an electron and a proton, however, leads to the same result. This latter mechanism applies, for example, for photo catalytic oxidations through the positive valence band holes, which result upon charge separation in semiconductors. In oxygenated environment either of the two radical types formed usually react very fast with O2 to the respective peroxyl radicals (Beckwith et al., 1984, 1995/ 96; Neta et al., 1996). The actual rate constant for the oxygen addition reflects both, the electrophilic nature of the oxygen and the electron density at the radical site. It is noted that even the dCCl3 radical adds O2 with a diffusion controlled rate constants (3.3 109 M1 s1) . (Monig et al., 1983b) despite the electron density withdrawing effect of the chlorine atoms. The rationale for the high reactivity is the pyramidal structure of the d CCl3 radical which provides a much more exposed
radical site (singly occupied sp3 orbital at C) as opposed to, for example, the dCH3 radical which is practically planar (with the radical electron in a p-type orbital) and which adds oxygen practically as fast as dCCl3. 2.2. Properties of peroxyl radicals Peroxyl radicals (generally denoted as ROOd) are, in principle, oxidizing species (Howard and Scaiano, 1984, 1995/96; Dohrmann et al., 1985, 1995/96). In their reaction with suitable molecules, M, this may manifest itself as an electron transfer (Eq. (1)) or as an H-atom abstraction (Eq. (2)). In both cases the peroxyl will be reduced to the corresponding hydroperoxide (in neutral and close to neutral aqueous solution the acid/base equilibrium ROO+H+"ROOH lies practically on the right-hand side). ROOd þ M-ROO þ Mdþ
ð1Þ
ROOd þ M-ROOH þ Mð HÞd
ð2Þ
Generally these reactions are, however, not very fast and occur with rate constants which are often many orders of magnitude below the diffusion limits (Howard and Scaiano, 1984, 1995/96; Dohrmann et al., 1985, 1995/96). An important consequence of this is that radical-radical termination reactions between two peroxyls may become significant despite the usually low steady-state concentration of radicals. The most important ones are schematically summarized in Scheme 2 (von Sonntag and Schuchmann, 1991, 1997; Asmus and Bonifacic, 2000). Reaction (a) applies, in principle, to all peroxyl radicals and affords the formation of oxyl radicals. Reactions (b) and (c) require the presence of at least one H-atom at the peroxyl carrying carbon. The termination process according to Eq. (c) is also known as Russell mechanism (Russell, 1957) and proceeds via a cyclic sixmembered ring mechanism (For further details on peroxyl radicals in general, the reader is referred to some excellent summarizing review articles and the original literature cited therein (von Sonntag and Schuchmann, 1991, 1997)).
–
H
b
–
c
O2
Scheme 2.
+
– C = O + – C – OH –
O – O•
–C=O –
– C – Hal
+
H –
Scheme 1.
•
–
– C – Hal
H2 O2
–
2 –C–O–O• –
– H or (– e– / –H+)
O2
2 –C–O• –
–
–
H –
oxidative initiation
O2 +
–C–O–O•
– H
a
–
–C• –
– C – Hal
–
–
– Hal –
O2
–
–
2 –C–O–O• reductive initiation
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
2.3. What is different when halogen functionalities are present? Introduction of halogen functionalities results in many chemical consequences. An especially important one concerns the oxidation state of the halogen-carrying carbon. Consider, for example, the products which are generated in Scheme 2 reaction (c). They are alcohols and aldehydes/ketones. However, if the hydrogen gets substituted by a halogen—as outlined in Scheme 3—the carbon assumes a higher ‘‘oxidation number’’ (because of the electronegativity of the halogen). This becomes immediately apparent if we subject the a-halogenated alcohol or aldehyde/ketone to hydrolysis, i.e., processes readily occurring whenever the C–Halogen bond is activated by a neighboring oxygen functionality. In summary, the a-halogenated alcohol constitutes the oxidation state of an aldehyde/ketone, and the ahalogenated aldehyde/ketone constitutes the oxidation state of an organic acid (Note that complete hydrolysis of CCl4 yields CO2, i.e., the highest oxidation state of carbon, namely, +4). An example for the above is the reductively initiated degradation of CF3CHClBr (known also under the name halothane and until recently frequently used as anaesthetic). As summarized in Scheme 4, the primary peroxyl radical derived from this compound, CF3CHClOOd, upon its bimolecular decay via the Russell mechanism, yields equal amounts of trifluoroacetaldehyde and trifluoroacetic acid (M.onig and Asmus, 1984; Asmus et al., 1989). 2.4. Halogenated peroxyl radicals as oxidants It can plausibly be expected that a-halogenation increases the oxidative power of peroxyl radicals because H
Hal –
–
– C = O + H + / Hal –
–
–
– C – OH
–
– C – OH
aldehyde / ketone
alcohol
H
Hal
OH –
–
– –C=O
–C=O
+ H + / Hal –
–C=O
aldehyde
acid
Scheme 3.
CF3 –CHClBr
e– – Br
2 CF 3 –C HCl(OO •)
•
–
– O2
CF 3 –CHCl
O2
CF 3 –CHCl(OH)
CF3 –CHO
Scheme 4.
CF 3 –C HCl(OO • ) +
CF 3 –C(O)Cl
CF3 –C(O)OH
301
electron density delocalization into the halogen atoms reduces the electron density at the peroxyl functionality. Accordingly, the CCl3OOd is the best and CH3OOd is the worst oxidant within the chloromethyl peroxyl series: CCl3 OOd > CHCl2 OOd > CH2 ClOOd > CH3 OOd However, while this is well in line with a number of experimental observations concerning, for example, the oxidation of certain phenolic compounds, ascorbate and phenothiazines, (Packer et al., 1980) there are other findings which seemingly contradict this conclusion . . (Asmus, unpublished results; Monig et al., 1983a; Monig . and Asmus, 1984; Schoneich et al., 1990). The rate constant for the general oxidation reaction (Eq. (3)) does, in fact, not necessarily coincide with expectation (D=electron donor; Dd+=one-electron oxidized form of donor). One observation is, for example, that despite high rate constants the yields of the one-electron oxidation transients are lower than the yield of peroxyl radicals. CCl3 OOd þ D-CCl3 OO þ Ddþ
ð3Þ
Another revealing example are the measured rate constants for the CCl3OOd-induced oxidation of ebselen (a selenium-containing drug) and 1,5-diselenocyclooctane. They are almost equal (amounting to 3 108 and 2 108 M1 s1, respectively) despite the fact that the reduction potential of the Dd+/D couple is much more positive for ebselen (E 0 ¼ 1:59 V vs. Ag/AgCl in CH3CN) than for the 1,5-diselenocyclooctane (E 0 ¼ 0:25 V vs. Ag/AgCl in CH3CN) (Asmus, unpublished . results; Schoneich et al., 1990). Given these redox properties, the oxidation of the 1,5-diselenocyclooctane should occur much faster than the oxidation of ebselen (equal rate constants for reactions involving substrates with different redox potentials could only be expected for diffusion controlled processes but not for reactions proceeding at rates which are at least one order of magnitude below the limits set by the diffusion). These findings, therefore, call for some different or additional reaction mechanism to a simple one-electron transfer process. The rationale for all this is that halogenated peroxyl radicals (possibly even most other peroxyls as well) do not seem to undergo classical one-electron transfer but rather to engage in addition/elimination mechanisms . (Bonifacic et al., 1991; Schoneich et al., 1991, 1993). This is exemplified in Scheme 5 for the oxidation of organic sulfides by halogenated peroxyl radicals. Corresponding mechanisms prevail for the peroxyl radical induced oxidation of organic chalcogenides, in general (especially selenides), and inorganic iodide. Mechanistically, the peroxyl radical-induced oxidation of a sulfide proceeds as shown in Scheme 5. In the first instance the peroxyl radical adds to the sulfur.
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
302
R(Hal)OO•
δ–
+
•
Me2S
OH
δ+
R(Hal)–O–O – SMe2 H + OH –
–
•
R(Hal)–O–O – SMe2 H
– OH
OH + Me2 S
+
Me2SO
R(Hal)O •
Me2 S
•
OH
R(Hal)–O –• O – SMe2 H
H+
+ S ∴S
Scheme 5.
From the redox point of view, this constitutes a first oneelectron oxidation step. The resulting sulfuranyl radical is polarized with slight positive charge at sulfur and a corresponding negative charge at the adjacent oxygen. In aqueous solution this facilitates protonation of the oxygen and hydroxylation of the sulfur. The next step is the transfer of the radical electron, which initially resides at sulfur, into the peroxide bridge. This step constitutes a second one-electron oxidation of the sulfur which thus has undergone an overall two-electron oxidation and consequently has assumed the oxidation level as in a sulfoxide. In fact, the charge separated transient resulting from this second oxidation step is now formally composed of a reduced hydroperoxide and a protonated sulfoxide moiety. It is easy to recognize its decay into a sulfoxide and an oxyl radical (besides OH and H+). With respect to the peroxyl moiety this mechanism is reminiscent of the well-known Fenton chemistry. It also explains the experimentally observed fact that the sulfoxide oxygen comes from the solvent water and is not one of the peroxyl oxygens . (Schoneich et al., 1991). A further argument in favor of this overall two-electron transfer mechanism is the possibility to intercept the one-electron intermediate sulfuranyl radical. Reaction of the latter with a second molecule of sulfide leads to a three-electron bonded dimer radical cation which is also formed as a transient in any one-electron oxidation (e.g., by dOH) and is easily detectable through its characteristic and strong . et al., optical absorption (Bonifacic et al., 1975; Gobl 1984). A most important parameter which helped to evaluate the mechanism are the sulfoxide yields which may differ significantly depending on the nature of the oxidant. Typically, they are much lower for a oneelectron oxidation which leads to radical cations as intermediates. In the dOH-induced oxidation, for example, the sulfoxide yields are about 20% (in deoxygenated solution) while an oxidation initiated by,
for example, CHCl2OOd results in sulfoxide yields of up . to 100% (Bonifacic et al., 1975; Schoneich et al., 1991, 1993). In conclusion, halogenated peroxyl radicals may not only act as one-electron oxidants but with many heteroatom-containing compounds engage in overall two-electron oxidations. This, in turn, leaves them as oxyl radicals, making it imperative to always consider and include the oxyl radical chemistry as well. 2.5. Features of oxyl radical chemistry Having identified the oxyl radicals as a possibly important follow-up species in the peroxyl radical chemistry, let us now focus on a specific example which illustrates the wealth of oxyl radical reactions and the interplay of oxyl/peroxyl chemistry. The system to be discussed is based on halothane (introduced above) as source for the peroxyl and oxyl radicals, and methionine, a sulfur-containing amino acid, as a marker for the radical-induced oxidation processes. A detailed report on that system has already been published; we shall, therefore, focus only on the essential features as they emerge from product studies. Table 1 summarizes the various products and their yields, which have been obtained upon g-irradiation of an aqueous, air-saturated, pH 6 solution containing also 5% 2-methyl-2-propanol, 102 M or no CF3CHClBr, and 103 M or no methionine (MetS) (Flyunt et al., 2000). Without going into the details (for them see reference (Flyunt et al., 2000)), the first to recognize is that the yield of bromide ions identifies the yield of halothane reduction (Eq. (4)) and, since the follow-up reaction of the thus formed CF3CdHCl radical with O2 (Eq. (5)) is fast and quantitative, it is also equal to the yield of CF3CHClOOd peroxyl radicals. As can be seen there is no difference between the system with and without methionine, CH3SCH2CH2CH(NH+ 3 )CO2 , up to this
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
303
Table 1 CF 3CHCl(OO•)
Br –
Cl –
F–
CF 3CO2–
CF 3CHO
CO2
Met(SO)
with Met(S)
3.4
3.4
3.4
6.1
1.4
0.0
3.8
5.6
without Met(S)
3.4
3.4
3.4
0.4
1.6
1.7
0.1 5
–– 0.4 without halothane
yields in G , unit:moles per 10 J
CO, oxalate, formate: ≤ 0.1
point. CF3 CHClBr þ
e aq =reducing
radicals
-CF3 Cd HCl þ Br ;
CF3 Cd HCl þ O2 -CF3 CHClOOd :
ð4Þ ð5Þ
All the other products are generated upon the subsequent reactions of the peroxyl radicals. Here it is noted that the chloride yield also quantitatively matches the bromide and peroxyl yields. Almost equal yields in both systems with and without methionine are also observed for trifluoroacetic acid, although on the absolute scale they are significantly lower and, as will be shown below, derive mechanistically via different routes. The presence or absence of methionine plays no role for the yields of CO, oxalate and formate, which all are almost negligible (Gp0:1). Dramatic differences become apparent, however, for the yields of the other products. Fluoride ions and CO2 are practically only formed in the presence of methionine, while trifluoroacetaldehyde is generated only in the absence of the sulfide. It should further be recognized that the methioninesulfoxide (MetSO) yield is much higher than in a system which was devoid of halothane. Finally, it should be noted that the MetSO yield in the halothane system significantly exceeds the yield of primary peroxyl radicals (G ¼ 5:6 vs. 3.4). All this clearly shows that (i) the peroxyl radicals derived from halothane induce an oxidation different to that of typical one-electron oxidants and (ii) the peroxyl radical alone, nevertheless, cannot account for the entire MetSO yield. Let us first evaluate the system without methionine. Under these circumstances the halothane peroxyl radicals will exclusively undergo a bimolecular termination process. The most likely will be the Russell mechanism yielding equal amounts of trifluoroacetyl chloride, CF3C(O)Cl, and 1,1,1-trifluoro-2-chloroethanol, CF3CH(OH)Cl (Eq. (6)). 2 CF3 CHClOOd - O2 þ CF3 CðOÞCl þ CF3 CHðOHÞCl
ð6Þ
Hydrolysis of these compounds directly yields the observed products, CF3CO 2 +Cl , and CF3CHO+Cl .
For an initial peroxyl radical yield of G ¼ 3:4; the expected trifluoroacetic acid, trifluoroacetaldehyde and chloride yields would be 1.7, 1.7 and 3.4, respectively, in perfect agreement with the experimentally measured values (see Table 1). How does it look like in the system with methionine where a bimolecular radical-radical termination cannot compete anymore with a peroxyl radical reaction with the methionine? As outlined in Scheme 3 in general terms, each halothane peroxyl radical may oxidize one methionine to MetSO in an overall two-electron oxidation mechanism according to Eq. (7). CF3 CHClOOd þ MetS-CF3 CHClOd þ MetSO
ð7Þ
Interception of the primary peroxyl-methionine adduct by a second methionine molecule, to yield the S‘Stype three-electron bonded radical cation, does not seem to occur to any significant extent under the experimental conditions, mainly because of the steric demand the methionine exerts. Therefore, we can reasonably assume that the efficiency of the sulfoxide formation via reaction 7 is close to 100%. However, the MetSO yield generated this way cannot exceed the yield of CF3CHClOOd radicals, i.e., G ¼ 3:4: This, in turn, means that the remainder of G ¼ 2:2 to the actually measured yield (G ¼ 5:6) must be formed in secondary processes. Not yet accounted for are also the yields of fluoride, CO2, and trifluoroacetic acid. Consequently, we conclude that the CF3CHClOd oxyl radical, the only remaining reactive radical species, must be responsible, directly and/or indirectly, for all other products listed in Table 1 for the methionine containing system. Oxyl radicals offer, in general, a greater wealth of reaction possibilities than peroxyl radicals. Let us first consider some processes which are feasible but, nevertheless, do not take place in the discussed example. A prominent property of oxyl radicals is, for example, their capability to undergo one-electron oxidations (Howard and Scaiano, 1984, 1995/96). With respect to methionine such a reaction would yield the sulfurcentered methionine radical cation and trifluoroacetaldehyde (Eqs. (8a) and (8b)) both of which were not detected. Consequently, this possibility must be
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
304
discarded.
d
dþ
CF3 CHClO þ MetS-CF3 CHClO þ MetðS CF3 CHClO -CF3 CHO þ Cl
Þ
ð8aÞ ð8bÞ
The same applies to a possible H-atom abstraction by the oxyl radical from any suitable functional group (Eq. (9)). Hydrolysis of the chloroalcohol formed in this reaction would also lead to the not observed trifluoroacetaldehyde. CF3 CHClOd þ R2H-Rd þ CF3 CHClOH ½-CF3 CHO þ Hþ =Cl
ð9Þ
Another type of reaction oxyl radicals readily undergo are b-fragmentations (Howard and Scaiano, 1984, 1995/ 96). As outlined in Scheme 6, two such processes can be envisaged. The first alternative would be cleavage of a chlorine atom. Irrespective of the fate of Cld, this possibility must, however, be dismissed because of the lack of CF3CHO formation. The second possibility involves C– C cleavage and formation of trifluoromethyl radicals and formyl chloride. While dCF3, after its conversion to CF3OOd, could well account for the fluoride, CO2 and additional MetSO, this route must, however, also be discarded because the simultaneously generated formyl chloride, in a fast hydrolysis reaction, should give rise to CO (Dowideit et al., 1996) a product which is not formed (this conclusion would even hold if the formyl chloride was hydrolyzed to formic acid, because the yield of the latter is also negligible). No precedence at all exists for the theoretical third fragmentation possibility, namely, H-atom cleavage. In any case, it would not provide any route to fluoride and CO2.
•
–
O•
–
CF3 – C – Cl H
•
Cl
+
CF3CHO
CF3
+
HCOCl H+ /Cl–
not formed
+
CO not formed
However, there is yet another reaction oxyl radicals readily undergo if the oxyl carrying carbon also carries an H-atom, as is the case for the halothane derived oxyl radical (Berdnikov et al., 1972; Gilbert et al., 1976, 1977; Schuchmann and von Sonntag, 1981, 1982; Asmus et al., 1985). This is a hydrogen shift (presumably solvent assisted) by which the oxygen-centered radical is converted into a carbon-centered radical, as shown in the first reaction of Scheme 7. Such rearrangement reactions are known to occur fast, typically on the lower microsecond/upper nanosecond time scale, and may thus well compete with or beat the b-fragmentation. In our system the newly formed Ccentered radical is likely to add oxygen. The a(hydroxychloro)peroxyl radical generated this way is prone to fast HOd2 elimination, thereby yielding trifluoroacetyl chloride which subsequently hydrolyzes to trifluoroacetic acid, one of the compounds still missing in our material balance. If hydrolysis of the chlorine function occurs at an earlier stage the result would be the same. Our result does not allow to distinguish between the various routes. Assuming that this rearrangement-based mechanism is indeed the one responsible for the trifluoroacetic acid, the measured yield of the latter (G ¼ 1:4) would account for about 40% of the maximum oxyl radical yield (Gp3:4). The question now arises: Is there a competing route which lets any of the transients in Scheme 7 decay without yielding trifluoroacetic acid but leads instead to fluoride and CO2, and a species which oxidizes MetS to MetSO? We propose the origin of such a competing route to be the rearranged, C-centered radical CF3CdCl(OH) or its hydrolyzed form CF3Cd(OH)2. This assumption is based on the results of an dOHinduced oxidation of the hydrated form of trifluoroacetaldehyde which generates CF3Cd(OH)2 and, in the presence of oxygen and methionine, yields all the products in question: CF3CO 2 , F , CO2 and MetSO (Eq. (10)). CF3 CHðOHÞ2 þd OH-CF3 Cd ðOHÞ2 ðþO2 =MetS-CF3 CO 2 ; F ; CO2 ; MetSOÞ
Scheme 6.
O•
–
–
OH
CF3 – C – Cl
CF3 – C – Cl
–
•
H
•
O2
•
O2
CF3CCl(OH)
CF3C(OO•)Cl(OH)
– HO 2•
CF3C(O)Cl CF3C(O)OH
CF3C(OH)2
– HO 2•
CF3C(OO•)(OH) 2
Scheme 7.
ð10Þ
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
A key question in this proposed mechanism concerns the elimination of fluorine, specifically the first of the three fluorines, from the CF3-group. We hypothesize that this takes place from, e.g., the CF3Cd(OH)2 radical, possibly its deprotonated form CF3Cd(OH)(O), as depicted in the encircled section of Scheme 8. Elimination of one fluoride ion would leave the difluoroacetyl radical dCF2CO 2 . This, upon oxygen addition, would convert into the dOOCF2CO 2 peroxyl radical which could then oxidize additional methionine via the 2electron mechanism outlined above in Scheme 5 and thus account for the still missing MetSO. As a result of this process we would be left with dOCF2CO 2 oxyl radicals which, lacking any C–H bond necessary for a 1,2-hydrogen shift (rearrangement), are prone for bfragmentation into CF2O and COd 2 . Hydrolysis of the fluoro-analog of phosgene and electron transfer from the COd to oxygen would finally result in the 2 experimentally observed ‘‘mineralization’’ products. This entire mechanistic idea is corroborated very nicely by an experiment in which the dCF2CO 2 radical is generated via reduction of CF2BrCO 2 by hydrated electrons and from which, in the presence of oxygen and methionine, the same products as outlined in the lower section of Scheme 8 are formed. The challenging part of our hypothesis clearly is the first fluoride elimination process. How that actually proceeds and at which stage hydrolysis of the chlorine occurs is still up for investigation. There is, however, an example for fluoride elimination from a CF3-group, as schematically depicted in Scheme 9, which may serve as a possible analog or, at least, supporting evidence . (Monig et al., 1983c). It has been found that the primary halothane radical CF3CdHCl, if offered another electron by a suitable donor (e.g., ascorbate, or conduction band electrons), is reduced to the corresponding carbanion. This, rather than undergoing protonation to CF3CH2Cl, immediately decays under fluoride elimination to the 1,1difluoro-2-chloroethene.
•
•
CF3-CHCl
e–
305 ••
H+
F – + CF2=CHCl
CF3-CH2Cl
Scheme 9.
Under the assumption that the mechanisms outlined in Schemes 7 and 8 are indeed applicable and contribute with 40% and 60%, respectively, we can now calculate the various product yields in the MetS-containing system and compare them with the experimental data. This is done in Table 2. As can be seen, the material balance is excellent. The largest deviation amounts to just G ¼ 0:2 (for MetSO), way below the acceptable typical radiation chemical error limit of 710%. This agreement between experimental and calculated yields should, nevertheless, not be mistaken as absolute proof of the proposed mechanism but it can certainly be viewed as a most credible support for it. By having chosen halothane as source for the peroxyl and oxyl radicals some light could be shed on the different behavior of fluorine, chlorine and bromine substituents. In this context, let us finally look at one more example. With reference to Scheme 8 and the described degradation of dOCF2CO 2 into two equivalents each of F and CO2, it may be worth mentioning that the alternatively thinkable b-fragmentation of a fluorine atom according to Eq. (11) does not take place. d
d OCF2 CO 2 –– // –> F þ CFðOÞ2CO2
•
– (2) H +
F
_ +
eaq– + CF2Br–C(O)O– •
CF 2–C(O)O– O2
Met(S) •OOCF2 –C(O)O
–
ð11Þ
Not only is this unfeasible thermodynamically (high C– F bond energy), this conclusion also rests on the fact that the hydrolysis product of the oxalylfluoride, namely, oxalate is not formed in this process (Flyunt, unpublished results). Interestingly, the decay mechanism of the dichloro and dibromo analogs of the dOCF2CO 2 radical follows entirely the opposite pattern, as depicted in Scheme 10.
CF3C(OH)O–
CF3C(OH)2
(–)
CF3-CHCl
•OCF2 –C(O)O–
CF2O
+
•–
CO2
O2
Met(SO)
O2 •–
2F
Scheme 8.
_
+
CO2
CO2
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
306 Table 2 –
–
Cl
F
experimental yields
3.4
calculated yields *
3.4
–
CO2
CF3 CO2
Met(SO)
6.1
3.8
1.4
5.6
6.0
3.7
1.4
5.4
Acknowledgements We gratefully acknowledge the support for our work by the Association for International Cancer Research (AICR) and the Office of Basic Energy Sciences within the US Department of Energy. As such this is publication No. NDRL-4317 of the Notre Dame Radiation Laboratory. K.-D.A. is currently on sabbatical leave from the Department of Chemistry & Biochemistry of the University of Notre Dame.
* calculated on basis of discussed mechanism and G = 3.4 µmoles / 10 J for CF3CHCl(OO•) and Br–
CO2
CO2
O2
Cl, Br
•–
CO2
2 Cl – / 2 Br–
+
calculations of thermodynamic and kinetic parameters at appropriate theoretical levels.
H2O CCl 2 O / CBr 2O
+
CCl(O)-CO2– / CBr(O)-CO2–
–
+
•O – C – CO2–
References
–
Cl, Br
Cl • / Br •
Cl–
/
Br–
CO
+
CO2
+
Cl–
/
Br–
Scheme 10.
In both cases it appears to be the halogen atom (Cld and Brd) which is exclusively eliminated as radical component in the b-fragmentation, leaving the corresponding oxalylchloride and oxalylbromide. This conclusion is drawn from the observation that these two oxalylhalides decay under halide elimination into an equal yield of CO and CO2 (Fliount et al., 1997; Makogon et al., 1998). (Note: this is different to the oxalylfluoride which quantitatively hydrolyzes to oxalate!) The generation of carbon monoxide is clearly of interest from the environmental and toxicological point of view. Also, the formation of the highly oxidizing and reactive chlorine and bromine atoms is noteworthy. In their follow-up reactions they will usually end up as halide ions.
3. Conclusion The few but, hopefully, interesting and instructive examples discussed in this paper indicate the great wealth of reactions halogenated oxyl and peroxyl radicals engage in. They also demonstrate how mechanisms may be influenced by the identity of the halogen atom, revealing in particular the special role of fluorine substituents. Furthermore, it clearly emerges from these studies that caution is advised for extrapolations from one halocarbon to another. Complete product analysis in combination with time-resolved studies of the transients are almost mandatory for the establishment of complete reaction mechanisms. Needless to say, that additional benefits may, of course, be drawn from
Asmus, K.-D., Bonifacic, M., 2000. Free radical chemistry. In: Sen, C.K., Packer, L., H.anninen, O. (Eds.), Handbook of Oxidants and Antioxidants in Exercise. Elsevier, Amsterdam, pp. 3–54. . Asmus, K.-D., Bahnemann, D., Krischer, K., Lal, M., Monig, J., 1985. One-electron induced degradation of halogenated methanes and ethanes in oxygenated and anoxic aqueous solutions. Life Chem. Rep. 3, 1–15. . . Asmus, K.-D., Lal, M., Monig, J., Schoneich, C., 1989. Radical induced degradation of organic halogen and sulfur compounds in oxygenated aqueous environment. In: Simic, M.G.M.G., Taylor, K.A., Ward, J.F., von Sonntag, C. (Eds.), Oxygen Radicals in Biology and Medicine. Plenum, New York, pp. 67–73. Beckwith, A.L.J., Griller, D., Lorand, J.P., 1984, 1995/96. . Landolt Bornstein Series. Carbon-Centered Radicals I. Springer, Berlin. Berdnikov, V.M., Bazhin, N.M., Fedorov, V.K., Polyakov, O.V., 1972. Isomerization of the ethoxyl radical to the ahydroxyethyl radical in aqueous solution. Kinet. Catal. (English translation) 13, 986–987. . Bonifacic, M., Mockel, H., Bahnemann, D., Asmus, K.-D., 1975. Formation of positive ions and other primary species in the oxidation of sulphides by hydroxyl radicals. J. Chem. Soc. Perkin Trans. 2, 675–685. . Bonifacic, M., Schoneich, C., Asmus, K.-D., 1991. Halogenated peroxyl radicals as multi-electron oxidants: pulse radiolysis study on the reaction of trichloromethyl peroxyl radicals with iodide. J. Chem. Soc. Chem. Commun., 1117–1119. Dohrmann, J.K., Scaiano, J.C., Steenken, S., 1985, 1995/96. Proton and Electron Transfer Biradicals. Springer, Berlin. Dowideit, P., Mertens, R., Sonntag, C.V., 1996. The nonhydrolytic decay of formyl chloride into CO and HCl. J. Am. Chem. Soc. 118, 11288–11292. Fliount, R., Makogon, O., Guldi, D.M., Asmus, K.-D., 1997. Radical mediated degradation mechanisms of tribromoand other trihalosubstituted acetic acids in oxygen-free solutions as studied by radiation chemistry methods. J. Chem. Soc. Perkin Trans. 2, 1535–1545. . Flyunt, R., Makogon, O., Schoneich, C., Asmus, K.-D., 2000. Radiolytically induced reductive degradation of halothane
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307 in air-saturated aqueous solutions in the presence of methionine. Nukleonika 45, 45–50. Gilbert, B.C., Holmes, R.G.G., Laue, H.A.H., Norman, R.O.C., 1976. Electron spin resonance studies. Part L. Reactions of the alkoxyl radicals generated from alkylhydroperoxides and titanium (III) ion in aqueous solution. J. Chem. Soc. Perkin Trans. 2, 1047–1052. Gilbert, B.C., Holmes, R.G.G., Norman, R.O.C., 1977. Electron spin resonance studies. Part LII. Reactions of secondary alkoxyl radicals. J. Chem. Res. (S) 1, 1. . Gobl, M., Bonifacic, M., Asmus, K.-D., 1984. Substituent effects on the stability of three-electron bonded radicals and radical ions from organic sulfur compounds. J. Am. Chem. Soc. 106, 5984–5988. . Howard, J.A., Scaiano, J.C., 1984, 1995/96. Landolt Bornstein Series. Oxyl, Peroxyl and Related Radicals. Springer, Berlin. Makogon, O., Fliount, R., Asmus, K.-D., 1998. Formation and degradation of halogenated organic acids. Radiation vs. photocatalytically induced processes. J. Adv. Oxid. Technol. 3, 11–21. . Monig, J., Asmus, K.-D., 1984. Formation and reactions of halothane peroxy free radicals, CF3CHClOd2 . In: Bors, W., Saran, M., Tait, D. (Eds.), Oxygen Radicals in Chemistry and Biology. Walter de Gruyter & Co, Berlin, pp. 57–63. . Monig, J., Asmus, K.-D., et al., 1983a. Electron transfer reactions of Halothane-derived free radicals, CF3CHClOd2 : measurement of absolute rate constants by pulse radiolysis. J. Chem. Soc. Perkin Trans. 2, 1133–1137. . Monig, J., Bahnemann, D., Asmus, K.-D., 1983b. One-electron reduction of CCl4 in oxygenated aqueous solutions: A CCl3Od2 free radical mediated formation of Cl and CO2. Chem.-Biol. Interactions 47, 15–17. . Monig, J., Krischer, K., Asmus, K.-D., 1983c. One-electron reduction of halothane and formation of halide ions in aqueous solutions. Chem.-Biol. Interactions 45, 43–52.
307
Neta, P., Grodkowski, J., Ross, A.B., 1996. Rate constants for reactions of aliphatic carbon-centered radicals in aqueous solution. J. Phys. Chem. Ref. Data 25 (3), 709–1050. Packer, J.E., Willson, R.L., Bahnemann, D., Asmus, K.-D., 1980. Electron transfer reactions of halogenated aliphatic peroxyl radicals: measurement of absolute rate constants by pulse radiolysis. J. Chem. Soc. Perkin Trans 2, 296–299. Russell, G.A., 1957. Russell mechanism. J. Am. Chem. Soc. 79, 3871–3877. . Schoneich, C., Narayanaswami, V., Asmus, K.-D., Sies, H., 1990. Reactivity of ebselen and related seleno-organic compounds with 1,2-dichloroethane radical cations and halogenated peroxyl radicals. Arch. Biochem. Biophys. 281, 18–27. . Schoneich, C., Aced, A., Asmus, K.-D., 1991. Halogenated peroxyl radicals as two-electron transfer agents. Oxidation of organic sulfides to sulfoxides. J. Am. Chem. Soc. 113, 375–376. . Schoneich, C., Aced, A., Asmus, K.-D., 1993. Mechanism of oxidation of aliphatic thioethers to sulfoxides by hydroxyl radicals. The importance of molecular oxygen. J. Am. Chem. Soc. 115, 11376–11383. Schuchmann, H.-P., von Sonntag, C., 1981. Photolysis at 185 nm of dimethyl ether in aqueous solution: involvement of the hydroxymethyl radical. J. Photochem. 16, 289–295. Schuchmann, H.-P., von Sonntag, C., 1982. Hydroxyl radical induced oxidation of diethyl ether in oxygenated aqueous solution. A product and pulse radiolysis study. J. Phys. Chem. 86, 1995–2000. von Sonntag, C., Schuchmann, H.-P., 1991. Peroxyl radicals— overview. Angew. Chem. 103, 1255–1279. von Sonntag, C., Schuchmann, H.-P., 1997. Peroxyl radicals in aqueous solution. In: Alfassi, Z.B. (Ed.), Peroxyl Radicals. Wiley, Chichester, pp. 173–234.
Some new aspects in the chemistry of halogenated oxyl and peroxyl radicals Roman Flyunta,b,1, Oksana Makogonb, Klaus-Dieter Asmusc,* b
a Institut fur IOM e,V., Permoserstr. 15, 04318 Leipzig, Germany . Oberflachenmodifizierung . Institute of Physico-Chemistry, National Academy of Science of the Ukraine, Naukova Street 3a, UA-79053 L’viv, Ukraine c Faculty of Chemistry, Adam-Mickiewicz-University, Grunwaldzka 6, 60-780 Poznan, Poland
Abstract Some characteristic features concerning the chemical properties of halogenated aliphatic oxyl and peroxyl radicals are presented and discussed. This includes, in particular, overall two-electron oxidation initiated by peroxyl radicals, and fragmentation and rearrangement reactions of oxyl radicals. A specific example elaborated in detail deals with the CF3CHClOOd-induced oxidation of methionine. A complete mechanism and material balance is proposed on the basis of quantitative analysis of the products of this reaction. These are: F, Cl, Br, CF3CHO, CF3CO 2 , CO2 and methioninesulfoxide. r 2002 Elsevier Science Ltd. All rights reserved. Keywords: Halogenated oxyl radicals; Halogenated peroxyl radicals; Halogenated aliphatics; Oxalyl halides; Halothane; Methionine; Electron transfer; Radical induced degradation
Halogenated organic compounds are well known, if not to say infamous, as environmental hazards. Particularly their toxic action, e.g., in the liver of animals and humans, has prompted a lot of research and corresponding attempts to minimize their effects by appropriate chemical deactivation. One of the important findings along this line was that the toxic action of halocarbons, to a decisive extent, involves free radicals. In vivo, these are readily generated, for example, by reductive and/or oxidative enzymatic initiation. It could also be demonstrated in numerous experiments employing environmental clean-up methods such as electron beam treatment, photo catalysis with semiconductor materials, ozonation, ultrasound, etc., that the most effective chemical degradation mechanisms also proceed via radical intermediates. The ultimate molecular products in all cases are CO2 and halide anions. This has prompted environmental chemists and engineers to coin the catch word ‘‘mineralization’’ for the breakdown of *Corresponding author. E-mail address: [email protected] (K.-D. Asmus). 1 Previous spelling: Fliount.
the halocarbons via the various free-radical-based degradation methods. The probably most important radical intermediates in an oxygenated environment are peroxyl and oxyl radicals. They exhibit some very interesting properties with respect to their generation as well as their subsequent reactions, particularly if the radical species still carry halogen functions. In the present paper we shall highlight some of the most striking and important features.
1. Experimental All experiments described and discussed in this article have been conducted by means of radiation chemical methods. For product studies, solutions were exposed to the fields of 60Co-g-radiation sources. Kinetic data have typically been obtained by applying time-resolved pulse radiolysis. Details on all experimental procedures have been published in the relevant literature and will, therefore, not specifically be mentioned. All data refer to the radiolysis of aqueous solutions conducted at ambient temperature.
0969-806X/02/$ - see front matter r 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 9 6 9 - 8 0 6 X ( 0 2 ) 0 0 3 3 4 - 1
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
300
Yields are given in terms of G, denoting mmol/10 J absorbed radiation energy. These numbers are almost equal to the classical radiation chemical yield unit of species per 100 eV absorbed energy (to convert into SI units, i.e., mmol/J absorbed energy, just divide the numbers by 10).
2. Results and discussion 2.1. Generation of radicals Considering a halocarbon in its most general form, i.e., a carbon functionality carrying a hydrogen and a halogen (Hal=F, Cl, Br, I) atom, a primary C-centered radical may be generated reductively as well as oxidatively, as outlined in Scheme 1. Reduction is typically initiated via reaction with or transfer of an electron to the halocarbon. Free electrons are conveniently provided as, for example, solvated electrons by radiolysis of water (high-energy electron beam and g-radiation), at electrodes in electrochemical devices, or in the form of conduction band electrons at the interface of illuminated semiconductors and a surrounding solvent phase. Electron transfer, on the other hand, may occur from reducing radicals or enzymatic systems. An oxidative radical formation usually involves an H-atom abstraction, e.g., by dOH radicals. A combined loss of an electron and a proton, however, leads to the same result. This latter mechanism applies, for example, for photo catalytic oxidations through the positive valence band holes, which result upon charge separation in semiconductors. In oxygenated environment either of the two radical types formed usually react very fast with O2 to the respective peroxyl radicals (Beckwith et al., 1984, 1995/ 96; Neta et al., 1996). The actual rate constant for the oxygen addition reflects both, the electrophilic nature of the oxygen and the electron density at the radical site. It is noted that even the dCCl3 radical adds O2 with a diffusion controlled rate constants (3.3 109 M1 s1) . (Monig et al., 1983b) despite the electron density withdrawing effect of the chlorine atoms. The rationale for the high reactivity is the pyramidal structure of the d CCl3 radical which provides a much more exposed
radical site (singly occupied sp3 orbital at C) as opposed to, for example, the dCH3 radical which is practically planar (with the radical electron in a p-type orbital) and which adds oxygen practically as fast as dCCl3. 2.2. Properties of peroxyl radicals Peroxyl radicals (generally denoted as ROOd) are, in principle, oxidizing species (Howard and Scaiano, 1984, 1995/96; Dohrmann et al., 1985, 1995/96). In their reaction with suitable molecules, M, this may manifest itself as an electron transfer (Eq. (1)) or as an H-atom abstraction (Eq. (2)). In both cases the peroxyl will be reduced to the corresponding hydroperoxide (in neutral and close to neutral aqueous solution the acid/base equilibrium ROO+H+"ROOH lies practically on the right-hand side). ROOd þ M-ROO þ Mdþ
ð1Þ
ROOd þ M-ROOH þ Mð HÞd
ð2Þ
Generally these reactions are, however, not very fast and occur with rate constants which are often many orders of magnitude below the diffusion limits (Howard and Scaiano, 1984, 1995/96; Dohrmann et al., 1985, 1995/96). An important consequence of this is that radical-radical termination reactions between two peroxyls may become significant despite the usually low steady-state concentration of radicals. The most important ones are schematically summarized in Scheme 2 (von Sonntag and Schuchmann, 1991, 1997; Asmus and Bonifacic, 2000). Reaction (a) applies, in principle, to all peroxyl radicals and affords the formation of oxyl radicals. Reactions (b) and (c) require the presence of at least one H-atom at the peroxyl carrying carbon. The termination process according to Eq. (c) is also known as Russell mechanism (Russell, 1957) and proceeds via a cyclic sixmembered ring mechanism (For further details on peroxyl radicals in general, the reader is referred to some excellent summarizing review articles and the original literature cited therein (von Sonntag and Schuchmann, 1991, 1997)).
–
H
b
–
c
O2
Scheme 2.
+
– C = O + – C – OH –
O – O•
–C=O –
– C – Hal
+
H –
Scheme 1.
•
–
– C – Hal
H2 O2
–
2 –C–O–O• –
– H or (– e– / –H+)
O2
2 –C–O• –
–
–
H –
oxidative initiation
O2 +
–C–O–O•
– H
a
–
–C• –
– C – Hal
–
–
– Hal –
O2
–
–
2 –C–O–O• reductive initiation
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
2.3. What is different when halogen functionalities are present? Introduction of halogen functionalities results in many chemical consequences. An especially important one concerns the oxidation state of the halogen-carrying carbon. Consider, for example, the products which are generated in Scheme 2 reaction (c). They are alcohols and aldehydes/ketones. However, if the hydrogen gets substituted by a halogen—as outlined in Scheme 3—the carbon assumes a higher ‘‘oxidation number’’ (because of the electronegativity of the halogen). This becomes immediately apparent if we subject the a-halogenated alcohol or aldehyde/ketone to hydrolysis, i.e., processes readily occurring whenever the C–Halogen bond is activated by a neighboring oxygen functionality. In summary, the a-halogenated alcohol constitutes the oxidation state of an aldehyde/ketone, and the ahalogenated aldehyde/ketone constitutes the oxidation state of an organic acid (Note that complete hydrolysis of CCl4 yields CO2, i.e., the highest oxidation state of carbon, namely, +4). An example for the above is the reductively initiated degradation of CF3CHClBr (known also under the name halothane and until recently frequently used as anaesthetic). As summarized in Scheme 4, the primary peroxyl radical derived from this compound, CF3CHClOOd, upon its bimolecular decay via the Russell mechanism, yields equal amounts of trifluoroacetaldehyde and trifluoroacetic acid (M.onig and Asmus, 1984; Asmus et al., 1989). 2.4. Halogenated peroxyl radicals as oxidants It can plausibly be expected that a-halogenation increases the oxidative power of peroxyl radicals because H
Hal –
–
– C = O + H + / Hal –
–
–
– C – OH
–
– C – OH
aldehyde / ketone
alcohol
H
Hal
OH –
–
– –C=O
–C=O
+ H + / Hal –
–C=O
aldehyde
acid
Scheme 3.
CF3 –CHClBr
e– – Br
2 CF 3 –C HCl(OO •)
•
–
– O2
CF 3 –CHCl
O2
CF 3 –CHCl(OH)
CF3 –CHO
Scheme 4.
CF 3 –C HCl(OO • ) +
CF 3 –C(O)Cl
CF3 –C(O)OH
301
electron density delocalization into the halogen atoms reduces the electron density at the peroxyl functionality. Accordingly, the CCl3OOd is the best and CH3OOd is the worst oxidant within the chloromethyl peroxyl series: CCl3 OOd > CHCl2 OOd > CH2 ClOOd > CH3 OOd However, while this is well in line with a number of experimental observations concerning, for example, the oxidation of certain phenolic compounds, ascorbate and phenothiazines, (Packer et al., 1980) there are other findings which seemingly contradict this conclusion . . (Asmus, unpublished results; Monig et al., 1983a; Monig . and Asmus, 1984; Schoneich et al., 1990). The rate constant for the general oxidation reaction (Eq. (3)) does, in fact, not necessarily coincide with expectation (D=electron donor; Dd+=one-electron oxidized form of donor). One observation is, for example, that despite high rate constants the yields of the one-electron oxidation transients are lower than the yield of peroxyl radicals. CCl3 OOd þ D-CCl3 OO þ Ddþ
ð3Þ
Another revealing example are the measured rate constants for the CCl3OOd-induced oxidation of ebselen (a selenium-containing drug) and 1,5-diselenocyclooctane. They are almost equal (amounting to 3 108 and 2 108 M1 s1, respectively) despite the fact that the reduction potential of the Dd+/D couple is much more positive for ebselen (E 0 ¼ 1:59 V vs. Ag/AgCl in CH3CN) than for the 1,5-diselenocyclooctane (E 0 ¼ 0:25 V vs. Ag/AgCl in CH3CN) (Asmus, unpublished . results; Schoneich et al., 1990). Given these redox properties, the oxidation of the 1,5-diselenocyclooctane should occur much faster than the oxidation of ebselen (equal rate constants for reactions involving substrates with different redox potentials could only be expected for diffusion controlled processes but not for reactions proceeding at rates which are at least one order of magnitude below the limits set by the diffusion). These findings, therefore, call for some different or additional reaction mechanism to a simple one-electron transfer process. The rationale for all this is that halogenated peroxyl radicals (possibly even most other peroxyls as well) do not seem to undergo classical one-electron transfer but rather to engage in addition/elimination mechanisms . (Bonifacic et al., 1991; Schoneich et al., 1991, 1993). This is exemplified in Scheme 5 for the oxidation of organic sulfides by halogenated peroxyl radicals. Corresponding mechanisms prevail for the peroxyl radical induced oxidation of organic chalcogenides, in general (especially selenides), and inorganic iodide. Mechanistically, the peroxyl radical-induced oxidation of a sulfide proceeds as shown in Scheme 5. In the first instance the peroxyl radical adds to the sulfur.
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
302
R(Hal)OO•
δ–
+
•
Me2S
OH
δ+
R(Hal)–O–O – SMe2 H + OH –
–
•
R(Hal)–O–O – SMe2 H
– OH
OH + Me2 S
+
Me2SO
R(Hal)O •
Me2 S
•
OH
R(Hal)–O –• O – SMe2 H
H+
+ S ∴S
Scheme 5.
From the redox point of view, this constitutes a first oneelectron oxidation step. The resulting sulfuranyl radical is polarized with slight positive charge at sulfur and a corresponding negative charge at the adjacent oxygen. In aqueous solution this facilitates protonation of the oxygen and hydroxylation of the sulfur. The next step is the transfer of the radical electron, which initially resides at sulfur, into the peroxide bridge. This step constitutes a second one-electron oxidation of the sulfur which thus has undergone an overall two-electron oxidation and consequently has assumed the oxidation level as in a sulfoxide. In fact, the charge separated transient resulting from this second oxidation step is now formally composed of a reduced hydroperoxide and a protonated sulfoxide moiety. It is easy to recognize its decay into a sulfoxide and an oxyl radical (besides OH and H+). With respect to the peroxyl moiety this mechanism is reminiscent of the well-known Fenton chemistry. It also explains the experimentally observed fact that the sulfoxide oxygen comes from the solvent water and is not one of the peroxyl oxygens . (Schoneich et al., 1991). A further argument in favor of this overall two-electron transfer mechanism is the possibility to intercept the one-electron intermediate sulfuranyl radical. Reaction of the latter with a second molecule of sulfide leads to a three-electron bonded dimer radical cation which is also formed as a transient in any one-electron oxidation (e.g., by dOH) and is easily detectable through its characteristic and strong . et al., optical absorption (Bonifacic et al., 1975; Gobl 1984). A most important parameter which helped to evaluate the mechanism are the sulfoxide yields which may differ significantly depending on the nature of the oxidant. Typically, they are much lower for a oneelectron oxidation which leads to radical cations as intermediates. In the dOH-induced oxidation, for example, the sulfoxide yields are about 20% (in deoxygenated solution) while an oxidation initiated by,
for example, CHCl2OOd results in sulfoxide yields of up . to 100% (Bonifacic et al., 1975; Schoneich et al., 1991, 1993). In conclusion, halogenated peroxyl radicals may not only act as one-electron oxidants but with many heteroatom-containing compounds engage in overall two-electron oxidations. This, in turn, leaves them as oxyl radicals, making it imperative to always consider and include the oxyl radical chemistry as well. 2.5. Features of oxyl radical chemistry Having identified the oxyl radicals as a possibly important follow-up species in the peroxyl radical chemistry, let us now focus on a specific example which illustrates the wealth of oxyl radical reactions and the interplay of oxyl/peroxyl chemistry. The system to be discussed is based on halothane (introduced above) as source for the peroxyl and oxyl radicals, and methionine, a sulfur-containing amino acid, as a marker for the radical-induced oxidation processes. A detailed report on that system has already been published; we shall, therefore, focus only on the essential features as they emerge from product studies. Table 1 summarizes the various products and their yields, which have been obtained upon g-irradiation of an aqueous, air-saturated, pH 6 solution containing also 5% 2-methyl-2-propanol, 102 M or no CF3CHClBr, and 103 M or no methionine (MetS) (Flyunt et al., 2000). Without going into the details (for them see reference (Flyunt et al., 2000)), the first to recognize is that the yield of bromide ions identifies the yield of halothane reduction (Eq. (4)) and, since the follow-up reaction of the thus formed CF3CdHCl radical with O2 (Eq. (5)) is fast and quantitative, it is also equal to the yield of CF3CHClOOd peroxyl radicals. As can be seen there is no difference between the system with and without methionine, CH3SCH2CH2CH(NH+ 3 )CO2 , up to this
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303
Table 1 CF 3CHCl(OO•)
Br –
Cl –
F–
CF 3CO2–
CF 3CHO
CO2
Met(SO)
with Met(S)
3.4
3.4
3.4
6.1
1.4
0.0
3.8
5.6
without Met(S)
3.4
3.4
3.4
0.4
1.6
1.7
0.1 5
–– 0.4 without halothane
yields in G , unit:moles per 10 J
CO, oxalate, formate: ≤ 0.1
point. CF3 CHClBr þ
e aq =reducing
radicals
-CF3 Cd HCl þ Br ;
CF3 Cd HCl þ O2 -CF3 CHClOOd :
ð4Þ ð5Þ
All the other products are generated upon the subsequent reactions of the peroxyl radicals. Here it is noted that the chloride yield also quantitatively matches the bromide and peroxyl yields. Almost equal yields in both systems with and without methionine are also observed for trifluoroacetic acid, although on the absolute scale they are significantly lower and, as will be shown below, derive mechanistically via different routes. The presence or absence of methionine plays no role for the yields of CO, oxalate and formate, which all are almost negligible (Gp0:1). Dramatic differences become apparent, however, for the yields of the other products. Fluoride ions and CO2 are practically only formed in the presence of methionine, while trifluoroacetaldehyde is generated only in the absence of the sulfide. It should further be recognized that the methioninesulfoxide (MetSO) yield is much higher than in a system which was devoid of halothane. Finally, it should be noted that the MetSO yield in the halothane system significantly exceeds the yield of primary peroxyl radicals (G ¼ 5:6 vs. 3.4). All this clearly shows that (i) the peroxyl radicals derived from halothane induce an oxidation different to that of typical one-electron oxidants and (ii) the peroxyl radical alone, nevertheless, cannot account for the entire MetSO yield. Let us first evaluate the system without methionine. Under these circumstances the halothane peroxyl radicals will exclusively undergo a bimolecular termination process. The most likely will be the Russell mechanism yielding equal amounts of trifluoroacetyl chloride, CF3C(O)Cl, and 1,1,1-trifluoro-2-chloroethanol, CF3CH(OH)Cl (Eq. (6)). 2 CF3 CHClOOd - O2 þ CF3 CðOÞCl þ CF3 CHðOHÞCl
ð6Þ
Hydrolysis of these compounds directly yields the observed products, CF3CO 2 +Cl , and CF3CHO+Cl .
For an initial peroxyl radical yield of G ¼ 3:4; the expected trifluoroacetic acid, trifluoroacetaldehyde and chloride yields would be 1.7, 1.7 and 3.4, respectively, in perfect agreement with the experimentally measured values (see Table 1). How does it look like in the system with methionine where a bimolecular radical-radical termination cannot compete anymore with a peroxyl radical reaction with the methionine? As outlined in Scheme 3 in general terms, each halothane peroxyl radical may oxidize one methionine to MetSO in an overall two-electron oxidation mechanism according to Eq. (7). CF3 CHClOOd þ MetS-CF3 CHClOd þ MetSO
ð7Þ
Interception of the primary peroxyl-methionine adduct by a second methionine molecule, to yield the S‘Stype three-electron bonded radical cation, does not seem to occur to any significant extent under the experimental conditions, mainly because of the steric demand the methionine exerts. Therefore, we can reasonably assume that the efficiency of the sulfoxide formation via reaction 7 is close to 100%. However, the MetSO yield generated this way cannot exceed the yield of CF3CHClOOd radicals, i.e., G ¼ 3:4: This, in turn, means that the remainder of G ¼ 2:2 to the actually measured yield (G ¼ 5:6) must be formed in secondary processes. Not yet accounted for are also the yields of fluoride, CO2, and trifluoroacetic acid. Consequently, we conclude that the CF3CHClOd oxyl radical, the only remaining reactive radical species, must be responsible, directly and/or indirectly, for all other products listed in Table 1 for the methionine containing system. Oxyl radicals offer, in general, a greater wealth of reaction possibilities than peroxyl radicals. Let us first consider some processes which are feasible but, nevertheless, do not take place in the discussed example. A prominent property of oxyl radicals is, for example, their capability to undergo one-electron oxidations (Howard and Scaiano, 1984, 1995/96). With respect to methionine such a reaction would yield the sulfurcentered methionine radical cation and trifluoroacetaldehyde (Eqs. (8a) and (8b)) both of which were not detected. Consequently, this possibility must be
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
304
discarded.
d
dþ
CF3 CHClO þ MetS-CF3 CHClO þ MetðS CF3 CHClO -CF3 CHO þ Cl
Þ
ð8aÞ ð8bÞ
The same applies to a possible H-atom abstraction by the oxyl radical from any suitable functional group (Eq. (9)). Hydrolysis of the chloroalcohol formed in this reaction would also lead to the not observed trifluoroacetaldehyde. CF3 CHClOd þ R2H-Rd þ CF3 CHClOH ½-CF3 CHO þ Hþ =Cl
ð9Þ
Another type of reaction oxyl radicals readily undergo are b-fragmentations (Howard and Scaiano, 1984, 1995/ 96). As outlined in Scheme 6, two such processes can be envisaged. The first alternative would be cleavage of a chlorine atom. Irrespective of the fate of Cld, this possibility must, however, be dismissed because of the lack of CF3CHO formation. The second possibility involves C– C cleavage and formation of trifluoromethyl radicals and formyl chloride. While dCF3, after its conversion to CF3OOd, could well account for the fluoride, CO2 and additional MetSO, this route must, however, also be discarded because the simultaneously generated formyl chloride, in a fast hydrolysis reaction, should give rise to CO (Dowideit et al., 1996) a product which is not formed (this conclusion would even hold if the formyl chloride was hydrolyzed to formic acid, because the yield of the latter is also negligible). No precedence at all exists for the theoretical third fragmentation possibility, namely, H-atom cleavage. In any case, it would not provide any route to fluoride and CO2.
•
–
O•
–
CF3 – C – Cl H
•
Cl
+
CF3CHO
CF3
+
HCOCl H+ /Cl–
not formed
+
CO not formed
However, there is yet another reaction oxyl radicals readily undergo if the oxyl carrying carbon also carries an H-atom, as is the case for the halothane derived oxyl radical (Berdnikov et al., 1972; Gilbert et al., 1976, 1977; Schuchmann and von Sonntag, 1981, 1982; Asmus et al., 1985). This is a hydrogen shift (presumably solvent assisted) by which the oxygen-centered radical is converted into a carbon-centered radical, as shown in the first reaction of Scheme 7. Such rearrangement reactions are known to occur fast, typically on the lower microsecond/upper nanosecond time scale, and may thus well compete with or beat the b-fragmentation. In our system the newly formed Ccentered radical is likely to add oxygen. The a(hydroxychloro)peroxyl radical generated this way is prone to fast HOd2 elimination, thereby yielding trifluoroacetyl chloride which subsequently hydrolyzes to trifluoroacetic acid, one of the compounds still missing in our material balance. If hydrolysis of the chlorine function occurs at an earlier stage the result would be the same. Our result does not allow to distinguish between the various routes. Assuming that this rearrangement-based mechanism is indeed the one responsible for the trifluoroacetic acid, the measured yield of the latter (G ¼ 1:4) would account for about 40% of the maximum oxyl radical yield (Gp3:4). The question now arises: Is there a competing route which lets any of the transients in Scheme 7 decay without yielding trifluoroacetic acid but leads instead to fluoride and CO2, and a species which oxidizes MetS to MetSO? We propose the origin of such a competing route to be the rearranged, C-centered radical CF3CdCl(OH) or its hydrolyzed form CF3Cd(OH)2. This assumption is based on the results of an dOHinduced oxidation of the hydrated form of trifluoroacetaldehyde which generates CF3Cd(OH)2 and, in the presence of oxygen and methionine, yields all the products in question: CF3CO 2 , F , CO2 and MetSO (Eq. (10)). CF3 CHðOHÞ2 þd OH-CF3 Cd ðOHÞ2 ðþO2 =MetS-CF3 CO 2 ; F ; CO2 ; MetSOÞ
Scheme 6.
O•
–
–
OH
CF3 – C – Cl
CF3 – C – Cl
–
•
H
•
O2
•
O2
CF3CCl(OH)
CF3C(OO•)Cl(OH)
– HO 2•
CF3C(O)Cl CF3C(O)OH
CF3C(OH)2
– HO 2•
CF3C(OO•)(OH) 2
Scheme 7.
ð10Þ
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
A key question in this proposed mechanism concerns the elimination of fluorine, specifically the first of the three fluorines, from the CF3-group. We hypothesize that this takes place from, e.g., the CF3Cd(OH)2 radical, possibly its deprotonated form CF3Cd(OH)(O), as depicted in the encircled section of Scheme 8. Elimination of one fluoride ion would leave the difluoroacetyl radical dCF2CO 2 . This, upon oxygen addition, would convert into the dOOCF2CO 2 peroxyl radical which could then oxidize additional methionine via the 2electron mechanism outlined above in Scheme 5 and thus account for the still missing MetSO. As a result of this process we would be left with dOCF2CO 2 oxyl radicals which, lacking any C–H bond necessary for a 1,2-hydrogen shift (rearrangement), are prone for bfragmentation into CF2O and COd 2 . Hydrolysis of the fluoro-analog of phosgene and electron transfer from the COd to oxygen would finally result in the 2 experimentally observed ‘‘mineralization’’ products. This entire mechanistic idea is corroborated very nicely by an experiment in which the dCF2CO 2 radical is generated via reduction of CF2BrCO 2 by hydrated electrons and from which, in the presence of oxygen and methionine, the same products as outlined in the lower section of Scheme 8 are formed. The challenging part of our hypothesis clearly is the first fluoride elimination process. How that actually proceeds and at which stage hydrolysis of the chlorine occurs is still up for investigation. There is, however, an example for fluoride elimination from a CF3-group, as schematically depicted in Scheme 9, which may serve as a possible analog or, at least, supporting evidence . (Monig et al., 1983c). It has been found that the primary halothane radical CF3CdHCl, if offered another electron by a suitable donor (e.g., ascorbate, or conduction band electrons), is reduced to the corresponding carbanion. This, rather than undergoing protonation to CF3CH2Cl, immediately decays under fluoride elimination to the 1,1difluoro-2-chloroethene.
•
•
CF3-CHCl
e–
305 ••
H+
F – + CF2=CHCl
CF3-CH2Cl
Scheme 9.
Under the assumption that the mechanisms outlined in Schemes 7 and 8 are indeed applicable and contribute with 40% and 60%, respectively, we can now calculate the various product yields in the MetS-containing system and compare them with the experimental data. This is done in Table 2. As can be seen, the material balance is excellent. The largest deviation amounts to just G ¼ 0:2 (for MetSO), way below the acceptable typical radiation chemical error limit of 710%. This agreement between experimental and calculated yields should, nevertheless, not be mistaken as absolute proof of the proposed mechanism but it can certainly be viewed as a most credible support for it. By having chosen halothane as source for the peroxyl and oxyl radicals some light could be shed on the different behavior of fluorine, chlorine and bromine substituents. In this context, let us finally look at one more example. With reference to Scheme 8 and the described degradation of dOCF2CO 2 into two equivalents each of F and CO2, it may be worth mentioning that the alternatively thinkable b-fragmentation of a fluorine atom according to Eq. (11) does not take place. d
d OCF2 CO 2 –– // –> F þ CFðOÞ2CO2
•
– (2) H +
F
_ +
eaq– + CF2Br–C(O)O– •
CF 2–C(O)O– O2
Met(S) •OOCF2 –C(O)O
–
ð11Þ
Not only is this unfeasible thermodynamically (high C– F bond energy), this conclusion also rests on the fact that the hydrolysis product of the oxalylfluoride, namely, oxalate is not formed in this process (Flyunt, unpublished results). Interestingly, the decay mechanism of the dichloro and dibromo analogs of the dOCF2CO 2 radical follows entirely the opposite pattern, as depicted in Scheme 10.
CF3C(OH)O–
CF3C(OH)2
(–)
CF3-CHCl
•OCF2 –C(O)O–
CF2O
+
•–
CO2
O2
Met(SO)
O2 •–
2F
Scheme 8.
_
+
CO2
CO2
R. Flyunt et al. / Radiation Physics and Chemistry 65 (2002) 299–307
306 Table 2 –
–
Cl
F
experimental yields
3.4
calculated yields *
3.4
–
CO2
CF3 CO2
Met(SO)
6.1
3.8
1.4
5.6
6.0
3.7
1.4
5.4
Acknowledgements We gratefully acknowledge the support for our work by the Association for International Cancer Research (AICR) and the Office of Basic Energy Sciences within the US Department of Energy. As such this is publication No. NDRL-4317 of the Notre Dame Radiation Laboratory. K.-D.A. is currently on sabbatical leave from the Department of Chemistry & Biochemistry of the University of Notre Dame.
* calculated on basis of discussed mechanism and G = 3.4 µmoles / 10 J for CF3CHCl(OO•) and Br–
CO2
CO2
O2
Cl, Br
•–
CO2
2 Cl – / 2 Br–
+
calculations of thermodynamic and kinetic parameters at appropriate theoretical levels.
H2O CCl 2 O / CBr 2O
+
CCl(O)-CO2– / CBr(O)-CO2–
–
+
•O – C – CO2–
References
–
Cl, Br
Cl • / Br •
Cl–
/
Br–
CO
+
CO2
+
Cl–
/
Br–
Scheme 10.
In both cases it appears to be the halogen atom (Cld and Brd) which is exclusively eliminated as radical component in the b-fragmentation, leaving the corresponding oxalylchloride and oxalylbromide. This conclusion is drawn from the observation that these two oxalylhalides decay under halide elimination into an equal yield of CO and CO2 (Fliount et al., 1997; Makogon et al., 1998). (Note: this is different to the oxalylfluoride which quantitatively hydrolyzes to oxalate!) The generation of carbon monoxide is clearly of interest from the environmental and toxicological point of view. Also, the formation of the highly oxidizing and reactive chlorine and bromine atoms is noteworthy. In their follow-up reactions they will usually end up as halide ions.
3. Conclusion The few but, hopefully, interesting and instructive examples discussed in this paper indicate the great wealth of reactions halogenated oxyl and peroxyl radicals engage in. They also demonstrate how mechanisms may be influenced by the identity of the halogen atom, revealing in particular the special role of fluorine substituents. Furthermore, it clearly emerges from these studies that caution is advised for extrapolations from one halocarbon to another. Complete product analysis in combination with time-resolved studies of the transients are almost mandatory for the establishment of complete reaction mechanisms. Needless to say, that additional benefits may, of course, be drawn from
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