Radical and non-radical mechanisms for alkane oxidations by hydrogen peroxide-trifluoroacetic acid

Article abstract of DOI:10.1021/jo005617d

The oxidation of cyclohexane by the H₂O₂-trifluoroacetic acid system is revisited. Consistent with a previous report (Deno, N.; Messer, L. A. Chem. Comm. 1976, 1051), cyclohexanol forms initially but then esterifies to cyclohexyl trifluoroacetate. Small amounts of trans-1,2-cyclohexadiyl bis-(trifluoroacetate) also form. Although these products form irrespective of the presence or absence of O₂, dual mechanisms are shown to operate. In the absence of O₂, the dominant mechanism is a radical chain reaction that is propagated by CF₃· abstracting H from C₆H₁₂ and S_H2 displacement of C₆H₁₁· on CF₃CO₂OH. The intermediacy of C₆H₁₁· and CF₃· is inferred from production of CHF₃ and CO₂ along with cyclohexyl trifluoroacetate, or CDF₃ when cyclohexane-d₁₂ is used. In the presence of O₂, fluoroform and CO₂ are suppressed, the reaction rate slows, and the rate law approaches second order (first order in peracid and in C₆H₁₂). Trapping of cyclohexyl radicals by quinoxaline is inefficient except at elevated (～75°C) temperatures. Fluoroform and CO₂, telltale evidence for the chain pathway, were not produced when quinoxaline was present in room temperature reactions. These observations suggest that a parallel, nonfree radical, oxenoid insertion mechanism dominates when O₂ is present. A pathway is discussed in which a biradicaloid-zwiterionic transition state is attained by hydrogen transfer from alkane to peroxide oxygen with synchronous O-O bond scission.

Full text of DOI:10.1021/jo005617d

J . Org. Chem. 2001, 66, 789-795
789
Ra d ica l a n d Non -Ra d ica l Mech a n ism s for Alk a n e Oxid a tion s by
Hyd r ogen P er oxid e-Tr iflu or oa cetic Acid
Donald M. Camaioni,* J . Timothy Bays,† Wendy J . Shaw, J ohn C. Linehan, and
J erome C. Birnbaum
Pacific Northwest National Laboratory, P.O. Box 999, Richland, Washington 99352
donald.camaioni@pnl.gov
Received August 22, 2000
The oxidation of cyclohexane by the H2O2-trifluoroacetic acid system is revisited. Consistent with
a previous report (Deno, N.; Messer, L. A. Chem. Comm. 1976, 1051), cyclohexanol forms initially
but then esterifies to cyclohexyl trifluoroacetate. Small amounts of trans-1,2-cyclohexadiyl bis-
(trifluoroacetate) also form. Although these products form irrespective of the presence or absence
of O2, dual mechanisms are shown to operate. In the absence of O2, the dominant mechanism is a
radical chain reaction that is propagated by CF3• abstracting H from C6H12 and SH2 displacement
•
•
•
of C6H11 on CF3CO2OH. The intermediacy of C6H11 and CF3 is inferred from production of CHF3
and CO2 along with cyclohexyl trifluoroacetate, or CDF3 when cyclohexane-d12 is used. In the
presence of O2, fluoroform and CO2 are suppressed, the reaction rate slows, and the rate law
approaches second order (first order in peracid and in C6H12). Trapping of cyclohexyl radicals by
quinoxaline is inefficient except at elevated (∼75 °C) temperatures. Fluoroform and CO2, telltale
evidence for the chain pathway, were not produced when quinoxaline was present in room
temperature reactions. These observations suggest that a parallel, nonfree radical, oxenoid insertion
mechanism dominates when O2 is present. A pathway is discussed in which a biradicaloid-zwiterionic
transition state is attained by hydrogen transfer from alkane to peroxide oxygen with synchronous
O-O bond scission.
In tr od u ction
alkanes, which are most prone to solvolytic reactions, give
complex products.
Mixtures of H2O2 and trifluoroacetic acid readily
oxidize alkanes to alkyl trifluoroacetates. The reaction
has been studied by Ullrich and Frommer,1 and by Deno.2
Trifluoroperoxyacetic acid (TFPA) is presumed to be the
agent that oxidizes the alkanes. The equilibrium (eq 1)
is rapidly established and shifted to the right under usual
conditions (large excess of TFA) for alkane oxidation.3
Alkane oxidation by TFPA is thought to occur by a
concerted mechanism. Frommer and Ullrich1 suggested
a 4-center transition state (I), but with discovery of
alcohol as the initial product, Deno2 suggested the
6-center transition state (II). The main evidence for the
reaction being concerted is a report by Smith and Sleath
that cis- and trans-decahydronaphthalenes are each
converted with 98% retention of configuration.4
CF3CO2H + H2O2 a CF3CO3H + H2O
(1)
Alkane reactivity depends strongly on the type and
number of C-H bonds present with relative reactivity
increasing sharply along the series 1° < 2° < 3°. Alkanes
with only primary and secondary C-H bonds convert
cleanly to esters, apparently with intermediate formation
of the precursor alcohols that readily esterify in trifluo-
roacetic acid. Formation of an ester in large part pro-
tects the product from further oxidation to ketones and
acids. This was clearly shown by Deno et al.,2 who
observed that positions 4 through 7 of 1-octanol were
most reactive. Therefore, the minor side product, 1,2-
trans-cyclohexadiyl bis(trifluoroacetate) is explained by
epoxidation of olefin formed by solvolysis of alcohol/ester
or another oxidation path. The products of tertiary
Related to this chemistry is the work with aroyl
peroxyacids of Schneider and Mu¨ller5 and more recently
† Associated Western Universities-Northwest Postdoctoral Fellow,
now at U.S. Military Academy, Dept. of Chemistry, Bldg. 753,West
Point, NY 10996.
(1) Frommer, U.; Ullrich, V. Z. Naturforsch. 1971, 26b, 322.
(2) Deno, N. C.; J edziniak, E. J .; Messer, L. A.; Meyer, M. D.; Stroud,
S. G.; Tomezsko, E. S. Tetrahedron 1977, 33, 2503-8.
(3) Swern, D. In Organic Peroxides; Swern, D., Ed.; Wiley-Inter-
science: New York, 1970; Vol. I, Chapter VII, p 493.
(4) (a) Smith, J . R. L.; Sleath, P. R. J . Chem. Soc., Perkin Trans. 2
1983, 1165-1169. (b) For description of experimental method, see:
Davison, A. J .; Norman, R. O. C.; J . Chem. Soc. 1964, 5404.
10.1021/jo005617d CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/16/2001

790 J . Org. Chem., Vol. 66, No. 3, 2001
Camaioni et al.
Minisci and co-workers.6 Schneider and Mu¨ller5 observed
that peroxybenzoic acids with chloro or nitro substituents
oxidize tertiary alkanes with high regio- and stereose-
lectivity. Reactions performed in chloroform gave “rea-
sonable” yields of tertiary alcohol and retention of
configuration. Accordingly, they suggested an oxenoid
insertion mechanism with transition state III. Minisci
and co-workers6 have challenged the mechanism, offering
a radical chain mechanism instead.
Ta ble 1. Oxid a tion of Cycloh exa n e in H2O2-TF A;
Effects of O2
% yielda
O2 (atm)
monoester
diester
CO2
CHF3
1
28
32
46
10
10
3
2
34
77
∼0.1
44c
0
28
0b
a
Based on H2O2, 0.18 M; [H2O2]/[C6H12] ) 0.2; each, entry is
an average of two experiments. b Cyclohexane-d12, one experiment.
c CDF3/CHF3 ) 21.
ArCO2• + ArCO2OH f ArCO2H + ArCO2O• (2)
ane-d12. Since radical reactions may be affected by O2,
both the products and reaction kinetics were measured
in the presence and absence of O2. Reactions were also
performed with added quinoxaline, an efficient radical
trapping agent.8 Yields of products are calculated based
on H2O2 used since in all our experiments it was the
limiting reagent. These yields are uniformly less than
100%.
ArCO2O• + RH f ArCO2OH + R•
ArCO2OH + R• f ArCO2• + ROH
(3)
(4)
To explain Schneider’s and Mu¨ller’s report5 of retention
of configuration, Minisci suggests that oxidation of the
alkyl radical by peracid (eq 4) is a fast cage reaction
analogous to the oxygen rebound mechanism for cyto-
chrome P450 oxidations.7
Effects of Oxygen on P r od u cts. Table 1 lists results
for reactions run at 25 °C for 24 h in the presence and
absence of an atmosphere of O2.11 The results of Table 1
show an unusual dependence on O2. Yields of cyclohexyl
trifluoroacetate (monoester) and trans-1,2-cyclohexadiyl
bis(trifluoroacetate) (diester) are relatively unaffected by
O2. However, yields of byproducts, CO2 and CHF3 are
significantly affected. The yields of CHF3 and CO2 in the
presence of O2 are small. Whereas, the yields in the
absence of O2 are significant, being comparable to the
combined yields of monoester and diester. The CHF3 was
In this paper, we report observations showing dual
mechanisms operate in the H2O2-TFA system. We
specifically investigated the role of O2 in the reactions,
analyzed for gaseous products, i.e., CO2 and CHF3, and
ran reactions in the presence of quinoxaline, which in
its protonated form traps alkyl radicals efficiently.8 For
convenience, we used cyclohexane as the prototypical
secondary alkane. We find that a free radical chain
mechanism clearly operates in the absence of O2. The
mechanism is different than that proposed by Minisci6
for aroyl peracids. Furthermore, although alkane-derived
products do not depend on the presence or absence of O2,
we observed that O2 retards the rate of oxidation and
stops production of CHF3 and CO2. Therefore, other
mechanisms must operate under these conditions. Pos-
sibly it is one of the concerted oxenoid insertion mecha-
nisms suggested above, although we favor and expand
on a pathway suggested long ago by Hamilton9 that well
accommodates the dual nature of this reaction.
1
identified by H NMR analyses of the reaction solutions
(e.g., see Figure 1) and by GC-MS analyses of the gases
above the reaction solutions. No C2F6 was detected in the
reactions. The yields reported in Table 1 for CO2 include
dissolved CO2, whereas yields of CHF3 represent only
what was measured in the gas phase. From the solution
NMR results, comparable amounts of CHF3 were in
solution. Thus, the yields of CO2, CHF3, and total
cyclohexane products show an approximate 1:1:1 stoi-
chiometry.
•
The production of CHF3 with CO2 suggests that CF3
radicals are intermediately formed, at least when O2 is
excluded from the reactions. To determine if CHF3 results
from attack on cyclohexane, an experiment was per-
formed using cylcohexane-d12 (entry 3, Table 1). The
fluoroform in this reaction was found to contain 96% D.
The cyclohexyl trifluoroacetate and 1,2-trans-diester
incorporated little hydrogen, i.e., they were the d11 and
d10 compounds, respectively.
NMR An a lyses of Cycloh exa n e-H2O2-TF A Sys-
tem . Spectra of cyclohexane-H2O2-TFA reactions were
recorded at intervals after the reagents were mixed (see
Figure 1) to obtain product and kinetic information. We
observed that alcohol formed initially and then disap-
peared. Small amounts (<5%) of diester were observed
at long times. Absence of additional resonances between
δ 2-4 showed little of the cyclohaxane is oxidized to
ketones or acids. Fluoroform was observed when oxygen
was absent. Methine 1H-resonances for alcohol, ester, and
fluoroform NMR resonances were integrated to obtain
concentration vs time data, in Figure 2.
Resu lts
Consistent with previous reports,2 we observed that
reactions of cyclohexane with H2O2-TFA give mainly
cyclohexyl trifluoroacetate and small amounts of trans-
1,2-cyclohexadiyl bis(trifluoroacetate). Experiments were
performed to determine specifically the role of free radical
intermediates in the absence of catalysts. Of particular
interest to us in this work was whether CO2 and CHF3
were byproducts of the oxidation. Therefore, yields of CO2
and CHF3 were measured. Since these products could
occur by reactions that are independent of alkane oxida-
tion,10 some experiments were performed using cyclohex-
(5) Schneider, H.-J .; Mu¨ller, W. J . Org. Chem. 1985, 50, 4609-4615.
(6) Bravo, A.; Bjorsvik, H.-R.; Fontana, F.; Minisci, F.; Serri, A. J .
Org. Chem. 1996, 61, 9409-9416.
(7) Groves, J . T. J . Chem. Educ. 1985, 62, 928-931.
(8) (a) Citterio, A.; Minisci, F.; Porta, O.; Sesana, G. J . Am. Chem.
Soc. 1977, 7960-7968. (b) Carona, T.; Citterio, A.; Crolla, T.; Minisci,
F. J . Chem. Soc., Perkin Trans. 1 1977, 865.
(9) (a) Hamilton, G. A.; Giacin, J . R.; Hellman, T. M.; Snook, M. E.;
Weller, J . W. Ann. N.Y. Acad. Sci. 1973, 212, 4-12. (b) Hamilton, G.
A. Chemical Models and Mechanisms for Oxygenases. In Molecular
Mechanisms of Oxygen Activation; Hayaishi, O., Ed.; Academic Press:
New York, 1974; pp 427-430.
(11) Additional reactions were run under more varied conditions but
are not shown here. Yields were variable and in some cases higher
than those for conditions reported in Table 1. The monoester always
dominated over the diester.
(10) Liotta, R.; Hoff, W. S. J . Org. Chem. 1980, 45, 2887-2890.

Alkane Oxidations by H2O2-Trifluoroacetic Acid
J . Org. Chem., Vol. 66, No. 3, 2001 791
Ta ble 2. Obser ved F ir st-Or d er Ra te Con sta n ts for
Oxid a tion of Cycloh exa n e in H2O2-TF A System
ester k5 + k7
k6
k5
k7
cyclohexane
(M)
O2
(atm)
yielda (×105) (×104) (×105) (×105)
(%)
(s-1
8.6
16
5.8
2.3
)
(s-1
)
(s-1
)
(s-1
)
0.84
0.42
0.84
0.084
0
0
1
1
60b
38c
50
3.2
3.6
3.2
2.9
5.1
6.1
2.9
3.5
9.9
2.9
1.9
37
0.86
a
b
Yield based on H2O2 concentration, 6.7 × 10-3 M. Maximum
yield of CHF3 in solution was 14%; final yield was 12%. c Maximum
yield of CHF3 in solution was 18%; final yield was 13%.
cyclohexane). Accordingly, the data were fit to the
integrated rate equations for parallel and series pseudo-
first-order reactions:
C6H12 + TFPA f C6H11OH
C6H11OH + TFA f C6H11OCOCF3
TFPA f X
(5)
(6)
(7)
Table 2 lists psuedo-first-order rate constants and
product yields extracted from these experiments. The rate
constants show complex dependencies on cyclohexane
and O2. Note that for reactions run in the absence of O2,
the observed pseudo-first-order rate constant for eq 5 is
roughly independent of cyclohexane, whereas the rate
constant for eq 7 is inversely dependent on cyclohexane.
Reactions run in the presence of O2 show different trends.
The observed combined rate of eqs 5 and 7 vary propor-
tionally with cyclohexane and the rates are slower. Since
a radical chain path would be inhibited, with O2 scaveng-
F igu r e 1. Time dependence of 1H NMR spectra of cyclohexane
reacting with H2O2-TFA in absence of O2: cyclohexanol
methine, multiplet, δ ) 3.65; cyclohexyl trifluoroacetate meth-
ine, multiplet, δ ) 4.85 ppm; CHF3, quartet δ ) 6.15 ppm.
Anomolous peaks (*) are modulation resonances associated
with the intense solvent (TFA) peak.
•
ing both CF3 and cyclohexyl radicals, slower reaction
rates are expected. Consistent with this view, reactions
run under an atmosphere of O2 produced little fluoroform
in either solution or gas phases (see Table 1).
From the data in Table 2, we derived the complex
overall rate laws for O2-free (eq 8) and 1 atm O2 (eq 9)
reactions:12
d[TFPA]/dt ) {5.6 × 10-5
s
-1 + 3.2 ×
10-5 M-1 s-1[C6H12]-1/2}[TFPA] (8)
d[TFPA]/dt ) {3.3 × 10-3 s-1 [C6H12]3/4 + 3.0 ×
10-5 M-1 s-1[C6H12]1/4}[TFPA] (9)
The first terms of these rate laws represent the process
that produces alcohol (eq 5). Both rate constant and
cyclohexane reaction order show a dependence on O2, the
dependence on cyclohexane being zero order in the
absence of O2 and ∼3/4 order in 1 atm of O2. The second
terms in eqs 8 and 9 correspond to the side reaction, eq
7. The terms also show dependencies on cyclohexane and
O2. The reaction order of cyclohexane is -0.5 in the
absence of O2 and ∼0.25 in 1 atm of O2.
F igu r e 2. Plot showing concentrations (NMR peak areas) of
cyclohexyl trifluoroacetate (O) and cyclohexanol (b) versus
time during oxidation of cyclohexane by H2O2-TFA in absence
of O2 (first entry in Table 2). Inset: blowup of early time data.
Solid lines are fits to kinetic model for eqs 5-7.
The kinetic data (Figure 2) show that the ester grows
in with time, but delayed relative to the appearance of
alcohol and fluoroform. This behavior suggests a sequen-
tial process, C6H12 f C6H11OH f C6H11OCOCF3. How-
ever, we observed that the final yields of ester depended
on the concentration of cyclohexane, even though it was
present in large excess (see Table 2). We suppose side
reactions occur that consume TFPA (i.e., production of
diester, as well as other reactions10 that do not involve
Qu in oxa lin e Tr a p p in g Exp er im en ts. Protonated
quinoxaline (pKa ) 1.5) has been used to scavenge alkyl
radicals in radical chain reactions.8a The resulting prod-
uct is cyclohexylquinoxaline. Both 2- and 6-substituted
(12) For cyclohexane/TFPA .1, eqs 5-7 predict for disappearance
of TFPA: R ) -k5[TFPA] - k7[TFPA]. Equations 8 and 9 were obtained
by assuming kobs ) k[cyclohexane]n for each k5 and k7 in Table 2 and
solving for the respective oxygen-free and oxygen-rich rate constants
and cyclohexane reaction orders.

792 J . Org. Chem., Vol. 66, No. 3, 2001
Camaioni et al.
Ta ble 3. Cycloh exyla tion of Qu in oxa lin e by th e
Sch em e 1
H2O2-TF A System
% yielda
PO2
T
cyclohexyl
quinoxaline (atm) (°C) quinoxaline monoester diester
0.1
0
0.1
0
0.1
0
1
1
0
0
0.2
0.2
25
25
25
25
70
70
3
33
49
34
51
17
70
5
7
4
3
2
8
nab
0.04
nab
36
nab
a
Based on H2O2, 0.18 M in 25 °C runs and 0.05 M in 70 °C
b
runs, [C6H12] ) 0.9 M. Not applicable.
The following propagation steps are consistent with
much of the data.
isomers may form, but the 2-isomer dominates at high
acidity.8a Table 3 lists yields of cyclohexylquinoxaline,
cyclohexyl trifluoroacetate, and diester obtained from
oxidations of cyclohexane in the presence of quinoxaline.
Results of control reactions run under similar conditions
in the absence of quinoxaline are also listed. Reactions
at 25 °C with quinoxaline yielded relatively little cyclo-
hexylquinoxalines in the absence or presence of O2.
Unlike experiments in Table 1, little CO2 and CDF3 were
produced in reactions of cyclohexane-d12 at 25 °C when
O2 was absent. In contrast to 25 °C results, reactions at
70 °C yielded significant cyclohexylquinoxaline and yields
of mono- and diesters were reduced relative to reactions
performed without added quinoxaline.
CF3• + C6H12 f C6H11• + CHF3
C6H11• + HOO2CCF3 f C6H11OH + CF3CO2 (11)
CF3CO2• f CF3• + CO2
(12)
(10)
•
This radical chain differs from the one that operates
in oxidations by m-chloroperoxybenzoic acid.6 There,
arylacylperoxy radicals, formed by reaction of acyloxy
radical with peracid, abstract H from alkanes. However,
H• abstraction by CF3CO2• is not important in the TFA-
H2O2 system because decarboxylation is too fast (k ≈ 5
× 10-9 s-1).13 Perfluoroalkyl radicals are electrophilic and
intrinsically much more reactive that alkyl radicals in
H-abstraction reactions. Dolbier and co-workers14 have
shown that the reactivity of n-perfluorobutyl radicals is
more like that of the tert-butoxy radical than the alkyl
radical. Reaction of CF3• with cyclohexane is exothermic
by -8 kcal/mol.15 Therefore, an efficient chain reaction
is plausible.
Equation 11 is an SH2 reaction. While we are not aware
that such a reaction has been documented for TFPA,
analogous reactions are known for other peroxides, and
Minisci6 has suggested the analogous reaction occurs in
the m-chloroperoxybenzoic acid system. In the case of
peresters, an 18O labeling study even shows that the alkyl
radical attacks the peroxidic oxygen.16,17
Con tr ol Exp er im en ts a n d th e Effect of Cl-. Sev-
eral control experiments were performed to elucidate the
heterolytic/solvolytic chemistry of the products and in-
termediates in TFA. Cyclohexanone in TFA did not
convert to mixed ester-alcohol or diester products when
heated for 4 h at 70 °C. Cyclohexene in TFA containing
10 wt % H2O converts to cyclohexyl trifluoroacetate at
room temperature with a rate constant of 1.3 × 10-4 s-1
.
Reaction of cyclohexane with H2O2 in TFA run at 70 °C
with added NH4Cl produced approximately 10% cyclo-
hexyl chloride, 20% cyclohexyl trifluoroacetate, and 10%
1,2-trans-diester based on H2O2. Less than 1% of cyclo-
hexyl chloride is formed when cyclohexanol is reacted
with 0.1 M NH4Cl in trifluoroacetic acid for 4 h at 70 °C.
With 0.1 M NH4Cl present, ∼30% of cyclohexene is
converted to cyclohexyl chloride. Less than 20% of
cyclohexyl chloride solvolyzes in TFA, even upon heating
to 70 °C for 4 h.
A zero-order dependence on cyclohexane of TFPA
disappearance to ester may be expected in the absence
of O2 where chain termination reactions may be domi-
nated by self-termination of cyclohexyl radicals:18
Discu ssion
Ra d ica l Ch a in Mech a n ism . Although previous re-
ports have ruled out free radical mechanisms in the
H2O2-TFA system, we find clear evidence that a radical
chain mechanism operates, at least under conditions of
low O2 partial pressure. Homolysis of TFPA and involve-
2C6H11• f C6H10 + C6H12 + C12H22
(13)
However, these steps alone may not explain the overall
reaction kinetics. Additional steps for consuming TFPA
•
ment of CF3 is indicated by the production of CO2 and
fluoroform-d in high yields when cyclohexane-d12 was
oxidized in the absence of O2. It is not clear why trapping
of cyclohexyl radicals was inefficient at 25 °C. However,
since little CO2 and fluoroform were produced in reactions
at 25 °C that contained quinoxaline, the results may be
rationalized by considering the steps necessary for form-
ing cyclohexylquinoxaline. These steps (Scheme 1) in-
clude radical addition, deprotonation, and oxidation by
peracid. The addition of cyclohexyl radical is expected to
be rapid. Therefore, if the deprotonation step is slow at
25 °C, then the radical chain reaction would be inhibited
by cyclohexylquinoxaline.
(13) (a) Francisco, J . S. Chem. Phys. Lett. 1992, 191, 7-12. (b)
Maricq, M. M.; Szente, J . J .; Khitrov, G. A.; Francisco, J . S. J . Phys.
Chem. 1996, 100, 4514-4520.
(14) Shtarev, A. B., Tian, F., Dolbier, W. R., J r., Smart, B. E. J .
Am. Chem. Soc. 1999, 121, 7335-7341.
(15) (a) Estimated using standard heats of formation (in kcal/mol):
CHF3, -166.6; i-C3H7, -21.6; CF3•, -112.4; C3H8, -25.0. (b) See NIST
Standard Reference Database Number 69; February 2000 Release.
(16) Koenig, T. In Free Radicals; Kochi, J . K., Ed.; Wiley: New York,
1973; Vol. 1, pp 116-120.
(17) Denney, D. B.; Feig, G. J . Am. Chem. Soc. 1959, 81, 5322.
(18) (a) Howard, J . A. In Organic Free Radicals; Kochi, J . K., Ed.;
Wiley-Interscience: New York, 1973; Vol. 2, Chapter 12, p 32. (b)
Walling, C. Free Radicals in Solution; J ohn Wiley and Sons: New York,
1957; pp 243, 244, 418-421.

Alkane Oxidations by H2O2-Trifluoroacetic Acid
J . Org. Chem., Vol. 66, No. 3, 2001 793
Sch em e 2
Sch em e 3
must be included. The chain reaction might operate even
in the presence of modest concentrations of O2, provided
propagation steps are rapid enough.
two channels, one leading to O-insertion products (alcohol
and ketone) and the other separating into alkyl and
R-hydroxyalkoxyl radicals (see Scheme 2).22a
When O2 is present, little CO2 and negligible CHF3
Hamilton did not elaborate a mechanism for peroxy
acids. Therefore, we suggest the mechanism in Scheme
3, which is analogous to the dioxirane mechanism.22a,b
The alkane H is transferred synchronous with peroxide
O-O bond scission leading to a transition state with alkyl
and acyloxy groups separated by an incipient water
molecule. The electron donating and electron withdraw-
ing properties of the respective groups favor zwitterionic
character in the TS and its subsequent collapse to
“concerted” products. Carbon-oxygen bond formation
may only require a rotation of the water molecule such
that front attack on the alkyl group occurs with retention
of configuration. If the alkyl group separates from the
TS complex, then radical character may develop in the
respective groups. Radicals that escape the solvent cage
initiate chain reactions 10-12, unless inhibitors are
present. The probability of radical escape need not be
high since the chain reaction multiplies the event.
were produced. Probably, CF3• radicals are scavenged by
•
O2 to form CF3O2 radical. The further involvement of a
chain reaction is speculative. Little information exists
about the reactivity of CF3OO• radical for H abstraction
from alkanes. A dilemma that any radical mechanism
must overcome is explaining how cyclohexanol and then
ester are produced without making CO2 and cyclohex-
anone or caprolactone. For example, Minisci and co-
workers6 report that oxidation of cyclohexane by m-
peroxybenzoic acid in dichloromethane (65 °C, air atmo-
sphere) produces cyclohexanol, cyclohexanone, and ca-
prolactone in ratios of 1:1:2, respectively. Therefore, we
do not rule out that both radical-chain and nonchain
mechanisms operate in such a way that O2 inhibits the
radical chain pathway allowing nonradical pathways to
dominate.
Non r a d ica l Mech a n ism s. The effects we observe for
O2 and quinoxaline and reports of retention of stereo-
chemistry at tertiary centers4,5,19 make a strong case for
an alternative pathway not involving diffusive intermedi-
ates. We favor a mechanism based on an explanation
given by Hamilton9 nearly 30 years ago. He described a
general mechanism for reaction of alkanes with oxenoid
agents, including TFPA, in which the reactions occur by
transfer of hydrogen from alkane to oxenoid reagent to
give a TS and/or intermediates that are a resonance
hybrid of radical and ionic structures. The resulting
products and their stereochemistry depend on the elec-
tronic character and relative stability of the TS/interme-
diates.
An upper limit for the activation barrier is roughly
estimated assuming homolytic intermediates. The en-
thalpy for reaction of propane with TFPA to form 2-propyl
(19) Both examples involve reactions in which dichloromethane, not
TFA, is the solvent. Also, while Schneider and Mu¨ller5 performed
peroxybenzoic acid reactions at reflux temperatures, Smith and Sleath4
ran TFPA reactions at 0 °C.
(20) (a) Minisci, F.; Zhao, L.; Fontana, F.; Bravo, A. Tetrahedron
Lett. 1995, 36, 1697. (b) Minisci, F.; Zhao, L.; Fontana, F.; Bravo, A.
Tetrahedron Lett. 1995, 36, 1895. (c) Bravo, A.; Fontana, F.; Fronza,
G.; Mele, A.; Minisci, F. J . Chem. Soc., Chem. Commun. 1995, 1573.
(d) Vanni, R.; Garden, S. J .; Banks, J . T.; Ingold, K. U. Tetrahedron
Lett. 1995, 36, 7999. (e) Bravo, A.; Fontana, F.; Fronza, G.; Minisci,
F.; Zhao, L. J . Org. Chem. 1998, 63, 254.
(21) (a) Murray, R. W.; J eyaraman, R.; Mohan, L. J . Am. Chem. Soc.
1986, 108, 2470. (b) Murray, R. W.; Gu, D. J . Chem. Soc., Perkin Trans.
2 1994, 451. (c) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J . Am.
Chem. Soc. 1989, 111, 6749. (d) Adam, W.; Asensio, G.; Curci, R.;
Gonzalez-Nunez, M. E.; Mello, R. J . Org. Chem. 1992, 57, 953. (e)
Asensio, G.; Mello, R.; Gonzalez-Nunez, M. E.; Castellano, G.; Corral,
J . Angew. Chem., Int. Ed. Engl. 1996, 35, 217. (f) Adam, W.; Curci, R.;
D’Accolti, L.; Dinoi, A.; Fusco, C.; Gasparrini, F.; Kluge, R.; Paredes,
R.; Schulz, M.; Smerz, A. K.; Veloza, L. A.; Weinkotz, S.; Winde, R.
Chem. Eur. J . 1997, 3, 105. (g) Curci, R.; Dinoi, A.; Fusco, C.; Lillo, M.
A. Tetrahedron Lett. 1996, 37, 249.
R-H + OdX f [R• H-O-X• T R+ H-O-X-] f
R-O-H + X (14)
Such a mechanism has recently been adopted for
dioxiranes, another class of oxenoid reagent that, like
peracids, react with alkanes and show evidence for both
radical and concerted mechanisms.20,21 Theoretical cal-
culations22 predict a TS, achieved by hydrogen transfer,
that is a polarized biradicaloid intermediate rather than
a radical pair. After the TS, the reaction path divides into
(22) (a) Shustov, G.; Rauk, A. J . Org. Chem. 1998, 63, 5413-5422.
(b) Du, X.; Houk, K. N. J . Org. Chem. 1998, 63, 6480-6483. (c)
Glukhovtsev, M. N.; Canepa, C.; Bach, R. D. J . Am. Chem. Soc. 1998,
120, 10528-10533.

794 J . Org. Chem., Vol. 66, No. 3, 2001
Camaioni et al.
radical, trifluoroacetoxy radical, and water, each in the
insertion. Although hydroxydioxiranes are relatively
unknown, recent studies by Porter et al.30 allow us to
consider this possibility in some detail. Their work
supports Mimoun’s proposal but limits the importance
of hydroxydioxiranes to base-promoted reactions. They
observed scrambling of 18O-peroxide label is facile in
peroxybenzoate anion but not in peroxybenzoic acid. Ab
initio structure-electronic calculations were consistent
with the observation. The calculations predict relatively
high energies for isomerization of several peroxy acids
(eq 17), including TPFA, whereas the energies for isomer-
ization of their conjugate anions (eq 18) are significantly
lower.
gas phase, is ∆H° ) 29 kcal/mol (eq 15).23,24
CH3CH2CH3 + RCO2OH f
RCO2• + H2O + CH3CH‚CH3 (15)
However, the energy to produce the radicals in a solvent
cage may be smaller as a result of hydrogen bonding of
water to the acyloxy radical. Although alkoxy radicals
are thought not to form hydrogen bonds,25 hydrogen
bonding of acyloxy radicals is, to our knowledge, an
unexplored topic. The strength of the intramolecular
hydrogen bond in peroxyformic and peroxyacetic acids
was estimated by Swern to be 6-7 kcal/mol.26 More
recently, Bach et al. have calculated ∼5 kcal/mol for the
strength of the hydrogen bond in peroxyacetic acid.27
A
similarly strong hydrogen bond of the incipient water to
acyloxy radical or to solvent (e.g., TFA) would cause the
homolytic reaction to occur with an energy of ∼24 kcal/
mol. The transition state in Scheme 3 may be earlier on
the reaction coordinate and be lower in energy than a
water-separated radical pair, depending on the zwitter-
ionic character and resulting solvation effects.
The large free energy for eq 17 makes it improbable
that hydroxytrifluoromethyldioxirane is involved in our
systems. That eq 18 is an isergonic reaction suggests that
the conjugate anion may form under conditions that
promote ionization of TFPA. In water, TFPA has a pKa
) 3.7 that corresponds to ∆Ga° ≈ 5 kcal/mol such that
the anion may readily equilibrate with the peroxy acid.
In TFA, a low dielectric solvent (ꢀ ) 8.55),33 ∆Ga° will be
larger. Therefore, involvement of the anion of hydroxy-
trifluoromethyldioxirane is probably negligible in our
system and in systems4,5 using dichloromethane (ꢀ )
9.0)33 as solvent.
Finally, we comment on the mechanism for the minor
product, trans-1,2-diester. This product is attributed to
epoxidation of cyclohexene. Although some cyclohexene
may come from solvolysis of cyclohexanol/cyclohexyl
trifluoroacetate,2 reactions that we ran with Cl- added
to scavenge carbocations show that other pathways may
contribute cyclohexene. We observed 10% cyclohexyl
chloride when 0.1 M NH4Cl was added. Presumably it
formed by ionic reaction of cyclohexene:
Another consideration is that C-C bond cleavage may
occur at some point along the reaction coordinate to form
CF3 , CO2, H2O, and R•. Having it occur after the TS, or
•
along a parallel path, seems more consistent since
efficient conversion of R• to ROH is difficult to envision,
except for the chain reaction (eqs 10-12). Although an
energetically less favorable trajectory, the potential for
initiating radical chain reactions amplifies its impor-
tance.
An alternate path transfers hydrogen to the peracid
carbonyl with concerted cleavage of the peroxide O-O
bond:
R-H + OdC(O2H)CF3 f
[•C6H11 HOC(dO)CF3 OH•] f
C6H11OH + HOC(dO)CF3 (16)
The energetics of this path seem prohibitive. We
estimate the enthalpy is ∼42 kcal/mol28 to produce
cyclohexyl, hydroxyl, and trifluoroacetic acid from cyclo-
hexane and TFPA. As implied by structure II, there
would have to be strong electrostatic or covalent bonding
interactions between hydroxyl and cyclohexyl groups for
this path to be competitive.
Cl
+
c-C6H10 + H+ a c-C6H11
-8 c-C6H11Cl (19)
In control experiments, little cyclohexyl chloride was
produced during solvolysis of cyclohexanol in trifluoro-
acetic acid with 0.1 M NH4Cl, but significant cyclohexyl
chloride was formed when cyclohexene was reacted in
trifluoroacetic acid with 0.1 M NH4Cl. Therefore, solvoly-
sis of cyclohexanol or cyclohexyl trifluoroacetate during
the reaction of TFPA with cyclohexane do not adequately
Yet another possibility stems from Mimoun’s proposal29
that peracids may isomerize to hydroxydioxiranes. By
analogy to dioxiranes, they should be capable of oxenoid
(23) Estimated from BDEs of propane (99 kcal/mol for 2° C-H),24
CF3CO2-OH (49 kcal/mol),27 and water (119 kcal/mol).24
(24) Tsang, W. Heats of Formation of Organic Free Radicals by
Kinetic Methods. In Energetics of Organic Free Radicals; Martinho
Simoes, J . A., Greenberg, A., Liebman, J . F., Eds., Blackie Academic
and Professional: London, 1996; pp 22-58.
(25) Avila, D. V.; Brown, C. E.; Ingold, K. U.; Lusztyk, J . J . Am.
Chem. Soc. 1993, 115, 466-470.
(26) Swern, D. Organic Peroxy Acids-Preparation, Properties, and
Structure. In Organic Peroxides; Swern, D., Ed.; Wiley-Interscience:
New York, 1970; Vol. I, p 449.
(30) Porter, N. A.; Yin, H.; Pratt, D. A. J . Am. Chem. Soc. 2000,
122, 11272-11273.
(31) Camaioni, D. Calculated for isomerization in water with Gauss-
ian 98 suite of programs (Rev. A.7, Gaussian Inc.: Pittsburgh, PA,
1998): B3LYP/6-311+G(d,p) level of theory (∆E )16.3 kcal/mol) with
zero point energy and 298K thermal corrections (1.1 kcal/mol) and
hydration free energies of gas-phase geometries (∆∆Gs ) -1.7) from
COSMO self-consistent reaction field32a/united atom topological cavity
model.32b Porter et al.30 report ∆E ) 14.4 kcal/mol (gas phase) at
B3LYP/6-31G(d) level of theory.
(27) Bach, R. D.; Ayala, P. Y.; Schlegel, H. B. J . Phys. Chem. 1996,
100, 12758-12765.
(28) Sum of 49 (CF3CO2-OH f CF3CO2 + OH),27 99 [(CH3)2CH-
H f H• + (CH3)2CH•),24 and -106 kcal/mol (CF3CO2• + •H f CF3CO2-
H). This last values is derived from thermochemical cycle using proton
•
•
(32) (a) Barone, V.; Cossi, M. J . Phys. Chem. 1998, 102, 1995. (b)
Barone, V.; Cossi, M.; Tomasi, J .; J . Chem. Phys. 1997, 107, 3210.
(33) Lange’s Handbook of Chemistry, 13th ed.; Dean, J . A., Ed.;
McGraw-Hill: New York, 1985; Chapter 10, p 113.
and electron affinities of CF3CO2 and ionization potential of H•.15b
•
(29) Mimoun, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 734-750.

Alkane Oxidations by H2O2-Trifluoroacetic Acid
J . Org. Chem., Vol. 66, No. 3, 2001 795
O2, reagents were added to an 8-mL screw-top glass vial, the
solution and headspace were purged with oxygen, and the vial
was closed with a Teflon-lined cap or mini-inert valve gas
sampling cap if gas samples were to be taken. Headspace gas
samples were taken with a gas-sampling syringe. For reactions
in sealed ampules, the ampule was placed in 250-mL round-
bottom flask, closed with a stopcock adapter, and then shaken
to cause the ampule seal to break and release its contents.
The adapter outlet was fitted with a serum cap so that gas
samples could be removed through the opened stopcock with
a gastight syringe. Solutions were prepared for analysis by
adding 300 µL samples to a test tube containing approximately
0.7 g of anhydrous NaCO3 and 3 mL of dichloromethane
containing decane as an internal standard. After release of
CO2, the dichloromethane layer was dried with magnesium
sulfate and analyzed by GC-MS (HP 5890 gas chromatograph
equipped with HP 5971 mass-selective detector and 30 m ×
0.25 mm i.d. capillary column (HP-5MS) with 0.25 µm film
thickness of cross-linked 5% phenyl methyl silicone. Headspace
gas analyses were performed on the same instrument using
the single-ion detection mode. 1H NMR spectra were recorded
at 300 MHz using a Varian VXR-300s spectrometer operating
at 7.01 T with a standard 5 mm multinuclear broad band
explain the 1,2-trans-diester. Cyclohexene might also
derive from reactions such as eqs 20 and 21.
-
C6H12 + HO3CCF3 f [C6H11+ H2O O2CCF3] f
C6H10 + H3O+ + -O2CCF3 (20)
C6H11• + HO3CCF3 f C6H10 + H2O + •O2CCF3 (21)
Con clu sion
We have obtained new results regarding the mecha-
nism of alkane oxidations in the H2O2-TFA system.
Previous reports suggested the mechanism does not
involve free radicals. However, we find that under certain
conditions the reaction clearly does. Reactions performed
in the absence of O2, or in air at 70 °C, seem best
explained by a radical-chain mechanism. Under these
conditions, (a) CO2 and CHF3 were produced in yields
that roughly correspond with the yields of cyclohexyl
trifluoroacetate; (b) CDF3 was produced when cyclohex-
ane-d12 was used; and (c) with added quinoxaline (70 °C),
cyclohexylquinoxalines were major products. Further-
more, the kinetics of the reaction are complex and
inconsistent with the process envisioned by Deno (bimo-
lecular involving transition structure II).2 Yet, we find
that, in the presence of O2 at 25 °C, similar evidence for
a free radical mechanism is lacking. Little CO2 and
negligible CHF3 are formed. Yields of cyclohexylquinoxa-
line are negligible. The kinetics of the oxidation, as
evidenced by the first term in eq 9, approach second
order-first order each in cyclohexane and TFPA. We
conclude a parallel mechanism not involving free radicals
must operate. On the basis of literature precedent, a
biradicaloid zwitterionic transition state is proposed for
this latter process. It is attained by cyclohexane transfer-
ring hydrogen to PTFA peroxidic oxygen. Consistent with
reports of retention of configuration in related systems,
this transition state may readily collapse to alcohol with
retention of configuration. Separation of the TS to free
radicals or ions may also be possible, thereby accounting
for products by radical chain reactions and for byproducts
such as cyclohexene. Our discussion and selection of
literature precedents have been influenced by structure-
electronic calculations currently in progress at our labo-
ratory. A thorough account of these calculations will be
reported later.
1
probe. H NMR spectra in TFA were run unlocked but were
referenced to cyclohexane (δ ) 1.2 ppm). Spectral and chro-
matographic properties of reaction products were matched
with data obtained from authentic samples of cyclohexanol and
1,2-cyclohexanediol in TFA. Cyclohexylquinoxaline was as-
signed on the baiss of its literature mass spectrum.8b
Rea ction Kin etics. Anaerobic experiments were run in 5
mm o.d. pressure/vacuum valve NMR tubes (Wilmad Glass,
Buena, NJ ). The TFA (0.5 mL) was degassed inside of the NMR
tube by three freeze-pump-thaw cycles. The tube was
warmed to room temperature and back-filled with nitrogen.
Then, hydrogen peroxide was added to the NMR tube through
a
septum using a gastight syringe. The stock hydrogen
peroxide solution had been subjected to a nitrogen purge for
10 min prior to the transfer. The mixture was allowed to
equilibrate for 30 min, after which time degassed cylcohexane
was injected using a gastight microliter syringe. The tube was
shaken vigorously to mix the contents and then immediately
placed inside the thermostated (25 °C) NMR probe.
Hen r y’s La w Con sta n t for CO2 in TF A. Henry’s law
constant for CO2 in the reaction mixtures was measured as
follows. To a reaction that had run its course in a sealed vessel,
10-µL aliquots of a 1 M Na2CO3 solution were added, and the
concentration of CO2 gas in the headspace was measured by
GC-MS. The gas phase concentration increased linearly with
the number of additions. The slope of the line equated to a
Henry’s law constant of 9 atm M-1. This number was used to
convert the yield of CO2 in a reactor headspace to total yield
(gas + solution).
Ack n ow led gm en t. D.M.C. thanks M. Dupuis and
J . A. Franz of PNNL for advice on structure-electronic
calculations and acknowledges support by the U.S.
Department of Energy, Office of Science, Advanced
Energy Projects and Office of Basic Energy Sciences.
The Pacific Northwest National Laboratory is a multi-
program national laboratory operated by Battelle Me-
morial Institute for the U. S. Department of Energy
under contract DE-AC06-76RLO 1830.
Exp er im en t Section
Generally, experiments were performed in TFA solutions
that contained the alkane and other reagents as described here
and in the tables and figures given below. A typical reaction
mixture contained 200 µL of cyclohexane (1.85 mmol) and 39.0
µL of 30% hydrogen peroxide (0.36 mmol) in 2.00 mL of TFA.
For anaerobic reactions, the reagents were added to a 5-mL
ampule and degassed using three freeze-pump-thaw cycles,
and then the ampule was flame-sealed. For reactions under
J O005617D