Oxygenation of alkane C-H bonds with methyl(trifluoromethyl)dioxirane: Effect of the substituents and the solvent on the reaction rate

Article abstract of DOI:10.1021/jo0509511

The mechanism of the oxygenation of alkane C-H bonds with methyl(trifluoromethyl)dioxirane (1a) is studied through the effect of the substituent and solvent on the rate of oxygenation of 2-substituted adamantanes (2). The results suggest a remarkable elec

Full text of DOI:10.1021/jo0509511

Oxygenation of Alkane C-H Bonds with
Methyl(trifluoromethyl)dioxirane: Effect of the Substituents and
the Solvent on the Reaction Rate
Mar´ıa E. Gonza´lez-Nu´n˜ez,† Jorge Royo,† Rossella Mello,† Minerva Ba´guena,†
Jaime Mart´ınez Ferrer,† Carmen Ram´ırez de Arellano,† Gregorio Asensio,*,† and
G. K. Surya Prakash‡
Departamento de Quı´mica Orga´nica, Universidad de Valencia, Avda. V. Andre´s Estelle´s s/n,
46100-Burjassot, Valencia, Spain, and Loker Hydrocarbon Research Institute and Department of
Chemistry, University of Southern California, University Park, Los Angeles, California 90089-1661
gregorio.asensio@uv.es
Received May 12, 2005
The mechanism of the oxygenation of alkane C-H bonds with methyl(trifluoromethyl)dioxirane
(1a) is studied through the effect of the substituent and solvent on the rate of oxygenation of
2-substituted adamantanes (2). The results suggest a remarkable electron deficiency at the reacting
carbon atom in the transition state leading to the regular oxygenation products. The linearity of
the Hammett plot reveals that the reaction mechanism does not change within a range of
0.15-0.67 units of σI. A change in the solvent does not affect the distribution of the products,
indicating a through-bond transmission of the substituent effect as the origin of the deactivation
of the substrate.
Introduction
of the dioxirane on the reacting C-H bond, which leads
to O-transfer reaction products through a concerted
oxenoid transition state (path a, Scheme 1).3 However,
the formation of epoxides and alkyl acetates in the
reaction of dimethyldioxirane (1b) with hydrocarbons
Dioxiranes 1 are three-membered cyclic peroxides that
can efficiently oxygenate saturated C-H bonds1 under
mild conditions. Methyl(trifluoromethyl)dioxirane (1a) is
the most effective reagent known in these reactions that
take place under very mild conditions and with high
selectivity, even on deactivated substrates.2
The mechanism of the oxygenation reaction has been
the subject of controversy (Scheme 1). Most of the ex-
perimental evidence regarding this process supports a
reaction mechanism that involves an electrophilic attack
(2) (a) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J. Am. Chem.
Soc. 1989, 111, 6749-6757. (b) Asensio, G.; Gonza´lez-Nu´n˜ez, M. E.;
Mello, R.; Boix-Bernardini, C.; Adam, W. J. Am. Chem. Soc. 1993, 115,
7250-7253. (c) Kuck, D.; Schuster, A.; Fusco, C.; Fiorentino, M.; Curci,
R. J. Am. Chem. Soc. 1994, 116, 2375-2381. (d) Asensio, G.; Mello,
R.; Gonza´lez-Nu´n˜ez, M. E.; Castellano, G.; Corral, J. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 217-218. (e) Asensio, G.; Castellano, G.; Mello,
R.; Gonza´lez-Nu´n˜ez, M. E. J. Org. Chem. 1996, 61, 5564-5566. (f)
Curci, R.; Detomaso, A.; Lattanzio, M. E.; Carpenter, G. B. J. Am.
Chem. Soc. 1996, 118, 11089-11092. (g) Fusco, C.; Fiorentino, M.;
Dinoi, A.; Curci, R. J. Org. Chem. 1996, 61, 8681-8684. (h) Yang, D.;
Wong, M. K.; Wang, X. C.; Tang, Y. C. J. Am. Chem. Soc. 1998, 120,
6611-6612. (i) D’Accolti, L.; Dinoi, A.; Fusco, C.; Russo, A.; Curci, R.
J. Org. Chem. 2003, 68, 7806-7810. (j) Won, M.-K.; Chung, N.-W.;
He, L.; Wang, X.-C.; Yan, Z.; Tang, Y.-C.; Yang, D. J. Org. Chem. 2003,
68, 6321-6328. (k) Wong, M. K.; Chung, N. W.; He, L.; Yang, D. J.
Am. Chem. Soc. 2003, 125, 158-162. (l) D’Accolti, L.; Fusco, C.; Annese,
C.; Rella, M. R.; Turteltaub, J. S.; Williard, P. G.; Curci, R. J. Org.
Chem. 2004, 69, 8510-8513.
* Corresponding author. Phone: 34-96-354-4272; fax: 34-96-354-
4939.
† Universidad de Valencia.
‡ University of Southern California.
(1) (a) Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem. Res. 1989,
22, 205-211. (b) Murray, R. W. Chem. Rev. 1989, 89, 1187-1201. (c)
Curci, R. Adv. Oxygenated Processes (1990) 2, 1-59. (d) Adam, W.;
Hadjiaropoglou, L.; Curci, R.; Mello, R. Organic Peroxides; Wiley:
Chichester, 1992; pp 195-219. (e) Clennan, E. L. Trends Org. Chem.
1995, 5, 231-252. (f) Adam, W.; Smerz, A. K. Bull. Soc. Chim. Belg.
1996, 105, 581-599. (g) Adam, W., Ed. Peroxide Chemistry; Wiley-
VCH: Weinheim, 2000. (h) Adam, W.; Saha-Moller, C. R.; Ganeshpure,
P. A. Chem. Rev. 2001, 101, 3499-3548.
(3) (a) Adam, W.; Asensio, G.; Curci, R.; Gonzalez-Nun˜ez, M. E.;
Mello, R. J. Org. Chem. 1992, 57, 953-955. (b) Curci, R.; Dinoi, A.;
Rubino, M. F. Pure Appl. Chem. 1995, 67, 811-822.
10.1021/jo0509511 CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/08/2005
J. Org. Chem. 2005, 70, 7919-7924
7919

Gonza´lez-Nu´n˜ez et al.
SCHEME 1. Mechanistic Pathways for the
Oxygenation of Alkane C-H Bonds by
Dioxiranes 1
relative position with respect to the reacting C-H bond
also have significant effects on the rate and selectivity
of this reaction. Thus, in our study8b on the oxygenation
of the tertiary C-H bonds of a 2-substituted adamantane
model with methyl(trifluoromethyl)dioxirane (1a), we
found that the Z/E selectivity depended on the electron-
withdrawing ability of the substituent. The plot of ln
Z/E versus σI of the substituents,9 within a range of
0.15-1.07 units of σI, showed two correlation lines with
opposite slopes, which were explained8b in terms of long-
range hyperconjugative interactions of the reaction center
with the remote substituent. However, within the mecha-
nistic context, these data raise the question as to whether
the change in the slope observed could indicate a change
in the reaction mechanism induced by the increasing
electron-withdrawing ability of the remote substituent.
The validity of our interpretation8 of the dependence of
Z/E selectivity on the electron-withdrawing ability of the
remote substituent requires that we verify that the
reaction mechanism remains unchanged along a series
of substituents.
In an earlier report, Murray et al. studied10 the effect
of the substituents on the oxygenation rate of 1-substi-
tuted adamantanes with dimethyldioxirane (1b) and
found evidence to support an electrophilic mechanism.
However, the range of substituents used was relatively
narrow (0.15-0.47 units of σI), and some substituents
remarkably deviated from the trend because the
model substrate allowed through-space interaction be-
tween the substituent and the reacting center in the
transition state. These data do not allow us to conclude
that the reaction mechanism is consistent along a broader
range of electron-withdrawing substituents with the more
reactive methyl(trifluoromethyl)dioxirane (1a). Further-
more, the literature contains little systematic experi-
mental data concerning the specific influence of the
substituents and the solvent on the oxygenation of satu-
rated substrates with methyl(trifluoromethyl)dioxirane
(1a).
We report here the effect of the substituents on the
rate of the oxygenation of substituted saturated hydro-
carbons with methyl(trifluoromethyl)dioxirane (1a). The
study was performed for a series of 2-substituted ada-
mantanes, a model substrate that avoids through-space
interaction of the substituent with the reacting center,
with a series of electron-withdrawing substituents cover-
ing a range of 0.15-0.67 units of σI.9 The Hammett plot
shows a straight line with a negative slope that suggests
a significant electronic deficiency at the substrate in the
transition state and indicates that the reaction mecha-
nism remains unchanged along the whole series of
substituents. The kinetic solvent effect found in the
oxygenation of 2-adamantyl acetate (2e) with methyl-
(trifluoromethyl)dioxirane (1a) is significant and makes
it possible to disregard a radical-mediated mechanism
as the main pathway to the regular oxygenation products
in these reactions. The absence of any significant influ-
ence of the solvent on the Z/E isomer ratio allows us to
also disregard the through-space transmission of the
substituent effect.
under an inert atmosphere has led other authors4 to
propose an alternative radical-mediated mechanism for
these reactions (path b, Scheme 1). In this mechanism,
the substrate-induced homolysis of the peroxidic O-O
bond of the dioxirane is followed by a rate-determining
H-abstraction from the substrate by the dioxyl biradical.
The coupling of the radical pair within the solvent cage
(oxygen-rebound) produces the regular oxygenation prod-
ucts, while the escape of the alkyl radical to the solution
gives rise to the minor products, esters, and epoxides.
Theoretical calculations5 support both alternative reac-
tion mechanisms as feasible reaction pathways for the
oxygenation of saturated C-H bonds with dioxiranes.
Raouk et al.5c also suggested that both concerted and
stepwise mechanisms could arise from the splitting of the
reaction pathway after a common transition state.
However, in our study6 of the reaction of saturated
hydrocarbons with dimethyldioxirane (1b), we found
differences in the kinetic isotopic effects for regular
oxygenation products (alcohols and ketones) and radical-
derived products (esters and epoxides). These results
strongly suggest a distinct mechanistic origin for each
type of product and support the notion that the concerted
reaction pathway leads to the oxygenation of saturated
C-H bonds while the molecule-induced homolysis of the
dioxirane leads to the minor radical-derived products.
The findings obtained by Schreiner et al.7 on the reaction
of propellanes with dimethyldioxirane also support the
notion that the molecule-induced homolysis pathway
plays a minor role in the oxygenation of alkanes with
dioxiranes.
Amid these conflicting reports,3-7 we have established8
that the electronic character of the substituent and its
(4) (a) Bravo, A.; Fontana, G.; Fronza, G.; Minisci, F. J. Chem. Soc.,
Chem. Commun. 1995, 1573-1574. (b) Bravo, A.; Fontana, G.; Minisci,
F. Tetrahedron Lett. 1995, 38, 6945-6948. (c) Minisci, F.; Zhao, L.;
Fontana, F.; Bravo, A. Tetrahedron Lett. 1995, 36, 1697-1700. (d)
Vanni, R.; Garden, S. J.; Banks, J.; Ingold, K. U. Tetrahedron Lett.
1995, 36, 7999-8002. (e) Bravo, A.; Fontana, F.; Fronza, G.; Minisci,
F.; Zhao, L. J. Org. Chem. 1998, 63, 254-263. (f) Simakov, P. A.; Choi,
S. Y.; Newcomb, M. Tetrahedron Lett. 1998, 39, 8187-8190.
(5) (a) Glukhovtsev, M. N.; Canepa, C.; Bach, R. D. J. Am. Chem.
Soc. 1998, 120, 10528-10533. (b) Du, X.; Houk, K. N. J. Org. Chem.
1998, 63, 6480-6483. (c) Shustov, G. V.; Rauk, A. J. Org. Chem. 1998,
63, 5413-5422. (c) Freccero, M.; Gandolfi, R.; Sarzi-Amade`, M.;
Rastelli, A. J. Org. Chem. 2003, 68, 811-823.
(6) Asensio, G.; Mello, R.; Gonza´lez-Nu´n˜ez, M. E.; Boix, C.; Royo, J.
Tetrahedron Lett. 1997, 38, 2373-2376.
(7) Fokin, A. A.; Tkachenko, B. A.; Korschunov, O. I.; Gunchenko,
P. A.; Schreiner, P. R. J. Am. Chem. Soc. 2001, 123, 11248-11252.
(8) (a) Gonza´lez-Nu´n˜ez, M. E.; Royo, J.; Castellano, G.; Andreu, C.;
Boix, C.; Mello, R.; Asensio, G. Org. Lett. 2000, 2, 831-834. (b)
Gonza´lez-Nu´n˜ez, M. E.; Castellano, G.; Andreu, C.; Royo, J.; Ba´guena,
M.; Mello, R.; Asensio, G. J. Am. Chem. Soc. 2001, 123, 7487-7491.
(9) Charton, M. Prog. Phys. Org. Chem. 1981, 13, 119-251.
(10) Murray, R. W.; Gu, H. J. Org. Chem. 1995, 60, 5673-5677.
7920 J. Org. Chem., Vol. 70, No. 20, 2005

C-H Bonds with Methyl(trifluoromethyl)dioxirane
TABLE 2. Absolute Rate Constants for Reaction of 2e
with 1a in Different Solvents
SCHEME 2. Determination of the Relative Rates
kX/kOAc in the Oxidation of Substrates 2 with
Dioxirane 1a
N a
solvent
ET
k2 (M-1 s-1
)
CCl4
0.052
0.309
0.46
0.0518 ( 0.022
0.0796 ( 0.015
0.1703 ( 0.010
0.0954 ( 0.008
CH2Cl2
CH3CN
CF3CH2OH
0.898
a Data from ref 17.
C5-H or C7-H bonds, with not even traces of oxygenation
at the tertiary C1-H or C3-H bonds or at the methylene
bridges. A change in the solvent (carbon tetrachloride,
dichloromethane, and 2,2,2-trifluoroethanol) did not sig-
nificantly affect these results (Table 1). The experimental
details concerning the synthesis and characterization of
the reaction products are provided in the Experimental
Procedures. The reactions take place with a high conver-
sion of the substrates into the corresponding oxygenated
products indicating the absence of free radicals in the
course of the reaction.11 Also, the GC-MS analysis of the
reaction mixtures showed the absence of the character-
istic products derived from the radical pathways (esters
or halogenated derivatives).
The influence of the solvent on the reaction rate of
2-adamantyl acetate (2e) with methyl(trifluoromethyl)-
dioxirane (1a) was determined in 2,2,2-trifluoroethanol,
dichloromethane, acetonitrile, and carbon tetrachloride.
The reactions were carried out at -15.0 ( 0.1 °C, under
second-order conditions ([1a]0 ) [2e]0 ) 0.016 M) by
adding an aliquot (-15.0 ( 0.1 °C) of a ketone-free
dichloromethane solution of methyl(trifluoromethyl)diox-
irane (1a) to a mixture of equimolar amounts of the
substrate 2e and the internal standard (methyl para-
chlorobenzoate) in the selected solvent. The ratios 2,2,2-
trifluoroethanol/dichloromethane, acetonitrile/dichlo-
romethane, and carbon tetrachloride/dichloromethane
were ca. 11:1 in all cases. The kinetic constants were
obtained from the plots of 1/[2e] versus kt, which were
linear up to a substrate conversion of ca. 70%. The values
shown in Table 2 are the averages of at least three
independent runs.
TABLE 1. Relative Rates and Effect of the Solvent on
Diastereoselectivity in the Oxygenation of Substrates 2
with Methyl(trifluoromethyl)dioxirane (1a)
Z attack %
b
c
c
2 (X)
σIa
krel
CCl4
CH2Cl2
CF3CH2OH
2a (CH2OAc)
2b (NHAc)
0.15 3.435
0.28 1.503
0.30 1.646
50.0
50.1d
60.6d
56.2
50.9
60.0
56.4
60.0
71.6
57.7
67.0
72.9
72.2
54.4
72.2
58.9
68.2
66.2
47.7d
2c (COCH3)
54.8
57.5
71.0
56.9
65.6
70.8
72.1
50.2
72.1
55.2
65.6
64.3
2d (COOCH3) 0.32 1.466
59.5
2e (OAc)
2f (CF3)
2g (Cl)
2h (F)
0.38 1.000
0.40 0.931
0.47 0.541
0.54 0.463
71.5d
57.0
66.6
72.0d
71.7d
53.3
2i (OSO2CH3) 0.55 0.425
2j (CN)
2k (OTs)
0.57 0.345
0.55
0.59 0.316
0.66 0.233
0.67 0.208
1.07
71.7d
57.3
2l (SO2CH3)
2m (ONO2)
2n (NO2+)
67.0d
65.8
2o (NH3
)
a Data from ref 9. b Measured in dichloromethane; the values
are the averages of at least three independent runs, and the
standard deviations are within 0.106 and 0.012. c The data are
limited by the solubility of the substrates 2 in the selected solvent.
d Data from ref 8a.
Results
The effect of the substituents on the relative rate of
oxygenation with methyl(trifluoromethyl)dioxirane (1a)
was determined for a series of 2-substituted adamantanes
(see Scheme 2). The relative reaction rates were deter-
mined by competition experiments between 2-adamantyl
acetate (2c) and the substrates 2 with methyl(trifluo-
romethyl)dioxirane (1a, Scheme 2). Reactions were car-
ried out at -15 °C under an air atmosphere by adding
an aliquot of a dichloromethane solution11 of the diox-
irane 1a to a solution containing a mixture of the
corresponding substrate 2, 2-adamantyl acetate (2e) and
methyl para-chlorobenzoate as an internal standard. In
all cases, the initial concentration of the reagents was
0.05 M with a molar ratio of 1:1:1. The relative rates were
obtained from the areas of the starting materials in GC
analysis, and the values are the averages of at least three
independent experiments. The calibration curves for the
different substrates and the internal standard were
determined before the GC analysis (see Experimental
Procedures). The results are shown in Table 1. The
relative rate for substrate 2o (X ) NH3+) was not
measured since it is insoluble in dichloromethane. The
values obtained for substrate 2k (X ) p-CH3C6H4SO3)
showed a large error due to the irregular response of the
substrate under the GC analysis conditions and thus are
not included in the table.
Discussion
The plot of log kX/kOAc versus σI of the substituents
(Figure 1) shows that the rate of the oxygenation reaction
progressively decreases as the electron-withdrawing abil-
ity of the substituent (σI) increases. This dependence is
consistent along the range of 0.15-0.67 units of σI,
indicating that the mechanism of the reaction does not
change along the whole series of substituents.
The large and negative slope of this Hammett plot (F
) -2.31) is consistent with a reaction mechanism involv-
ing a strongly electron-demanding transition state, in
agreement with the electrophilic character of the diox-
irane (1a). The plot of the data versus σQ values12 yields
again a straight line with a slope (-0.47, R2 ) 0.9865)
that is comparable to the F values obtained for some
reactions that proceed through carbocation intermedi-
(11) Adam, W.; Curci, R.; Gonza´lez-Nu´n˜ez, M. E.; Mello, R. J. Am.
Chem. Soc. 1991, 113, 7654-7658.
(12) (a) Grob, C. A.; Schlageter, M. G. Helv. Chim. Acta 1976, 59,
264-276. (b) Grob, C. A.; Schaub, B.; Schalgeter, M. G. Helv. Chim.
Acta 1980, 63, 57-62.
In all cases, the reactions gave only products that
resulted from the oxygenation of the distant tertiary
J. Org. Chem, Vol. 70, No. 20, 2005 7921

Gonza´lez-Nu´n˜ez et al.
for a series of 2-substituted adamantanes by triplet
biacetyl correlate with the σI of the substituent with
slopes of -1.4 and -1.8 for syn and anti C-H σ-bonds,
respectively. However, these data were interpreted in
terms of the electric field model for transmission of the
inductive substituent effect.16
Therefore, the high sensitivity of the oxygenation of
2-substituted adamantanes with methyl(trifluoromethyl)-
dioxirane (1a) to the electron-withdrawing ability of the
remote substituent, placed in a distance of four σ-bonds
from the reacting center, is consistent with an electro-
philic concerted O-atom insertion mechanism as the main
route to the regular oxygenation products in these
reactions.
The effects of the substituents on the relative reaction
rates (Figure 1) evidence their relative abilities to dimin-
ish the electron density of the substrate molecule. The
reactions take place at the tertiary C-H bonds that are
furthest from the substituent at C2, which are the less-
deactivated positions with regard to the electrophilic
oxygenation. These results are in agreement with previ-
ous data reported on the effect of the substituents on the
regioselectivity of the oxygenation of C-H bonds with
dioxirane 1a.2b,d,e,8b The effect of the substituents shows
a nondirectional character and weakens with distance,
suggesting a through-bond mode of transmission of the
inductive electron-withdrawing effect. In this way, the
substituent withdraws electron density from the entire
substrate through successive polarization of the adjacent
bonds. The intensity of this effect will depend on the
electron-withdrawing ability of the substituent. Since the
relative reactivity of the diastereotopic C-H bonds is
scarcely affected by the polarity and dielectric constant
of the solvent (Table 1), neither the different reactivity
of the substrates in the oxygenation reaction nor the
diastereoselectivity of the reaction can be attributed to
the through-space mode of transmission of the inductive
effect of the substituent. These results support our
previous interpretation8 of the effect of remote substit-
uents on the diastereoselectivity of the oxygenation
reaction in terms of hyperconjugative through-bond
transmission of the substituent effect.
The kinetic solvent effect on the reaction rate is
modest, although significant. The relative reaction rates
found in carbon tetrachloride, dichloromethane, aceto-
nitrile, and 2,2,2-trifluoroethanol were 1:1.54:1.84:3.29,
which indicates that an increase in the polarity and
hydrogen-bond donor (HBD) ability of the solvent en-
hances the reaction rate. This trend indicates increasing
charge separation upon going from the reactants to the
transition state.17 Since both 2-adamantyl acetate (2e)
and methyl(trifluoromethyl)dioxirane (1a) are polar hy-
drogen-bond acceptors, an increase in the polarity of the
solvent increases the solvation of the reactant molecules
and lowers their free energy. Thus, the experimental data
indicate that the lowering of the transition-state free
energy due to solvation is greater than that of the
reagents and support a significant increase in the dipole
moment and charge separation upon going from the
reactants to the transition state.17
FIGURE 1. Relative rates of reaction of substrates 2 with
dioxirane 1a vs Charton’s preferred9 σI constants (log kX/kOAc
) -2.31577σI + 0.8793, R2 ) 0.9934). The values are the
averages of at least three independent experiments.
ates,13 such as the solvolysis of 4-substituted 2-adamantyl
para-toluensulfonates (F ) -0.53), 7-substituted 2-nor-
bornyl para-toluensulfonates (F ) -0.72), and tertiary
alkyl chlorides (F ) -0.71). Murray et al. reported10
a
slope of -0.371 in the plot of the rate constants of the
oxygenation of 1-substituted adamantanes with dimeth-
yldioxirane (1b) versus σQ substituent constants,12 which
is in agreement with the less electrophilic nature of this
dioxirane as compared with methyl(trifluoromethyl)-
dioxirane (1a). The models used in these studies place
the substituent one bond closer to the reacting carbon
atom than our model substrate 2. The results are also in
good agreement with the effect of the substituents on the
rate of oxygenation of saturated hydrocarbons with
peracids.14
The theoretical descriptions5 of the transition struc-
tures for alkane oxidation with dioxiranes define a highly
asynchronous and polar transition state for the concerted
electrophilic O-atom insertion mechanism, in which the
reacting carbon atom develops a significant electron
deficiency. Conversely, the transition state for H-atom
abstraction from the substrate by the dioxyl biradical,
which is the rate-determining step of the alternative
radical-mediated mechanism, shows a much lower dipole
moment and also a lower charge density at the reacting
carbon atom.5 It is known15 that reactions involving
radical intermediates are less sensitive to remote sub-
stituent effects than ionic processes. Thus, the data
reported16 on the relative rates of hydrogen abstraction
(13) (a) Grob, C. A.; Schlageter, M. G. Helv. Chim. Acta 1976, 59,
264-276. (b) Grob, C. A.; Schaub, B.; Schlageter, M. G. Helv. Chim.
Acta 1980, 63, 57-62. (c) Grob, C. A. Acc. Chem. Res. 1983, 16, 426-
431.
(14) Schneider, H.-J.; Mu¨ller, W. J. Org. Chem. 1985, 50, 4609-
4615.
(15) (a) Lovins, R. E.; Andrews, L. J.; Keefer, R. M. J. Org. Chem.
1965, 30, 1577-1580. (b) Fischer, T. H.; Meierhoefer, A. W. J. Org.
Chem.1978, 43, 220-224. (c) Davies, W. H., Jr.; Pryor, W. A. J. Am.
Chem. Soc. 1977, 99, 6365-6372. (d) Tanner, D. D.; Samal, P. W.; Ruo,
T. C.-S.; Henriquez, R. J. Am. Chem. Soc. 1979, 101, 1168-1175. (e)
Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry, 3rd ed.; Harper and Row: New York, 1987.
(16) Fukunichi, K.; Kohno, A.; Kojo, S. J. Org. Chem. 1988, 53,
4369-4374.
(17) (a) Reichardt, C. Pure Appl. Chem. 1982, 54, 1867-1884. (b)
Reichardt, C. Solvents and Solvent Effects in Organic Chemistry, 2nd
ed.; VCH: Weinheim, Germany, 1988.
7922 J. Org. Chem., Vol. 70, No. 20, 2005

C-H Bonds with Methyl(trifluoromethyl)dioxirane
of the solvent molecules has been affected by the solute.
N
The ET parameter thus measures the specific Lewis
acidity of the solvent in addition to its dipolarity, polar-
izability, and cohesion forces, which are the effects that
the cybotactic region has on the model solute molecules.
Murray et al. reported21 that the rate constants for the
oxygenation of cis-1,2-dimethylcyclohexane with dimeth-
yldioxirane (1b) show a good correlation with the Kam-
let-Taft R parameter.22 Significantly, these data do not
N
correlate with the ET parameter, while our data fail to
correlate with the Kamlet-Taft R values or any of the
solvent parameters which, like R, specifically measure
the HBD ability of the solvent.17 These observations
reveal that the oxygenation of saturated C-H bonds with
dimethyldioxirane (1b) is more sensitive to the specific
HBD ability of the solvent than the reaction with the
more electrophilic methyl(trifluoromethyl)dioxirane (1a).
These results agree with the more localized and basic
character developed by the dimethyldioxirane (1b) oxy-
gen atom in the transition state, with respect to that
developed by the oxygen atom in methyl(trifluoromethyl)-
dioxirane (1a), in which the negative charge is delocalized
through the strong electron-withdrawing trifluoromethyl
group. Also, methyl(trifluoromethyl)dioxirane (1a) in-
duces a more intense charge separation in the transition
state than dimethyldioxirane (1b). The solvation of the
transition state for oxygenation with methyl(trifluoro-
methyl)dioxirane (1a) becomes more sensitive to the
nonspecific dipole-dipole, dipole-induced dipole, and
dispersion forces that solvate the charge separation
induced by the interaction between the substrate and the
electrophile. The correlation of the rate constants found
for the oxygenation of 2-adamantyl acetate (2e) with
methyl(trifluoromethyl)dioxirane (1a) with the Dimroth-
Reichardt ETN parameter of the solvent results from the
relative abilities of the solvents to provide these types of
solvating interactions.
FIGURE 2. Correlation of log k2 with ETN for the reaction of
N
2e with 1a (log k2 ) 0.6028ET - 1.3025, R2 ) 0.9958).
Ingold et al. established18 that the kinetic solvent
effects observed in hydrogen-abstraction reactions are
related in many cases to the hydrogen-bond acceptor
(HBA) ability of the solvent since the approaching radical
must replace the solvent molecule in the substrate-
solvent HBD-HBA complex before the hydrogen-abstrac-
tion process can occur. Thus, the rate of hydrogen-atom
abstraction from a C-H bond by a reactive radical18 is
insensitive to a change in the solvent, according to the
poor HBD ability of the substrate and the absence of any
significant increase in charge separation upon going from
the reactants to the transition state. On these grounds,
the stepwise radical mechanism should be insensitive to
the solvent since the formation of the dioxyl biradical
takes place by interaction of the molecules of substrate
and dioxirane that are already within the solvent cage.
On the other hand, the effect of the solvent on the
substrate-induced homolysis step would hardly account
for the observed kinetic solvent effect since in this case
the charge separation on going from the reactants to the
transition state would be even lower than in the H-
abstraction step. Therefore, the kinetic solvent effect
found in the oxygenation of 2-adamantyl acetate (2e) with
methyl(trifluoromethyl)dioxirane (1a) would be more
consistent with a concerted electrophilic O-atom transfer
mechanism than with a stepwise radical mechanism.
In any analysis of solvent effects on chemical reactions,
it is customary to seek a linear relation between a sol-
vent parameter and the logarithm of the rate constant
(i.e., a linear free energy relationship). Among the
different empirical solvent parameters described, the
rate constants for the oxygenation of 2e with 1a yield a
fairly good correlation (R2 ) 0.996) with the Dimroth-
Reichardt ETN solvent polarity parameter,19 with a posi-
tive slope of 0.603 (Figure 2). This solvent parameter is
not a macroscopic property of the bulk solvent but probes
the cybotactic region20 of the solvent in which the order
Thus, the experimental data available2,6,7 on the oxy-
genation of alkane C-H bonds with dioxiranes 1 config-
ure a mechanistic picture in which the formation of the
regular oxidation products (alcohols and carbonyl com-
pounds) takes place through an electrophilic O-atom
insertion mechanism, while the radical-derived products
arise from the substrate-induced homolysis of dioxirane
1 and the escape of the radical pair from the solvent cage.
The alkyl radical formed reacts with either the dioxirane
1 (an extremely efficient spin-trap),11 to give the corre-
sponding esters and the radical-chain decomposition of
the peroxide,11 or the solvent, to give chlorinated prod-
ucts. The distinct kinetic isotopic effect found6 for each
type of product indicates that after the initial interaction
between substrate and dioxirane 1, the process splits into
two reaction pathways with different transition states
leading to the O-O bond-homolysis and the O-atom
insertion, respectively. The incidence of each process
depends on the structure of the dioxirane 1, dimethyl-
dioxirane (1b) being more prone to homolysis than the
more electrophilic methyl(trifluoromethyl)dioxirane (1a).
In summary, we have found that the relative rate
of oxygenation of 2-substituted adamantanes (2) with
(18) (a) Avila, D. V.; Brown, C. E.; Ingold, K. U.; Lusztyk, J. J. Am.
Chem. Soc. 1993, 115, 466-470. (b) Lucarini, M.; Pedulli, G. F.;
Valgimigli, L. J. Org. Chem. 1998, 63, 4497-4499. (c) Snelgrove, D.
W.; Lusztyk, J.; Banks, J. T.; Mulder, P.; Ingold, K. U. J. Am. Chem.
Soc. 2001, 123, 469-477.
(19) Dimroth, K.; Reichardt, C.; Siepmann, T.; Bohlmann, F. Liebigs
Ann. Chem. 1963, 661, 1-37.
(20) (a) Partington, J. R. An Advanced Treatise on Physical Chem-
istry; Longmans, Green and Co.: London, 1951; Vol. 2, p 2ff and Vol.
5, p 390ff. (b) Knauer, B. R.; Napier, J. J. J. Am. Chem. Soc. 1976, 98,
4395-4400. (c) Beckwith, A. L. J.; Bowry, V. W.; Ingold, K. H. J. Am.
Chem. Soc. 1992, 114, 4983-4992.
(21) Murray, R. W.; Gu, D. J. Chem. Soc., Perkin Trans. 2 1994,
451-453.
(22) Kamlet, M. J.; Abboud, J.-L. M.; Abraham, M. H.; Taft, R. W.
J. Org. Chem. 1983, 48, 2877-2887.
J. Org. Chem, Vol. 70, No. 20, 2005 7923

Gonza´lez-Nu´n˜ez et al.
lowed to stand at -15 °C for 2 h in the dark. The solvent was
removed under vacuum, and the products were separated by
column chromatography (silica gel, hexane/ethyl acetate 2:1).
The isomer (Z)-2-chloro-5-hydroxy-adamantane [(Z)-3g] was
eluted first, and the isomer [(E)-3g] was eluted last.
The oxidation of 2-adamantylammonium para-chloroben-
zenesulfonate (2o) was carried out by adding an aliquot of a
dichloromethane methyl(trifluoromethyl)dioxirane (1a) solu-
tion to the ammonium salt dissolved in 2,2,2-trifluoroethanol.
After 2 h, the reaction was treated with 5 equiv of anhydrous
potassium carbonate and allowed to stand for 48 h at room
temperature with stirring. The solids were filtered off, the
solvent was removed under vacuum, and the residue was
chromatographed on silica gel with a mixture of ethyl acetate/
methanol (98:2 f 0:100). A ca. 20:80 Z/E mixture of both
isomers 3o was eluted first, and a ca. 80:20 Z/E mixture was
eluted last.
methyl(trifluoromethyl)dioxirane (1a) consistently de-
creases as the electron-withdrawing effect of the remote
substituent increases. The data support a concerted elec-
trophilic O-atom insertion as the main reaction pathway
leading to the regular oxygenation products, which does
not change along the whole series of substituents tested.
The kinetic solvent effect also suggests a significant
increase in charge separation upon going from the
reactants to the transition state. The distribution of the
reaction products is not affected by the polarity or the
dielectric constant of the solvent, indicating that through-
bond transmission of the inductive effect of the substitu-
ent is the origin of deactivation of the substrate.
Experimental Procedures
The diastereoselectivity of the reaction was determined by
GC analysis of an aliquot of the crude reaction mixture
sampled before chromatographic separation. The products
were identified by comparison with authentic samples. In the
case of compounds 2e, 2i, and 2k, samples of the crude reaction
mixtures were quantitatively trifluoroacetylated before the GC
analysis. For compound 2o, the reaction mixture was treated
with sodium carbonate before treatment with trifluoroacetic
anhydride.
In the cases of substrates 2c, 2l, 2m, and 2n, only the (Z)-3
isomers could be isolated in pure form by column chromatog-
raphy, and the (E)-3 isomers were characterized in a (E)-
enriched mixture. For substrate 2a, only the (E)-3a isomer
could be isolated in pure form by column chromatography, and
(Z)-3a was characterized in a (Z)-enriched mixture. The (Z)-
and (E)-isomers of 3b, 3d, 3e, and 3o could not be separated
by column chromatography and were characterized in a ca.
75:25 (Z)-isomer-enriched mixture.
Determination of the Relative Rates of Oxygenation
of 2-Adamantane Derivatives (2) by Methyl(trifluoro-
methyl)dioxirane (1a). General Procedure. To a stirred
0.1 M solution (2 mL) of substrate 2, 2-adamantyl acetate (2e)
and methyl para-chlorobenzoate in dichloromethane, thermo-
stated at -15 ( 0.1 °C was added an aliquot (2 mL) of a
thermostated 0.1 M solution of methyl(trifluoromethyl)diox-
irane (1a) in dichloromethane.11 The initial concentration of
the reagents was 0.05 M, and the initial molar ratio 2:2e:1
was 1:1:1 in all cases. The reaction was carried out under air
and protected from the light for 2 h. The reaction mixtures
were directly analyzed by GC. The substrate conversions were
obtained from the areas of the starting materials at t ) 0 and
after the reaction was complete, by applying the equation
kX/kOAc ) fX [(AX/AST)0 - (AX/AST)t ]/fOAc[(AOAc/AST)0 -
(AOAc/AST)t]
The (Z)- and (E)-isomers of the 5-hydroxylated products (3)
were characterized by 13C NMR spectroscopy. The extensive
available data23 on the 13C NMR spectra of substituted 2,5-
adamantane derivatives show characteristic patterns for each
isomer, which allows a straightforward identification. Tables
1 and 2 (Supporting Information) show 13C NMR data for
compounds (Z)-3 and (E)-3. Once the (Z)- and (E)-isomers were
fully characterized, retention times in GC were unequivocally
assigned. The structures of compounds (Z)-3g, (Z)-3i, (E)-3i,
(Z)-3c, (Z)-3l, and (E)-3l were confirmed by X-ray diffraction
analyses (Supporting Information).
The factors fX for the different substrates were determined by
analyzing a series of standard solutions of the substrate and
the internal standard, over the concentration range from 0.01
to 0.1 M. The values, obtained from the slopes of the plots of
[2]/[ST] versus A2/AST, were f2a ) 0.942, f2b ) 1.204, f2c ) 0.845,
f2d ) 0.758, f2e ) 0.715, f2f ) 0.914, f2g ) 0.713, f2h ) 0.597, f2i
) 1.616, f2j ) 0.800, f2l ) 1.485, f2m ) 1.103, and f2n ) 0.958.
The values of the relative rate of reaction were the averages
of at least three independent experiments.
Kinetic Measurements. General Procedure. To a stirred
0.0175 M solution (4 mL) of 2-adamantyl acetate (2e) and
0.0148 M of the internal standard (methyl para-chloroben-
zoate) in the selected solvent (2,2,2-trifluoroethanol, dichlo-
romethane, acetonitrile, or carbon tetrachloride), thermostated
at -15 ( 0.1 °C, was added an aliquot (0.35 mL) of a
thermostated 0.2 M solution of methyl(trifluoromethyl)diox-
irane (1a) in dichloromethane (solvent/dichloromethane 11.4:
1, Ct)0 ) 0.016 M). The reaction mixture was sampled (0.2
mL) every ca. 10 s, and the aliquots were quenched at 0 °C
with 0.05 mL of tetramethylethylene and 0.01 g of sodium
carbonate in 0.2 mL of dichloromethane. The reaction mixtures
were analyzed by GC, and substrate conversion was obtained
from the areas of the starting materials. The rate constant k2
was obtained from the slope of the plot of [1/Ct - 1/C0] versus
t. The results are the averages of at least three independent
runs.
Acknowledgment. Financial support from the Span-
ish Direccio´n General de Investigacio´n (BQU2003-
00315) and Generalitat Valenciana (Grupos 03/120) is
gratefully acknowledged. J.R. thanks the Spanish Min-
isterio de Educacio´n y Ciencia for a fellowship. We
thank S.C.S.I.E. (UVEG) for access to their instrumen-
tal facilities.
Supporting Information Available: Synthetic proce-
dures for compounds 2. Spectroscopic characterization of (Z)-
and (E)-5-hydroxy derivatives 3. X-ray crystal data for com-
pounds (Z)-3g, (Z)-3i, (E)-3i, (Z)-3c, (Z)-3l, and (E)-3l. 13C NMR
spectra for compounds 3. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0509511
Synthesis of (Z)- and (E)-5-Hydroxy Derivatives (3).
General Procedure. To a stirred solution of 0.15 g (0.88
mmol) of 2g in 4.8 mL of the selected solvent cooled at -15 °C
was added 5.8 mL of a 0.15 M dichloromethane solution of
methyl(trifluoromethyl)dioxirane (1a). The reaction was al-
(23) (a) Adcock, W.; Trout, N. A. Magn. Res. Chem. 1998, 36, 181-
195. (b) Adcock, W.; Trout, N. A. J. Org. Chem. 1991, 56, 3229-3238.
(c) Cheung, C. K.; Tseng, L. T.; Lin, M.-H.; Srivastava, S.; le Noble,
W. J. J. Am. Chem. Soc. 1986, 108, 1598-1605.
7924 J. Org. Chem., Vol. 70, No. 20, 2005