Mechanistic studies of Ce(IV)-mediated oxidation of β-dicarbonyls: Solvent-dependent behavior of radical cation intermediates

Article abstract of DOI:10.1021/jo0625406

(Chemical Equation Presented) The Ce(IV)-initiated oxidation of synthetically relevant β-diketones and β-keto silyl enol ethers was explored in three solvents: acetonitrile, methylene chloride, and methanol. The studies presented herein show that the rate of reaction between Ce(IV) and the substrates is dependent upon the polarity of the solvent. Thermochemical studies and analysis are interpreted to be consistent with transition state stabilization by solvent being primarily responsible for the rate of substrate oxidation. Kinetic investigation of radical cations obtained from oxidations of β-diketones reveals that a more ordered transition state for the radical cation decay is achieved through the direct involvement of methanol in the deprotonation of the intermediate. In the case of radical cations derived from β-keto silyl enol ethers, experimental data support a mechanism involving unimolecular decay of the intermediate. Remarkably, radical cations derived from β-diketones and β-keto silyl enol ethers are surprisingly stable in methylene chloride.

Full text of DOI:10.1021/jo0625406

Mechanistic Studies of Ce(IV)-Mediated Oxidation of
â-Dicarbonyls: Solvent-Dependent Behavior of Radical Cation
Intermediates
Jingliang Jiao, Yang Zhang, James J. Devery, III, Luna Xu, Jennifer Deng, and
Robert A. Flowers, II*
Department of Chemistry, Lehigh UniVersity, Bethlehem, PennsylVania 18015
rof2@lehigh.edu
ReceiVed December 12, 2006
The Ce(IV)-initiated oxidation of synthetically relevant â-diketones and â-keto silyl enol ethers was
explored in three solvents: acetonitrile, methylene chloride, and methanol. The studies presented herein
show that the rate of reaction between Ce(IV) and the substrates is dependent upon the polarity of the
solvent. Thermochemical studies and analysis are interpreted to be consistent with transition state
stabilization by solvent being primarily responsible for the rate of substrate oxidation. Kinetic investigation
of radical cations obtained from oxidations of â-diketones reveals that a more ordered transition state for
the radical cation decay is achieved through the direct involvement of methanol in the deprotonation of
the intermediate. In the case of radical cations derived from â-keto silyl enol ethers, experimental data
support a mechanism involving unimolecular decay of the intermediate. Remarkably, radical cations
derived from â-diketones and â-keto silyl enol ethers are surprisingly stable in methylene chloride.
Introduction
can be used to drive an array of important bond-forming
reactions. Several methods can be employed to generate radical
cations, including anodic oxidation of electron-rich olefins,
photochemical excitation of a neutral substrate, and SET
oxidation of a neutral species initiated by a chemical oxidant.4a
In the latter context, reagents based on Ce(IV) (most notably
ceric ammonium nitrate (CAN)) have emerged as valuable SET
oxidants for a variety of reactions due to their relative
abundance, ease of preparation, low cost, and low toxicity.
Oxidations utilizing CAN and other Ce(IV)-based reagents
have been used to carry out a number of bond-forming
During the past two decades, there has been an increasing
acceptance of single electron transfer (SET) oxidation as a means
to promote bond-forming reactions in organic synthesis.1-3
During the SET oxidation of a neutral organic substrate, a radical
cation is formed and the seminal work of a range of chemists4-8
has shown that the intrinsic properties of these intermediates
(1) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, Germany, 2001; Vol. 1. (b) Chanon, M.; Rajz-
mann, M.; Chanon, F. Tetrahedron 1990, 46, 6193-6299. (c) Eberson, L.
Electron Transfer Reactions in Organic Chemistry; Springer-Verlag: Berlin,
Germany, 1987.
(2) (a) Schmittel, M. J. Am. Chem. Soc. 1993, 115, 2165-2177. (b)
Schmittel, M.; Soehrle, C. Tetrahedron Lett. 1993, 34, 8431-8434. (c)
Bauld, N. L. AdV. Electron Transfer Chem. 1992, 2, 1-66. (d) Gieseler,
A.; Steckhan, E.; Wiest, O.; Knoch, F. J. Org. Chem. 1991, 56, 1405-
1411. (e) Schmittel, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 999-1001.
(f) Bauld, N. L. Tetrahedron 1989, 45, 5307-5363.
(3) (a) Floreancig, P. E. Synlett 2007, 191-203. (b) Schmittel, M. Top.
Curr. Chem. 1994, 169, 183-230.
(4) (a) Schmittel, M.; Burghart, A. Angew. Chem., Int. Ed. Engl. 1997,
36, 2550-2589. (b) Schmittel, M.; Langels, A. Angew. Chem., Int. Ed.
Engl. 1997, 36, 392-395. (c) Rock, M.; Schmittel, M. J. Chem. Soc., Chem.
Commun. 1993, 1739-1741.
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D. Org. Lett. 1999, 1, 153-156. (b) Newcomb, M.; Miranda, N.; Huang,
X.; Crich, D. J. Am. Chem. Soc. 2000, 122, 6128-6129. (c) Newcomb,
M.; Miranda, N.; Sannigrahi, M.; Huang, X.; Crich, D. J. Am. Chem. Soc.
2001, 123, 6445-6446. (d) Crich, D.; Neelamkavil, S. Org. Lett. 2002, 4,
2573-2575.
(6) (a) Horner, J. H.; Taxil, E.; Newcomb, M. J. Am. Chem. Soc. 2002,
124, 5402-5410. (b) Horner, J. H.; Newcomb, M. J. Am. Chem. Soc. 2001,
123, 4364-4365.
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2003, 125, 2406-2407. (b) Wang, L.; Seiders, J. R., II; Floreancig, P. E.
J. Am. Chem. Soc. 2004, 126, 12596-12603.
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10.1021/jo0625406 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/28/2007
5486
J. Org. Chem. 2007, 72, 5486-5492

Ce(IV)-Mediated Oxidation of â-Dicarbonyls
reactions.9 Ce(IV)-mediated oxidative additions of silyl enol
ethers and diones to dienes,10 activated alkenes,11 and unacti-
vated alkenes12 proceed in good to excellent yields. More
recently, intramolecular versions of the aforementioned reactions
including the oxidative addition of silyl enol ethers13 and
â-diketones14 to olefins have been developed as well. While
the usefulness of radical cation intermediates generated through
Ce(IV)-initiated oxidation in organic synthesis is recognized,
there are potential drawbacks as well. During the oxidation of
organic substrates, the initial formation of a radical cation is
usually followed by rearrangement or follow-up reactions that
lead to free radical intermediates. Typically, the free radical
reacts with another substrate (olefin, etc.) to form a new C-C
bond and a product radical. Oxidation of the free radical
intermediate to a cation leads to capture of solvent or nitrate
expelled from CAN upon its reduction to Ce(III) and these
alternative mechanistic pathways result in many of the side
products prevalent in oxidations. Therefore, preparative Ce(IV)
initiated oxidations cannot be achieved in many instances.
Chemical intuition suggests that these pathways can be de-
pressed by understanding the interrelationship between the
mechanism of oxidation by Ce(IV), the effect of solvent on the
stability of the initially formed radical cation intermediate, and
the rates (mechanisms) of the various available pathways.
Previous studies have shown that the oxidation of enols and
their structurally related silyl enol ethers generate radical
cations10 which undergo deprotonation by solvent assistance to
generate the corresponding radicals.15 Although these studies
provide an important mechanistic framework for understanding
the interrelationship between the solvent milieu, the stability
of the radical cation, and follow-up reactions with solvent or
substrate, many of these studies utilized sterically hindered
starting materials whose structures are not representative of
substrates used in organic synthesis. The goal of the present
work was to examine the solvent dependence of the rate of
oxidation of commonly utilized â-diketones and their related
â-keto silyl enol ethers by Ce(IV) reagents. The surprising
stability of radical cations derived through these oxidations also
allowed us to assess the role of solvent on the mechanism of
decay of the reactive intermediates.
Ce(IV) maximum absorbance at 330 nm. The structures of the
substrates are contained in Table 1. All reactions provided
carboxylic acids in CH3CN and CH2Cl2 as previously reported.16
Oxidation of 1 in CH3OH provided 1-acetyl-2-tetralone as the
major product17 whereas all other oxidations provided methyl
esters as the major products.16
Recent work in our group has revealed that while CTAN oxi-
dizes substrates more slowly than CAN by a factor of 2, they
behave in a mechanistically analogous manner.18 Since CTAN
and CAN are soluble in CH3CN, the rates were compared in
the same solvent for three â-diketones and two â-keto silyl enol
ethers to compare both the impact of the bulky tetra-n-butyl-
ammonium countercation and solvent on oxidation rates. All
oxidations were carried out under pseudo-first-order conditions
employing concentrations 1 mM of Ce(IV) and 20 mM of sub-
strate. The data for the observed rate constants obtained by moni-
toring the decay of the Ce(IV) absorption are contained in Table
1. In all cases, the rates display a first-order dependence on
[Ce(IV)] and [substrate] consistent with the rate law shown in
eq 1.
rate ) k[Ce(IV)][substrate]
(1)
During the course of synthetic studies, the orange color of
the Ce(IV) ion was found to disappear rapidly upon addition
of substrate and a subsequent appearance of a persistent red
color was observed in the solutions that faded with time. To
examine this in detail, time-resolved absorption spectra were
obtained with use of stopped-flow spectrophotometry. Figure
1 contains the time-resolved absorption spectrum for the
oxidation of 1 by CAN in CH3CN at room temperature. An
isosbestic point was observed at 400 nm, which indicates that
an intermediate is formed in solution. Closer inspection of Figure
1 shows the growth of an absorption between 430 and 480 nm,
with a maximum at 460 nm. Since no absorption was observed
for CAN, â-diketones, or the Ce(III) reaction product beyond
400 nm (Supporting Information), the absorption at 460 nm was
interpreted to be the formation of the radical cation of 1. This
observation is consistent with the fact that many radical cations
have an absorption in the range of 400 to 500 nm.19 The inset
in Figure 1 shows a closer view of the growth of the radical
cation with time. A very similar time-resolved absorption
spectrum was obtained for the oxidation of 1 by CTAN in
CH2Cl2 at room temperature (Supporting Information). Oxida-
tion of other â-diketones shows similar time-resolved spectra
in the different solvents. It is worth noting that this is the first
time that radical cations from such simple substrates have been
observed spectroscopically under standard laboratory conditions.
With these data in hand, the rate of the increase in absorption
at 460 nm was monitored as a function of time and the
subsequent decay of the radical cation was monitored as well.
These data are also contained in Table 1.
Results and Discussion
Rate of Oxidation of â-Diketones and Related Substrates.
The influence of solvent on the rate of oxidation of a series of
â-diketones (1-3 and 5) and two â-keto silyl enol ethers (4
and 6) by CAN or Ceric tetra-n-butylammonium nitrate (CTAN)
was examined by using stopped-flow spectrophotometry and
the rate of reaction was monitored through the decay of the
(9) (a) Nair, V.; Balagopal, L.; Rajan, R.; Mathew, J. Acc. Chem. Res.
2004, 37, 21-30. (b) Nair, V.; Mathew, J.; Prabhakaran, J. Chem. Soc.
ReV. 1997, 26, 127-132.
(10) (a) Baciocchi, E.; Ruzziconi, R. J. Org. Chem. 1986, 51, 1645-
1649. (b) Paolobelli, A. B.; Ceccherelli, P.; Pizzo, F.; Ruzziconi, R. J. Org.
Chem. 1995, 60, 4954-4958.
(16) Zhang, Y.; Jiao, J.; Flowers, R. A., II J. Org. Chem. 2006, 71, 4516-
4520.
(11) Hwu, J. R.; Chen, C. N.; Shiao, S. S. J. Org. Chem. 1995, 60, 856-
862.
(17) (a) Citterio, A.; Pesce, L.; Sebastiano, R.; Santi, R. Synthesis 1990,
142-144. (b) Jamie, J. F.; Rickards, R. W. J. Chem. Soc., Perkin Trans. 1
1996, 2603-2613. The authors of these studies have reported that the
reactions of δ-aryl-â-dicarbonyls in CH3OH produce tetralone and we have
reproduced this result with 1 in the present study. The oxidation of non-
aryl-substituted â-dicarbonyls by CAN in CH3OH forms esters as major
products. All reactions in CH3CN or CH2Cl2 produce the carboxylic acids.
(18) Zhang, Y.; Flowers, R. A., II J. Org. Chem. 2003, 68, 4560-4562.
(19) (a) Courtneidge, J. L.; Davies, A. G. Acc. Chem. Res. 1987, 20,
90-97. (b) Schepp, N. P. J. Org. Chem. 2004, 69, 4931-4935. (c)
Dombrowski, G. J. Org. Chem. 2005, 70, 3791-3800. (d) Bietti, M.;
Capone, A. J. Org. Chem. 2006, 71, 5260-5267.
(12) (a) Nair, V.; Mathew, J. J. Chem. Soc., Perkin Trans. 1 1995, 187-
188. (b) Nair, V.; Mathew, J.; Alexander, S. Synth. Commun. 1995, 25,
3981-3991.
(13) Snider, B. B.; Kwon, T. J. Org. Chem. 1992, 57, 2399-2410.
(14) Clark, A. J.; Dell, C. P.; McDonagh, J. M.; Geden, J.; Mawdsley,
P. Org. Lett. 2003, 5, 2063-2066.
(15) (a) Schmittel, M.; Gescheidt, G.; Rock, M. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1961-1963. (b) Schmittel, M.; Langels, A. J. Chem. Soc.,
Perkin Trans. 2 1998, 565-571. (c) Schmittel, M.; Langels, A. J. Org.
Chem. 1998, 63, 7328-7337.
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Jiao et al.
TABLE 1. Observed Rate Constants for the Oxidation of 1,3-Diketones and Two Related â-Keto Silyl Enol Ethers by CAN in CH3OH or
CH3CN and CTAN in CH2Cl2 or CH3CN
a All rate data are the average of at least two independent runs. b Experimental uncertainties were propagated through these calculations, and all values
are reported as (σ. c All rate studies were carried out at 25 °C, [substrate] ) 20 mM, [Ce(IV)] ) 1 mM.
Evaluation of the data clearly shows that the observed rate
constants for Ce(IV) decay (k1) at 330 nm are equivalent to the
observed rate constants of the radical cation formation (k1′) at
460 nm within experimental error for all of the substrates and
all oxidant/solvent combinations.
Further examination of the rate data in Table 1 shows a
number of interesting trends. The rate constants for the oxidation
of â-diketones by Ce(IV) (or conversely, the formation of the
radical cations) are solvent dependent in the order of CH3OH
. CH3CN > CH2Cl2. Generally, the rate of oxidation in
CH3OH is 70-100 times faster than those in CH3CN for all
â-diketones. Comparison of the rate of substrate oxidation in
CH3CN shows that CTAN oxidizes â-diketones at a slower rate
than CAN. Evaluation of the rate of substrate oxidation by
CTAN in CH2Cl2 and CH3CN shows that the rate of oxidation
is slower in CH2Cl2. Overall, oxidation in CH2Cl2 is ap-
proximately half of the rate in CH3CN.
To further explore the role of solvent, the rates of oxidation
of two â-keto silyl enol ethers 4 and 6 were studied. Examina-
tion of the data for the â-keto silyl enol ethers contained in
Table 1 shows that the rate of oxidation by CAN is greater in
CH3OH than in CH3CN. Use of CTAN in CH3CN showed that
this reagent oxidized the substrate more slowly than CAN, a
finding analogous to observations made for the â-diketones.
Oxidation of the substrate by CTAN in CH2Cl2 provided the
same rate as the trials in CH3CN within experimental error for
5488 J. Org. Chem., Vol. 72, No. 15, 2007

Ce(IV)-Mediated Oxidation of â-Dicarbonyls
oxidation rate could be due to the impact of solvent on the
oxidizing power of Ce(IV) or the ease of oxidation of the
substrate. To further clarify the role of solvent, the redox
potentials of Ce(IV) were compared. Previous studies in our
group have shown that changing the ammonium counterion to
tetra-n-butylammonium has no impact (within experimental
error) on the redox potential of Ce(IV), so the small differences
in the rate of oxidation between CAN and CTAN are likely
due to the steric bulk of the tetra-n-butylammonium counter-
ion.18 Cyclic voltammetry (CV) was utilized in a previous study
to determine the redox potential of CTAN in CH2Cl2 and
CH3CN to establish whether solvent had a measureable impact
on the ease of oxidation of Ce(IV). The measured potentials
were 510 ( 20 and 540 ( 10 mV vs saturated Ag/AgNO3. The
redox potential of CTAN in CH2Cl2 was lower by 30 mV.24 To
determine the effect of CH3OH on the redox potential of
Ce(IV), CV experiments were carried out under identical
conditions to those utilized previously. The E1/2 of CAN in
MeOH was determined to be 570 ( 20 mV vs saturated
Ag/AgNO3 (Supporting Information). These results show that
Ce(IV) becomes a slightly better oxidant as the solvent polarity
is increased, but the differences are small (60 mV through the
range of solvents).
Unfortunately, attempts to measure the redox potentials of
â-diketones and â-keto silyl enol ethers used in this study were
unsuccessful as they provided irreproducible results. Previous
studies by Schmittel have shown that there are only small
differences (60 mV) in the oxidation potential for silyl enol
ethers in CH3CN and CH2Cl2 and that related enol ethers are
only marginally easier to oxidize.25 For example, the oxidation
potentials of 1-(tert-butyldimethylsiloxy)-2,2-dimesityl-1-phen-
ylethene vs the ferrocene/ferrocenium couple were found to be
0.73 and 0.67 V in CH3CN and CH2Cl2, respectively, whereas
the oxidation potential of 2,2-dimesityl-1-phenylethenol in
CH3CN was 0.61 V. On the basis of this analysis and the study
of solvent on the redox potential of Ce(IV), it is unlikely that
solvent has a major impact on the thermodynamic ease of
substrate oxidation by CAN or CTAN. The lack of consistent
trends among the solvent-dependent enol content of â-diketones
1-3 and 5 and the rate of oxidation suggest that the rate of
oxidation may be due to transition state stabilization by a more
polar solvent. This is supported by results with silyl enol ethers
4 and 6 (where enol content is not a consideration) displaying
solvent-dependent oxidation trends similar to those of structur-
ally related â-diketones. The somewhat decreased sensitivity
of the silyl enol ethers to solvent may be due to the relatively
large trimethylsilyl group, which leads to steric interactions
between oxidant and the substrate.
FIGURE 1. Time-resolved absorption spectrum observed from CAN
and 6-phenyl-2,4-hexanedione in CH3CN in the range of 320-520 nm
([diketone]:[CAN] ) 20 mM:1 mM) at 25 °C. Inset: Wavelength range
of 380-480 nm.
the silyl enol ether of 2,4-pentanedione 4 whereas the silyl enol
ether of 1,3-cyclohexanedione 6 is slightly faster in CH3CN than
in CH2Cl2. Closer inspection of the data reveals other differences
as well. The rates of oxidation of â-diketones are faster than
their corresponding silyl enol ethers in CH3OH while the rates
of oxidation in CH3CN are nearly the same within experimental
error. In contrast, the rates of oxidation of the silyl enol ethers
in CH2Cl2 are nearly double those observed for the â-diketones.
Overall, these findings indicate that oxidation of the â-keto silyl
enol ethers used in this study is less sensitive to solvent than
structurally similar â-diketones.
While it is reasonable to expect that polar solvents will
stabilize a charge-separated transition state and subsequently
increase the rate of reaction, solvent can also affect the keto-
enol tautomerism of â-diketones.20 Enols and enol ethers are
known to be oxidized more readily than the corresponding
â-diketones.4c Since the enol content of â-diketones is solvent
dependent, it is reasonable to expect that solvents promoting a
high enol content should also lead to a greater rate of oxidation.
The seminal study of Beak on the solvent-dependent enol
content of â-diketones showed that in general, for keto-enol
pairs in which the enol cannot form an internal hydrogen bond
(such as 5 in this study), the equilibrium is predominantly
controlled by the hydrogen-bonding basicity of the solvent,
whereas for keto-enol pairs where intramolecular hydrogen
bonding is possible (substrates 1-3 in this study), the polarity
of the solvent plays a more important role in the equilibrium.20
Results from the study of Beak show that the enol content of 3
follows the trend CH2Cl2 > CH3OH > CH3CN. Although 5
was not examined in this study, structurally similar 5,5-
dimethylcyclohexane-1,3-dione was examined and the enol
content followed the trend CH3OH > CH3CN > CH2Cl2. While
the trend in the solvent-dependent enol content of 5 follows
the rate of oxidation by Ce(IV) in these solvents, the rate of
oxidation of 3 does not. Furthermore, the rates of oxidation of
substrates 1-3 and 5 do not differ significantly in each solvent.
Another caveat with the present analysis is that the redox
potentials of lanthanides are known to be sensitive to the solvent
milieu.21-23 As a result, it is possible that the solvent-dependent
Role of Solvent in Radical Cation Stability. Examination
of the observed rate constants of radical cation decay (k2)
contained in Table 1 reveals a marked solvent dependence in
every case in the order CH3OH > CH3CN > CH2Cl2. Typically,
the k2 in CH3OH is 10-100 times greater than that in CH3CN
and the k2 value in CH3CN is 5-10 times larger than that in
CH2Cl2. The decay rates (k2) of radical cations 1+•, 2+•, and
(22) Shabangi, M.; Sealy, J. M.; Fuchs, J. R.; Flowers, R. A., II
Tetrahedron Lett. 1998 39, 4429-4432.
(23) Kuhlman, M. L.; Flowers, R. A., II Tetrahedron Lett. 2000, 41,
8049-8052.
(24) Zhang, Y.; Raines, A. J.; Flowers, R. A., II Org. Lett. 2003, 5, 2363-
2365.
(20) Mills, S. G.; Beak, P. J. Org. Chem. 1985, 50, 1216-1224.
(21) Shabangi, M.; Flowers, R. A., II Tetrahedron Lett. 1997, 38, 1137-
1140.
(25) (a) Schmittel, M.; Keller, M.; Burghart, A. J. Chem. Soc., Perkin
Trans. 2 1995, 2327-2333. (b) Ro¨ck, M.; Schmittel, M. J. Chem. Soc.,
Chem. Commun. 1993, 1739-1741.
J. Org. Chem, Vol. 72, No. 15, 2007 5489

Jiao et al.
accounting for 27% of ∆Gq (18.4 kcal mol-1), whereas -T∆Sq
accounts for 73% of ∆Gq.
TABLE 2. Observed Rate Constants for the Decay of the Radical
Cation of 3,3-Dideuterio-2,4-pentanedione in MeOH, CH3CN, and
CH2Cl2
Comparison of the role of solvent in the decay of the radical
cation derived from a â-keto silyl enol ether, 4+•, with those
derived from â-diketones shows that the decay is enthalpy driven
in all solvents. As a consequence, a less ordered transition state
was observed for 4+• in the three solvents as well. These
experimental observations are consistent with a higher energy
barrier for O-Si bond cleavage than the O-H bond cleavage.
Although the decay of 4+• is enthalpy driven in all solvents,
the order followed solvent polarity with ∆Hq having the lowest
value in CH3OH and the largest value in CH2Cl2.
a-c
entry
oxidant and solvent
k
D (s-1
)
kH/kD
1
2
3
CAN+ CH3OH
CAN+CH3CN
CTAN+CH2Cl2
2.8 ( 0.1
1.50 ( 0.06
2.19 ( 0.05
2.17 ( 0.09
(2.7 ( 0.1) × 10-2
(1.2 ( 0.1) × 10-2
a Observed rate constant for decay of the radical cation of 3,3-dideuterio-
2,4-pentanedione. All rate data are the average of at least two independent
runs. b Experimental uncertainties were propagated through these calcula-
tions, and all values are reported as (σ. c All rate studies were carried out
at 25 °C, [substrate] ) 20 mM, [Ce(IV)] ) 1 mM.
The evidence described above suggests that the activated
complexes for the decay of radical cations derived from
â-diketones vary significantly in different solvents. The depro-
tonation of radical cations 1+• and 3+• in methanol proceed
through a more ordered transition state and the energy re-
quired for bond reorganization and bond cleavage is sub-
stantially lower than that of less polar solvents (acetonitrile and
methylene chloride). This is likely due to the direct involvement
of CH3OH in the deprotonation of 1+• and 3+•. In the case of
radical cation 4+•, the decay is enthalpy driven in all cases with
∆Hq showing an increase with decreasing solvent polarity.
All the kinetic data presented so far indicate CH3OH may be
intimately involved in the decay of radical cations as previously
reported for other systems.25a,28 To further investigate the role
of CH3OH in the decay of radical cations, the decay rates of
3+• in the nonnucleophilic solvent CH2Cl2 were measured by
using samples containing increasing amounts of CH3OH. Figure
2 shows the plot with the rate constants of 3+• decaying as a
function of the concentration of CH3OH. The plot in Figure 2
shows a linear relationship between the kobs for 3+• in CH2Cl2
and [CH3OH]. On the basis of this analysis, the reaction order
of CH3OH was determined to be 0.94 ( 0.05 demonstrating
that the decay is first order in CH3OH and that solvent is
intimately involved in the deprotonation of the radical cation
and conversion to a radical intermediate. When experiments
were carried out to determine the impact of [CH3OH] on the
decay of radical cation 4+• in CH2Cl2, the reaction order of
CH3OH was found to be 0.24 ( 0.03 based on a plot of lnkobs
vs ln[CH3OH].
With these experiments in hand, it is instructive to place them
in perspective with other mechanistic studies of radical cations.
Kinetic studies of radical cations derived from a series of silyl
enol ethers of 2,2-dimesityl-1-phenylethenol show that there is
a strong solvent dependence on the rate of radical cation decay
with an acceleration of >103 in CH3CN vs CH2Cl2.25a Further-
more, nucleophiles present during the oxidation further enhanced
the rates of radical cation decay. As a result, a nucleophile-
assisted O-Si bond cleavage mechanism was proposed for the
decay of this family of radical cations. In contrast, radical cations
derived from enol acetates of 2,2-dimesityl-1-alkylethenol were
shown to decay through a unimolecular pathway rather than a
solvent-assisted mechanism.27 In these studies, modest rate
increases for the decay of radical cations on the order of 10- to
20-fold were observed in CH3CN compared to CH2Cl2.
Previous studies taken together with the mechanistic data
described herein support a mechanism where hydrogen bonding
3+• in methanol are within experimental error indicating that
intramolecular cyclization of 1+• in this solvent occurs after the
rate-limiting step of the reaction. Comparison of k1, k1′, and k2
shows that the decay of radical cations is the rate-determining
step in all solvents. To further test this supposition, deuterium-
labeled 3,3,-dideuterio-2,4-pentanedione was prepared and the
observed rate constants of its radical cation decay were measured
under identical conditions to those described previously. The
data are summarized in Table 2. These experiments show that
a primary isotope effect (kH/kD) of approximately 2 was observed
in CH3CN and CH2Cl2 whereas a kH/kD of 1.5 was found in
CH3OH. A similar primary kinetic isotope effect (kH/kD ) 2.7
( 0.5) has been reported by Schmittel for the deprotonation of
the anisyldimesitylethenol radical cation.15a The lower value in
methanol is likely due to exchange between CH3OH and
deuterium in the substrate.
The deuterium isotope study coupled with the observation
that more polar solvents lead to faster decay of a radical cation
are consistent with the known solvent-assistant mechanism of
O-H bond cleavage.26,27 Comparison of k2 for radical cations
derived from oxidation of 2,4-pentanedione, 1,3-cyclohexanedi-
one, and their structurally related silyl enol ethers shows that
the presence of the silyl group stabilizes the radical cation
intermediate in each solvent. These observations further support
the role of solvent in the reaction of radical cations through
O-H and O-Si cleavage since the larger trimethylsilyl group
would be expected to react more slowly through a solvent-
assisted O-Si bond cleavage mechanism.25a
To obtain more information on the behavior of radical cations
in the different solvents, the activation parameters for the decay
of radical cations at 460 nm were determined under pseudo-
first-order conditions. The results and comparison with different
radical cations, solvent, and Ce(IV) reagents are given in Table
3. Inspection of the activation data in Table 3 shows that
changing the structure of â-diketones while keeping other
conditions constant does not change the activation parameters
greatly in this reaction system. Further evaluation of the
activation parameters of the 6-phenyl-2,4-hexanedione radical
cation, 1+•, and the 2,4-pentanedione radical cation, 3+•, decay
demonstrates that there is a greater contribution from ∆Hq than
-T∆Sq to ∆Gq in acetonitrile and dichloromethane. Conversely,
-T∆Sq provides a greater contribution than ∆Hq to ∆Gq in
methanol. For instance, ∆Hq for the decay of 1+• in acetonitrile
is 17 kcal mol-1, accounting for 89% of ∆Gq (19 kcal mol-1),
while -T∆Sq only accounts for 11% of ∆Gq. By comparison,
∆Hq for the decay of 1+• in methanol is 5.0 kcal mol-1
,
(26) Bockman, T. M.; Kochi, J. K. J. Chem. Soc., Perkin Trans. 2 1996,
(28) (a) Dinnocenzo, D. P.; Farid, S.; Goodman, J. L.; Gould, I. R.; Todd,
W. P.; Mattes, S. L. J. Am. Chem. Soc. 1989, 111, 8973-8975. (b) Dockery,
K. P.; Dinnocenzo, J. P.; Farid, S.; Goodman, J. L.; Gould, I. R.; Todd, W.
P. J. Am. Chem. Soc. 1997, 119, 1876-1883.
1633-1643.
(27) Schmittel, M.; Heinze, J.; Trenkle, H. J. Org. Chem. 1995, 60,
2726-2733.
5490 J. Org. Chem., Vol. 72, No. 15, 2007

Ce(IV)-Mediated Oxidation of â-Dicarbonyls
TABLE 3. Activation Parameters for the Decay of Selected Radical Cationsa-c
a All rate data are the average of at least two independent runs. b Experimental uncertainties were propagated through these calculations, and all values
are reported as (σ. c All rate studies were carried out over a temperature range between 15 and 40 °C, [substrate] ) 20 mM, [Ce(IV)] ) 1 mM. d Eyring
activation parameters were obtained from ln(kobsh/kT) ) -∆Hq/RT + ∆Sq/R. e Calculated from ∆Gq ) ∆Hq - T∆Sq.
pathway for cleavage of O-H and O-Si bonds in these
solvents. Overall, the combination of present and previous
studies shows that the mechanism of decay of radical cations
is highly dependent on structure.
One potential problem with the present analysis is the
presence of nitrate in the reaction medium. During the oxidation
of substrate, Ce(IV) is reduced to Ce(III) and as a result expels
1 equiv of nitrate during the course of the reaction. Although
nitrate is not a good nucleophile (or base), the presence of this
adventitious anion has the potential to accelerate radical cation
decay in nonnucleophilic solvents either through nucleophilic
displacement of a silyl or removal of a proton from the
respective radical cations. While no products expected from
FIGURE 2. Plot of kobs vs [CH3OH] for the decay of 3+• in CH2Cl2.
nitrate-induced displacement were isolated, this mechanistic
possibility cannot be discounted.
between radical cations derived from â-diketones and one
molecule of CH3OH leads to a more ordered transition state
and accelerates the conversion to a radical intermediate through
Conclusion
a nucleophile-assisted cleavage of an O-H bond as shown in
Scheme 1. Conversely, the non-integer reaction order less than
unity for [CH3OH] in the decay of 4+• indicates that CH3OH is
less likely to be intimately involved in the decay of radical
cations derived from â-keto silyl enol ethers through a direct
nucleophilic displacement mechanism.
Studies of radical cations obtained from â-diketones and their
structurally related silyl enol ethers in CH3CN and CH2Cl2 show
that there is a less pronounced difference between these solvents.
Rates of decay are on the order of 2- to 12-fold faster in
CH3CN, but there is no clear trend among the two types of
radical cations. These findings are consistent with a unimolecular
The spectroscopic, kinetic, and mechanistic data described
herein collectively show that solvent plays an important role in
the rate of the Ce(IV)-mediated oxidation of â-diketones and
related â-keto silyl enol ethers. Substrate oxidation and the
follow-up decay of radical cations are significantly accelerated
in CH3OH compared to CH3CN and CH2Cl2. Kinetic investiga-
tions of radical cations derived from â-diketones reveal that a
more ordered transition state for the radical cation decay is
achieved through heterolytic cleavage of the O-H bond of the
intermediate by CH3OH. In the case of radical cations derived
from â-keto silyl enol ethers, the rate of desilylation is
proportional to the polarity of the solvent medium consistent
J. Org. Chem, Vol. 72, No. 15, 2007 5491

Jiao et al.
SCHEME 1. Transition State for Deprotonation of Radical
Cation by CH3OH Leading to Free Radical Intermediate
mL of distilled cold water was added to work up the reaction. The
organic layer was extracted with 4 × 25 mL of ether, washed with
distilled cold water, and dried over MgSO4. After filtration, the
organic solution was concentrated and then subjected to silica gel
chromatography to afford 1-acetyl-2-tetralone in 73% isolated
yield.17
General Procedure for Preparation of 3,3-Dideuterio-2,4-
pentanedione. 2,4-Pentanedione (20 mL) was added into D2O (20
mL), potassium carbonate (2 g), and tetra-n-butyl ammonium
bromide (1 g) in a round-bottom flask. The mixture was stirred for
3 days at rt. After filtration, the organic layer was extracted with
dry diethyl ether and concentrated via rotary evaporation. The
synthesis of 3,3-dideuterio-2,4-pentanedione was confirmed by
NMR and GC-MS analysis.
Stopped-Flow Studies. Kinetic experiments in methanol, aceto-
nitrile, and dichloromethane were performed with a computer-
controlled stopped-flow reaction spectrophotometer. The Ce(IV)
oxidant and substrates were taken separately in airtight syringes
from a drybox and injected into the stopped-flow system. The cell
block and the drive syringes of the stopped-flow reaction analyzer
were flushed at least three times with dry and degassed solvents to
make the system oxygen free. The concentration of Ce(IV) used
for the study was 1 mM. The concentration of substrates was kept
high relative to that of [Ce(IV)] (0.02 M) to maintain pseudo-first-
order conditions. The rates of Ce(IV) decay were determined from
the decrease of the Ce(IV) absorbance at 330 nm. The rates of
radical cation formation and radical cation decay were determined
from the absorbance change of the radical cation at 460 nm.
Reaction rates for the initial oxidation step were determined from
the decay of the Ce4+ absorbance at 330 nm. The decay of Ce(IV)
displayed first-order behavior over >4 half-lives for all Ce(IV)-
substrate combinations. Time-resolved spectra were obtained from
the stopped-flow reaction analyzer at 25 °C. The temperature studies
were carried out over a range between 15 and 40 °C with an interval
of 5 °C, using a refrigerated circulator connected to the sample-
handling unit of the stopped-flow reaction analyzer. The kinetic
trace was recorded at a known temperature that was measured by
a thermocouple in the reaction cell.
with a mechanism involving unimolecular decay of the inter-
mediate. Remarkably, radical cations derived from â-diketones
and â-keto silyl enol ethers are surprisingly stable in methylene
chloride. This finding suggests that in nonpolar solvents, radical
cations may be the species responsible for C-C bond formation
in reactions with olefins. Studies are currently underway to
determine whether the solvent milieu alters the intermediate
(radical vs radical cation) responsible for bond formation with
radicophiles and the degree this plays a role in the solvent-
dependent chemoselectivity of many reactions initiated by
Ce(IV).
Experimental Section
Materials and General Procedures. Acetonitrile, methanol,
methylene chloride, and diethyl ether were distilled before use. All
of the other chemical reagents were purchased from Aldrich and
used without further purification. Column chromatography was
performed with 65-250 mesh silica gel. Compound 1 was prepared
by using a previously reported method.29 CTAN was prepared
following the procedure reported by Muathen.30 1H and 13C NMR
spectra were recorded on a 500 MHz spectrometer. UV-vis
experiments were performed on a spectrophotometer that operates
in a wavelength range of 190-1100 nm. Oxidation of â-diketones
with CAN and CTAN in CH3CN or CH2Cl2 were carried out with
use of a recently reported procedure.16
Acknowledgment. R.A.F. is grateful to the National Insti-
tutes of Health (1R15GM075960-01) for support of this work
and to Dr. Rebecca Miller at Lehigh University for her useful
comments on the manuscript. L.X. and J.D. acknowledge the
Center for Emeritus Scientists in Academic Research at Lehigh
University for support of their research on this project.
Oxidation of 1 with CAN in CH3OH. Ceric ammonium nitrate
(CAN, 4.4 mmol, in 10 mL of MeOH) solution was added to a
solution of 1 (2 mmol) in 40 mL of MeOH within 2 min under
nitrogen atmosphere. After the mixture was stirred for 4 h at rt, 30
Supporting Information Available: General methods, experi-
mental protocols, and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(29) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082-1087.
(30) Muathen, H. A. Ind. J. Chem. 1991, 30B (5), 522-524.
JO0625406
5492 J. Org. Chem., Vol. 72, No. 15, 2007