Oxidation of benzyl alcohols by dimethyldioxirane. The question of concerted versus stepwise mechanisms probed by kinetic isotope effects

Article abstract of DOI:10.1016/S0040-4039(01)00539-1

The primary and β-secondary kinetic isotope effects in the oxidation of secondary alcohols with dimethyl dioxirane were measured. The substantial primary and the absence of a β-secondary kinetic isotope effect support a concerted mechanism for the title reaction.

Full text of DOI:10.1016/S0040-4039(01)00539-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3753–3756
Oxidation of benzyl alcohols by dimethyldioxirane. The question
of concerted versus stepwise mechanisms probed by kinetic
isotope effects
Yiannis S. Angelis, Nikos S. Hatzakis, Ioulia Smonou and Michael Orfanopoulos*
Department of Chemistry, University of Crete, Iraklion 71409, Crete, Greece
Received 15 February 2001; revised 16 March 2001; accepted 29 March 2001
Abstract—The primary and b-secondary kinetic isotope effects in the oxidation of secondary alcohols with dimethyl dioxirane
were measured. The substantial primary and the absence of a b-secondary kinetic isotope effect support a concerted mechanism
for the title reaction. © 2001 Elsevier Science Ltd. All rights reserved.
Dimethyldioxirane (DMD) and its trifluoromethyl ana-
logue (TFMD) are very potent oxidizing agents.1 They
react stereoselectively under mild conditions with alkenes
to produce epoxides with nonactivated hydrocarbons to
insert an oxygen atom, whereas with alcohols they afford
carbonyl products. Several mechanisms for the oxidation
of secondary alcohols by dioxirane have been reported.
For example, Curci and co-workers2 proposed an elec-
trophilic one-step insertion mechanism (Scheme 1) and
excluded a radical-chain pathway. Similar conclusions
support later studies involving the ‘radical clock’ test.3
the b-secondary isotope effect of the DMD oxidation of
alcohols and discuss the mechanism of this reaction.8
Phenylethanols 1-d0, 2-d0 and benzyl alcohol 3-d0, as well
as their deuterated analogues 1-d4, 2-d1, 3-d2 and 4-d1
were suitable substrates for the measurement of the
O
O
H
H
O
O
R2
R2
HO
R1
O
HO
R2
R1
R1
Baumstark and Kova˘c, based on results involving Ham-
mett correlations, primary isotope effects and the charac-
terization of a minor product of this reaction, suggested
a radical-cage mechanism.4 However, they stated that a
concerted insertion process cannot be excluded. More
recently, computational work by Rauk and Shustov
suggested5 that the regioselectivity of the title reaction
may be rationalized by a hydride-like transfer mecha-
nism. Both reactive intermediates proposed earlier are
shown in Scheme 2.
Scheme 1. Concerted mechanism for the DMD oxidation of
alcohols.
HO
O
O
R1
H
R2
H
.
The controversy in the literature regarding the mecha-
nism of the synthetically useful6 DMD oxidation of
alcohols, as well as our own mechanistic study on the
DMD epoxidation of alkenes,7 prompted us to investi-
gate the nature of the transition state of the title reaction.
In this paper we report the primary and, for the first time,
O
O
.
R2
HO
HO
O
HO
R1
R1 R2
hydride trasfer
radical-cage
O
R2
R1
Keywords: dioxiranes; isotope effects; mechanisms.
* Corresponding author. Fax: +30 81 393601; e-mail: orfanop@
chemistry.uoc.gr
Scheme 2. Proposed radical and polar intermediates for the
DMD oxidation of alcohols.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00539-1

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Y. S. Angelis et al. / Tetrahedron Letters 42 (2001) 3753–3756
Table 1. Inter- and intramolecular primary isotope effects of DMD oxidation of secondary alcohols 1, 2, 3 and 4
X
R1
H
D
H
D
H
D
D
R2
H
CH3
CD3
CH3
CH3
H
1-d0
1-d4
2-d0
2-d1
3-d0
3-d2
4-d1
H
O
O
O
HO
R1
R2
CF3
CF3
H
R2
X
X
H
D
H
H
Entry
1
Substrate
% Conversion
kH/kD
1-d0/1-d4
8
15
32
20
31
8
23
7
18
3.690.1a
3.690.1a
3.690.1a
4.890.2b
4.890.2b
4.590.2b
4.690.2b
4.490.2b
4.590.2b
2
3
4
2-d0/2-d1
3-d0/3-d2
4-d1
a The values of the isotope effect were determined by GC.
b Determined by 1H NMR integration of the appropriate signals.
primary inter- and intramolecular isotope effects (Table
1). Equimolar quantities of protio and deutero sub-
strates were dissolved in acetone as the solvent. Small
quantities of DMD in acetone (0.05–0.1 M) were added
to the reaction mixture at 0°C. The reaction was moni-
tored by gas chromatography. The inter- (entries 1, 2
and 3) and intramolecular (entry 4) isotope effects were
discussed later, the negligible b-secondary isotope effect
influences little, if at all, the total value of the primary
isotope effect. The GC retention times of the products
and starting materials matched those of the authentic
samples, as confirmed by control experiments.
The substantial kinetic and product isotope effects in
the inter- and intramolecular competition (Table 1)
support a concerted one-step reaction, i.e. TSI in
Scheme 3, with CꢀH(D) bond breaking in the rate-
determining step. These results are consistent with pre-
vious findings1 and support a one-step mechanism for
1
measured by gas chromatography or H NMR integra-
tions of the signals of the carbonyl products or the
remaining starting alcohols and the kH/kD values were
calculated9 according to Eq. (1).† Reactions were run to
less than 32% conversion to products. These results are
summarized in Table 1.
The primary intermolecular isotope effect, kH/kD, which
is the result of an intermolecular isotopic competition
between 2-d0 and 2-d1, is proportional to the ratio of
protio/deutero carbonyl products.
kH log[1−Hr/Ht]
kD log[1−Dr/Dt]
=
(1)
In entry 1, the advantage of the 1-d4 analogue instead
of 1-d1 for the intermolecular competition between 1-d0
versus 1-d4 is that both the ratio of the oxidation
products acetophenone-d0/acetophenone-d3, as well as
the ratio of the remaining benzylic alcohols 1-d0/1-d4
may be accurately determined by the areas under their
well-separated capillary column GC signals‡ (Fig. 1). In
this case, a small b-secondary IE could contribute to
the total measured isotope effect; however, as shall be
† For example, Hr and Dr are the amounts of products 1-d0 and 1-d4,
Ht and Dt are the initial amounts of 1-d0 and 1-d4.
‡ The GC response factors for the deuterated and the nondeuterated
substances were measured against methyl benzoate as internal stan-
dard; the relative response factors were in the range of 1.00–1.02.
Figure 1. Primary isotope effect measurements of 1-d0 versus
1-d4 determined by the areas under the product signals on a
60 m GC (5% phenyl methylpolysiloxane) capillary column.

Y. S. Angelis et al. / Tetrahedron Letters 42 (2001) 3753–3756
3755
δ.
δ -
H
.
δ
OH
δ+
H
H
δ -
O
δ+
O
O
O
R2
O
HO
1 R2
HO
R1 R2
R
.
δ
R1
O
.
δ
TS I
TS III
TS II
Scheme 3. Proposed concerted, diradical- and dipolar-type transition states for the DMD oxidation of alcohols.
Table 2. b-Secondary kinetic isotope effects
R1
R2
O
O
Ph
CH3
CD3
CH3
CD3
1-d0
1-d3
6-d0
6-d5
OH
O
Ph
R1 R2
R1 R2
PhCH2
PhCD2
a
Entry
1
Substrate
% Conversion
kH/kD
1-d0/1-d3
6
11
18
32
4
8
17
35
1.0090.02
0.9990.02
1.0190.02
0.9890.02
0.9890.02
0.9990.02
1.0190.02
0.9890.02
2
6-d0/6-d5
a The values of the isotope effects were determined by GC analysis of the product or the remaining starting alcohol signals; each value is the
average of three consecutive measurements; the error was 2%.
and their carbonyl products, after oxidation, are shown
in Fig. 2. The small inverse isotope effects found in the
intermolecular competition between 1-d0 and 1-d3, as
well as in 6-d0 and 6-d5, exclude the formation of a
the DMD oxidation of secondary alcohols or
hydrocarbons.1
However, these and previous2,4 results on primary iso-
tope effects cannot exclude the intervention of a diradi-
cal or dipolar intermediates with CH(D) bond breaking
in the transition states TSII and TSIII, as shown in
Scheme 3.
To probe the mechanism further and obtain informa-
tion on the formation of diradical or dipolar intermedi-
ates, we measured the b-secondary intermolecular
isotope effects of this DMD-alcohol oxidation. For this
purpose, 1-phenylethanol (1-d0) and 1-phenyl-2-
propanol (6-d0) with their deuterated analogues 1-
phenylethanol-2,2,2-d3 (1-d3) and 1-phenyl-2-propanol-
2,2,3,3,3-d5 (6-d5) were prepared. The kH/kD values for
the intermolecular secondary isotope effect were
obtained from the equimolar competition of 1-d0 versus
1-d3 and 6-d0 versus 6-d5 by DMD. The experimental
and analytical conditions were similar to those
described here for the measurements of the primary
isotope effect; again the product ratio is proportional to
the kH/kD isotope effect. Analogously, the b-secondary
IE (kH/kD) was determined from the area of the appro-
priate capillary column GC signals of the carbonyl
products; these results are summarized in Table 2.
Figure 2. GC capillary column (5% phenyl methylpolysilox-
ane) determination of the b-secondary isotope effects by the
areas under the appropriate product or the remaining alcohol
signals.
A typical capillary column gas chromatographic analy-
sis of the unreacted 1-phenyl-2-propanols 6-d0 and 6-d5

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Y. S. Angelis et al. / Tetrahedron Letters 42 (2001) 3753–3756
diradical- or dipolar-type transition state TSII and TSIII,
as shown in Scheme 3.
References
1. (a) Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem.
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In the transition states TSII and TSIII, the hyperconjuga-
tive effect of the five hydrogen atoms in 6-d0 versus the
five deuterium atoms in 6-d5 are expected to give a
substantial normal secondary IE (kH/kD:1.03–1.1 per
deuterium atom), as found in the oxidation of propanol
by organo ruthenium(III) complexes10 and in the dipolar
cycloadditions of TCNE to 2,4-dimethylhexadiene.11
3. Adam, W.; Prechtl, F.; Richter, M. J.; Smerz, A. K.
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The results are consistent with a concerted mechanism,
as shown in TSI (Scheme 3). In the nonpolar transition
state TSI, the steric interactions in going from a less
crowded ground state to a more crowded transition state
would lead to a small inverse secondary IE, as found.
This inverse b-secondary isotope effect is comparable to
previously calculated12 or measured ones for other reac-
tions,13 which were taken as support for a concerted
mechanism.
5. Shustov, G. V.; Rauk, A. J. Org. Chem. 1998, 63, 5413.
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The small amount of a-hydroxy acetophenone (2–3%),
which was observed previously4 in the DMD oxidation
of 1-phenylethanol and confirmed by us, may be formed
by a minor radical-chain process, which is irrelevant to
the major concerted oxidation mechanism. Thus, in
conclusion, the present isotope effects (primary and
b-secondary), when taken in conjunction, exclude the
formation of any diradical- or dipolar-type intermediate
and suggest a concerted transition state for the DMD
oxidation of alcohols.
7. Angelis, Y.; Zhang, X.; Orfanopoulos, M. Tetrahedron
Lett. 1996, 37, 5991.
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Isotopic Molecules; Wiley–Interscience: New York, 1980;
(b) Carpenter, B. K. Determination of Organic Reaction
Mechanism; Wiley–Interscience: New York, 1984.
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Acknowledgements
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We thank the Greek Secretariat of Research and Tech-
nology (PENED 1999 to I.S. and PENED 1999 to M.O.)
for financial support and for a research fellowship to
Y.S.A. and N.S.H. Professor W. Adam is also acknowl-
edged for valuable comments.
.