The oxidation of secondary alcohols by dimethyldioxirane: Re-examination of kinetic isotope effects

Article abstract of DOI:10.1515/HC.2010.016

The kinetic isotope effects for the oxidation of a series of deuterated isopropanols and a -trideuteromethyl benzyl alcohol by dimethyldioxirane ( 1 ) to the corresponding ketones were determined in dried acetone at 23 ° C. A primary kinetic isotope effect (PKIE) of 5.2 for the oxidation of isopropyl-2-d alcohol by 1 was obtained. The SKIEs for oxidation of a -trideuteromethyl benzyl alcohol and isopropyl-1,1,1,3,3,3-d₆ alcohol were found to be 1.07 and 0.98, respectively. Oxidation of isopropanol-d by 1 yielded a k _OH /k _OD value of 1.12, which is similar to that previously reported for α -methylbenzyl alcohol-d. Both normal and inverse secondary kinetic isotope effect (SKIEs) are observed. Mechanistically, the results indicate that the process is more complex than the previously proposed models.

Full text of DOI:10.1515/HC.2010.016

Heterocycl. Commun., Vol. 16(4-6), pp. 217–220, 2010 • Copyright © by Walter de Gruyter • Berlin • New York. DOI 10.1515/HC.2010.016
Preliminary Communication
The oxidation of secondary alcohols by dimethyldioxirane:
re-examination of kinetic isotope effects
1991; Denmark and Wu, 1998; Frohn et al., 1998) or in an
isolated solution (Murray and Jeyaraman, 1985; Baumstark
and McCloskey, 1987). The epoxidation of alkenes and het-
eroatom oxidation by isolated solutions of 1 in acetone have
been extensively investigated (Murray and Jeyaraman, 1985;
Baumstark and McCloskey, 1987; Baumstark and Vasquez,
1988; Winkeljohn et al., 2004, 2007). Dioxiranes can also
insert oxygen into unactivated CH bonds of alkanes (Murray
et al., 1986). However, this important reaction generally
requires a dioxirane more reactive than dimethyldioxirane to
be of utility (Kuck et al., 1994; D’Accolti et al., 2003). The
oxidation of secondary alcohols by dimethyldioxirane, 1, to
ketones can be achieved in high yield under mild conditions
and with convenient reaction times (Kovac and Baumstark,
1994; Cunningham et al., 1998; Baumstark, 1999). Two
mechanistic extremes have been proposed for secondary alco-
hol oxidation by 1: a) concerted insertion (Mello et al., 1991;
Angelis et al., 2001) and b) direct radical-cage processes
(Kovac and Baumstark, 1994). Computational model studies
(Shustov and Rank, 1998; Freccero et al., 2001) on dioxirane
oxyfunctionalization of C-H bonds have been carried out and
seem to support a stepwise process. Reported kinetic isoto-
pic studies have come to differing conclusions concerning the
secondary alcohol oxidation process: the initial study (Kovac
and Baumstark, 1994) favored a radical-cage process while a
subsequent study (Angelis et al., 2001) supported a concerted
mechanism. We report here a re-examination of the kinetic
isotope effects for the oxidation of selected secondary alco-
hols by dimethyldioxirane.
Alfons L. Baumstark*, Pedro C. Vasquez, Mark
Cunninghama and Pamela M. Leggett-Robinsonb
Department of Chemistry, Center for Biotech and Drug
Design, Georgia State University, Atlanta, Georgia
30302-4098, USA
*Corresponding author
e-mail: chealb@langate.gsu.edu
Abstract
The kinetic isotope effects for the oxidation of a series of
deuterated isopropanols and α-trideuteromethyl benzyl alco-
hol by dimethyldioxirane (1) to the corresponding ketones
were determined in dried acetone at 23°C. A primary kinetic
isotope effect (PKIE) of 5.2 for the oxidation of isopropyl-
2-d alcohol by 1 was obtained. The SKIEs for oxidation of
α-trideuteromethyl benzyl alcohol and isopropyl-1,1,1,3,3,3-
d6 alcohol were found to be 1.07 and 0.98, respectively.
Oxidation of isopropanol-d by 1 yielded a kOH/kOD value
of 1.12, which is similar to that previously reported for
α-methylbenzylalcohol-d. Bothnormalandinversesecondary
kinetic isotope effect (SKIEs) are observed. Mechanistically,
the results indicate that the process is more complex than the
previously proposed models.
Keywords: dimethyldioxirane; isotope effects; secondary
alcohol oxidation.
Results and discussion
Introduction
The reaction of dimethyldioxirane (1, in excess) with 2-pro-
panol (2), isopropyl-2-d alcohol (3), isopropyl-1,1,1,3,3,3-d6
alcohol (4), 2-propanol-d (5), α-methyl benzyl alcohol (6),
and α-trideuteromethyl benzyl alcohol (7) (Rxn 1) produced
the corresponding ketones in excellent yields. The products
were characterized (where possible) by gas chromatograhy/
mass spectrometry (GC/MS) data and by comparison of spec-
tra properties with those of authentic samples. The reaction
was of the second order overall, first order in both dioxirane
and alcohol. Pseudo-first order kinetic studies were carried
out in dried acetone with at least a 10-fold excess of the sec-
ondary alcohol at 23.0 0.3°C employing ultraviolet method-
ology. For all cases excellent pseudo-first order plots were
obtained (r values were greater than 0.99). Reproducibility
between the kinetics runs of the k2 values was excellent,
Dimethyldioxirane (1) has been shown to be an extremely
versatile oxygen-atom transfer reagent for the oxidation of a
wide range of substrates under mild conditions (for selected
reviews, see Curci, 1990; Adam et al., 1992; Adam and
Hadjiarapoglou, 1993; Curci et al., 1995; Adam and Zhao,
2006). In addition, oxidations by 1 can be carried out con-
veniently either in situ (Corey and Ward, 1986; Adam et al.,
Present addresses:
a1630 Metropolitan Parkway, Atlanta, GA 30310, USA,
e-mail: mcunningham@altm.edu
bGeorgia Perimeter College – Decatur Campus, Science Department,
3251 Panthersville Road, Decatur, GA 30034, USA,
e-mail: Pamela.leggett-robinson@gpc.edu
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218 A.L. Baumstark et al.
Table 1 Kinetic isotope effects for the reaction of secondary alcohols 2–7 with 1 at 23°C in dried acetone.
Compound number
Structure
k2/M/s
Kinetic isotope effect
kH /kD=5.2 0.1
2
3
CH3CHOHCH3
CH3CDOHCH3
1.62 0.01×10-2
0.31 0.01×10-2
4
5
6
7
CD3CHOHCD3
CH3CHODCH3
PhCHOHCH3
PhCHOHCD3
1.67 0.01×10-2
1.46 0.01×10-2
2.17 0.06×10-2
2.02 0 .0 2 ×10-2
kCH3/kCD3= 0 .9 8 0.01
kOH/kOD= 1 .1 2 0.01
kCH3/kCD3= 1 .0 7 0.05
Table 2 Summary of PKIE data for the oxidation of secondary alcohols by 1.
Entry
Alcohol/deuterated alcohol
Method (T)
kH/kD
Reference/Comment
1
2
CH3CHOHCH3/CH3CDOHCH3
PhCHOHCH3/PhCDOHCH3
Kinetics (23°C)
Kinetics (25°C)
5.23
3.55
Current results
(Kovac and Baumstark,
1994)
3
PhCHOHCD3/PhCDOHCD3
GC (0°C)
3.6
(Angelis et al., 2001);
SKIE effects included
(Angelis et al., 2001)
(Angelis et al., 2001);
SKIE effect included
(Angelis et al., 2001);
SKIE effect included
4
5
CF3ArCHOHCH3/CF3ArCDOHCH3
PhCH2OH/PhCD2OH
NMR (0°C)
NMR (0°C)
4.8
4.6
6
PhCH2OH/PhCHDOH
NMR (0°C)
4.5
NMR, nuclear magnetic resonance spectroscopy.
secondary alcohols by dioxirane 1 fall in the range of 3.6 to
4.6. Clearly, all the data are consistent with breaking the sec-
ondary C-H of the alcohol in the rate-determining step (rds)
of rxn 1. The current and published PKIE results for second-
ary alcohol oxidation by 1 are summarized in Table 2.
Differentiation between the proposed mechanistic
extremes (concerted-direct insertion vs. radical-cage models)
is focused on expectations of the secondary kinetic isotope
effects (SKIE) for each process. Scheme 1 shows the expected
transition states for the extremes. An inverse SKIE would be
expected for the concerted route and a normal value for the
other. The current and previous SKIE results for the oxidation
of secondary alcohols by 1 are summarized in Table 3.
generally 1–2%. Second-order rate constants (k2 values)
obtained with a 10-fold excess of dioxirane yielded data con-
sistent with those with excess alcohol but with a larger error
range. The primary kinetic isotope effect (PKIE) results for
the oxidation of isopropanol (2/3) was found to be 5.2. The
overall secondary kinetic isotope effect for the double CD3
formal substitution (2/4) was found to be inverse, while that
1
O
O
Y
OZ
R2
k2
O
Dried acetone
23ºC
R1
In general, the current and published isotope effect data are
in good agreement, except for the SKIE effect measured for
α-trideuteromethyl benzyl alcohol oxidation. Entries 4 and 5
appear to be contradictory, but the discrepancy may be due to
O
(1)
R2
R1
2 R1=R2=Me, Y=Z=H
3 R1=R2=Me, Y=D, Z=H
4 R1=R2=CD3, Y=Z=H
5 R1=R2=Me, Y=H, Z=D
6 R1=Ph, R2=Me, Y=Z=H
7 R1=Ph, R2=CD3, Y=Z=H
‡
‡
OH
H
.
OH
H
δ
R
R
R
R
O
O
O
O
Me
.
δ
for single CD3 formal substitution (6/7) was found to be nor-
mal. The secondary kinetic isotope effect for deuteration of
the alcohol proton on isopropanol (2/5) was normal: 1.12. The
results for compounds 2-7 are summarized in Table 1.
Me
Me
Me
Concerted
Radical-cage
The current PKIE of 5.2 for oxidation of the secondary ali-
phatic alcohol 3 to a ketone is in good agreement with those in
the literature. The published data for the oxidation of various
Scheme 1 Expected transition states for rds for concerted and radi-
cal-cage mechanisms of secondary alcohol oxidation by 1.
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Secondary alcohol oxidation by dimethyldioxirane 219
Table 3 Summary of ‘secondary’ kinetic isotope effect data for oxidation of secondary alcohols by 1.
Entry
Alcohol/deuterated alcohol
Method (T)
Isotope effect
1
2
3
4
5
6
CH3CHOHCH3/CH3CHODCH3
PhCHOHCH3/PhCHODCH3
CH3CHOCH3/CD3CHOHCD3
PhCHOHCH3/PhCHOHCD3
PhCHOHCH3/PhCHOHCD3
PhCH2CHOHCH3/PhCD2CHOHCD3
Kinetics (23°C)
Kinetics (25°C)
Kinetics (23°C)
Kinetics (23°C)
GC (0°C)a
kOH/kOD=1.12 0.02
kOH/kOD=1.09 0.06 (Kovac, 1994)
kCH3/kCD3=0.98 0.01
kCH3/kCD3=1.07 0.04
kCH3/kCD3=0.98 0.02 to 1.01 0.02 (Angelis et al., 2001)
kH5/kD5=0.98 0.02 to 1.01 0.02 (Angelis et al., 2001)
GC (0°C)a
aVia product studies.
‡
deuteration on the R groups would be due to the position-
ing of the dioxirane in the transition state. Of course, an
explanation in which a caged-radical with a strong hydro-
gen-bonding component cannot be excluded. Computational
modeling studies will need to be carried out to evaluate this
novel process.
H
O
O
O
Me
Me
H
R
R
Acknowledgements
Scheme 2 Proposed multi-centered transition state for the con-
certed oxidation of secondary alcohols by 1.
Acknowledgements are made to the US Army ERDEC SEAS subcon-
tract and to the Georgia State Research Fund for support of this work.
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