Oxidative cleavage of N,N-dimethylhydrazones to ketones with hydrogen peroxide, catalyzed by methyltrioxorhenium(VII)

Full text of DOI:10.1021/jo991390e

2218
J . Org. Chem. 2000, 65, 2218-2221
Notes
added and the mixture refluxed with continuous removal of
Oxid a tive Clea va ge of
water using a Dean-Stark trap. Depending on the nature of
the ketone, the reaction times ranged from several hours to
several days. The hydrazones were purified either by distillation
or column chromatography.
N,N-Dim eth ylh yd r a zon es to Keton es w ith
Hyd r ogen P er oxid e, Ca ta lyzed by
Meth yltr ioxor h en iu m (VII)
Oxid a tive Clea va ge of Hyd r a zon es. The ketone hydrazone
(2.5 mmol) was added dropwise via syringe to a cooled (0 °C)
and well-stirred solution of acetonitrile-acetic acid 95:5, hydro-
gen peroxide (7.5 mmol), and MTO (0.025 mmol). The addition
took approximately 5 min, after which the reaction mixture was
allowed to warm to room temperature during the next 5-10 min.
The mixture was then poured into dichloromethane and washed
with saturated sodium bicarbonate solution. The dichloromethane
extract was dried over anhydrous sodium sulfate. After filtration
and solvent removal, most ketones were colored but otherwise
pure as determined by GC/MS. Additional purification was
achieved by flash chromatography through a short column
(petroleum ether/acetone).
Kin etics. Experiments were carried out with substituted
benzophenone hydrazones, the least reactive of these substrates,
to simplify the measurements. The choice of a medium was
critical because the inherent basicity of the hydrazones4 deac-
tivates the MTO catalyst.5,6 Our experiments used a 95:5
mixture of acetonitrile and acetic acid. To protect MTO and its
peroxo complexes, 25 mM pyridine was introduced into the
reaction mixture.7,8 Other concentrations were 0.2 M hydrogen
peroxide and 1 mM ketone hydrazone. The reaction was followed
spectrophotometrically in quartz cuvettes of 1 cm optical path.
The runs were performed under air (which has no effect) at 23
°C. The MTO solutions used in these experiments was freshly
prepared.
Sasˇa Stankovic´ and J ames H. Espenson*
Ames Laboratory and Department of Chemistry, Iowa State
University of Science and Technology, Ames, Iowa 50011
Received September 2, 1999
In tr od u ction
N,N-Dialkylhydrazones are valuable derivatives in
synthetic organic chemistry, especially as sources of
carbanions. They serve as equivalents of carbanions
derived from aldehydes and ketones in electrophilic
substitutions. The final stages of chemical manipulation
frequently require their cleavage, so as to regenerate the
parent carbonyl compound. To do so, a number of
procedures have been developed, both hydrolytic and
oxidative.1
By way of preface, it should be noted that hydrogen
peroxide, catalyzed by methyltrioxorhenium (CH3ReO3
or MTO), converts N,N-dimethylhydrazones derived from
aldehydes into nitriles:2,3
The procedure used for kinetics was as follows: all ingredients
save the catalyst and substrate were mixed in the cuvette, giving
a total volume of 3.0 mL. The catalyst was then added, and after
30 s the substrate was introduced. The decrease in absorbance
at 430 nm, corresponding to the decrease in the concentration
of the ketone hydrazone, was recorded with time. The absor-
bance-time curves were analyzed by the nonlinear least-squares
method, to obtain the pseudo-first-order rate constant according
to the equation:
We have now used the same reagents for N,N-dimeth-
ylhydrazones derived from ketones. In this case, the
hydrazone reverts to the parent carbonyl compound, eq
2. Herein we report the effectiveness of this reaction as
well as certain kinetics and isotopic tracer experiments
pertaining to its mechanism.
Abst ) Abs∞ + (Abs0 - Abs∞)e-k
ψt
Isotop ic La belin g. These experiments were performed in the
following manner. Urea hydrogen peroxide was used to avoid
isotopic dilution. UHP (0.3 mmol), 18O-labeled water (90% 18O,
0.03 mL), and pyridine (0.1 mmol) were mixed in 1.0 mL of
acetonitrile. Acetic acid was not added in these experiments.
Catalyst was added, 0.001 mmol, followed by acetophenone
hydrazone (0.025 mmol). After 2 min, the sample was diluted
200-fold with acetonitrile. A small sample was then injected into
the GC/MS instrument. A separate experiment was done with
10-times higher catalyst concentration. The ratio of the signals
at m/z 105 and 107 in the MS spectrum of acetophenone was
monitored. A control experiment was performed with acetophe-
none itself, and it showed no incorporation of 18O on this time
scale.
Exp er im en ta l Section
Rea gen ts. The ketone hydrazones were prepared by either
of two methods. Aliphatic hydrazones were prepared by mixing
the ketone with 3 equiv of 1,1-dimethylhydrazine without solvent
at room temperature. The progress of this reaction was moni-
tored either by TLC or GC/MS. The reactions were typically
complete in 30 min; the reaction mixture was dissolved in ether
and then washed and dried. Crude hydrazones were obtained
after solvent removal. For the less reactive aromatic ketones a
more vigorous procedure was required. The ketone (50 mmol)
and N,N-dimethylhydrazine (75 mmol) were dissolved in ben-
zene (20 mL). Two or three drops of trifluoroacetic acid were
(4) Hinman, R. L. J . Org. Chem. 1960, 25, 1775.
(5) Abu-Omar, M.; Hansen, P. J .; Espenson, J . H. J . Am. Chem. Soc.
1996, 118, 4966-4974.
(1) Bergbreiter, D. E.; Momongan, M. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 2, p 503.
(2) Stankovic´, S.; Espenson, J . H. J . Chem. Soc., Chem. Commun.
1998, 1579-1580.
(3) Rudler, H.; Denise, B. J . Chem. Soc., Chem. Commun. 1998,
2145-2146.
(6) Espenson, J . H.; Tan, H.; Mollah, S.; Houk, R. S.; Eager, R. D.
Inorg. Chem. 1998, 37, 4621-4624.
(7) Rudolph, J .; Reddy, K. L.; Chiang, J . P.; Sharpless, K. B. J . Am.
Chem. Soc. 1997, 119, 6189.
(8) Wang, W.-D.; Espenson, J . H. J . Am. Chem. Soc. 1998, 120,
11335-11341.
10.1021/jo991390e CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/16/2000

Notes
Ta ble 1. Oxid a tive Clea va ge of Keton e Hyd r a zon es
J . Org. Chem., Vol. 65, No. 7, 2000 2219
F igu r e 1. Pseudo-first-order rate constants (at 25 °C in 95:5
acetonitrile/acetic acid) for the oxidation of substituted ben-
zophenone hydrazones vary linearly with the total concentra-
tion of the rhenium catalyst. In order of decreasing slope the
data for (XC6H4)2CdNNMe2 refer to X ) p-MeO, H, m-CF3,
and m-NO2.
Resu lts
Ta ble 2. Ra te Con sta n ts for th e Bim olecu la r Rea ction
betw een Su bstitu ted Ben zop h on e Hyd r a zon es a n d
CH3Re(O)(η2-O2)2(H2O), Ba
P er oxor h en iu m In ter m ed ia tes. The active forms of
the catalyst are peroxorhenium complexes, designated A
and B. As shown in eq 4, they are in equilibrium with
MTO, H2O2, and one another. These steps are, howev-
er,not always rapid relative to the ones involved in
catalysis.9
(X2C6H3)2CdNNMe2 X )
k4/L mol-1 s-1
4,4′-MeO
H
3,3′-CF3
3,3′-NO2
127 ( 4
85 ( 1
44.5
27.9 ( 0.4
a
In acetonitrile-acetic acid (95:5) in the presence of 25 mM
pyridine at 25 °C.
acceleration of the peroxide binding step, as demon-
strated previously.8 The rate law is:
Rea ction Con d ition s a n d Yield s. Ketone hydra-
zones were oxidized by the MTO/H2O2 system in a solvent
mixture composed of acetonitrile and acetic acid in a 95:5
ratio. Because the hydrazones are basic, acetic acid is
helpful in stabilizing MTO against decomposition to the
catalytically inactive perrhenate ion.5 Acetic acid is,
however, insufficiently acidic to protonate the hydrazones
that would render them inactive toward A or B. The
oxidations are so exothermic on a preparative scale that
it was necessary to cool the reaction to 0 °C and slowly
introduce the hydrazone into the reaction mixture. Cool-
ing also stabilizes MTO, allowing these reactions to be
performed with 1% of catalyst relative to the hydrazone.
Under these conditions, the ketones were formed in a
matter of minutes. Specific data are given in Table 1.
Kin etics. Hydrazones are noted for their nucleophi-
licity.10 It came as no surprise, then, that they are
reactive substrates toward MTO/hydrogen peroxide. The
conditions of the experiments were designed to permit a
simple measurement of the rate constant for the one
reaction between substrate and B. To do so, 0.2 M
hydrogen peroxide was used so that B was the only
significant species of those in eq 4. Also, and just as
important, one must ensure that the reaction between
A and hydrogen peroxide is accelerated, to ensure that
this reaction does not become rate-controlling; the 25 mM
pyridine present in the kinetics provides the necessary
d[Ar2CdNNMe2]
-
) k4[Ar2CdNNMe2][Re]T
dt
Different tests were performed to demonstrate the
correctness of this equation. Experiments at several
concentrations of hydrogen peroxide, 0.1-0.3 M, showed
that the rate constant is independent of its concentration.
The kinetics data gave excellent fits to first-order kinetics
in each experiment. A few experiments were carried out
at different concentrations for one substrate, benzophe-
none hydrazone, 0.5-5 mM. For each compound the
variation of kψ against [Re]T, which is essentially [B], was
a straight line that passed through the origin (Figure 1).
The slopes of these lines are the values of k4, the values
of which are summarized in Table 2.
Isotop ic La belin g. To learn more about the interme-
diates in this reaction, experiments were performed to
measure the extent to which the carbonyl oxygen of the
produced acetophenone incorporates oxygen-18 from
water added at the start of the experiment. Some 20% of
the resulting acetophenone was 18O-labeled. This experi-
ment, first performed with 0.010 mM MTO, was then
repeated with about 1/10 that level of catalyst. The
second experiment also gave 20% 18O incorporation. This
result shows that the partitioning of the intermediate
along a different course does not occur in a step in which
there is competition between oxidation and hydrolysis
steps. This issue will be taken up in a subsequent section.
(9) Espenson, J . H. J . Chem. Soc., Chem. Commun. 1999, 479-488.
(10) Grekov, A. P.; Veselov, V. Y. Russ. Chem. Rev. 1978, 47, 631.

2220 J . Org. Chem., Vol. 65, No. 7, 2000
Notes
Sch em e 1
it might partition between oxidation (80%, to account for
the 18O labeling result) and hydrolysis (20%), because the
stage at which an intermediate partitions must either
be the one with two competing oxidations or two hydroly-
sis or rearrangement steps. That feature is required by
the finding of 20% 18O incorporation, irrespective of a 10-
fold lowering of the MTO concentration. As a result,
either the competing pathways are both oxidations or
neither is.
F igu r e 2. Linear free energy correlation of the kinetic data
for the oxidation of substituted benzophenone hydrazones with
the peroxorhenium compound B, CH3ReO(η2-O2)2(H2O) against
the Hammett substituent constant σ.
On that basis, several mechanistic possiblities can be
seen, Scheme 1. The reaction may partition to I and II
in the initial oxidation stage, steps 1a and 2a. An
attractive feature of this assignment is that partitioning
resides in the slowest (rate-controlling) stage, which
should be the most selective. Intermediate II should
solvolyze; with H218O, Ar2Cd18O will result. If these
assignments are correct, then 80% of oxidation leads to
I, giving unlabeled ketone, as in step 1b. Arguing against
these assignments are two findings: (a) the linearity of
the Hammett LFER and (b) the well-documented mech-
anism operable in the case of aldehyde N,N-dimethylhy-
drazones. The Hammett plot, where the experimental
rate constant is the sum of those for steps 1a and 2a,
would show distinct curvature unless the two F values
were coincidentally the same. Indeed, we have previously
encountered one instance where exactly that was found
when parallel pathways for the oxidation coexisted.12 It
is a particularly telling point that the oxidation occurs
exclusively at the dimethylamino nitrogen of aldehyde
N,N-dimethylhydrazones.3 There is no plausible basis for
imagining that a ketone hydrazone would be different.
We therefore propose a different sequence of steps,
which are included as a part of Scheme 1. The initial
oxygen-atom transfer is proposed to occur exclusively at
the dimethylamino nitrogen, just as with the aldehyde-
derived hydrazones. The reaction yields intermediate II,
which can partition to hydrolysis to a ketone (labeled
with H218O) or rearrange. The rearrangement of II to III
may be a 1,3-shift or, perhaps less plausibly, two 1,2-
shifts. In any event, this leads to (unlabeled) ketone. It
is the partitioning of II between hydrolysis and rear-
rangement that gives rise, in this model, to the partial
incorporation of the oxygen-18 label from the solvent.
Much less likely, II might itself be further oxidized, but
this is not likely in that the addition of one oxygen atom
always reduces greatly the propensity for further oxida-
tion.
Discu ssion
Kin etics. Comparing this pattern to others found,9,11
we conclude that this reaction resembles others in which
an electron-rich substrate is oxidized by peroxorhenium
complexes. On that basis, one imagines that a nucleo-
philic center of the ketone hydrazone attacks a peroxo
oxygen of B. The electronic requirements can be inferred
from the quantitative kinetics effect of substituents on
the aromatic rings of substituted benzophenone hydra-
zones. The data in Table 2 were analyzed according to
the Hammett equation. As shown in Figure 2, the plot
of log k4 against σ is linear (correlation coefficient 0.999).
Its slope is the reaction constant, F ) -0.72. The
substantial negative value supports the model proposed,
in that the reaction center (either or both of the N atoms)
becomes more positive in the transition state than it was
at the outset.
Molecu la r Mech a n ism . MTO activates hydrogen
peroxide in such a way that one oxygen atom of the
peroxorhenium intermediate is transferred to the sub-
strate in the transition state. The first transition state,
corresponding to O-atom transfer from B to the substrate,
is the rate-controlling process. This substrate offers, in
principle, at least three options for the intermediate(s)
produced from it. The three are depicted as follows:
Structure II was proposed to account for the reaction
of aldehyde hydrazones.2,3 It is consistent with the simple
transfer of an oxygen to the most basic site. This
intermediate is, however, incapable of carrying the
reaction further, at least in the same manner as the
aldehyde derivatives, in that dimethylhydroxylamine
cannot be eliminated through hydrogen abstraction. It
may, of course, react in another way. On the other hand,
the formation of alternative I (directly or via III) as the
sole pathway cannot account for the data, even though
The ultimate fate of the nitrogen part of the hydra-
zones was not examined. Certainly, a mixture of oxida-
tion products could be found. Organonitrogen compounds
(11) Espenson, J . H.; Abu-Omar, M. M. Adv. Chem. Ser. 1997, 253,
99-134.
(12) Huang, R.; Espenson, J . H. J . Org. Chem. 1999, 64, 6374.

Notes
J . Org. Chem., Vol. 65, No. 7, 2000 2221
are oxidized by the H2O2/MTO, often in a complex
sequence of reactions. Consider dimethylhydroxylamine,
for example, which may be an intermediate in this
chemistry. It is oxidized in several steps to a nitrone.13
The oxidation products of the nitrogen part of the ketone
were not investigated, because it seemed little new
information would result.
Sciences, Division of Chemical Sciences under contract
W-7405-Eng-82. We are grateful to Professors W. S.
Trahanovsky and G. A. Kraus for helpful discussions
and to a reviewer for comments that led to a more
precise view of the mechanism.
Su p p or tin g In for m a tion Ava ila ble: Tables of 1H and 13C
NMR chemical shifts are presented. This material is available
free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. This research was supported by
the U. S. Department of Energy, Office of Basic Energy
J O991390E
(13) Zauche, T. H.; Espenson, J . H. Inorg. Chem. 1997, 22, 55257.