Twist does a twist to the reactivity: Stoichiometric and catalytic oxidations with twisted tetramethyl-IBX

Article abstract of DOI:10.1021/jo201491q

The methyl groups in TetMe-IBX lower the activation energy corresponding to the rate-determining hypervalent twisting (theoretical calculations), and the steric relay between successive methyl groups twists the structure, which manifests in significant solubility in common organic solvents. Consequently, oxidations of alcohols and sulfides occur at room temperature in common organic solvents. In situ generation of the reactive TetMe-IBX from its precursor iodo-acid, i.e., 3,4,5,6-tetramethyl-2-iodobenzoic acid, in the presence of oxone as a co-oxidant facilitates the oxidation of diverse alcohols at room temperature.

Full text of DOI:10.1021/jo201491q

Article
pubs.acs.org/joc
Twist Does a Twist to the Reactivity: Stoichiometric and Catalytic
Oxidations with Twisted Tetramethyl-IBX
Jarugu Narasimha Moorthy,* Kalyan Senapati, Keshaba Nanda Parida, Samik Jhulki, Kunnikuruvan Sooraj,
and Nisanth N. Nair*
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
S
* Supporting Information
ABSTRACT: The methyl groups in TetMe-IBX lower the activation
energy corresponding to the rate-determining hypervalent twisting
(theoretical calculations), and the steric relay between successive methyl
groups twists the structure, which manifests in significant solubility in
common organic solvents. Consequently, oxidations of alcohols and sulfides
occur at room temperature in common organic solvents. In situ generation
of the reactive TetMe-IBX from its precursor iodo-acid, i.e., 3,4,5,6-
tetramethyl-2-iodobenzoic acid, in the presence of oxone as a co-oxidant
facilitates the oxidation of diverse alcohols at room temperature.
Chart 1
INTRODUCTION
■
2-Iodoxybenzoic acid, referred to popularly as IBX, is an
indispensable organic oxidation reagent in contemporary
oxidation chemistry.1 The reasons for a surge of interest in
this reagent are its cheapness, ready accessibility, and
environmentally benign characteristics that obviate the use of
copious amounts of transition-metal-based reagents. Because of
its astounding reactivity, a myriad of organic transformations
continue to be unraveled.2 The use of this simple IBX reagent
is, however, plagued by certain drawbacks such as its
insolubility in common organic solvents with the exception of
polar DMSO, its explosive property at high temperatures,3 and
the need to conduct a majority of the reactions at high
temperatures.4 The insolubility and the explosive nature have
been attributed to strong intermolecular interactions (O−H···O
hydrogen bonds, C−I···O halogen bonds, and aromatic
stacking interactions) that hold the molecules cohesively in
the crystal lattice.5 In view of the innocuous and eco-friendly
attributes of IBX, the quest in pursuit of modified IBX
analogues that are more reactive, nonexplosive, and common
organic solvent soluble continues unabated. In Chart 1 are
shown some of the modified IBXs that have been employed in
solvents other than DMSO and at room temperature. One of
the early modified IBXs reported by Dess and Martin, i.e.,
bis(trifluoromethyl)-substituted hydroxyiodinane oxide (CF3-
IBX),6 was shown to oxidize alcohols at rt in acetonitrile; this
reagent has, however, not received much attention, presumably
because of the difficulty associated with its synthesis.
Tetrafluoro-IBX (FIBX) was conceived by Wirth et al. on the
basis of better solubility of fluorous compounds in organic
solvents in general.7 They showed that FIBX can indeed be
employed in solvents such as acetonitrile. By combining the so-
called sterically accelerated hypervalent twisting due to the
presence of an o-methyl group and improved solubility in
common organic solvents brought about as a result of
weakening of the intermolecular interactions, the modified
MeOMe-IBX was shown by us to be an exceptional reagent for
oxidation of alcohols at room temperature.8 The modified IBXs
with significantly enhanced reactivity may allow their synthesis
in situ and application catalytically. Ishihara et al. have recently
shown that the 2-iodoxybenzenesulfonic acid (IBS),9 generated
in situ from a catalytic amount of the precursor o-
iodobenzenesulfonic acid in the presence of oxone, can be
Received: March 20, 2011
Published: October 31, 2011
© 2011 American Chemical Society
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Scheme 1. Synthetic Routes for the Modified IBXs
employed in nitromethane at 70 °C for a range of organic
oxidation reactions. Incidentally, the catalytic oxidations at rt by
reactive IBXs generated in situ are heretofore unprecedented.10
In continuing efforts toward exploring the inscrutable
reactivity of IBX,11 we surmised that sterically induced
structural deformation and enhanced hypervalent twisting12
via tetramethyl substitution of the parent IBX as in TetMe-IBX
(Chart 1) should render it to be an invaluable reagent for
oxidations. Herein, we report that tetramethylation twists the
structure, in addition to lowering the rate-determining
activation barrier associated with hypervalent twisting in alcohol
oxidations, as revealed by theoretical (DFT, B3LYP functional)
calculations.13 The steric cascade-induced twisting of the
structure manifests in significant solubility to allow oxidation
of a variety of alcohols (within a few minutes) and sulfides (in a
few minutes to 2 h) in solvents such as DCM at rt. The
enhanced reactivity of TetMe-IBX also permits development of
a catalytic protocol for facile oxidation of diverse alcohols,
which continues to be an intensively investigated trans-
formation.1e,14
methylbenzoic acid was reduced to 3-methylanthranilic acid
under catalytic hydrogenation conditions. The resultant amino
acid was converted to the corresponding 2-iodo-3-methyl-
benzoic acid by Sandmeyer reaction. The iodo-acid thus
derived was subjected to oxidation with oxone in water at 70 °C
to yield Me-IBX in 78% yield. A nitration−reduction−
Sandmeyer reaction sequence on the commercially available
3,5-dimethylbenzoic acid led to 2-iodo-3,5-dimethylbenzoic
acid, which on oxidation with oxone under standard conditions
yielded DiMe-IBX.15 The modified TetMe-IBX was conven-
iently prepared from durene. The latter was acetylated to yield
acetyldurene,16 which was subjected to Lewis acid-mediated
rearrangement,17 followed by bromoform reaction18 to obtain
2,3,4,5-tetramethylbenzoic acid. This compound was subse-
quently iodinated by NIS in acidic medium to afford the
required iodo-acid. Oxidation of the latter under standard
conditions with oxone led to the isolation of TetMe-IBX in a
respectable yield. It should be mentioned that IBX is known to
be explosive as mentioned earlier;3 in fact, when one attempts
to determine the melting point in a capillary, it explodes with
an audible noise. In contrast, TetMe-IBX was found to undergo
clean visible melting to a colorless liquid without any
perceptible hazards.
RESULTS AND DISCUSSION
■
Syntheses of Modified Me-IBX, DiMe-IBX, and TetMe-
IBX. For comparison of the oxidation efficiencies of TetMe-
IBX, mono- and dimethyl-substituted IBXs, i.e., Me-IBX and
DiMe-IBX, were also synthesized along with TetMe-IBX
(Scheme 1). Thus, the commercially available 2-nitro-3-
Oxidation of Alcohols with Modified IBXs. The
oxidation of a variety of alcohols by the modified reagents
was explored at room temperature in a range of organic
solvents that include acetonitrile, dichloromethane, chloroform,
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ethyl acetate, etc. As the oxidations were indeed found to occur
at rt, DCM was deemed to be a better solvent on the basis of a
solvent screening to conduct the oxidations. Thus, by
employing 1.2 equiv of Me-IBX, DiMe-IBX, and TetMe-IBX,
the oxidations of a variety of alcohols were run in DCM at rt.
The results of oxidations are given in Table 1. It is apparent
complete agreement with those of the X-ray determined
structure.5a,c Similar calculations on Me-IBX and TetMe-IBX
(Chart 1) revealed notable differences in the structures. The
sterically induced deformation can be readily deciphered from
the angles between the mean plane of the benzene ring and that
constituted by the atoms C2, I1, O2, and O3 in Figure 1. The
Table 1. Oxidation of Alcohols with Me-IBX, DiMe-IBX, and
a
TetMe-IBX at rt
Figure 1. The DFT optimized structures of IBX, Me-IBX, and TetMe-
IBX; notice the puckering induced in the latter by tetramethylation.
The values refer to the angles between the plane of the Ph ring and
that constituted by the atoms C2, I1, O2, and O3.
angles between the plane of the benzene ring and that of the
selected atoms of the heteroaryl ring for IBX, Me-IBX, and
TetMe-IBX are 1.72, 1.74, and 10.7°, respectively.
Insofar as alcohol oxidations are concerned, it was established
by Santagostino et al.19 on the basis of NMR analysis and
1
inverse dependence of the rate of oxidation of alcohols on
[H2O] that disproportionation of the alkoxyperiodinane (B,
Scheme 2), formed via initial equilibrium exchange of the
Scheme 2. Mechanism of Oxidation of Alcohols Using IBX
and Its Modified Analogues
a
b
All oxidations were performed in DCM as a solvent at rt. 1.2 equiv
c
d
of the reagent was employed. Isolated yields. The reactions were run
for 10 min in CD2Cl2 at rt and monitored directly by 500 MHz NMR.
e
1.5 equiv of IBX of the reagent was employed.
from a perusal of the results that the primary benzylic and
allylic alcohols are oxidized to the corresponding aldehydes by
TetMe-IBX within a few minutes, whereas the reaction
durations are longer for Me-IBX and DiMe-IBX. As monitored
by 500 MHz NMR spectroscopy for p-methylbenzyl alcohol, a
representative case, conversions of the alcohol were 17, 30, and
41% when the oxidations were conducted with Me-IBX, DiMe-
IBX, and TetMe-IBX under uniformly identical conditions at
room temperature for 10 min. That the tetramethylation brings
about a dramatic acceleration of the rate of oxidation when
compared with Me-IBX and DiMe-IBX is also strikingly evident
from the reaction times for the oxidation of secondary benzylic
alcohol and sterically hindered menthol; although the reaction
is complete within 2 h (entry 24, Table 1) with TetMe-IBX, the
reaction times for Me-IBX and DiMe-IBX are significantly
longer (24 h, entries 22 and 23, Table 1). We attribute the
origin of enhanced reactivity of TetMe-IBX to the accelerated
hypervalent twisting12 promoted by sterics, vide infra, and
increased solubility due to weaker intermolecular interactions;
the solubilities determined for Me-IBX, DiMe-IBX, and TetMe-
IBX are 0.12, 0.24, and 1.37 g/L, respectively. In all of these
oxidations, the reduction product was found to be the
iodosobenzoic acid (IBA).
alcohol, to the carbonyl compound and reduced IBA (D) is
rate-determining. Subsequently, Goddard et al.12 showed from
DFT calculations that the disproportionation of alkoxyper-
iodinane B is indeed a two-step process and is accompanied by
a rate-determining so-called hypervalent twisting that leads to
isomeric periodinane intermediate C, which eliminates D and
the carbonyl compound; hypervalent twisting is a coordinated
motion of the ligands attached to iodine driven by the necessity
of generating a stable and planar form of IBA (D). They further
showed that the energy barrier for the rate-determining
hypervalent twisting of IO bond in alkoxyperiodinane gets
lowered when a methyl group is located at the ortho position
with respect to iodine as in Me-IBX (Scheme 2);12 the lowering
in the activation energy when o-methyl group is present as in
Me-IBX is a result of relief of strain induced by the steric effect.
The subsequent proton transfer step, i.e., C → D, was shown to
require less energy from theoretical calculations. Recently,
Ishihara et al. have performed analogous calculations and found
that the twisting is indeed rate-limiting;9 they showed that the
Theoretical Calculations. To gauge how the steric
interactions between methyl, CO, and I−OH groups in
TetMe-IBX influence the planar nature of IBX, DFT
calculations were performed initially on the parent IBX. The
metrics of the energy-minimized structure were found to be in
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stiochiometric oxidation reactivities of substituted IBX and IBS
can be rationalized from hypervalent twisting barriers. In
general, the rotations about the bonds involved in hypervalent
twisting are very different from the usual torsional motions as,
for example, the rotation about the C−C bond in ethane. The
hypervalent twisting involves major reorganization of the
electronic structure at iodine. In particular, the iodine−oxygen
dative bond that lies perpendicular to the plane in structure B
transforms to a conventional covalent bond after twisting
(Scheme 2). Therefore, the potential energy changes involved
in twisting at the hypervalent iodine are appreciable. It was
logical for us to expect that considerable strain built into the
structure of TetMe-IBX via sterics between successive methyl
groups and the substituents of hypervalent iodine as well as the
carbonyl oxygen of the iodoxolone moiety should manifest in
further acceleration of hypervalent twisting in pursuit of steric
relief.
IBX was found to further amplify the lowering by 1.56 kcal/
mol, suggesting that the oxidations of alcohols should occur at
much more enhanced rates. Evidently, tetramethylation has a
much lesser effect than what one observes with monomethy-
lation as in Me-IBX. The fact that the activation barriers
calculated for methanol oxidation with IBX, Me-IBX, and
TetMe-IBX apply equally well to the alcohols examined in
Table 1 was established by computing energies for p-
methylbenzyl alcohol as a representative case, cf. Supporting
Information. Similar energy barriers as those calculated for
methanol were in fact observed. Experimentally, it was
established that p-methylbenzyl alcohol undergoes faster
oxidation with TetMe-IBX than others, i.e., Me-IBX and
DiMe-IBX, under uniformly identical experimental conditions,
cf. Table 1. Thus, when the oxidation of p-methylbenzyl alcohol
was performed for 10 min in CD2Cl2 with IBX, Me-IBX, and
TetMe-IBX at rt, the conversions, as determined from 500
MHz 1H NMR spectral analyses, were 0, 17, and 41%,
respectively. Clearly, the observed rapid oxidation of a variety of
alcohols at rt in Table 1 using TetMe-IBX are consistent with
sterically accelarated rate-determing hypervalent twisting
barriers calculated by DFT calculations; of course, the solubility
of the reagent is another factor that contributes to the overall
reactivity.
Be this as it may, the mechanism of alcohol oxidations using
IBX was revisited in a more detail at the behest of a very
insightful anonymous referee, who suggested that we probe the
kinetic isotope effect in the oxidation of MeOH and MeOH-d4.
A careful literature survey revealed that Corey et al.20 indeed
performed kinetic analysis to establish the fact that the
disproportionation is indeed rate-determining. Under con-
ditions that involve a large excess of IBX in DMSO, they found
that the oxidation of C6H5CH2CD2OH is subject a strong
primary kinetic isotope effect (kH/kD ca. 6.3). In an analogous
manner, we have carried out the oxidation of MeOH and
MeOH-d4 in DCM in the presence of excess TetMe-IBX at 20
°C. Monitoring of the disappearance of the alcohol by GC
analysis with an internal standard led to good pseudo-first-order
kinetics up to 60−75% conversion of the methanol, cf.
Supporting Information. Thus, rates of disappearance for
MeOH and MeOH-d4 were determined to be 18.4 and 5.56
× 10−5 s−1, respectively, leading to a kinetic isotope effect, i.e.,
kH/kD, of ca. 3.3.
We performed DFT calculations13 to ascertain the steric
effect on the twisting barrier for reagents IBX, Me-IBX, and
TetMe-IBX using methanol as the reactant; the initial
equilibrium exchange of the alcohol (A → B) was assumed
to be favored under nonaqueous conditions, as was presumed
by Ishihara et al.9 This step was thus ignored from the
calculations. The transition state structure in each case was
obtained from the saddle point along the optimized reaction
pathway connecting reactant and product. The saddle point
featured one negative frequency along a particular vibrational
mode, which takes the system from reactant to products.
Vibrational contributions to the free energies and zero point
energies were accounted while computing the free energy
barriers. Figure 2 also shows the results of DFT calculations, cf.
The observation of kinetic isotope by Corey et al. for
oxidation of C6H5CH2CD2OH/C6H5CH2CD2OH with IBX
and that by us for oxidation of MeOH/MeOH-d4 with TetMe-
IBX is inconsistent with a two-step mechanism of oxidation,
which involves hypervalent twisting of B as the rate-
determining step followed by disproportionation of the
isomeric alkoxyperiodinane C to the products, cf. Scheme 2.
As the hypervalent twist involves a simple motion of IO
group and the alkoxy moiety, the isotope effect should not be
expected. What then should be the mechanism that accounts
for (i) acceleration of reactivity with an o-methyl group and (ii)
kinetic isotope effect for α-protons of the alcohol? We
suspected that the hypervalent twisting of B presumably occurs
in concert with disproportionation in a direct single step, cf.
Scheme 2. To verify this possibility, molecular dynamics
simulations for the conversion of B → D were performed for
the oxidation of MeOH with TetMe-IBX, which might offer
better insights than static calculations. In several simulations,
both two-step and direct disproportionation pathways (Scheme
2) were observed, but with a very marginal (ca. 1.0 kcal/mol)
Figure 2. The activation barriers for hypervalent twisting of
methoxyperiodinanes derived from IBX, Me-IBX, and TetMe-IBX
and subsequent elimination to IBA. The dotted line is meant to
indicate that energy levels are not drawn to a scale.
Supporting Information for details. Whereas the monomethyl-
substitution at ortho position of the iodine in Me-IBX was
found to lower the twisting barrier by 6.06 kcal/mol in close
agreement with Goddard’s calculations12 under conditions that
exclude solvent effects, the tetramethyl substitution in TetMe-
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difference in free energy barriers, cf. Supporting Information for
details. This shows that there exists a finite probability for
certain reactive trajectories that bypass the species C and lead
directly to the products. It should be mentioned that the
accuracy of the present level of calculations is of the order of
the differences that we observe.
3,5-dimethyl-2-iodobenzoic (DiMe-BA) acid as the catalyst. Of
course, the primary alcohols were converted to their
corresponding carboxylic acids. As revealed by the results in
Table 2, oxidations with DiMe-BA as the catalyst are rather
sluggish, which underscores the importance of tetramethyla-
tion. Selective oxidation of primary alcohols to aldehydes was
also accomplished by employing the conditions of Ishihara et
al.9 Thus, primary benzylic alcohols were oxidized selectively to
their corresponding aldehydes at room temperature by employ-
ing 10 mol % of TetMe-BA with 1.0 equiv of oxone in
nitromethane and anhydrous Na2SO4, cf. Table 3. The reason
Catalytic Oxidations in the Presence of Oxone.
Buoyed by the facile room temperature oxidation of alcohols
and sulfides, catalytic oxidation of alcohols with the precursor
3,4,5,6-tetramethyl-2-iodobenzoic acid (TetMe-BA) in the
presence of oxone was investigated. The catalytic oxidation of
alcohols with IBX that is generated in situ by the oxidation of
precursor o-iodobenzoic acid with oxone in acetonitrile−water
(1:1) at 70 °C was reported for the first time by Vinod et al.;21
as the oxone is known to convert aldehydes to acids,22 primary
alcohols are oxidized to carboxylic acids under the employed
conditions. As mentioned at the outset, Ishihara et al. showed
that o-iodosulfonic acid can be employed in catalytic amounts
in the presence of oxone in nitromethane for oxidation of
alcohols to the corresponding carbonyl compounds at 70 °C in
short durations.9 We found that the tetramethyl iodo-acid (10
mol %), the precursor of TetMe-IBX, in the presence of oxone
co-oxidant acetonitrile−water (1:1) ratio works very nicely for
oxidation of a variety of alcohols at room temperature. The
results are summarized in Table 2 together with those using
Table 3. Catalytic Oxidation of a Variety of Alcohols using
3,4,5,6-Tetramethyl-2-iodobenzoic Acid (TetMe-BA, 10 mol
a
%) as a Catalyst in the Presence of Oxone in MeNO2 at rt
Table 2. Catalytic Oxidation of a Variety of Alcohols using
3,5-Dimethyl-2-iodobenzoic Acid (DiMe-BA) and 3,4,5,6-
Tetramethyl-2-iodobenzoic Acid (TetMe-BA) as a Catalyst
(10 mol %) in the Presence of Oxone in CH3CN/H2O (1:1)
a
All oxidations were performed by employing 1.0 equiv of oxone in
b
c
a
nitromethane at rt. Isolated yields. Bis(4-methoxybenzyl)ether
formed as a side product in 35% isolated yield.
at rt
why the oxidation occurs selectively, leading to aldehydes in
nitromethane but to acids in acetonitrile−water, can be
rationalized on the basis of the solubility of oxone in the two
media and the absence of water in the former medium. The
oxidation of aldehydes in NO2Me is slow, whereas that in
acetonitrile−water is faster. This is because the co-oxidant, viz.,
oxone, is more soluble in the latter solvent system as
mentioned earlier. As a result, selective oxidation is observed
when the oxidation of alcohols is carried out in NO2Me. To
establish if the overoxidation to acids is indeed slow or does not
occur at all, the reaction of p-bromobenzyl alcohol, a
representative case, was conducted in NO2Me for ca. 36 h on
a preparative scale. The acid was isolated in only 12% yield,
which attests to the fact that the rate of oxidation of the
aldehyde formed to the corresponding acid is very slow.
Further, given that the very preparation of the IBX/modified
IBX involves reaction of the precursor iodo-acid at 60−70 °C,
the question that arises is as to how the IBX formation occurs
at room temperature. The point to note here is that that the co-
oxidant, i.e., oxone, is present in 10-fold excess with respect to
the iodo-acid, when catalytic oxidations are carried out at rt.
The concentration effect must take care of the temperature
influence. Further, it has been shown by Ishihara and co-
workers that electron-donating substituents facilitate generation
of the I(V) catalyst;9 that is, oxone oxidation of o-iodobenzoic
acid is faster when the latter contains electron-donating
substituents. Thus, tetramethylation may render oxidation of
the precursor o-iodobenzoic acid with oxone more facile. To
verify if one does observe the formation of IBX at room
temperature when oxone is present in 10-fold excess (mol %),
a
All oxidations were performed in (1:1) MeCN/H2O by employing
b
c
oxone at rt, see text. Isolated yields. Benzoic acid formation (ca.
30%) was observed as a side product.
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we have carried out the oxidation of the tetramethyl-o-
iodobenzoic acid to TetMe-IBX. Indeed, the latter was isolated
in 84% yield when the reaction was conducted in a preparative
scale at rt for 8 h. Thus, enhanced reactivity due to sterically-
accelerated hypervalent twisting and ease of catalyst generation
from tetramethyl o-iodobenzoic acid permit a facile catalytic
approach; of course, the rate of oxidation under catalytic
conditions is likely to be limited by catalyst regeneration with
oxone unlike that in stoichiometric oxidations. Otherwise, the
unique advantage of catalytic oxidation reported by Ishihara et
al. with o-iodobenzene sulfonic acid is very low catalyst loading
(0.5 mol %). The present protocol is appealing from the point
of view of low acidity of tetramethyl-substituted benzoic acid
̀
(pKa > 4.5 vis-a-vis ca. −6.5 for benezensulfonic acid) and room
temperature for conducting the oxidations.
Oxidation of Sulfides to Sulfoxides at Room Temper-
ature and Mechanistic Considerations. The facile oxida-
tion of alcohols observed with TetMe-IBX spurred us to
explore the oxidation of sulfides to sulfoxides; notably, the latter
process is heretofore unknown to occur at rt with any of the
IBX reagents reported thus far. Remarkably, all the three
modified IBXs were found to oxidize the sulfides to sulfoxides
selectively in DCM at rt. Dialkyl sulfides were found to undergo
oxidation rapidly at rt with all the three reagents. The oxidation
of alkyl phenyl sulfide such as ethyl phenyl sulfide was found to
be rather slow (16−24 h, entries 4 and 5, Table 4) with Me-
Figure 3. The mechanism of oxidation of dimethyl sulfide with IBX
(top) and the activation barriers for the oxygen-transfer process for
IBX and TetMe-IBX (bottom). The dotted line is meant to indicate
that the energy levels are not drawn to scale.
Table 4. Oxidation of Sulfides to Sulfoxides with Me-IBX,
a
DiMe-IBX, and TetMe-IBX at rt
oxygen of IO on the sulfur should be assisted by a partial
charge transfer initially. The Mulliken charge density analyses
of the reactants, transition state species, and products
confirmed this trend, cf. Supporting Information; the initial
charge transfer between IBX and the sulfide explains the reason
as to why p-nitrophenyl phenyl sulfide undergoes oxidation at
higher temperatures requiring some activation (entries 13−15,
Table 4). The mechanism involving initial attack of the sulfur
atom of the disulfide on iodine atom is ruled out on the basis of
the steep increase of the energy. Indeed, the one-step oxygen-
transfer mechanism that is deduced from DFT theoretical
calculations herein agrees precisely with the one reported
recently by Ruff et al.23 for oxidation of sulfides with a variety of
periodates. The calculations for the oxidation of dimethyl
sulfide with IBX and TetMe-IBX reveal that the activation
barriers are not influenced much by the modification of IBX
structure, Figure 3. Why, then, one observes oxidation at room
temperature with TetMe-IBX should be traceable to the
considerable solubility of the reagent in DCM. In other words,
the differences in the rates of the reactions as reflected by the
durations of oxidations in Table 4 for different sulfides with the
three reagents are largely a consequence of the differences in
the solubilities of the IBX reagents in DCM.
a
b
All oxidations were performed in DCM as solvent at rt. 1.1 equiv of
c
d
the reagent was employed. Isolated yields. Reactions were performed
at reflux in DCE.
IBX and DiMe-IBX, whereas it occurred smoothly with TetMe-
IBX within 1 h (entry 6, Table 4). A similar trend in the rates of
oxidation was observed for the three IBX reagents for oxidation
of diphenyl sulfide and phenyl p-bromobenzyl sulfide, as
reflected from the durations of the reactions. Intriguingly, the
oxidation of p-nitrophenyl phenyl sulfide was found to be
sluggish at room temperature, but occurred smoothly in DCE
at reflux (entries 13−15, Table 4).
DFT computations were undertaken to gain insights into the
mechanism of oxidation. The theoretical calculations revealed a
single-step mechanism involving the attack of IBX on dimethyl
sulfide leading to the formation of O−S bond with concomitant
cleavage of the IO double bond; in the transition state, one
observes partial breaking of the double bond of the IBX oxygen
with concomitant formation of the bond between iodine and
sulfur of the sulfide (Figure 3). We believe that the attack of the
CONCLUSIONS
■
The sterics built via tetramethylation of IBX are shown to lead
to considerable twisting of the structure, which manifests in
considerable solubility. The DFT calculations reveal that the
twisting of the structure with tetramethylation brings about
further reduction in the activation energy corresponding to the
rate determining hypervalent twisting. The increase in solubility
via twisting in conjunction with enhancement of reactivity as a
result of tetramethylation permit room temperature oxidation
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of diverse alcohols to the corresponding carbonyl compounds.
Indeed, oxidation of sulfides to sulfoxides is found to occur at
room temperature, which is reasoned on the basis of the
increase in the solubility of TetMe-IBX in DCM. The DFT
calculations reveal a single-step mechanism for the oxidation of
sulfides, the activation barrier for which is not much influenced
by the structural modifications of IBX. The composite effect of
solubility and enhanced reactivity of TetMe-IBX was exploited
to develop a heretofore unprecedented room-temperature
catalytic protocol for convenient oxidation of alcohols to the
corresponding aldehydes and acids using its precursor o-iodo
acid, i.e., TetMe-BA, and oxone; the oxidation of primary
alcohols to aldehydes selectively can be accomplished when the
reactions are run in nitromethane, whereas carboxylic acids are
the end products when the solvent system is acetonitrile−water
(1:1). We are endeavoring to exploit the very high reactivity of
TetMe-IBX to unravel novel synthetic methodologies that
surpass the existing ones.
dioxane, and the mixture was allowed to stir for another 1 h at
rt. The resultant mixture was heated at reflux for 1 h.
Subsequently, the reaction mixture was acidified with dilute
HCl and extracted with EtOAc, washed with brine and
Na2S2O3 solution, and dried over anhydrous Na2SO4. The
combined extract was concentrated in vacuo, and the residue
was subjected to silica gel chromatography to isolate 2,3,4,5-
tetramethylbenzoic acid as a colorless solid in 75% yield (8.4 g,
46.9 mmol): mp 165−167 °C; 1H NMR (CDCl3, 500 MHz) δ
2.26 (s, 6H), 2.31 (s, 3H), 2.54 (s, 3H), 7.64 (s, 1H).
Preparation of 2-Iodo-3,4,5,6-tetramethylbenzoic
Acid. To a solution of 2,3,4,5-tetramethylbenzoic acid (5.5 g,
30.9 mmol) in 50 mL of acetonitrile, N-iodosuccinimide (7.7 g,
34.0 mmol) was added. Subsequently, 0.5 mL of concentrated
H2SO4 and TFA (0.7 mL, 9.3 mmol) were introduced at rt.
The resulting reaction mixture was allowed to stir at rt
overnight. It was subsequently quenched by adding crushed ice.
Filtration of the solid by washing with a small amount of H2O
and petroleum ether, followed by drying under vacuum, led to
the pure product in 92% yield (8.6 g, 28.3 mmol): mp 204−207
EXPERIMENTAL SECTION
■
1
°C; IR (KBr) cm−1 2919, 2513, 1663; H NMR (CDCl3, 500
General Aspects. Column chromatography was conducted
with silica gel of 100−200 μm particle size. NMR spectra were
recorded with 400 and 500 MHz spectrometers. IR spectra
were recorded on an FT-IR spectrophotometer. Mass spectral
analyses were carried out with an ESI-QTOF instrument.
MHz) δ 2.20 (s, 3H), 2.32 (s, 3H), 2.33 (s, 3H), 2.51 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 16.3, 18.4, 18.5, 26.7, 95.5,
131.1, 136.0, 137.0, 137.3, 138.5, 174.8; ESI-MS+ m/z Calcd for
C11H13IO2 305.0038 [M + H], found 305.0034.
Preparation of 2,3,5,6-Tetramethylacetophenone.24
To a suspension of AlCl3 (16.5 g, 123.1 mmol) in 45 mL of
CCl4 cooled to 5 °C was added acetyl chloride (7.9 mL, 111.9
mmol) slowly. The resulting solution was allowed to stir for 1
h. Subsequently, durene (15.0 g, 111.9 mmol) dissolved in 45
mL of CCl4 was slowly introduced into the above solution,
while the temperature was maintained below 5 °C. The
resultant reaction mixture was allowed to stir for 2 h at 0−10
°C and then for another 2 h at room temperature. At the end of
this period, it was poured into crushed ice, and 13 mL of
concentrated HCl was added. The organic matter was extracted
with CHCl3, washed with NaHCO3 and brine, dried over
anhydrous Na2SO4, and concentrated in vacuo to obtain the
crude product, which was purified by silica-gel column
chromatography to isolate 2,3,5,6-tetramethylacetophenone as
pure colorless solid in 80% yield (15.76 g, 89.5 mmol): mp 69−
Preparation of 3,4,5,6-Tetramethyl-2-iodoxybenzoic
Acid, TetMe-IBX. To a solution of oxone (8.1 g, 13.16 mmol)
dissolved in 50 mL of water and 10 mL of acetonitrile was
added 2-iodo-3,4,5,6-tetramethylbenzoic acid (2.0 g, 6.58
mmol), and the resultant suspension was heated at 70 °C for
3.5 h with vigorous stirring. The white precipitate that formed
was collected by filtration. The precipitate was washed with
water and acetone and dried under vacuum to obtain 3,4,5,6-
tetramethyl-2-iodoxybenzoic acid as a colorless solid in 82%
yield (1.81 g, 5.4 mmol): mp 138−140 °C; IR (KBr) cm−1
1
3447, 1662, 727; H NMR (DMSO-d6, 500 MHz) δ 2.28 (s,
6H), 2.62 (s, 3H), 2.67 (s, 3H); 13C NMR (DMSO-d6, 125
MHz) δ 15.9, 16.8, 16.9, 17.4, 127.5, 134.5, 138.6, 141.0, 142.0,
149.6, 168.9; ESI-MS+ m/z [M − H] Calcd for C11H13IO4
334.9780, found 334.9786.
3,4,5,6-Tetramethyl-2-iodosobenzoic Acid. Colorless
solid: mp 148−150 °C; IR (KBr) cm−1 3427, 1660; 1H
NMR (DMSO-d6, 500 MHz) δ 2.26 (s, 3H), 2.27 (s, 3H), 2.45
(s, 3H), 2.64 (s, 3H), 8.08 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ 15.6, 16.4, 17.3, 19.6, 122.5, 127.7, 135.1, 139.8, 149.0,
169.1; ESI-MS+ m/z Calcd for C11H13IO3 318.9831 [M − H],
found 318.9833.
1
71 °C; H NMR (CDCl3, 500 MHz) δ 2.09 (s, 6H), 2.20 (s,
6H), 2.46 (s, 3H), 6.95 (s, 1H).
Procedure for the Preparation of 2,3,4,5-Tetramethy-
lacetopheone.25 A round-bottom flask was charged with
2,3,5,6-tetramethylacetophenone (15.0 g, 85.2 mmol), AlCl3
(31.9 g, 224.1 mmol), NaCl (2.1 g, 34.1 mmol), and H2O (12
mol %), and the contents were heated at 100 °C for 2 h. Later,
the reaction mixture was quenched by adding water. The
organic matter was extracted with CHCl3, washed with
NaHCO3 and brine, dried over anhydrous Na2SO4, and
concentrated in vacuo to obtain the crude product, which
was purified by column chromatography to isolate 2,3,4,5-
tetramethylacetopheone as a pure colorless liquid in 75% yield
Preparation of 3,5-Dimethyl-2-nitrobenzoic Acid.27
To a solution of 3,5-dimethylbenzoic acid (7.9 g, 52.5 mmol) in
41.0 mL of AcOH, 8.8 mL of HNO3 was introduced. The
resultant mixture was stirred at 80 °C, and 7.9 mL of H2SO4
was added at this temperature dropwise to the reaction mixture.
The resultant mixture was stirred at the same temperature for
30 min. Subsequently, it was cooled and poured into ice cold
water. The solid precipitate was collected by filtration. The
colorless solid thus obtained was dried under vacuum to afford
3,5-dimethyl-2-nitrobenzoic acid in 93% yield (9.5 g, 48.9
1
(11.3 g, 63.9 mmol): H NMR (CDCl3, 500 MHz) δ 2.23 (s,
6H), 2.30 (s, 3H), 2.34 (s, 3H), 2.54 (s, 3H), 7.20 (s, 1H).
Procedure for the Preparation of 2,3,4,5-Tetrame-
thylbenzoic Acid.26 A round-bottom flask containing 80 mL
of water was charged with potassium hydroxide (35.0 g, 625.0
mmol) and bromine (9.7 mL, 187.5 mmol) one after the other
at 0 °C. The resulting mixture was allowed to stir for 15−20
min. This solution was slowly added to the solution of 2,3,4,5-
tetramethylacetopheone (11.0 g 62.5 mmol) in 160 mL of
1
mmol): mp 186−188 °C; H NMR (CDCl3 + DMSO-d6, 400
MHz) δ 2.15 (s, 3H), 2.25 (s, 3H), 7.13 (s, 1H), 7.51 (s, 1H),
11.01 (brs, 1H).
Preparation of 2-Amino-3,5-dimethylbenzoic Acid.28
To a solution of 3,5-dimethyl-2-nitrobenzoic acid (9.4 g, 47.9
mmol) in 37.0 mL of EtOH, Sn powder (17.1 g, 143.7 mmol)
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was added. The resultant mixture was stirred at 50−60 °C. To
this solution was added 93 mL of concentrated HCl dropwise,
and the mixture was heated at 70 °C for 1.5 h. Subsequently,
the reaction mixture was made alkaline with aqueous NH3, and
the inorganic salts that precipitated out were filtered off. The
filtrate was concentrated and acidified with AcOH. The
precipitate was collected by filtration, washed with water, and
dried under vacuum. 2-Amino-3,5-dimethylbenzoic acid was
obtained as a colorless solid in 91% yield (7.2 g, 43.6 mmol):
mp 188−190 °C; 1H NMR (CDCl3, 400 MHz) δ 2.24 (s, 3H),
2.27 (s, 3H), 7.13 (s, 1H), 7.64 (s, 1H).
Preparation of 3,5-Dimethyl-2-iodobenzoic Acid. A
solution of 2-amino-3,5-dimethylbenzoic acid (6.8 g, 41.3
mmol) in H2SO4−H2O (25 mL in 50 mL of water) was stirred
for 0.2 h at rt and cooled to 0 °C. To this suspension, a solution
of NaNO2 (3.7 g, 53.6 mmol) in 7 mL of H2O was added
dropwise to the reaction mixture at 0 °C. The temperature of
the reaction was maintained at 0 °C for 1.5 h. To this solution
were added a catalytic amount of Cu powder and a solution of
KI (34.3 g, 206.5 mmol) in 35 mL of H2O slowly. The brown-
colored mixture was vigorously stirred at room temperature for
3.0 h and allowed to stand overnight. Subsequently, the
reaction mixture was diluted with water and extracted with
EtOAc, washed with brine and Na2S2O3 solution, and dried
over anhydrous Na2SO4. The combined extract was concen-
trated in vacuo, and the residue was subjected to silica-gel
chromatography to isolate 3,5-dimethyl-2-iodobenzoic acid as a
colorless solid in 50% yield (5.7 g, 20.6 mmol): mp 158−160
°C; 1H NMR (CDCl3, 400 MHz) δ 2.31 (s, 3H), 2.50 (s, 3H),
7.23 (d, J = 1.5 Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 20.6, 29.8, 96.5, 129.2, 133.9, 135.8,
137.8, 143.6, 173.0; ESI-MS+ m/z Calcd for C9H9IO2 274.9569
[M − H], found 274.9569.
Preparation of 2-Iodo-3-methylbenzoic Acid.29
A
solution of 2-amino-3-methylbenzoic acid (4.0 g, 26.5 mmol)
was stirred in H2SO4−H2O (15 mL of H2SO4 in 30 mL of
water) for 0.2 h. The resultant suspension was cooled to 0 °C,
and a solution of NaNO2 (2.4 g, 34.4 mmol) in 5 mL of H2O
was added dropwise to the reaction mixture at 0 °C. The
temperature of the reaction mixture was maintained at 0 °C for
1.5 h. To this reaction mixture, a solution of KI (22.0 g, 132.4
mmol) in 25 mL of H2O was added slowly. The brown-colored
mixture was vigorously stirred at room temperature overnight.
Subsequently, the reaction mixture was diluted with water and
extracted with EtOAc. The combined extract was washed with
brine and Na2S2O3 solution followed by water and dried over
anhydrous Na2SO4. Solvent was removed in vacuo, and the
residue was subjected to silica-gel chromatography to isolate 2-
iodo-3-methylbenzoic acid as a colorless solid in 86% yield (6.0
g, 22.8 mmol): mp 142−145 °C; 1H NMR (CDCl3, 400 MHz)
δ 2.57 (s, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.40(d, J = 7.6 Hz, 1H),
7.63(d, J = 7.6 Hz, 1H).
Preparation of 3-Methyl-2-iodoxybenzoic Acid, Me-
IBX. To a solution of oxone (14.1 g, 22.9 mmol) in 50 mL of
distilled water, 2-iodo-3-methylbenzoic acid (3.0 g, 11.5 mmol)
was added over a period of 5 min. The resultant mixture was
stirred at 70 °C for 4 h. Subsequently, the reaction mixture was
cooled to 5−10 °C, and the solid precipitate was filtered,
washed with cold acetone, and dried under vacuum to afford
Me-IBX as a colorless solid in 78% isolated yield (2.6 g, 8.9
−1
mmol): mp 146−148 °C (190−192); IR (KBr) cm
3450,
1671, 751,728; 1H NMR (DMSO-d6, 500 MHz) δ 2.78 (s, 3H),
7.61 (d, J = 5.5 Hz, 1H), 7.65 (d, J = 5.8 Hz, 1H), 7.88 (d, J =
5.8 Hz, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 19.8, 128.9,
132.2, 132.9, 138.1, 139.3, 147.6, 168.1; ESI-MS+ m/z Calcd for
C8H7IO4 292.9310 [M − H], found 292.9315.
Preparation of 3,5-Dimethyl-2-iodoxybenzoic Acid.
To a solution of oxone (15.6 g, 25.4 mmol) in 60 mL of
distilled water, 3,5-dimethyl-2-iodobenzoic acid (3.5 g, 12.7
mmol) was added over a period of 30 min. The resultant
mixture was stirred at 70 °C for 5 h. The reaction mixture was
cooled to 5−10 °C. The solid precipitate was filtered and dried
under vacuum to afford 3,5-dimethyl-2-iodoxybenzoic acid as a
colorless solid in 82% yield (3.2 g, 10.4 mmol): mp 151−152
3-Methyl-2-iodosobenzoic Acid. Colorless solid: mp
168−170 °C; IR (KBr) cm −13449, 1642; H NMR (DMSO-
1
d6, 500 MHz) δ 2.63 (s, 3H), 7.55−7.56 (m, 2H), 7.84 (d, J =
6.55 Hz, 1H), 8.30 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ
20.5, 118.7, 130.1, 130.3, 132.6, 138.8, 141.1, 168.0; ESI-MS+
m/z Calcd for C8H7IO3 276.9361 [M − H], found 276.9360.
Procedure for Oxidation of Alcohols and Sulfides with
Modified IBXs. In a typical experiment, 0.5−1.0 mmol of the
alcohol/sulfide was taken in 10.0 mL of DCM, and to it, 1.2/
1.1 equiv of modified methyl-IBX was introduced. The reaction
mixture was stirred for the durations mentioned in Tables 1 and
2 at rt (25−30 °C). The progress of the reaction was monitored
by TLC analysis. After completion of the reaction, the solid
material from the reaction mixture was filtered in vacuo.
Concentration of the filtrate afforded the product, which was
subjected to silica-gel column chromatography to isolate the
pure product.
Procedure for Catalytic Oxidation of Alcohols with
3,5-Dimethyl-2-iodobenzoic Acid and 2-Iodo-3,4,5,6-
tetramethylbenzoic Acid in the Presence of Oxone in
CH3CN/H2O (1:1). In a typical experiment, to a solution of
0.5−1.05 mmol of the alcohol in 9 mL of 1:1 acetonitrile and
water mixture was added powdered oxone (1 equiv for
secondary alcohols and 2 equiv for primary alcohols). To this
reaction mixture was introduced 10 mol % of 3,5-dimethyl-2-
iodobenzoic acid/2-iodo-3,4,5,6-tetramethylbenzoic acid, and
the mixture was stirred at rt for the durations given in Table 3.
After completion of the reaction as monitored by TLC analysis,
a small amount of water was added to dissolve the inorganic
salts. Acetonitrile solvent was removed in vacuo, and the
1
°C (201−203); IR (KBr) cm−1 3462, 1665, 733; H NMR
(DMSO-d6, 400 MHz) δ 2.39 (s, 3H), 2.74 (s, 3H), 7.43 (s,
1H), 7.71 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 19.6,
20.3, 129.2, 133.0, 138.5, 139.0, 142.5, 144.5, 167.9; ESI-MS+
m/z Calcd for C9H9IO4 306.9467 [M − H], found 306.9464.
3,5-Dimethyl-2-iodosobenzoic Acid. Colorless solid:
mp 155−156 °C; IR (KBr) cm−1 3186, 1607; 1H NMR
(DMSO-d6, 500 MHz) δ 2.37 (s, 3H), 2.57 (s, 3H), 7.40 (s,
1H), 7.66 (s, 1H), 8.24 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ 19.8, 20.3, 115.0, 130.5, 132.6, 139.6, 140.3, 140.6,
168.0; ESI-MS+ m/z Calcd for C9H9IO3 290.9518 [M − H],
found 290.9519.
Preparation of 2-Amino-3-methylbenzoic Acid.29 To
a solution of 3-methyl-2-nitrobenzoic acid (5.0 g, 27.6 mmol)
in 70 mL of EtOH, 10% Pd−C (0.4 g) was added, and the
mixture was stirred under H2 atm for overnight. After
completion of the reaction, the reaction mixture was filtered
through Celite, and the filtrate was evaporated under reduced
pressure to yield 2-amino-3-methylbenzoic acid in 98% yield
1
(4.1 g, 27.0 mmol): mp 170−172 °C; H NMR (CDCl3, 400
MHz) δ 2.19 (s, 3H), 6.62 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.1
Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H).
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Article
(8) Moorthy, J. N.; Singhal, N.; Senapati, K. Tetrahedron Lett. 2008,
49, 80.
(9) Uyanik, M.; Akakura, M.; Ishihara, K. J. Am. Chem. Soc. 2009,
organic matter was extracted with ethyl acetate. The combined
extract was washed with brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. The residue was subjected to
column chromatography to isolate the pure oxidation product.
Procedure for Catalytic and Selective Oxidation of
Primary Alcohols with 2-Iodo-3,4,5,6-tetramethylben-
zoic Acid in the Presence of Oxone in CH3NO2. The same
procedure as above was employed, and the reactions were run
at room temperature when CH3NO2 was used as a solvent.
131, 251.
(10) For a recent application of fluorous IBX catalytically, see:
Miura, T.; Nakashima, K.; Tata, N.; Itoh, A. Chem. Commun. 2011, 47,
1875.
(11) (a) Moorthy, J. N.; Singhal, N.; Mal, P. Tetrahedron Lett. 2004,
45, 309. (b) Moorthy, J. N.; Singhal, N.; Venkatakrishnan, P.
Tetrahedron Lett. 2004, 45, 5419. (c) Moorthy, J. N.; Singhal, N.;
Senapati, K. Tetrahedron Lett. 2006, 47, 1757. (d) Moorthy, J. N.;
Singhal, N.; Senapati, K. Org. Biomol. Chem. 2007, 5, 767. (e) Moorthy,
J. N.; Senapati, K.; Singhal, N. Tetrahedron Lett. 2009, 50, 2493.
(f) Moorthy, J. N.; Senapati, K.; Kumar, S. J. Org. Chem. 2009, 74,
6287. (g) Moorthy, J. N.; Senapati, K.; Parida, K. N. J. Org. Chem.
2010, 75, 8416.
ASSOCIATED CONTENT
■
S
* Supporting Information
Details of theoretical calculations and 1H and 13C NMR
spectral reproductions of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) Su, J. T.; Goddard, W. A. III. J. Am. Chem. Soc. 2005, 127,
14146.
(13) All DFT calculations were performed using the Gaussian03
package. The gas-phase geometries were optimized using DFT with
B3LYP functional, employing MWB basis set for iodine and 6-
31G(d,p) basis set for all other atoms. More details are described in
the Supporting Information.
(14) Tojo, G.; Fernandez, M. In Oxidation of Alcohols to Aldehydes
and Ketones; Tojo, G., Ed.; Springer Science+Business Media Inc.:
New York, 2006.
(15) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999,
64, 4537.
(16) Budesinsky, M.; Kulhanek, J.; Boehm, S.; Cigler, P.; Exner, O.
Magn. Reson. Chem. 2004, 42, 844.
(17) Andreou, A. D.; Bulbulian, R. V.; Gore, P. H. Tetrahedron 1980,
36, 2101.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: moorthy@iitk.ac.in (J.N.M.), nnair@iitk.ac.in
(N.N.N.).
ACKNOWLEDGMENTS
■
We thank the Department of Science and Technology (DST),
India for financial support. K.S. and K.N.P. are grateful to UGC
and CSIR for their research fellowships. All computations were
carried out at the ChemFIST Computer Lab, Department of
Chemistry, IIT Kanpur. We thankfully acknowledge the
invaluable suggestions and criticisms of the anonymous
referees.
(18) Moss, J.; Thomas, J.; Ashley, A.; Cowley, A. R.; O′Hare, D.
Organometallics 2006, 25, 4279.
(19) Munari, S. D.; Frigerio, M.; Santagostino, M. J. Org. Chem.
1996, 61, 9272.
(20) Corey, E. J.; Palani, A. Tetrahedron Lett. 1995, 36, 7945.
(21) Thottumkara, A. P.; Bowsher, M. S.; Vinod, T. K. Org. Lett.
2005, 7, 2933.
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2003, 5, 1031.
(23) Ruff, F.; Fabian, A.; Farkas, O.; Kucsman, A. Eur. J. Org. Chem.
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