On the reactivity of C(sp3)-H σ-bonds: Oxygenation with methyl(trifluoromethyl)dioxirane

Article abstract of DOI:10.1002/ejoc.200700773

The reactivity of C-H σ-bonds of a series of 2-substituted adamantanes 2 towards methyl(trifluoromethyl)dioxirane (1) shows a consistent dependence on the electron-withdrawing ability, either inductive or by resonance, of the substituent. The results are

Full text of DOI:10.1002/ejoc.200700773

FULL PAPER
DOI: 10.1002/ejoc.200700773
On the Reactivity of C(sp3)–H σ-Bonds: Oxygenation with
Methyl(trifluoromethyl)dioxirane
Rossella Mello,[a] Jorge Royo,[a] Cecilia Andreu,[a] Minerva Báguena-Añó,[a]
Gregorio Asensio,*[a] and María Elena González-Núñez[a]
Keywords: Oxygenation / Dioxiranes / C–H activation / Hyperconjugation / Substituent effects
The reactivity of C–H σ-bonds of a series of 2-substituted ad-
amantanes 2 towards methyl(trifluoromethyl)dioxirane (1)
shows a consistent dependence on the electron-withdrawing
ability, either inductive or by resonance, of the substituent.
The results are interpreted in terms of the ability of the sub-
strate molecule to delocalize the electronic perturbation of
the reacting center at the beginning of the reaction path. The
model shows that the electronic demand from the reacting
C–H σ-bond is transmitted along the substrate through a
chain of hyperconjugative interactions, the relative inten-
sities of which depend on the σ-bonds involved. The sub-
strate molecule simultaneously provides positive and nega-
tive stabilizing hyperconjugative interactions to the reacting
center, their balance defining the geometry of the system at
the beginning of the reaction path. The model constitutes a
new experimental approach to measurement of the pertur-
bation induced by substituents with significant resonance
contributions on an adjacent C–H σ-bond.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
for instance, alcohols are much easier to oxidize than hydro-
carbons.
Introduction
C(sp3)–H σ-bonds, the commonest σ-bonds in organic
compounds, are involved in a variety of fundamental pro-
cesses of organic chemistry[1] such as H-atom abstraction,
tautomeric and acid-base equilibria, elimination and oxi-
dation reactions, and also the hyperconjugative stabilization
of reactive species such as radicals or carbocations. C(sp3)–
H σ-bonds of hydrocarbons are chemically inert towards
most conventional reagents, but it is known that the pres-
ence of substituents in saturated systems induces changes
in the electronic structures of the adjacent C–H σ-bonds,
which then become suitable targets for free radicals or for
electrophilic, nucleophilic, or basic reagents. It is well
known, for instance, that tertiary C–H σ-bonds react more
rapidly than secondary ones, and that these in turn react
more rapidly than primary C–H σ-bonds in H-abstraction
reactions, an experimental fact that is interpreted in terms
of the hyperconjugative stabilization exerted by the adjacent
alkyl groups on the carbon-centered radical intermediates.
It is also well known that electron-withdrawing substituents
increase the acidities of adjacent C–H σ-bonds, which then
react with bases in deprotonation or elimination reactions.
In addition, electron-releasing substituents activate adja-
cent C–H σ-bonds towards electrophiles in such a way that,
The effect of substituents on the relative reactivities of
remote C–H σ-bonds, however, has been much more diffi-
cult to assess, as the chemical inertness of saturated sub-
strates poses a major difficulty to the achievement of selec-
tive reactions at these positions. The scarcity of systematic
studies on this subject has the consequence that there is
poor understanding of the way in which a saturated sub-
strate responds to the electronic demand originating from a
reacting C–H σ-bond and of the influence of substituents
on the reaction path. The development of efficient C–H σ-
bond activation reactions[2] is a subject of major interest in
fundamental and synthetic organic chemistry and, in this
context, understanding of those factors governing the rela-
tive reactivity of C–H σ-bonds has become a significant
target of chemical research.
Methyl(trifluoromethyl)dioxirane (1) is an efficient tool
with which to bridge this gap, since it is able to insert an
O-atom efficiently into a C–H σ-bond under very mild con-
ditions.[3] Dioxirane 1 is also highly selective and sensitive
to substituents in substrate molecules, which influences the
rates and the regio- and stereoselectivities of these oxygena-
tion reactions.[3,4] These characteristics prompted us to ap-
ply the oxygenation of C–H σ-bonds with methyl(trifluoro-
methyl)dioxirane (1) to suitable saturated substrates as a
unique probe with which to monitor the influence of sub-
stituents on the reactivities of remote C–H σ-bonds.
Our work has allowed us to establish[4k,4m,5] that elec-
tron-withdrawing substituents deactivate saturated sub-
strates towards dioxirane 1 and direct the oxygenation to
[a] Departmento de Química Orgánica, Facultad de Farmacia,
Universidad de Valencia,
Avda. Vicente Andrés Estellés s.n., 46100 Burjassot (Valencia),
Spain
Fax: +34-963544939
E-mail: gregorio.asensio@uv.es
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G. Asensio et al.
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the C–H σ-bonds furthest from the substituent. The linear
and negative slope (ρ = –2.31) observed[5c] in the Hammett
plot of the relative rates of reaction of a series of 2-substi-
tuted adamantanes (2) against the electron-withdrawing
abilities of the substituents gave evidence not only of the
electrophilic character of dioxirane 1 in these reactions, but
also of its sensitivity towards the deactivation of the C(sp3)–
H σ-bonds caused by remote substituents. The observed
distance-dependent deactivation of alkyl chains was inter-
preted[4k,4m,5] as a result of the through-bond transmission
of the inductive substituent effect by a successive polariza-
tion of adjacent σ-bonds.
The reactivities of C–H σ-bonds in saturated substrates
also depend on the relative positions and orientations of
the remote substituents.[5] In previous papers we have re-
ported that monooxygenations of a series of 2-substituted
adamantanes[5a] 2 and substituted cyclohexanes[5b] 3 (Fig-
ure 1) with dioxirane 1 showed significant differences in the
relative reactivities of the diastereotopic C5–H and C7–H σ-
bonds and the C–Hax and C–Heq σ-bonds, respectively.
These results provided evidence of a long-range and
strongly directional substituent effect that, superposing on
the undifferentiated through-bond inductive deactivation,
distinctly modifies the electronic characters of the remote
C–H σ-bonds. The results were interpreted[5a,5b] in terms of
hyperconjugative interactions[6] operating in the stabiliza-
tion of the diastereomeric reacting systems. The relative re-
activities of the diastereotopic C–H σ-bonds were then at-
tributed to the abilities of the remote substituents to modu-
late the relative intensities of these interactions at each re-
acting position.
Results
Our study of the oxygenation of 2-substituted ada-
mantanes 2 with methyl(trifluoromethyl)dioxirane (1) at
–15 °C covered 15 electron-withdrawing substituents:
namely, CH2OAc (2a), NHCOCH3 (2b), OCOCH3 (2c), F
(2d), OSO2CH3 (2e), OSO2C6H5CH3 (2f), ONO2 (2g),
+
NH3 (2h), Cl (2i), COCH3 (2j), COOCH3 (2k), CF3 (2l),
CN (2m), SO2CH3 (2n), and NO2 (2o) (Scheme 1). Isomeric
alcohols (Z)-4 and (E)-4 were prepared by treatment of the
corresponding substrates with dioxirane 1 (Scheme 1). The
reaction products were isolated by column chromatography
and characterized by 13C NMR spectroscopy.[5c] The struc-
tures of (Z)-4e (OMs), (E)-4e (OMs), (Z)-4i (Cl), (Z)-4j
(COCH3), (Z)-4n (SO2CH3), and (E)-4n (SO2CH3) were as-
certained by X-ray diffraction.[5c] This preparative work en-
abled us to establish suitable GC analysis conditions for
each pair of isomeric alcohols (Z)-4 and (E)-4 and to deter-
mine their retention times unequivocally. GC analyses of
compounds 4c (OAc), 4e (OMs), 4f (OTs), and 4h (NH3
were performed on their trifluoroacetylated derivatives (for
details see Exp. Sect.).
+
)
Figure 1. 2-Substituted adamantane and monosubstituted cyclo-
hexane models 2 and 3.
Scheme 1. Oxygenation of 2-substituted adamantanes 2 with meth-
yl(trifluoromethyl)dioxirane (1).
In a previous communication we reported a bell-shaped
The oxygenation reactions addressed towards determi-
correlation between Z/E stereoselectivities and the substitu- nation of the relative reactivities of C5–H and C7–H σ-
ent constants (σI) for compounds 2a–h.[5a] Here we report bonds were each performed at –15 °C by addition of an
a thorough study of the substituent effects on the relative aliquot of a dichloromethane solution of methyl(trifluoro-
reactivities of C5–H and C7–H σ-bonds in 2-substituted ad- methyl)dioxirane (1) to a solution of the substrate 2 in the
amantanes (2) towards methyl(trifluoromethyl)dioxirane same solvent (Scheme 1). The initial 2/1 molar ratio was
(1). The distinct reactivities of the tertiary C(sp3)–H σ- 3:2, with an initial concentration [2]0 = 0.05 . Crude reac-
bonds are interpreted in terms of the different abilities of tion mixtures were directly analyzed by GC, except in those
remote C2–H and C2–W σ-bonds to provide hyperconjuga- cases in which derivatization of the reaction products was
tive stabilization to the Z and E reacting systems as a re- required (for details see Exp. Sect.). The results shown in
sponse of the substrate molecules to the electronic demands Table 1 are each the average of at least three independent
exerted by interaction with the electrophilic dioxirane 1. experiments.
Quantitative application of orbital interaction principles ex-
The oxygenations of substrates 2 in all cases took place
plains the experimental facts and establishes the depen- exclusively at the tertiary C5–H and C7–H σ-bonds. GC-
dence of the hyperconjugative abilities of C2–H σ-bonds on MS analyses of the reaction mixtures showed no evidence
the electronic characters of the adjacent W substituents.
of the characteristic products originating from the radical-
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Methyl(trifluoromethyl)dioxirane Oxygenation
Table 1. Z/E Selectivity in the oxygenation of 2-substituted ada-
mantanes 2 with methyl(trifluoromethyl)dioxirane (1).[a]
[b]
2
W (X/Z)
Z/E
a[c]
b[c]
c[c]
d[c]
e[c]
f[c]
g[c]
h[c]
i
CH2OCOCH3
NHCOCH3
OCOCH3
F
1.006Ϯ0.022
1.538Ϯ0.017
2.504Ϯ0.055
2.572Ϯ0.014
2.534Ϯ0.016
2.365Ϯ0.051
2.030Ϯ0.045
0.914Ϯ0.028
1.994Ϯ0.021
1.469Ϯ0.040
1.281Ϯ0.021
1.328Ϯ0.000
1.143Ϯ0.014
1.340Ϯ0.036
1.927Ϯ0.005
OSO2CH3
OSO2C6H4-p-CH3
ONO2
+[d]
NH3
Cl
j
COOCH3
COCH3
CF3
CN
SO2CH3
NO2
k
l
m
n
o
Figure 2. Z/E Selectivity in the oxygenation of 2-substituted ada-
mantanes 2 with dioxirane 1 vs. σI values.[8] Error bars represent
standard deviation.
[a] Reactions were each carried out at –15 °C in dichloromethane
with an initial 2/1 molar ratio of 3:2. [b] From VPC analysis; values
are each the average of at least three independent runs. [c] Data
from ref.[5a] [d] The counteranion was p-chlorobenzenesulfonate.
The reaction was carried out in 2,2,2-trifluoroethanol.
o bearing substituents with low-energy empty orbitals that
can interact with adjacent filled orbitals (Z-type). All these
substituents are able to withdraw electron density by reso-
nance. This observation prompted us to plot lnZ/E against
triggered decomposition of dioxirane 1, such as trifluoro-
acetic or acetic acid esters or chlorinated products.[7] As
previously described,[4m] protonation efficiently prevented
any oxygenation at the nitrogen atom in compound 2h.
The data show that substituents at C2 induce stereodif-
ferentiation of the remote tertiary C5–H and C7–H σ-
bonds, which results in the diastereoselective oxygenation
of compounds 2 (Table 1). In order to visualize the effects
of the electron-withdrawing abilities of the W substituents
on the relative reactivities of the remote C–H σ-bonds, we
plotted lnZ/E versus σI of the substituent[8] (Figure 2). At
first glance, the data in the plot show no further coherence,
rather a general preference for the oxygenation of the C5–
H σ-bonds to provide the corresponding Z-hydroxylated
products (Z)-3. In fact, substituents with similar electron-
withdrawing abilities give different values of Z/E selectivity:
for instance, 1.143 for CN (σI = 0.59) and 2.365 for
OSO2C6H4-p-CH3 (σI = 0.58).
[9]
σp for substrates 2i–o (Figure 3). In this instance, the plot
showed a V-shaped correlation with two lines of comple-
mentary slopes opposite to those observed in the plot of
lnZ/E against σI for substrates with X substituents 2a–h.
Thus, Z/E selectivity initially decreases as the σp value of
the substituent increases, and the reverse trend is observed
after a minimum value has been reached (Figure 3). The
results show that Z-type substituents at C2 induce lower Z/
E selectivity than X-type substituents with similar σI values
(Figure 2).
However, a closer examination of the data allowed us to
observe that the Z/E selectivities for substrates 2a–h showed
a consistent dependence on the σI values of the substituents,
with two lines of complementary slopes (Figure 2). In this
case, the Z/E selectivity initially increases as the electron-
withdrawing ability of the substituent increases, and the re-
verse trend is observed after a maximum value has been
reached (Figure 2). This result contradicts the intuitive ex-
pectation for a C5–H σ-bond becoming progressively more
reactive than C7–H σ-bond as σI of the W substituent in-
creases.
Figure 3. Z/E selectivity in the oxygenation of 2-substituted ada-
Conversely, the Z/E selectivity data for substrates 2i–o
did not show any definite trend when plotted against the σI
values of the substituents. Significantly, the Z/E selectivity
data that correlate with the σI values of the W substituents
correspond to substrates (2a–h) carrying inductive electron-
[9]
mantanes 2 with dioxirane 1 vs. σI[8] (line) and σp (dashed line)
for X- and Z-series of substituents, respectively. Error bars repre-
sent standard deviations.
The experimental data on the oxygenation of 2-substi-
withdrawing groups (X-type) at C2, while the data that fail tuted adamantanes 2 with methyl(trifluoromethyl)dioxirane
to correlate with the σI values correspond to substrates 2i– (1) indicate a definite and systematic influence of the elec-
Eur. J. Org. Chem. 2008, 455–466
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tronic characters, either inductive or resonance, of the W vincingly explains the most important experimental observa-
substituents on the relative reactivities of the remote C5–H tions.” Since theoretical methods, at the present state of the
and C7–H σ-bonds.
art and technique, cannot provide definite help in interpret-
ing the reactivities of C–H σ-bonds of saturated substrates
towards methyl(trifluoromethyl)dioxirane (1), our attempt
to explain the experimental results rests on the powerful
tools to interpret chemical reactivity provided by pertur-
bation theory.[13]
Discussion
Reaction Mechanism
Within a mechanistic context, the question could be
raised as to whether the change of slope in the plot of Z/E
selectivity versus the parameter quantifying the electronic
effect of the substituent is indicative of a change in the reac-
tion mechanism[10,11] induced by the increasing electron-
withdrawing abilities of the W substituents. However, we
have previously reported[5c] that the Hammett plot for the
oxygenation of 2-substituted adamantanes 2 with methyl-
(trifluoromethyl)dioxirane (1) showed a linear correlation
(ρ = –2.31), consistent throughout a series of substituents
ranging from 0.15 to 0.67 units of σI. The experimental data
allow a change in the reaction mechanism to be disregarded
as the origin of the inversion of slope found in the depen-
dence of Z/E selectivity on the electronic characters of the
substituents.
Transmission of the Substituent Effect
The experimental data are indicative of a long-range and
strongly directional substituent effect that, superposing on
the undifferentiated through-bond inductive effect (A, Fig-
ure 5), distinctly activates C5–H and C7–H σ-bonds towards
the electrophilic dioxirane 1. Both through-space[14,15] and
hyperconjugative[16] modes of transmission of the substitu-
ent effect would fit this description (B, C and D, Figure 5).
The major experimental evidence presently available[10]
on the oxygenation of alkane C–H bonds with methyl(tri-
fluoromethyl)dioxirane (1) supports a concerted “oxenoid”
O-atom insertion mechanism as the main reaction pathway
(Figure 4).
Figure 5. Inductive (A), electrostatic (B), and hyperconjugative (C
and D) effects in the 2-substituted adamantane model 2.
Electric fields associated with substituents have success-
fully justified the relative reactivities of diastereotopic posi-
tions in a variety of organic reactions, particularly in those
involving charged reagents or intermediates.[15] However, we
have previously reported[5c] that changing the solvent (CCl4,
CH2Cl2, CH3CN, CF3CH2OH) in oxygenations of 2-substi-
tuted adamantanes 2 with dioxirane 1 does not significantly
modify the Z/E selectivity found for X-type and Z-type sub-
stituents.[5c] The insensitivity of these reactions to drastic
Figure 4. Concerted O-atom insertion mechanism for the oxygena-
tion of C–H σ-bonds with methyl(trifluoromethyl)dioxirane (1).
Theoretical calculations[12] indicate an asynchronous and changes in both polarity and dielectric constant of the reac-
early transition state in which the breaking of the C–H σ- tion medium strongly suggests that, in this instance, the dif-
bond and the forming of the O–H σ-bond are significantly ferent reactivities of C5–H and C7–H σ-bonds cannot be
more advanced than the forming of the C–O σ-bond. attributed to electrostatic effects derived from the substitu-
Raouk et al. showed[12b] that electron-releasing substituents ents (B, Figure 5).
enhance the hydride-transfer characters of the transition
The hyperconjugative transmission of the substituent ef-
states, which show higher positive charge densities at the fect[16] (C and D, Figure 5) has a strongly directional char-
reacting carbon atoms, longer C–H and C–O distances, and acter since it takes place through the overlap of filled and
more advanced formation of the O–H σ-bonds than those empty orbitals of adjacent antiperiplanar σ-bonds through-
found for nonsubstituted substrates. Conversely, electron- out the substrate molecule (C and D, Figure 5).
withdrawing substituents favor tighter transition states with
Qualitative models for interpreting the diastereoselectivi-
lower positive charge densities at the reacting carbon atoms, ties of chemical reactions on the basis of perturbation
shorter C–H and C–O bond lengths, and longer O–H dis- theory[13] assume that the slope of the energy profile at the
tances, in agreement with the electrophilic character of di- earliest reaction pathway stages determines (or is directly
oxirane 1.
related to) the energy of the transition state. These models
However, Sarzi-Amadè et al.[12a] stated that: “... con- interpret the relative reactivities of two diastereotopic posi-
certed TSs for alkane hydroxylations are seriously flawed by tions in terms of the distinct abilities of their corresponding
the drawback of wave function instability (as a result of their chemical environments to modulate the energy of the re-
significant diradicaloid character) and, consequently, cannot acting system through hyperconjugative interactions at the
be definitely considered genuine transition structures. Actu- beginning of the reaction pathway. These concepts[13] are
ally, no TSs could be located by the more adequate UB3LYP applicable only to that part of the reaction path that in-
method. This is a real pity as the concerted mechanism con- cludes a rather small deformation of the initial structures,
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Methyl(trifluoromethyl)dioxirane Oxygenation
and this restriction obviously deters investigation in the vi- tion path promote hyperconjugative interactions between
cinity of transition states whose structures significantly dif- the reacting center and its chemical environment, and these
fer from those of the reactants.
contribute significantly to the total energy of the reacting
system. These interactions are generally analyzed in terms
of the incipient bond,[6,17] which in our concerted model re-
action would represent the progressive reorganization of
bonding electrons from the C–H to the C–O σ-bonds.
In accordance with the asynchronous character[12] of this
formal hydride-transfer process, electron delocalization be-
tween reactant molecules promotes an initial loss of bond-
ing between carbon and hydrogen atoms that is not fully
compensated by C–O σ-bond formation. Therefore, as the
reacting system starts to move along the reaction path, the
energy gap between the bonding (σinc) and antibonding
(σ*inc) orbitals of the so defined incipient bond decreases
and their interactions with adjacent bonds progressively
strengthen.
On the other hand, an increase in the electron-with-
drawing ability of the substituent diminishes both the elec-
tron delocalization between reactants and the loss of bond-
ing character of the incipient bond. Consequently, for a
given degree of advance of the reacting system, the energy
gap between the bonding and antibonding orbitals of the
incipient bond is broader for the more strongly electron-
withdrawing substituent.
The Beginning of the Reaction Path
The reactions of methyl(trifluoromethyl)dioxirane (1)
with alkane C–H σ-bonds start with the interaction of the
low-lying σ*OO antibonding orbital of the electrophile with
the bonding σCH local orbital of the C–H σ-bond (Fig-
ure 6). Electron delocalization between frontier orbitals
promotes the weakening of both C–H and O–O σ-bonds
and causes a narrowing of the energy gap between their
filled and empty orbitals (σCH, σ*CH) and (σOO, σ*OO),
respectively.[13g] The lowering in energy of the σ*CH orbital
(LUMO of the C–H σ-bond) promotes its interaction with
the nonbonding nO orbital of the oxygen atom (HOMO of
dioxirane 1), and thus initiates the O–H σ-bond-forming
process required for the concerted O atom insertion to take
place (Figure 6).
Figure 6. Orbital interactions of dioxirane 1 with a C–H σ-bond.
It is worth noting that the H-shift from carbon to oxygen
atoms in the concerted O-atom insertion is not a proper
hydride-transfer process, but instead has a mixed-in proton-
transfer character deriving from the electron deficiency gen-
erated at both carbon and hydrogen atoms in the process
of electron delocalization from substrate to electrophile. In
a true hydride-transfer process the system would adopt a
linear arrangement of carbon, hydrogen, and oxygen atoms
and the frontier orbital interaction would transfer electron
density from C–H into O–H σ-bonds without contributing
to C–O σ-bond formation. Conversely, in the concerted O-
atom insertion into a C–H σ-bond by dioxirane 1, the sub-
strate molecule holds its bonding electrons as they are
transferred from the C–H to the C–O σ-bonds while the
H-shift takes place through a different bonding interaction
between oxygen and hydrogen atoms. The concerted charac-
ter of the reaction is then better depicted (Figure 7) as a
hybrid of resonance structures that represent elemental hy-
dride-transfer (I), carbanion-transfer (II), and proton-trans-
fer (III) processes.
Hyperconjugative Interactions
Three types of hyperconjugative interactions can be en-
visaged as the reacting system starts to move along the reac-
tion path (Figure 8). The structure of the 2-substituted ada-
mantane model (2) permits Anh’s [σinc, σCC*] and Cieplak’s
[σ*inc, σCC] hyperconjugative interactions[6] between filled
and empty orbitals of the incipient bond and their corre-
sponding antiperiplanar C–C σ-bonds (see A and C in Fig-
ure 8). Conversely, the geometry of the system prevents Fel-
kin’s destabilizing interaction[17] [σinc, σ] (torsional strain)
(F, Figure 8) between filled orbitals of the incipient bond
and synperiplanar adjacent bonds from being significant
enough to differentiate the diastereotopic reacting posi-
tions.
Figure 8. Felkin’s [σinc, σCH] (F), Anh’s [σinc, σCH *] (A), and Cie-
plak’s [σ*inc, σCH] (C) hyperconjugative interactions in the 2-substi-
tuted adamantane model (2).
Both Ahn’s and Cieplak’s stabilizing interactions[6] (A
and C in Figure 8) strengthen as the reacting system pro-
gresses along the reaction path, and both favor the initial
loosening of bonds required for the reaction to advance
towards the transition state.[13g] The involvement of these
interactions is restricted to the earliest stages of the reaction
Figure 7. Resonance structures describing the concerted character
of O-atom insertion into a C–H σ-bond with dioxirane 1.
Incipient Bond
Loosened bonds arising from incipient bond-forming path, where the concepts of qualitative perturbation theory
and bond-breaking processes at the beginning of the reac- still apply.
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The Substituent Effect
reaction is determined by the relative ability of the C2–H σ-
bond to stabilize the Z reaction pathway in relation to that
of the C2–W σ-bond to stabilize the E reaction pathway.
According to the σI value of the H substituent, Anh’s
stabilization of the Z reacting system is the weakest of the
whole series, while Cieplak’s is the strongest. If the elec-
tronic character of the C2–H σ-bond does not change
throughout the series of substituents (Figure 9), nor does
the hyperconjugative stabilization of the Z reacting system.
Then, as the electron-withdrawing ability of the W substitu-
ent increases, Anh’s interaction [σinc, σCC*] strengthens and
leads to an increase in the stabilization of the E reacting
system. Therefore, Anh’s model predicts a consistent de-
crease in the Z/E selectivity throughout the series (Fig-
ure 9). Conversely, Cieplak’s model, [σ*inc, σCC], predicts a
decreasing stabilization of the E reacting system and a
steady increase in the Z/E selectivity throughout the series
of substituents (Figure 9).
Anh’s and Cieplak’s hyperconjugative interactions[6] im-
ply either placing electrons into antibonding σ*CC orbitals
or removing electron density from bonding σCC orbitals,
and consequently they promote the loosening of the C–C
σ-bonds antiperiplanar to the incipient bond as well as the
narrowing of the energy gap between their bonding and
antibonding orbitals. These perturbed C–C σ-bonds can
then interact efficiently with the next antiperiplanar σ-
bonds and transmit the electronic demand from the reacting
center one step further. The diastereotopic C5–HZ and C7–
HE reacting σ-bonds are connected through the adjacent
antiperiplanar C–C σ-bonds to the C2–H and C2–W bonds,
respectively, which then respond to the perturbation ac-
cording to the relative energies of their bonding and anti-
bonding orbitals. In this way, remote substituents receive
the electronic demand from the reacting centers through
chains of hyperconjugative interactions that, starting at the
incipient bond, extend along the whole substrate molecule.
In order to simplify our approach we will consider that
C2–H and C2–W σ-bonds perturb their corresponding anti-
periplanar C–C σ-bonds and, in this way, modulate the hy-
perconjugative interactions with the Z and E incipient
bonds, respectively.
According to the principles of orbital interaction, the en-
ergies of the bonding and antibonding orbitals of a C–W
σ-bond – σCW and σCW* – decrease as the electronegativity
of the W substituent[13a,16] increases, and this perturbation
is hyperconjugatively transmitted to the adjacent antiperi-
planar C–C σ-bonds. The higher the electron-withdrawing
ability of the substituent at C2, the lower the energies of
the adjacent σCC and σCC* orbitals become (Figure 9). This
effect is more intense on filled orbitals and, consequently,
Cieplak’s interaction decreases faster than Anh’s interaction
increases (Figure 9).
The Model
The experimental data (Figure 3) show that the relative
reactivities of C5–H and C7–H σ-bonds depend on the elec-
tronic characters of the W substituents in a more complex
way than predicted by the straightforward application of
Anh’s or Cieplak’s models of hyperconjugative interac-
tions[6] (Figures 2 and 3).
If the Z/E selectivity is considered to arise from the bal-
ance between the relative ability of the C2–H σ-bond to
stabilize the Z reaction pathway in relation to that of the
C2–W σ-bond to stabilize the E reaction pathway, the exis-
tence of two correlation lines with opposite slopes for each
series of substituents indicates that the two hyperconjuga-
tive interactions alternate in the control of the diastereo-
selectivity depending on the electron-withdrawing ability of
the W substituent. Since the energies of bonding and anti-
bonding orbitals of the C–C σ-bonds involved in the hyper-
conjugative interactions progressively decrease as σI of the
W substituent increases (Figure 9), the data strongly sug-
gest that both hyperconjugative interactions operate simul-
taneously in the stabilization of each diastereomeric reac-
tion pathway.
Simultaneous operation of Anh’s and Cieplak’s models
implies that the stabilization received by the reacting system
corresponds to the sum of the two types of hyperconjuga-
tive interactions. Cieplak’s interaction – [σCC–σinc*] – repre-
sents electron donation from the substrate to dioxirane 1,
stabilizing the developing positive charge at the reacting
carbon atom and enhancing the hydride-transfer character
of the reacting system (I, Figure 7). Anh’s interaction –
Figure 9. Effect of increasing electron-withdrawing ability of W
substituents on Anh’s [σinc, σCC *] (A) and Cieplak’s [σ*inc, σCC] (C)
hyperconjugative interactions for the Z and E reacting systems.
In the case of 2-substituted adamantanes (2), the effect [σinc–σCC*] – balances these effects, since it helps the sub-
of the C2–H and C2–W σ-bonds on the energies of the strate molecule to hold the electron density shifting from
bonding and antibonding orbitals of the C1–C9/C3–C8 and the C–H to the C–O σ-bonds. In this way, it promotes C–
C1–C10/C3–C4 σ-bonds, respectively, determines the inten- O σ-bond formation and enhances the proton-transfer
sity of Anh’s and Cieplak’s hyperconjugative interactions character of H-shift from carbon to oxygen atoms (II, III,
for the reacting systems at positions C5(Z) and C7(E), Figure 7). Cieplak’s and Anh’s hyperconjugative interac-
respectively (Figure 9). Therefore, the Z/E selectivity of the tions distinctly stabilize the resonance forms that describe
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Methyl(trifluoromethyl)dioxirane Oxygenation
the concerted O-atom insertion reaction (Figure 7) and energy vacant orbital associated with the adjacent Z sub-
their relative intensities determine the geometry of the re- stituent lowers the energy of both the bonding and the anti-
acting system.
bonding C2–H σ-bond orbitals (Figure 10). If σp is consid-
With regard to Z substituents, they exert both inductive ered to represent the relative energy of the low-energy vac-
and resonance electron-withdrawing effects that are quanti- ant orbital associated with the Z substituent, the higher σp
fied by σI and σp, respectively. Therefore, the hyperconjuga- is, the lower the energy of the vacant orbital interacting
tive character of the C–Z σ-bond, associated with the in- with the C2–H σ-bond orbitals, and the more intense the
ductive electron-withdrawing ability of the Z substituent, interaction. Perturbation of C–H σ-bonds by adjacent reso-
superposes with the perturbation of the adjacent C2–H σ- nance substituents (either electron-withdrawing or electron-
bond associated with the presence of a low-energy empty p, releasing) is well known in organic chemistry. For instance,
d, π* or σ* orbital.[18] This characteristic allows substitu- this perturbation is responsible for the increased acidity of
ents such as Cl or CF3 to be included in this class. In this hydrogen atoms at the α-position to the Z substituent,[13a]
instance, changes in the Z/E selectivity could be attributed since in this case lowering the energy of the antibonding
to variations in the hyperconjugative stabilization received σ*CH orbital of the C–H σ-bond facilitates an interaction
by the Z reacting system from the remote C2–H σ-bond.
with the filled orbital of the base.
The X-Series
The model applies straightforwardly to the series of X-
substituted substrates 2 (Figure 9, W = X). In this case, the
Z/E selectivity arises from the variable stabilization of the
E reacting system provided by the C2–X σ-bond while the
stabilization of the Z reacting system provided by the C2– Figure 10. Interaction of the low-energy empty orbital of a Z sub-
stituent with the filled and the empty orbitals of the adjacent C–H
σ-bond.
H σ-bond is mostly invariant in this series. Actually, an in-
crease in the electron-withdrawing ability of the X substitu-
ent modifies the relative energies of both the σCH and σ*CH
The effect of the Z substituent on the adjacent C2–H σ-
orbitals of the C2–H σ-bond, but, as these changes would
bond can be represented as a formal variation in the elec-
not be comparatively as large as the changes in the relative
tron-withdrawing ability of the hydrogen atom [σI(HZ)],
energies of the σC–X and σ*C–X orbitals of the C2–X σ-bond
since such a perturbation would also result in a lowering in
within the same range of σI values, the stabilization of the
energy of both σCH and σCH* orbitals. However, we must
Z reacting system can be considered roughly invariant
keep in mind that the parameter σI(HZ) is just a formal
throughout the series of substituents.
value that actually represents the perturbation exerted by
The branch with a positive slope in the plot of Z/E selec-
the resonance contribution of the Z substituent on the adja-
tivity versus σI of X substituents corresponds to the pro-
cent C2–H σ-bond.
gressive loss of Cieplak’s stabilization of the E reacting sys-
The model of simultaneous operation of Anh’s and Cie-
tem, which is not fully compensated by the slow increase in
plak’s hyperconjugative interactions throughout the Z-
Anh’s stabilization (Figure 9, W = X). This trend reaches a
series involves having to consider that the Z reacting system
point of minimum stabilization for the E reacting system,
in this instance receives variable stabilization from the re-
which corresponds to the maximum Z/E selectivity in this
mote C2–H σ-bond (Figure 11). The correlation line with a
series of substituents. The branch with a negative slope cor-
negative slope corresponds to a region where σI(HZ) is
responds to increasing stabilization of the E reacting system
lower than σI(Z), although it progressively increases as σp
provided by Anh’s interaction, which is dominant in this
of the Z substituent increases (Z1 substituent in Figure 11).
region (Figure 9, W = X). Significantly, the slopes of these
This region is mainly controlled by Cieplak’s hyperconjuga-
branches are different, according to the distinct effect that
tive interaction; here the σI(HZ) and σI(Z) values progress-
the substituent has on the filled and empty orbitals of the
ively converge and the trend shows that the C2–H bond’s
interacting C–C σ-bonds.
ability to provide hyperconjugative stabilization to the Z
reaction path decreases when compared to the C2–Z bond’s
ability to stabilize the E transition state (Z1 substituent in
The Z-Series
Figure 11). Selectivity reaches a minimum when σI(HZ) and
Z/E selectivity in the oxygenation of 2-substituted ada- σI(Z) are the same. The correlation line with a positive
mantanes (2) bearing Z substituents at C2 shows a signifi- slope appears when σI(HZ) exceeds σI(Z) (Z2 substituent in
cant dependence on the resonance effect of the electron- Figure 11). This region is mainly controlled by Anh’s hyper-
withdrawing group. This result indicates that the reacting conjugative interaction; here the σI(HZ) and σI(Z) values
C5–H σ-bond receives the effect from the remote Z substit- progressively diverge as σp of the Z substituent increases.
uent through the modification of the electronic character of The data show that the C2–H bond’s ability to provide Anh-
the adjacent C2–H σ-bond. The interaction[13] of filled σCH type stabilization to the Z reaction path is increasingly
and empty σ*CH orbitals of the C2–H σ-bond with the low- higher than that of C2–Z σ-bond for the E reaction path.
Eur. J. Org. Chem. 2008, 455–466
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461

G. Asensio et al.
FULL PAPER
degree of advance of the reacting system the energy gap
between the bonding and antibonding orbitals of the incipi-
ent bond is broader for the more strongly electron-with-
drawing substituent. On the other hand, the energies of the
σCC and σCC* orbitals are represented as linear functions
of σI of the W substituent, with intercepts H and H* and
slopes kc and ka, respectively (Figure 12).
Figure 11. Anh’s [σinc, σCC *] (A) and Cieplak’s [σ*inc, σCC] (B)
hyperconjugative interactions for a Z1 substituent (with low σI and
σp) as well as a Z2 substituent (with high σI and σp) along with
those of their adjacent α-hydrogen atoms.
Application of PMO Theory
The rate constants for the oxygenation of C5–H and C7–
H σ-bonds of 2-substituted adamantanes 2 can be ex-
pressed in terms of the hyperconjugative stabilization (∆E)
received by the Z and E reacting systems at the beginning
of the reaction path in relation to a reference reacting sys-
tem devoid of stabilization (∆G0) [Equation (1)].
Figure 12. Relative energies of orbitals involved in hyperconjuga-
tive stabilizing interactions versus the electron-withdrawing ability
(σI) of the substituent.
LnkZ/kE ϰ ∆GE – ∆GZ = (∆G0 – ∆EE) – (∆G0 – ∆EZ) = ∆EZ
–
∆EE (1)
According to the diagram (Figure 12), the energy gaps
for Anh’s and Cieplak’s interactions for a given remote sub-
stituent W – [σinc – σCC*] and [σCC – σinc*], respectively –
are Equation (5) and Equation (6),
Principles of orbital interaction[13] establish that the sta-
bilization of the bonding combination of two interacting
orbitals depends directly on the overlap integral (S) and
inversely on the difference in energy of the orbitals involved.
If we consider that the Z and E reacting systems simulta-
neously receive Cieplak’s and Anh’s stabilizations (Figure 9)
from remote C2–H and C2–W σ-bonds, respectively, we ob-
tain Equation (2) and Equation (3),
∆εW = (εinc* – εCC) = H + kc σI + [n σI(W)]2
(5)
∆εW* = (εCC* – εinc) = H* – ka σI + [n σI(W)]2
(6)
where H and H* represent the energy gaps for Cieplak’s
and Anh’s interactions, respectively, for σI = 0 (Figure 12).
Thus, the equation that represents the Z/E selectivity of the
reaction in terms of the simultaneous operation of Cieplak’s
and Anh’s hyperconjugative interactions in the diasterom-
eric reaction pathways becomes Equation (7).
∆EZ = [2 k2 SC(H)/(εinc* – εCC)] + [2 k2 SA(H)/(εCC* – εinc)]
(2)
∆EE = [2 k2 SC(W)/(εinc* – εCC)] + [2 k2 SA(W)/(εCC* – εinc)]
(3)
where εCC, εCC*, εinc, and εinc* represent the energies of the
interacting orbitals σCC, σCC*, σinc, and σinc*, and SC and
SA are the overlap integrals for Cieplak’s and Anh’s hyper-
conjugative interactions, respectively. By considering SC(H)
= SC(W) = SA(H) = SA(W), and by substituting 2 and 3 into
Equation (1), we obtain [Equation (4)],
(7)
It is worth noting that the parameter σI is used to define
the relative energies of the interacting orbitals of the incipi-
(4)
where SЈ is the proportionality constant, which comprises ent bond and the adjacent C–C σ-bonds. In this context,
all the invariant magnitudes derived from the different σI(H) is a formal value that allows the perturbation of the
equations applied. This expression can be parameterized C2–H σ-bond exerted by the adjacent W substituents to be
from a simplified energy diagram that shows the depen- introduced.
dence of the relative energy of the interacting orbitals on
Equation (7) expresses the relative reactivities of C5–H
the electron-withdrawing ability of the remote substituent and C7–H σ-bonds as a function of σI of the remote substit-
(Figure 12). In this diagram, the dependence of the energies uent, either H or W, in terms of six invariant parameters:
of σinc and σinc* orbitals on σI of the remote substituent is namely, H, kc, n, H*, ka, and the proportionality constant
represented as two opposing parabolas, since for a given SЈ. This equation can be resolved by iterative methods, pro-
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Methyl(trifluoromethyl)dioxirane Oxygenation
vided that enough experimental data are available. Experi-
mentally determined Z/E selectivity data for the series of 2-
substituted adamantanes with X-type substituents are par-
ticularly suitable for this calculation since, in this instance,
the electronic character of the C2–H σ-bond [σI(HX)] can
be assumed to be roughly invariant along the series.
The calculation was performed on the experimentally de-
termined values of Z/E selectivity for the substituents X =
+
CH2OAc, OAc, OSO2C6H4CH3, and NH3 by using the
Solver implemented in Microsoft Excel® software. The sys-
tem was restricted by requiring that H*ՆH and kc Նka,
in accordance both with the electrophilic character of the
reaction on the saturated substrate and with the stronger
effect of the substituents on the filled orbitals. The iterative
numerical calculation performed by the Solver led to dif-
ferent sets of valid solutions for Equation (7). The set with
H = =
3.6539ϫ10–4, H*
Figure 14. Plot of lnZ/E vs. σI(W) and σI(HZ), according to Equa-
tion (7).
the smallest values was:
3.6629ϫ10–4, kc = 3.5172ϫ10–5, ka = 3.5171ϫ10–5, n =
1.8101ϫ10–3, and SЈ = 8.2676. We made no further attempt
to optimize these results. The model described here predicts
that Z/E selectivity should be unity when the σI values for
H and W are the same. As the experimental data show that
lnZ/E ≈ 0 for X = CH2OCOCH3 with σI = 0.15 (2a), then
σI(HX) for the series of X substituents should carry a value
of ca. 0.15, which would be in agreement with the pertur-
bation exerted by the X substituent on the C2–H σ-bond.
Figure 13 shows the plot of Equation (7) for σI(H) = 0.15
and the experimentally determined Z/E values found for the
X-type substituents.
Figure 14 shows that the model combining the concepts
of the simultaneous operation of Anh’s and Cieplak’s inter-
actions and the variable hyperconjugative character for the
C2–H σ-bond depending on the adjacent substituent cor-
rectly explains the observed experimental data. Thus, the
model predicts different profiles for the dependence of Z/E
selectivity on the electronic character of the substituent for
the series of X and Z substituents (Figure 14). In fact, the
plot shows a U-shaped dependence of Z/E selectivity on the
formal σI(HZ) of the hydrogen atom, which according to
our model is related to σp(Z) of the Z substituent.
Dependence of σI(HZ) on σp(Z)
Formal σI(HZ) values for C2–H can be calculated for dif-
ferent Z substituents by substituting the experimentally ob-
served Z/E selectivity data for the Z-series – σI(Z) – and
the previously calculated parameters in Equation (7). The
σI(HZ) values thus obtained are those required for the ex-
perimentally observed value of lnZ/E to fit in the surface
shown in Figure 14. These values are collected in Table 2.
Table 2. σI(HZ) values calculated for Z substituents from Equa-
tion (7).
(Z)-2
σI (Z)[a]
σp (Z)[b]
σI (HZ)
Figure 13. Plots of Equation (7) for σI(HX) = 0.15 and of lnZ/E
vs. σI(X) for the oxygenation of 2-substituted adamantanes 2a–h
with dioxirane 1.
Cl (2i)
0.47
0.32
0.30
0.40
0.57
0.59
0.67
0.22 (0.24)
0.45 (0.44)
0.49 (0.47)
0.53 (0.53)
0.67 (0.70)
0.72 (0.73)
0.78 (0.81)
0.200
0.221
0.234
0.284
0.655
0.705
0.950
COOCH3 (2j)
COCH3 (2k)
CF3 (2l)
CN (2m)
SO2CH3 (2n)
NO2 (2o)
When σI(HZ) of the hydrogen atom is allowed to vary,
Equation (7) gives rise to a 3-D plot which represents the
relative reactivities of the C5–H and C7–H σ-bonds of the
2-substituted adamantanes (2) towards methyl(trifluoro-
methyl)dioxirane (1) as a function of the electronic charac-
[a] Data from ref.[9] [b] Data from Shorter;[9] data in brackets are
from Exner.[19]
Parent Equation (7) was constructed by considering only
ter of each substituent at C2 (Figure 14). The different sets the inductive electron-withdrawing ability of the remote W
of solutions for Equation (7) provide similar wave-shaped substituent, either X- or Z-type, σI(W), and resolved from
plots for this dependence.
the experimentally determined values of Z/E selectivity for
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463

G. Asensio et al.
FULL PAPER
the X substituents series. In this sense, calculated formal
σI(HZ) values do not contain any reference to σp of the Z
substituent except for the concept of variable σI(HZ) of the
hydrogen atom derived from the principles of orbital inter-
action that were applied for developing the model. In order
to gain a deeper insight into this relationship, we have to
consider those principles in detail and verify whether the
experimentally obtained values fit them.
By assuming that the energy of the bonding σCH of the
C–H σ-bond depends directly on σI(HZ) (Figure 12) we ob-
tain Equation (8),
ε(σCH Z
)
= ε(σCH)0 – A σI(HZ)
(8)
where ε(σCH Z
)
and ε(σCH)0 represent the energies of bond-
Figure 15. Plot of σI(HZ) and AЈ/1 – BЈσp (AЈ = 0.108 and BЈ =
1.158 determined numerically) vs. Shorter[19] (O), Exner[19] (X), and
Taft[20] (∆) sets of σp.
ing orbitals for a C–H σ-bond modified by the adjacent Z
substituent and an unperturbed C–H σ-bond, respectively,
and A is a proportionality constant.
On the other hand, the orbital interaction theory estab-
lishes[13] that the energy of the bonding orbital resulting
from interaction between bonding and antibonding orbitals
of an unperturbed C–H σ-bond with the low-energy vacant
orbital of the Z substituent (Figure 10) is Equation (9),
tively. It is noteworthy that the σI(HZ) values were obtained
from experimental Z/E selectivity data found in the oxygen-
ation of 2-substituted adamantanes (2) with methyl(trifluo-
romethyl)dioxirane (1) by applying fundamental principles
of the perturbation theory, and that σI(Z) and σp(Z) were
obtained from acid ionization equilibrium constants in
water for model aliphatic and aromatic carboxylic acids,
respectively. In this context, the data shown in Figure 15
are significant and indicate that the empirical parameters
σI and σp contain valuable information on the electronic
characters of the substituents which is consistent through-
out a broad variety of chemical and electronic properties of
organic compounds.[21]
The results shown in Table 2 and Figure 15 quantify the
perturbation of a C–H σ-bond exerted by an adjacent Z-
functional group by means of σI(HZ), a formal value which
represents the relative energies of the bonding and anti-
bonding orbitals of the perturbed C–H σ-bond (Figure 12).
Increasing values of σI(HZ) imply lower energies for both
σCH and σCH* orbitals, in agreement with the well known
activation of σ-bonds towards basic reagents exerted by ad-
jacent Z substituents. Notably, these features of functional
group interaction have been revealed by the relative rates of
oxygenation of C5–H and C7–H σ-bonds of 2-substituted
adamantanes (2) with methyl(trifluoromethyl)dioxirane (1).
In this context, σI(HZ) values quantify the acidities of C–
H σ-bonds adjacent to Z substituents without interference
originating from the solvation of ion pairs or from the
changes of solvents and bases commonly associated with
the methods used to determine the pKa values of carbon
acids.[22]
ε(σCH Z
)
= ε(σCH)0 – {H2/[ε(Z) – ε(σCH)0] }
(9)
where ε(Z) represents the energy of the low-energy vacant
orbital of the Z substituent and H is the energy integral
corresponding to the orbital interaction. By equating Equa-
tions (8) and (9), we obtain Equation (10),
σI(HZ) = AЈ/[ε(Z) – ε(σCH)0]
(10)
where AЈ represents invariant magnitudes and proportion-
ality constants. By expressing ε(Z) as directly proportional
to σp, we obtain Equation (11),
σI(HZ) = AЈ/{[ε(Z)0 – B σp(Z)] – ε(σCH)0}
(11)
where ε(Z)0 represents the energy of the low-energy vacant
orbital of a Z substituent with σp = 0, and B is a propor-
tionality constant. By grouping invariant magnitudes and
making BЈ = B/[ε(Z)0 – ε(σCH)0] we obtain Equation (12),
σI(HZ) = AЈ/[1 – BЈ σp(Z)]
(12)
AЈ and BЈ were determined numerically by using our cal-
culated values for σI(HZ) (Table 2) and reported data on
σp(Z); we found that AЈ = 0.1080 and BЈ = 1.1584. Plots of
σI(HZ) values and Equation (12) versus σp(Z) are shown in
Figure 15.
Since calculated σI(HZ) values carry no reference to
σp(Z) of the Z substituent, the goodness of the correlation
line depends on the set of σp(Z) values selected. Thus, the
plot of σI(HZ) values versus AЈ/[1 – BЈ σp(Z)] with use of
the σp(Z) values collected by Exner[19] provides a good lin-
ear correlation (R2 = 0.9853) with slope 1.0442 and inter-
cept at 0.0069 for all Z substituents except for NO2. On the
other hand, our data indicate that σp(Cl) should be 0.40,
Conclusions
The relative reactivities of the C5–H and C7–H σ-bonds
while tabulated values range between 0.22–0.24. In ad- of 2-substituted adamantanes 2 towards methyl(trifluoro-
dition, the σp(Z) values reported by Exner[19] for CN (0.70) methyl)dioxirane (1) show a consistent dependence on the
and NO2 (0.81) differ slightly from those required for per- electron-withdrawing abilities, either inductive or by reso-
fect fitting in our plots, which are 0.72 and 0.77, respec- nance, of the W substituents that cannot be attributed to
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Methyl(trifluoromethyl)dioxirane Oxygenation
romethane (2 mL) and cooled to 0 °C. The solution was then added
dropwise to a cooled solution of trifluoroacetic anhydride (5 equiv.)
in dichloromethane (1.5 mL). The reaction mixture was allowed to
stand at 0 °C and protected from moisture for 18 h. The mixture
was treated with anhydrous potassium carbonate (5 equiv. with re-
spect to trifluoroacetic anhydride) for 3 h. The mixture was diluted
with dichloromethane, and the solids were filtered off. The effi-
ciency of the trifluoroacetylation was monitored by glc with use of
methyl p-chlorobenzoate as an internal standard. The same pro-
cedure was applied for 4e and 4f.
changes in the reaction mechanism. The results are inter-
preted in terms of the relative abilities of the C2–H and C2–
W σ-bonds to provide hyperconjugative stabilization to the
Z and E reacting centers, respectively, at the beginning of
the reaction pathway. The electronic demand from the re-
acting C–H σ-bonds is transmitted along the substrate
molecule through chains of electron-releasing and electron-
withdrawing hyperconjugative interactions, both operating
simultaneously. In this way, the remote C2–H and C2–W σ-
bonds receive perturbation from the Z and E reacting cen-
ters, respectively, and provide differentiated hyerconjugative
stabilization according to their electronic characters. The
experimental data reveal that electron-withdrawing substit-
uents with low-energy empty orbitals, strongly perturb the
hyperconjugative abilities of their adjacent C2–H σ-bonds.
The experimental results fit nicely to the trends predicted
by the orbital interaction theory, which allows the effects of
Z–substituents on the electronic characters of the adjacent
C–H σ-bonds to be determined. Consequently, the role of
the hydrogen atom as a reference substituent should be
taken with care. Our results have revealed the exquisite sen-
sitivity of methyl(trifluoromethyl)dioxirane (1) to subtle
electronic effects operating in the substrate molecules and
the deep insight into chemical reactivity provided by pertur-
bation theory.
Quantitative Trifluoroacetylation of 4h: Once the reaction of 4h
with methyl(trifluoromethyl)dioxirane (1) was complete, the sol-
vents were removed under vacuum. The residue was redissolved in
acetonitrile (substrate concentration ca. 0.05 ) and treated with
five equiv. of anhydrous potassium carbonate at room temperature
for 48 h. The mixture was cooled to 0 °C and was then added drop-
wise at 0 °C to a stirred solution of trifluoroacetic anhydride
(10 equiv.) in dichloromethane (2 mL). After 48 h the mixture was
treated with solid anhydrous potassium carbonate (5 equiv.) for 3 h.
The solvents were removed under vacuum, and the residue was
redissolved in dichloromethane (10 mL). The solids were filtered
off and the solution was analyzed by glc. The efficiency of this
trifluoroacetylation procedure was monitored by glc with methyl p-
chlorobenzoate as an internal standard.
Acknowledgments
Financial support from the Dirección General de Investigación
(DGI) (Spanish General Research Management Board)
(BQU2003-00315) and the Generalitat Valenciana (Valencian Re-
gional Government) (Grupos 2001–2003, GV06/217) is acknowl-
edged. We thank the S.C.S.I.E. (University of Valencia) for access
to their instrumental facilities. J. R. and M. B. thank the Spanish
Ministerio de Educación y Ciencia (MEC) for a fellowship.
Experimental Section
Solvents were purified by standard procedures[23] and distilled be-
fore use. Methyl(trifluoromethyl)dioxirane[24] (1) in ketone-free
dichloromethane solution was prepared as described[7] and the per-
oxide contents of the solutions were determined by iodometric ti-
tration.[25] Solvents were removed under vacuum at 0 °C in all
cases. 2-Substituted adamantyl derivatives 2 were prepared by re-
ported procedures.[5c] The Z and E isomers of 5-hydroxy-2-ada-
mantyl derivatives (3) were prepared by oxidation with methyl(tri-
fluoromethyl)dioxirane (1) and unequivocally characterized as de-
scribed previously.[5c] 1H and 13C NMR spectra of compounds 4
[1] F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry,
4th ed., Kluwer Academic/Plenum Publishers, New York, 2001.
[2] a) B. L. Conley, W. J. Tenn, K. J. H. Young, S. K. Ganesh, S. K.
Meier, V. R. Ziatdinov, O. Mironov, J. Oxgaard, J. Gonzales,
W. A. Goddard, R. A. Periana, J. Mol. Catal. A 2006, 251, 8–
23; b) I. J. S. Fairlamb, Annu. Rep. Prog. Chem., Sect. B: Org.
Chem. 2006, 102, 50–80; c) J. A. Labinger, Nature 2002, 417,
507–514; d) W. D. Jones, Science 2000, 287, 1942–1943; e) G. A.
Olah, A. Molnar, Hydrocarbon Chemistry, John Wiley & Sons,
New York, 1995.
[3] a) R. Curci, L. D’Accolti, C. Fusco, Acc. Chem. Res. 2006, 39,
1–9; b) W. Adam, C. R. Saha-Moller, P. A. Ganeshpure, Chem.
Rev. 2001, 101, 3499–3548; c) Peroxide Chemistry (Ed.: W.
Adam), Wiley-VCH, Weinheim, 2000; d) W. Adam, A. K.
Smerz, Bull. Soc. Chim. Belg. 1996, 105, 581–599; e) E. L. Clen-
nan, Trends Org. Chem. 1995, 5, 231–252; f) R. Curci, A. Di-
noi, M. F. Rubino, Pure Appl. Chem. 1995, 67, 811–822; g) W.
Adam, L. Hadjiaropoglou, R. Curci, R. Mello, in Organic Per-
oxides, Wiley, Chichester. 1992, pp. 195–219; h) R. Curci, Adv.
Oxygenated Processes 1990, 2, 1–59; i) R. W. Murray, Chem.
Rev. 1989, 89, 1187–1201; j) W. Adam, R. Curci, J. O. Edwards,
Acc. Chem. Res. 1989, 22, 205–211.
are reported as Supporting Information in ref.[5c]
.
Determination of the Z/E Selectivity in the Oxidation of 2-Substi-
tuted Adamantanes 2 by Methyl(trifluoromethyl)dioxirane (1): Ge-
neral procedure. An aliquot of a methyl(trifluoromethyl)dioxirane
(1) solution in dichloromethane (initial 2/1 molar ratio 3:2) was
added in one portion to a stirred solution of 2 in dichloromethane
(0.05 ), cooled to –15 °C. The reaction was maintained at –15 °C
in the dark for 2 h, and then the solvent was evaporated under
vacuum to remove the unreacted peroxide. The residue was redis-
solved in the same volume of dichloromethane, and the solution
was analyzed by glc. The products were identified by comparison
with authentic samples.[5c] The Z/E selectivity was determined from
the peak areas corresponding to each isomer. The samples were
analyzed at least three times by glc. The Z/E selectivity values re-
ported are each the average of at least three independent experi-
ments. In the case of compounds 2c, 2e, 2f, and 2h, the crude reac-
tion mixtures were quantitatively trifluoroacetylated by the pro-
cedures reported below.
[4] a) L. D’Accolti, C. Fusco, C. Annese, M. R. Rella, J. S. Turtel-
taub, P. G. Williard, R. Curci, J. Org. Chem. 2004, 69, 8510–
8513; b) M. K. Wong, N. W. Chung, D. Yang, J. Am. Chem.
Soc. 2003, 125, 158–162; c) M. K. Wong, N. W. Chung, L. He,
D. Yang, J. Am. Chem. Soc. 2003, 125, 158–162; d) M. K.
Wong, N. W. Chung, L. He, X. C. Wang, Z. Yan, Y. C. Tang,
D. Yang, J. Org. Chem. 2003, 68, 6321–6328; e) L. D’Accolti,
A. Dinoi, C. Fusco, A. Russo, R. Curci, J. Org. Chem. 2003,
Quantitative Trifluoroacetylation of 4c: Once the reaction of 2c with
methyl(trifluoromethyl)dioxirane (1) was complete, the solvent was
removed under vacuum and the residue was redissolved in dichlo-
Eur. J. Org. Chem. 2008, 455–466
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
465

G. Asensio et al.
FULL PAPER
68, 7806–7810; f) L. D’Accolti, P. Kang, S. Khan, R. Curci,
C. S. Foote, Tetrahedron Lett. 2002, 43, 4649–4652; g) D. Yang,
M. K. Wong, X. C. Wang, Y. C. Tang, J. Am. Chem. Soc. 1998,
120, 6611; h) C. Fusco, M. Fiorentino, A. Dinoi, R. Curci, J.
Org. Chem. 1996, 61, 8681; i) R. Curci, A. Detomaso, M. E.
Lattanzio, G. B. Carpenter, J. Am. Chem. Soc. 1996, 118,
11089; j) G. Asensio, R. Mello, M. E. González-Núñez, G.
Castellano, J. Corral, Angew. Chem. Int. Ed. Engl. 1996, 35,
217–218; k) G. Asensio, G. Castellano, R. Mello, M. E.
González-Núñez, J. Org. Chem. 1996, 61, 5564–5566; l) D.
Kuck, A. Schuster, C. Fusco, M. Fiorentino, R. Curci, J. Am.
Chem. Soc. 1994, 116, 2375; m) G. Asensio, M. González-
Núñez, R. Mello, C. Boix-Bernardini, W. Adam, J. Am. Chem.
Soc. 1993, 115, 7250; n) R. Mello, M. Fiorentino, C. Fusco, R.
Curci, J. Am. Chem. Soc. 1989, 111, 6749–6757.
Chem. Res. 1971, 4, 57–64; j) G. Klopman, J. Am. Chem. Soc.
1968, 90, 223–234; k) L. Salem, J. Am. Chem. Soc. 1968, 90,
543–552; l) L. Salem, J. Am. Chem. Soc. 1968, 90, 553–566.
[14]
a) C. G. Derick, J. Am. Chem. Soc. 1911, 33, 1152–1162; b)
J. G. Kirkwood, F. H. Westheimer, J. Chem. Phys. 1938, 6, 506–
512; c) J. G. Kirkwood, F. H. Westheimer, J. Chem. Phys. 1938,
6, 513–517; d) R. D. Topsom, Acc. Chem. Res. 1983, 16, 292–
298; e) W. F. Reynolds, Prog. Phys. Org. Chem. 1983, 14, 165–
203; f) R. W. Taft, R. D. Topsom, Prog. Phys. Org. Chem. 1987,
16, 1–83; g) G. Bianchi, O. W. Howarth, C. J. Samuel, G. Vla-
hov, J. Chem. Soc. Chem. Commun. 1994, 627–628; h) K.
Bowden, E. J. Grubbs, Chem. Soc. Rev. 1996, 25, 171–182; i) O.
Exner, J. Phys. Org. Chem. 1999, 12, 265–274; j) M. Charton, J.
Phys. Org. Chem. 1999, 12, 275–282; k) R. Ponec, X. Girones,
R. Carbó-Dorca, J. Chem. Inf. Comput. Sci. 2002, 42, 564–570.
[5] a) M. E. González-Núñez, J. Royo, G. Castellano, C. Andreu,
C. Boix, R. Mello, G. Asensio, Org. Lett. 2000, 2, 831–834; b)
M. E. González-Núñez, G. Castellano, C. Andreu, J. Royo, M.
Báguena, R. Mello, G. Asensio, J. Am. Chem. Soc. 2001, 123,
7487–7491; c) M. E. González-Núñez, J. Royo, R. Mello, M.
Báguena, J. M. Ferrer, C. R. deArellano, G. Asensio, G. K. S.
Prakash, J. Org. Chem. 2005, 70, 7919–7924.
[6] a) N. T. Ahn, O. Eisenstein, Tetrahedron Lett. 1976, 17, 155–
158; b) N. T. Ahn, O. Eisenstein, New J. Chem. 1977, 61–70; c)
A. S. Cieplak, J. Am. Chem. Soc. 1981, 102, 4540–4552; d) A. S.
Cieplak, B. D. Tait, C. R. Johnson, J. Am. Chem. Soc. 1989,
111, 8447–8462.
[7] W. Adam, R. Curci, M. E. González-Núñez, R. Mello, J. Am.
Chem. Soc. 1991, 113, 7654–7658.
[8] M. Charton, Prog. Phys. Org. Chem. 1981, 13, 119–251.
[9] a) J. Shorter, Pure Appl. Chem. 1994, 66, 2451–2468; b) J.
Shorter, Pure Appl. Chem. 1997, 69, 2497–2510.
[15]
[16]
a) Y. Xiong, C.-G. Zhan, J. Org. Chem. 2004, 69, 8451–8458;
b) M. M. Toteva, J. P. Richard, J. Am. Chem. Soc. 2000, 122,
11073–11083; c) P. Pérez, A. Toro-Labbé, R. Contreras, J. Phys.
Chem. A 2000, 104, 11993–11998; d) W. Adcock, N. A. Trout,
Chem. Rev. 1999, 99, 1415–1435; e) P. Wipf, J.-K. Jung, Chem.
Rev. 1999, 99, 1469–1480; f) B. Galabov, P. Bobadova-Parv-
anova, J. Phys. Chem. A 1999, 103, 6793–6799.
a) I. V. Alabugin, M. Manoharan, J. Org. Chem. 2004, 69,
9011–9024; b) I. V. Alabugin, T. A. Zeidan, J. Am. Chem. Soc.
2002, 124, 3175–3185; c) I. V. Alabugin, J. Org. Chem. 2000,
65, 3910–3919.
[17]
[18]
a) M. Cherest, H. Felkin, N. Prudent, Tetrahedron Lett. 1968,
9, 2199–2204; b) M. Cherest, H. Felkin, Tetrahedron Lett. 1968,
9, 2205–2208; c) M. Cherest, Tetrahedron 1980, 36, 1593–1598.
Dual effects of substituents originating from their inductive
and their resonance contributions – such as, for instance, on
reaction rate and orientation in aromatic electrophilic substitu-
[10] a) W. Adam, G. Asensio, R. Curci, M. E. González-Núñez, R.
Mello, J. Org. Chem. 1992, 57, 953–955; b) R. Vanni, S. J. Gar-
den, J. T. Banks, K. U. Ingold, Tetrahedron Lett. 1995, 36,
7999–8002; c) G. Asensio, R. Mello, M. E. González-Núñez,
C. Boix, J. Royo, Tetrahedron Lett. 1997, 38, 2373–2376; d)
P. A. Simakov, S. Y. Choi, M. Newcomb, Tetrahedron Lett.
1
tion, or on acidity and H NMR chemical shifts of α-C–H σ-
bonds – are well known in organic chemistry.
O. Exner, in Correlation Analysis in Chemistry (Eds.: N. B.
Chapman, J. Shorter), Plenum Press, New York, 1978, Chapter
10.
[19]
1998, 39, 8187–8190; e) R. Curci, L. DЈAccolti, C. Fusco, Tet- [20]
C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165–195.
rahedron Lett. 2001, 42, 7087–7090; f) W. Adam, R. Mello, R.
Curci, Angew. Chem. Int. Ed. Engl. 1990, 29, 890–891.
[21]
a) I. Fernández, G. Frenking, J. Org. Chem. 2006, 71, 2251–
2256; b) J. B. Barbour, J. M. Karty, J. Phys. Org. Chem. 2005,
18, 210–216; c) Y. Simón-Manso, J. Phys. Chem. A 2005, 109,
2006–2011; d) B. Galabov, D. Cheshmedzhieva, S. Ilieva, B.
Hadjieva, J. Phys. Chem. A 2004, 108, 11457–11462; e) B. G.
Janesko, C. J. Gallek, D. Yaron, J. Phys. Chem. A 2003, 107,
1655–1663; f) O. Exner, S. Böhm, Chem. Eur. J. 2002, 8, 5147–
5152; g) K. B. Wiberg, J. Org. Chem. 2002, 67, 1613–1617; h)
O. Exner, S. Böhm, Chem. Eur. J. 2002, 8, 5147–5152; i) O.
Exner, S. Böhm, J. Org. Chem. 2002, 67, 6320–6327; j) O. Ex-
ner, M. Ingr, P. Cársky, J. Mol. Struct. (THEOCHEM) 1997,
397, 231–238; k) S. Marriot, R. D. Topsom, J. Am. Chem. Soc.
1984, 106, 7–10.
[11] a) A. Bravo, G. Fontana, G. Fronza, F. Minisci, J. Chem. Soc.
Chem. Commun. 1995, 1573–1574; b) A. Bravo, G. Fontana, F.
Minisci, Tetrahedron Lett. 1995, 38, 1895–1898; c) F. Minisci,
L. Zhao, F. Fontana, A. Bravo, Tetrahedron Lett. 1995, 36,
1697–1700; d) A. Bravo, F. Fontana, G. Fronza, F. Minisci, L.
Zhao, J. Org. Chem. 1998, 63, 254–263.
[12] a) M. Freccero, R. Gandolfi, M. Sarzi-Amadè, A. Rastelli, J.
Org. Chem. 2003, 68, 811–823; b) G. V. Shustov, A. Rauk, J.
Org. Chem. 1998, 63, 5413–5422; c) X. Du, K. N. Houk, J. Org.
Chem. 1998, 63, 6480–6483; d) M. N. Glukhovtsev, C. Canepa,
R. D. Bach, J. Am. Chem. Soc. 1998, 120, 10528–10533; e)
R. D. Bach, J. L. Andrés, M. D. Su, J. W. McDouall, J. Am.
Chem. Soc. 1993, 115, 5768–5775.
[22]
a) M. Schlosser, Angew. Chem. Int. Ed. Engl. 1998, 110, 1496–
1513; b) F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456–463; c)
R. W. Taft, F. G. Bordwell, Acc. Chem. Res. 1988, 21, 463–469.
[13] a) A. Rauk, Orbital Interaction Theory of Organic Chemistry,
John Wiley & Sons, New York, 1994; b) T. A. Albright, J. K.
Burdett, M. H. Whangboo, Orbital Interactions in Chemistry,
John Wiley & Sons, New York, 1985; c) K. Fukui, Science
1982, 218, 747–754; d) O. Henri-Rousseau, F. Texier, J. Chem.
Educ. 1978, 55, 437–441; e) N. D. Epiotis, W. R. Cherry, S.
Shaik, R. L. Yates, F. Bernardi, Top. Curr. Chem. 1977, 70, 1–
242; f) I. Fleming, Frontier Orbitals and Organic Chemical Re-
actions, Wiley, New York, 1976; g) K. Fukui, Theory of Orien-
tation and Stereoselection, Springer-Verlag, Berlin, 1975; h) R.
Hoffmann, Acc. Chem. Res. 1971, 4, 1–9; i) K. Fukui, Acc.
[23]
[24]
D. D. Perrin, W. L. F. Armarego, Purification of Laboratory
Chemicals, 3rd ed., Pergamon, New York, 1988.
J. K. Crandall, in Encyclopedia of Reagents for Organic Synthe-
sis (Ed.: L. A. Paquette), John Wiley & Sons, New York, 1995,
vol. 3, pp. 3622–3624.
W. Adam, G. Asensio, R. Curci, M. E. González-Núñez, R.
Mello, J. Am. Chem. Soc. 1992, 114, 8345–8349.
Received: August 20, 2007
[25]
Published Online: November 21, 2007
466
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