Oxidation with a “Stopover” – Stable Zwitterions as Intermediates in the Oxidation of α-Tocopherol (Vitamin E) Model Compounds to their Corresponding ortho-Quinone Methides

Article abstract of DOI:10.1002/open.202000306

As a prominent member of the vitamin E group, α-tocopherol is an important lipophilic antioxidant. It has a special oxidation chemistry that involves phenoxyl radicals, quinones and quinone methides. During the oxidation to the ortho-quinone methide, an intermediary zwitterion is formed. This aromatic intermediate turns into the quinone methide by simply rotating the initially oxidized, exocyclic methyl group into the molecule's plane. This initial zwitterionic intermediate and the quinone methide are not resonance structures but individual species, whose distinct electronic structures are separated by a mere 90° bond rotation. In this work, we hindered this crucial rotation, by substituting the affected methyl group with alkyl or phenyl groups. The alkyl groups slowed down the conversion to the quinone methide by 18-times, while the phenyl substituents, which additionally stabilize the zwitterion electronically, completely halted the conversion to the quinone methide at ?78 °C, allowing for the first time the direct observation of a tocopherol-derived zwitterion. Employing a ¹³C-labeled model, the individual steps of the oxidation sequence could be observed directly by NMR, and the activation energy for the rotation could be estimated to be approximately 2.8 kcal/mol. Reaction rates were solvent dependent, with polar solvents exerting a stabilizing effect on the zwitterion. The observed effects confirmed the central relevance of the rotation step in the change from the aromatic to the quinoid state and allowed a more detailed examination of the oxidation behavior of tocopherol. The concept that a simple bond rotation can be used to switch between an aromatic and an anti-aromatic structure could find its use in molecular switches or molecular engines, driven by the specific absorption of external energy.

Full text of DOI:10.1002/open.202000306

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Oxidation with a “Stopover” – Stable Zwitterions as
Intermediates in the Oxidation of α-Tocopherol (Vitamin E)
Model Compounds to their Corresponding ortho-Quinone
Methides
Stefan Böhmdorfer[a] and Thomas Rosenau*[a, b]
°
As a prominent member of the vitamin E group, α-tocopherol is
an important lipophilic antioxidant. It has a special oxidation
chemistry that involves phenoxyl radicals, quinones and
quinone methides. During the oxidation to the ortho-quinone
methide, an intermediary zwitterion is formed. This aromatic
intermediate turns into the quinone methide by simply rotating
the initially oxidized, exocyclic methyl group into the molecule’s
plane. This initial zwitterionic intermediate and the quinone
methide are not resonance structures but individual species,
whose distinct electronic structures are separated by a mere
methide at À 78 C, allowing for the first time the direct
observation of a tocopherol-derived zwitterion. Employing a
13C-labeled model, the individual steps of the oxidation
sequence could be observed directly by NMR, and the
activation energy for the rotation could be estimated to be
approximately 2.8 kcal/mol. Reaction rates were solvent de-
pendent, with polar solvents exerting a stabilizing effect on the
zwitterion.
The observed effects confirmed the central relevance of the
rotation step in the change from the aromatic to the quinoid
state and allowed a more detailed examination of the oxidation
behavior of tocopherol. The concept that a simple bond
rotation can be used to switch between an aromatic and an
anti-aromatic structure could find its use in molecular switches
or molecular engines, driven by the specific absorption of
external energy.
°
90 bond rotation. In this work, we hindered this crucial
rotation, by substituting the affected methyl group with alkyl or
phenyl groups. The alkyl groups slowed down the conversion
to the quinone methide by 18-times, while the phenyl
substituents, which additionally stabilize the zwitterion elec-
tronically, completely halted the conversion to the quinone
1. Introduction
the most important and effective (Scheme 1). As a lipophilic
antioxidant, it prevents the radical breakdown of lipids in the
cell membrane by capturing free radicals. While the isoprenoid
side chain anchors the molecule in the cell membrane, the
phenolic OH group is the basis of the antioxidative effect, which
is remarkably high due to the special chemical properties of the
substituted chroman rings.
The vitamin E group plays an important role in protecting the
cell membranes of the body from oxidation. It is the biologically
most important fat-soluble antioxidant, which has become a
commodity product and bulk chemical since its first report
about 100 years ago. Besides its antioxidant function, several
non-antioxidant actions of the compound have been identified
recently, and new ones are still being discovered.[1–5] The
vitamin E group is divided into α-, β-, γ- and δ-tocopherol
according to the number and position of methyl substituents
on the aromatic ring. Of these substances, α-tocopherol (1) is
The
model
substance
PMC
(2,2,5,7,8-pentameth-
ylchromanol, 1a),[6] permethylated at the aromatic ring, was
used as model compound of α-tocopherol in our studies. This
compound has already been used almost ubiquitously as model
compound in studies of tocopherol chemistry, for example on
the formation of the corresponding ortho-quinone methide.
Although the activity of the vitamin depends on the length and
stereochemistry of the side chain in vivo, in vitro studies of the
chemical behavior of tocopherols usually use model com-
pounds that contains a methyl group instead of tocopherol’s
long C16 chain. This simplifies synthesis, workup and analysis of
vitamin E derivatives without changing the antioxidant behav-
ior of the chromanol system.
[a] Dr. S. Böhmdorfer, Prof. T. Rosenau
University of Natural Resources and Life Sciences, Vienna
Institute of Chemistry of Renewable Resources
Konrad-Lorenz-Straße 24
3430 Tulln an der Donau (Austria)
[b] Prof. T. Rosenau
Johan Gadolin Process Chemistry Centre
Åbo Akademi University
Porthansgatan 3
The general oxidation behavior of vitamin E is well
established.[7] Upon oxidation of α-tocopherol, three different
intermediates are formed depending on the reaction medium: a
tocopheroxyl radical (2)[8–11] is obtained by one-electron
oxidation, i.e. by abstracting a hydrogen atom (=one electron
plus a proton) from the phenolic OH group. A second one-
electron oxidation of the tocopheroxyl radical leads to the
Turku, 20500 Åbo/Turku (Finland)
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Scheme 1. Important structural features of α-tocopherol (1) and its model compounds PMC (1a). a: phenolic OH group, b: chroman skeleton, c: isoprenoid C16
side chain.
formation of a resonance-stabilized chromanoxylium cation
(3).[12] Else, if α-tocopherol is directly subjected to two-electron
oxidation, or if a proton is abstracted from the chromanoxylium
cation (3), the ortho-quinone methide (oQM, 4)[13] is formed,
which in previous work was directly spectroscopically observed
(NMR) for the first time.[14] Characteristic subsequent reactions
of ortho-quinone methide that convert it into stable products
are the 1,4-addition of nucleophiles to 5a-substituted α-
tocopherol and the hetero-Diels-Alder reaction with olefins. A
special case of this reaction is the reaction of two ortho-quinone
methide molecules to the α-tocopherol spirodimer (5),[15–18]
a
very frequent end product of vitamin E oxidation chemistry. In
this spiro-dimerization, one oQM reacts as the diene and the
other as the dienophile.
The detailed steps in the formation of the ortho-quinone
methide of α-tocopherol (4) was the subject of our present
investigations because of its crucial importance as a central
intermediate in vitamin E chemistry. The starting point for the
study was the consideration that oQM generation from ortho-
methylphenols is not an elementary reaction, i.e., it can be
divided into different steps. Altogether, the system loses two
protons and two electrons, mostly as a proton and a hydride,
but also other combinations are possible (single-electron steps,
cf. Scheme 2). A zwitterionic, still aromatic, intermediate with an
out-of-plane benzylic methylene group is formed (Scheme 3). A
simple bond rotation, which brings the exocyclic methylene
group in plane with the aromatic ring system, would cause the
change from an aromatic to a quinoid system. This intermediate
can be stabilized electronically, by Coulomb interactions with
another zwitterion.[13,14] But also hindering this rotation “me-
chanically”, e.g. by steric properties, or electronically, e.g. by
conjugation effects, should stabilize the zwitterion and delay
the formation of the oQM.
If indeed provable, such a mechanically or electronically
restrained oQM structure would be the first chemical system
where such a fundamental property change as the aromatic-to-
quinone transition (and back) is coupled to and governed by a
very simple molecular process, namely the rotation around a
single bond. Studies of such a system could not only shed new
light on the tocopherol system in particular, but contribute to
our understanding of aromaticity/antiaromaticity as one of the
basic concepts in organic chemistry. To find out more about
this system, special derivatives of tocopherol were synthesized
and their oxidation to oQMs studied.
Scheme 2. Typical oxidation reactions of α-tocopherol (1) or its model
compound PMC (1a).
The detailed mechanism of oQM formation from α-
tocopherol with silver oxide as oxidant has already been
established: in two steps – abstraction of a proton from the
phenolic OH group and a hydride ion from the 5-methyl group
– elemental silver, water and an α-tocopherol zwitterion are
formed (Scheme 4).[7,13,14] This zwitterion carries a negative
charge on the phenolic oxygen and a positive charge on a
benzylic carbon, which is always the 5a-carbon, not the
seemingly equivalent 7a-carbon. The reason for this nearly
complete regioselectivity has been explained previously based
on the theory of strain-induced bond localization (SIBL)[19–21]
which has been reviewed later.[22,23] Due to the spatial arrange-
Scheme 3. Oxidation of ortho-methylphenols to oQMs involves a zwitter-
ionic, aromatic intermediate. In-plane rotation of the methylene group goes
hand in hand with the transition from an aromatic to a quinoid system.
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2. Results and Discussion
As a first approach, a vitamin E model compound carrying a 4-
octyl residue in 5-position instead of the “usual” methyl group
was synthesized. 2,2,7,8-Tetramethyl-5-(4-octyl)-chroman-6-ol
(7) represents an α-tocopherol, in which two of the three
protons at the CÀ 5a methyl group are replaced by alkyl groups,
a propyl and a butyl moiety, so that CÀ 5a is being placed in the
middle of an octyl chain. These substituents are evidently much
larger than a hydrogen atom and have a much higher angular
momentum when rotation around the C5À C5a bond is to occur.
The synthesis (Scheme 5) did not follow the obvious path,
alkylation of the γ-tocopherol model 2,2,7,8-tetramethyl-chro-
man-6-ol (8) at the free aromatic 5-position, because the yields
of the attempted variants were rather inferior, no matter
whether olefin or alkyl halides were employed as the alkylating
agents or whether the phenol was temporarily OH-protected.
Instead, 2,3-dimethylbenzoquinone was equipped with the 4-
octyl moiety by hydroboration with 3-octene and the product
was then reduced to the corresponding hydroquinone and
further converted to the target chromanol 7 by reaction with 2-
methyl-3-butene-2-ol (Scheme 5, upper row). This last step, an
alkylation/cyclization process, resembles the conversion of
trimethylhydroquinone to α-tocopherol in today's standard
industrial synthesis of α-tocopherol.[1,2] Although this three-step
sequence might seem rather lengthy and indirect at a first
glance, it provided a much better yield than all direct alkylation
approaches and was thus clearly superior.
Scheme 4. Zwitterionic intermediate 6a stabilized by electrostatic interac-
tion with another zwitterion, before bond rotation leads on to oQM 4a and
further dimerization to spiro-dimer 5a.
ment necessary for hydride abstraction, the two hydrogens
remaining on the benzylic 5a-carbocation are initially placed
perpendicular to the ring plane of the chroman, and the
benzene ring still retains its aromaticity. The conjugated
quinoid double bond system of the ortho-quinone methide can
only form when this methylene group rotates into the ring
plane by spinning around the bond between CÀ 5 and CÀ 5a, so
that the two 5a-hydrogens now lie in the ring plane (cf.
Schemes 3 and 4). The pronounced resonance stabilization of
the oQM favors it over the aromatic zwitterion. This is why the
reverse reaction – which would require further CÀ 5/CÀ 5a bond
rotation for an out-of-plane movement of the two hydrogens –
is not observed. At low temperatures, the initial zwitterionic
state can be stabilized by complexation with the likewise
zwitterionic N-methylmorpholine N-oxide or the zwitterionic bis
(dimethylsulfonium)ylide from 2,5-dihydroxy[1,4]benzoquinone
(cf. Scheme 4).[24] The strong electrostatic zwitterion-zwitterion
interactions play a major role in this stabilization, which allowed
to observe the α-tocopherol derived oQM, or more correctly, its
zwitterionic precursor, directly by spectroscopic (NMR, UV)
means.[14] It should be noted once more, that the initial
zwitterionic intermediate and the actual oQM are not resonance
structures, but individual species, “separated” by the molecular
movement of the C5À C5a bond rotation.
When the 5-octyl tocopherol model was oxidized with silver
°
oxide at À 78 C, the corresponding ortho-quinone methide was
formed 18 times slower than in the case of α-tocopherol
(Scheme 5, lower row). The complex of the oxidized 5-(3-octyl)-
tocopherol model with the bis(dimethylsulfonium)ylide of 2,5-
dihydroxy-[1,4]benzoquinone decomposed about 10 times
slower than the corresponding complex with α-tocopherol. This
was clear evidence of the involvement of C5À C5a bond rotation
in the process and pointed to its importance in the transition
from the zwitterion to the oQM. Two separate properties of the
alkyl substituents at CÀ 5a are responsible for the observed
stabilization of the zwitterionic transition state: first, the larger
Since this C5À C5a bond rotation occurs very easily – given
the two hydrogens as the smallest possible substituents at
CÀ 5a – it was logical to assume that larger substituents would
restrict the rotatability, in this way making the zwitterionic
intermediate more stable by impeding transition into the oQM.
Also the stabilization of the cationic charge at CÀ 5a by
resonance effects should render the zwitterionic intermediate
more permanent. Therefore, the aim of this study was the
preparation of α-tocopheryl derivatives of which the zwitter-
ions, as first oxidation intermediates, are significantly more
stable, in order to make these intermediates more accessible
and perhaps observable without stabilization by interaction
with other zwitterions.
Scheme 5. Synthesis of 2,2,7,8-tetramethyl-5-(4-octyl)-chroman-6-ol (7)
(upper row) and its oxidation to the corresponding ortho-quinone methide
(lower row). i=4-octene, 1,3,2-benzodioxaborol, DCM, reflux, 5 h; then N,N'-
dimethylpropylene urea, air, r.t., 2 h, ii=NaBH4, THF, r.t., 140 min, iii=2-
°
methyl-3-buten-2-ol, HCOOH, 110 C, 4 h.
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alkyl chains make the rotation about the CÀ 5/CÀ 5a axis more
difficult due to steric requirements for the movement, and
second their significantly higher angular momentum increases
the energy required for bond rotation. The rotation of the
chains into the ring plane requires a higher rotational torque,
which translates into to a slower rotation. This effect can be
easily imagined by means of a figure skater, whose pirouette is
much faster with arms on than with arms off.
As a second approach, a 5a,5a-diphenyl-α-tocopherol model
(5-benzhydryl-2,2,7,8-tetramethyl-chroman-6-ol, 9) was synthe-
sized, which bears two phenyl rings at the CÀ 5a methyl group.
The synthetic path and the X-ray structure of this compound
are presented in Scheme 6. The γ-tocopherol model compound
2,2,7,8-tetramethyl-chroman-6-ol (8) was alkylated with diphe-
nylmethanol, and the same general approach was used to
introduce a 13C-label at CÀ 5a position (9*), the required
diphenyl-13C-methanol being synthesized from ethyl 13C-formi-
ate and phenylmagnesium bromide.
Replacing the two C5a-hydrogens of α-tocopherol model
1a by the two aromatic substituents had a significant effect on
the oxidation behavior, in particular on the rate of conversion
of the corresponding zwitterionic intermediate into the corre-
sponding oQM. First, the phenyl groups are significantly larger
than even the alkyl groups of the above octyl-substituted
model compound (7). The in-plane arrangement – as the
Scheme 7. Oxidation of 5a-13CÀ 5a,5a-diphenyl-2,2,7,8-tetramethyl-chroman-
6-ol (9*), monitored by changes of the 13C5a-resonance (13C NMR, CDCl3, 4
scans). The starting compound (δ5a 49 ppm) treated with Ag2O initially yields
the zwitterionic compound with perpendicularly oriented phenyl substitu-
ents (δ5a 205 ppm), which is transformed into the oQM (δ5a 129 ppm) upon
C5À C5a bond rotation. The final stable product is a xanthene derivative (δ5a
33 ppm) formed by ring closure and rearomatization.
prerequisite of oQM-formation
–
is sterically additionally
this way, however, the electrons of the aromatic systems in the
phenyl substituents cannot participate in conjugation with the
planar double bond system of the ortho-quinone methide. This
is why the ortho-quinone methide from 9 is not additionally
favored over the aromatic state of the intermediate zwitterion,
this missing preference being different from the case of α-
tocopherol (1) and its truncated model compound 1a.
disadvantaged, and the perpendicular alignment of the C5a-
substituents in the zwitterion is favoured. In other words, the
bulky C5a-phenyl substituents effectively impede the rotation
around the C5À C5a bond that is necessary for the formation of
ortho-quinone methide from the initial zwitterionic oxidation
intermediate.
In addition to these steric effects, also electronic effects
become active. The aromatic substituents electronically strongly
stabilize the positive charge at C5a, the cation being actually
embedded in a triphenylmethyl (trityl) structure. Quantum
chemical calculations indicate that the HOMO of the zwitterion
of the biphenyl-α-tocopherol model (9) is distributed across all
three aromatic rings. Therefore, the zwitterionic intermediate
from model compound 9 is stabilized by both steric effects and
electronic stabilization. After the C5À C5a bond rotation has
eventually taken place and the ortho-quinone methide has
been formed, the phenyl substituents, for steric reasons, cannot
lie in the chroman plane and must protrude from it. Oriented in
Using the 13C-isotopically labeled model compound 9* with
a
13C-label at C5a (see Scheme 6), the individual steps of the
oxidation – formation of the primary zwitterionic intermediate
(9a*), rotation to give the ortho-quinone methide (9b*), and
subsequent generation of a stable end product (10) – became
directly observable by 13C NMR spectroscopy by following the
peak of C5a, which was now about 100 times enhanced by the
increased isotopic abundance compared to the natural 13C
isotopic abundance of approx. 1% (Scheme 7). Accumulation of
only 4 scans was (more than) sufficient to report the state of
the isotopic label, while all other carbons of natural isotopic
abundance are blinded out.
Scheme 6. Synthesis and X-ray structure of 5a,5a-diphenyl-2,2,5,7,8-pentamethyl-chroman-6-ol (9). The same approach was used for the 13C-isotopically
13
°
labeled compound 5a- CÀ 5a,5a-diphenyl-2,2,5,7,8-pentamethyl-chroman-6-ol (9*). i=AlCl3, THF, r.t., 42 h, ii=THF, 0 C, 2 h.
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The chemical environment of C5a is heavily affected by the
oxidation process: being aliphatic (benzylic) in the starting
material 9*, C5a first becomes the cationic center of the
zwitterionic intermediate (9a*) and after that a part of the
oQM's double bond system (9b*), see Scheme 7. In each of
these states, C5a has a significantly different 13C NMR shift,
which enabled us to determine the concentration of each
intermediate directly. Model compound 9* was dissolved in
°
chloroform at À 78 C, and the C5-resonance appeared at
°
49 ppm. Upon addition of silver oxide as the oxidant at À 78 C,
the resonance changed fast (within seconds) to 205 ppm. This
chemical shift agrees with the structure of a carbocation with
three phenyl substituents – the zwitterionic intermediate – and
corresponds excellently with the chemical shift of
triphenylmethylium (tritylium) cations.[25] At À 78 C, this zwitter-
°
Scheme 8. Three-step synthesis of xanthene 10 for independent structure
confirmation. i=Cu(OAc)2, NEt3, DCM, r.t., 17 h, ii=THF, r.t. 30 min, iii=cat.
ion was obviously stable, since no decrease in its concentration
was observed and no other signals indicative of decomposition
products appeared (Figure 1). Notably, an inherently stable
tocopherol-type zwitterion has never been observed before,
previous stabilization attempts had to resort to chemical
stabilization by interaction with other zwitterions.[14] When the
sample was warmed to room temperature within 20 s and kept
at this temperature for 10 min, the signal intensity of the peak
at 205 ppm decreased, and a new signal at 128 ppm appeared
within 60 s, which was assigned to the now “olefinic” C5a in the
ortho-quinone methide (9b*). The intensity of this signal
decreased slowly during the next 9 min at room temperature
and then also after the temperature had been quickly lowered
°
H2SO4 conc., 0 C, 5 min.
UV/Vis as 3,3,5,6-tetramethyl-12-phenyl-1,2,3,12-tetrahydro-pyr-
ano[3,2-a]xanthene (10). Subsequently the structure was con-
firmed by independent synthesis of an authentic sample (see
Scheme 8).
°
When the sample was cooled down again to À 78 C after
the intermission of 10 min at room temperature, no new ortho-
quinone methide (9b*) was formed from the zwitterion (9a*),
because the zwitterion concentration did not change even over
hours. However, oQM still present in the reaction mixture slowly
continued to react to the xanthene (10), easily recognizable by
the decreasing peak at 128 ppm and the corresponding
increase of the resonance at 33 ppm (Figure 1, Scheme 7).
Evidently, the underlying ring closure reaction proceeded even
at this low temperature. It was intriguing to see that this
°
again to À 78 C. The temperature profile and the concentration
profiles of starting material 9* and intermediates (9a* and 9b)
are shown in Figure 1.
During the 10 min room temperature interval, a new signal
at 33 ppm appeared and increased at the same rate as the
128 ppm-resonance decreased. The new signal constantly
increased and then kept constant, but never decreased, so it
obviously originated from a final, stable product (Figure 1). It
was the only resonance detectable when the reaction mixture
was left standing at room temperature for several hours. This
end product was, at first, preliminarily identified by NMR and
°
reaction apparently proceeded even faster at À 78 C than at
room temperature, as was evident in Figure 1 from the faster
consumption of the oQM after decreasing the temperature
°
from r.t. to À 78 C. This result was counterintuitive at a first
glance and seemed to collide with basic kinetic laws. However,
Figure 1. Oxidation of 5a-13C-5a,5a-diphenyl-2,2,7,8-tetramethyl-chroman-6-ol (9*) by Ag2O in CDCl. 13C-peak intensities (4 scans per data point) of the CÀ 5a
resonances of zwitterion intermediate 9a* (squares), the oQM 9b* (circles) und final xanthene product 10 (crosses) in dependence of the temperature
(temperature profile: solid line without symbols, right y-axis).
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it became understandable when the geometric conditions were
taken into account: formation of the xanthene requires chro-
man and phenyl ring to be arranged in the same plane. Even
with the oQM's C5À C5a double bond properly in place, the
phenyl rings would easily remain in rotational motion. At room
temperature, both the rotation around the C5À C5a bond and
the rotation of the phenyl rings would be much faster than at
mere rotation around a single bond. Substitution of two
hydrogens of the crucial exocyclic methyl group with alkyl
chains increased both the angular momentum and the steric
demand of this rotation, which was sufficiently hindered to
result in an 18 times slower oQM-formation compared to the
methylene structure. When aromatic substituents were attached
to the ortho-methyl group, the additional steric and electronic
°
°
À 78 C, so that the rings align only fleetingly in a geometry
effects stabilized the intermediate zwitterion at À 78 C com-
optimal for xanthene formation. The lower the temperature, the
more frequent become the “opportunities” for the rings to
“meet” in an in-plane arrangement suitable for ring closure,
pletely so that it became stable at this temperature. By means
of 13C-labeling, all stages of the oxidation reaction – starting
material, zwitterion, oQM, final oxidation product – were
observed in the order of their appearance and recording
kinetics became possible. At room temperature, the conversion
of zwitterion 9a to oQM 9b was still slow enough to determine
its activation energy to be 2.8 kcal/mol, which corresponds to
the rotational barrier of the C5À C5a bond. Reaction rates were
found to be solvent dependent, with polar solvent having a
stabilizing effect on the zwitterion. The oxidation product, a
xanthene derivative, was fully analytically characterized and its
identity additionally confirmed by independent synthesis.
The fact that a simple rotation around a single bond can act
as a switch between aromaticity and antiaromaticity, such as
between 9a and 9b, might in future allow to construct
molecular switches, to assemble uniformly moving molecular
arrays or to drive molecular machines by the absorption energy
of aromatic/antiaromatic structures. While these applications lie
in the future, the findings certainly give more detailed insights
into ortho-quinone methide chemistry already now, and they
complement conventional teaching about oQM formation and
oQM chemistry.
°
which explains the faster reaction at À 78 C.
Since NMR-signal intensities correspond directly to concen-
trations, we were able to determine the concentrations of all
four substances at any time of measurement. This data was
used to approximate the difference in activation energies for
the reaction of the zwitterion to the oQM, according to a simple
Arrhenius-type equation. At 295 K, the ratio of zwitterion to
oQM was constantly 3.1:1. Assuming both compounds to be in
equilibrium is justified since the “reaction” consists only in the
rotation of the phenyl groups in and out of the plane of the
chroman. This yields an approximated activation energy (rota-
tional barrier) of 2.8 kJ/mol.
The influence of the solvent on the reaction rate of the
formation of the oQM was investigated as well. Apolar solvents
favoured oQM formation, and the ratio of the reaction rates in
d6-DMSO, CDCl3 and C6D6 was 1:8:13, respectively. This
corresponds to observations from the chemistry of α-tocopher-
ol, for which apolar-aprotic media favour oxidation to the oQM,
while polar media promote formation of the chromanoxylium
intermediate (Scheme 7). Since the formation of the ortho-
quinone methide is slower in polar solvents and can even be
stopped temporarily by zwitterionic stabilizers, it was expected Experimental Section
that ionic liquids – due to their permanently present cations
and anions – might also delay the formation of the oQM by
stabilization of the zwitterion. This effect was indeed observed,
but was not particularly pronounced. In 1-butyl-3-meth-
ylimidazolium ionic liquids with different anions, the conversion
to the oQM was only 22 times slower than in C6D6, i.e. about
1.5 times slower than in DMSO-d6. It was speculated that the
two opposite charges in the stabilizing agent must be arranged
in quite close proximity and must be quite localized to exert a
large stabilizing effect. While this is the case in amine N-oxides
and in the sulfonium ylide, bulky ions and additionally
delocalized charges, as in the case of ions with solvent shells
and ionic liquids, are probably too scattered to exert a strong
effect.
Materials and Methods
Commercial chemicals were of the highest grade available and
were used without further purification. 2,2,7,8-Tetrameth-
ylchroman-6-ol was available from previous projects. Reagent-grade
solvents were used for all extractions and workup procedures.
Dichloromethane (DCM) was dried over P2O5, while dry THF and
ethyl ether (EE) were obtained by refluxing over from sodium.
Distilled water was used for all aqueous extractions and for all
aqueous solutions. All reactions involving non-aqueous conditions
°
were conducted in oven-dried (140 C, overnight) or flame-dried
glassware under argon or nitrogen. TLC was performed with Merck
silica gel 60 F254 pre-coated plates. Flash chromatography was
performed with Baker silica gel (40 μm particle size). All products
were purified to homogeneity as checked by TLC/GC-MS analysis.
The use of brine refers to saturated NaCl (aq.). All given yields refer
to isolated, pure products.
1H NMR spectra were recorded at 300.13 MHz (400.13 MHz,
3. Conclusion
1
respectively) for H and at 75.47 MHz (100.41 MHz, respectively) for
13C NMR with CDCl3 as the solvent if not otherwise stated. Chemical
shifts, relative to TMS as internal standard, are given as δ values,
coupling constants in Hz. 13C peaks were assigned with the aid of
APT, HMQC, and HMBC spectra.
The zwitterionic intermediate in the formation of ortho-quinone
methides from the parent ortho-alkylphenols was observed
directly by spectroscopy for vitamin E-related compounds,
without the addition of stabilizing zwitterionic molecules. The
transition from the primary aromatic, zwitterionic oxidation
intermediate to the ortho-quinone methide is effected by a
GC-MS was performed on a GC 6890N/MSD 5973B instrument with
a fused silica HP-5 ms (30 m, 0.25 mm, 25 μm) column and helium
as carrier gas. Total flow was 27.5 mLminÀ 1 at 46.9 kPa carrier gas
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pressure and the resulting column flow was 0.9 mLminÀ 1. The
The obtained residue was dissolved in methanol (25 mL) and
concentrated hydrochloric acid (1 mL), and the solution was heated
À 1
°
°
temperature programs were as follows: 100 C (5 min), 10 C min
°
°
to 280 C (20 min). Aliquots (0.2 μL) of the dissolved samples were
to 65 C to cleave the formic acid ester formed in the previous step.
°
injected at 230 C inlet temperature in split mode (25:1). Ionization
After 70 minutes, the solvent was evaporated, and diethyl ether
was added. The organic solution was washed two times with
distilled water and once with saturated NaHCO3-solution, dried over
MgSO4, filtered, and evaporated in vacuo. Column chromatography
(silica gel, hexane:EE, v/v=100:1) yielded 104 mg of 2,2,7,8-
tetramethyl-5-(4-octyl)-chroman-6-ol as a yellow oil (42% yield).
was performed in EI mode at 70 eV.
X-ray Crystallographic Study: X-ray data collection was performed
with a Bruker AXS Smart APEX CCD diffractometer and graphite-
monochromatized Mo-Kα radiation, λ=0.71073 Å; corrections for
absorption with the program SADABS, structure solution with direct
methods, structure refinement on F2 (Bruker AXS, 2001: programs
SMART, version 5.626; SAINT, version 6.36 A; SADABS version 2.05;
XPREP, version 6.12; SHELXTL, version 6.10. Bruker AXS Inc.,
Madison, WI, USA).
1H NMR: δ=0.80–0.89 (m, 6H, H-ɛ, H-γ’), 1.07–1.32 (m, 6H, H-δ, H-γ,
3
H-β’), 1.26 (s, 6H, H-2a), 1.60–1.90 (m, 4H, H-β, H-α’), 1.76 (t, JHH
=
=
3
6.9 Hz, H-3), 2.10 (s, 3H, H-7a), 2.11 (s, 3H, H-8b), 2.66 (t, JH,H
6.9 Hz, H-4), 2.87 (m, 1H, H-α), 4.21 (s, 1H, OH). 13C NMR: δ=12.0 (C-
8b/C-7a), 12.1 (C-7a/C-8b), 14.1 (C-ɛ), 14.8 (C-γ’), 21.7 (C-4/ C-β’),
21.8 (C-β’/C-4), 23.1 (C-δ), 26.5 (C-2a), 26.6 (C-2a), 30.8 (C-γ), 33.5 (C-
3), 34.1 (C-β/C-α’), 36.6 (C-α’/C-β), 38.5 (C-α), 72.1 (C-2), 117.5 (C-8),
121.7 (C-7), 122.9 (C-4a), 126.3(C-5), 127.1 (C-6), 145.5 (C-8a).
2,2,7,8-Tetramethyl-5-(4-octyl)-chroman-6-ol (7)
The alkylated model compounds were prepared in two steps via
2,3-dimethyl-5-(1-propyl-pentyl)-[1,4]benzoquinone.
EI-MS (70 eV): 318 (100%), 219 (62%), 319 (22%), 165 (21%), 164
(13%), 220 (10%).
2,3-Dimethyl-5-(4-octyl)-[1,4]-benzoquinone. (Z)-4-Octene (659 mg,
5.88 mmol, 2.0 eq.) and N,N-dimethylacetamide (DMAc, 51 mg,
0.588 mmol, 0.2 eq.) were dissolved in dry DCM (6 mL) under an
Rf (n-hexane/ethyl acetate, v/v=5:1)=0.53.
°
atmosphere of argon. The solution was cooled to 0 C and 1,3,2-
5a,5a-Diphenyl-2,2,5,7,8-pentamethylchroman-6-ol (9)
benzodioxaborole (880 mg, 7.34 mmol, 2.5 eq.) was added slowly.
The solution was heated to reflux for 5 h, water (317 mg, 6.0 eq.)
was added slowly, and the mixture was stirred for another 20 min.
N,N’-Dimethylpropylene urea (753 mg, 5.88 mmol, 2.0 eq.) and 2,3-
dimethyl-[1,4]-benzoquinone (400 mg, 2.94 mmol, 1.0 eq., dissolved
in 5 ml of DCM) were added. Air (3 mL) was bubbled into the
solutions with a syringe to increase radical formation. After two
hours, the reaction was quenched with saturated NH4Cl-solution
and extracted two times with diethyl ether. The combined organic
extracts were washed with brine, dried over MgSO4, filtered, and
evaporated in vacuo. Column chromatography (silica gel, hexa-
ne:EE, v/v=50:1) yielded 245 mg of 2,3-dimethyl-5-(4-octyl)-[1,4]-
benzoquinone (34%) as a yellow oil.
Aluminum chloride (262 mg, 1.96 mmol, 4.0 eq.) and 2,2,7,8-
tetramethylchroman-6-ol (101 mg, 490 μmol, 1.0 eq.) were placed
in a dry 2-necked round bottom flask equipped with a drying tube
and were dissolved in dry THF (3 mL). Diphenylcarbinol (90 mg,
490 μmol, 1.0 eq.) was dissolved in dry THF (1 mL) and added to
the reaction mixture. The reaction was stirred at room temperature
for 42 h, and then distilled water was added. The aqueous mixture
was extracted three times with EE. The organic layers were
combined and washed three times with saturated NaHCO3-solution
and two times with brine. The organic phase was dried over
Na2SO4, filtered, and evaporated in vacuo. The crude product
(172 mg of a yellow oil) was purified by column chromatography
(hexane:ethyl acetate, v/v=50:1, 6 g of silica gel), yield: 151 mg of
colorless crystals (83%).
1H NMR: δ=0.78-0.99 (m, 6H, alkyl CH3), 1.07–1.61 (m, 12H, 10H
alkyl CH2), 2.00–2.03 (m, 6H, H-2a, H-3a), 2.86 (m, 1H, H-5a), 6.44 (s,
1H, 6-H). 13C NMR: δ=12.0 (C2a/C3a), 12.5 (C3a/C2a), 13.9 (Cɛ), 14.1
(Cγ’), 20.4 (Cβ’), 22.7 (Cδ), 29.5 (Cγ), 34.2 (Cβ), 36.8 (Cα’), 37.1 (Cα),
131.5 (C6), 140.1 (C2/C3), 141.2 (C3/C2), 152.7 (C5), 187.9 (C1, C4).
1H NMR: δ=1.27 (s, 6H, H-2a), 1.72 (t, 2H, 3JH,H =6.4 Hz, H-3), 2.08 (s,
3
3H, H-8b), 2.13 (s, 3H, H-7a), 2.69 (t, 2H, JH,H =6.4 Hz, H-4), 4.36 (s,
1H, OH), 5.77 (s, 1H, H-5a), 7.17–7.34 (m, 10 H, ArÀ H). 13C NMR: δ=
12.1 (C-7a), 12.2 (C-8b), 21.3 (C-4), 26.6 (C-2a), 33.2 (C-3), 49.1 (C-5a),
72.3 (C-2), 116.7 (C-8), 124.2 (C-5), 124.3 (C-4a), 125.2 (C-7), 126.9 (C-
4’), 128.9 (C-2’, C-6’), 129.0 (C-3’, C-5’), 141.6 (C-1’) 145.7 (C-8a),
145.9 (C-6).
EI-MS (70 eV): 151 (100%), 150 (93%), 122 (82%), 248 (55%), 137
(37%), 91 (31%), 205 (28%), 177 (28%), 178 (27%), 152 (27%), 135
(26%), 138 (25%), 163 (25%), 41 (25%), 179 (24%), 191 (23%), 192
(22%), 77 (20%), 164 (20%), 53 (19%), 79 (%), 165 (19%), 219(18%),
107 (18%), 55 (18%), 123 (17%), 136 (16%), 43 (16%), 159 (15%),
121 (15%), 149 (15%), 105 (15%), 206 (14%), 193 (14%), 39 (13%),
93 (13%), 67 (13%), 161 (10%), 81 (10%), 249 (10%), 54 (10%).
EI-MS (70 eV): 372 (100%), 239 (39%), 238 (31%), 373 (28%), 225
(19%), 315 (15%), 301 (14%), 165 (12%), 224 (12%), 316 (10%).
Rf (n-hexane/ethyl acetate, v/v=5:1)=0.56.
Rf (n-hexane/ethyl acetate, v/v=5:1)=0.51.
2,2,7,8-Tetramethyl-5-(4-octyl)-chroman-6-ol (7). The above benzo-
quinone (195 mg, 785 μmol, 1.0 eq.) was dissolved in THF (2 mL)
5a-13C-5a,5a-Diphenyl-2,2,5,7,8-pentamethylchroman-6-ol
(9*)
°
under an argon-atmosphere and cooled to 0 C. Sodium borohy-
dride (45 mg, 1.18 mmol, 1.5 eq.) was added to reduce the
benzoquinone to the hydroquinone, and the reaction mixture was
The 13C-labeled biphenyl model compound was prepared in two
steps. Ethyl 13C-formate (75 mg, 999 μmol, 1.0 eq.) was dissolved in
°
stirred at 0 C for five minutes and for 130 minutes at room
temperature. Formic acid (8 mL) was added, the flask equipped
°
dry THF (2 mL) under argon and cooled to 0 C. Phenylmagnesium
bromide (666 μL, 3 M in diethyl ether, 1.99 mmol, 2.0 eq.) was
°
with a condenser, and the mixture heated to 110 C. 2-Methyl-3-
diluted with dry THF (3 mL) and added dropwise. The solution was
buten-2-ol (135 mg, 1.57 mmol, 2.0 eq.) was added slowly. After
4 hours, the reaction was quenched with ice water and extracted
three times with diethyl ether (~40 ml in total). n-Hexane (40 mL)
was added to the organic extract, which was washed with distilled
water, dried over MgSO4, filtered, and evaporated in vacuo.
°
stirred at 0 C for two hours, and then quenched with distilled water
(5 mL). The obtained mixture was extracted three times with EE.
The combined organic extracts were washed with water, dried over
Na2SO4, filtered, and evaporated in vacuo to obtain crude
diphenyl-13C-carbinol, which was used further without purification.
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2,2,7,8-Tetramethylchroman-6-ol (207 mg, 1.00 mmol, 1.0 eq.) and
aluminum chloride (268 mg, 2.01 mmol, 2.0 eq.) were placed into
an oven-dried three-necked round bottom flask with reflux
condenser under argon and dissolved in dry THF (2.5 mL). The
crude diphenyl-13C-carbinol (prepared according to the above
protocol) was dissolved in dry THF (1 mL) and added dropwise to
the reaction mixture. After 15 h at room temperature, another 5 ml
of dry THF and some aluminum chloride (67 mg, 0.5 mmol,
0.50 eq.) were added to the suspension. The reaction was quenched
after 70 h at room temperature by adding distilled water (5 mL).
The mixture was extracted three times with EE. The combined
organic extracts were washed with saturated NaHCO3-solution and
water, dried over Na2SO4, filtered, and evaporated in vacuo. Column
chromatography (16 g of silica gel, hexane:EE, v/v=50:1) yielded
252 mg of 5a-13C-5a,5a-diphenyl-2,2,5,7,8-pentamethylchroman-6-ol
(9*) as colorless crystals (68% overall yield).
Phenyl-[2-(2,2,7,8-tetrameth-
ylchroman-6-yloxy)-phenyl]-methanol
The crude residue was dissolved in dry THF (10 mL) and phenyl-
magnesium bromide (930 μL, 2.5 M in THF, 2.33 mmol, 2.0 eq.) was
added dropwise. After 30 minutes, the reaction was quenched with
saturated NH4Cl-solution (5 mL). The mixture was extracted three
times with EE. The combined organic extracts were washed with
brine, dried over MgSO4, filtered, and evaporated in vacuo. Column
chromatography yielded 103 mg (23%) of phenyl-[2-(2,2,7,8-
tetramethylchroman-6-yloxy)-phenyl]-methanol as a colorless solid.
1H NMR: δ=1.24 (s, 6H, H-2a), 1.67 (t, 2H, 3JH,H =6.9 Hz, H-3), 1.78 (s,
3H, H-7a), 2.03 (s, 3H, H-8b), 2.57 (t, 2H, JH,H =6.9 Hz, H-4), 2.88 (br,
1H, OH), 6.11 (s, 1H, CHOH), 6.30 (s, 1H, H-6’), 6.41 (d, 1H, J=8.2 Hz,
H-2’), 6.91 (t, 1H, J=7.6 Hz, H-4’), 7.03 (t, 1H, J=7.6 Hz, H-5’), 7.13–
7.28 (m, 3H, H-3’’, H-4’’, H-5’’), 7.33–7.40 (m, 3H, H-3’, H-2’’, H-6’’).
3
1H NMR: δ=1.27 (s, 6H, H-2a), 1.72 (t, 2H, 3JH,H =6.8 Hz, H-3), 2.08 (s,
13C NMR: δ=12.0 (C-7a), 12.3 (C-8b), 22.5 (C-4), 27.0 (C-2a), 32.7 (C-
3), 72.5 (CHOH), 73.9 (C-2), 114.6 (C-6’), 118.2 (C-5), 118.7 (C-4a),
121.5 (C-4’), 126.1 (C-8), 126.6 (C-2’’, C-6’’), 127.2 (C-4’’), 127.7 (C-3’),
127.9 (C-7), 128.2 (H-3’’, H-5’’), 128.5 (C-5’), 132.2 (C-2’), 143.5 (C-1’’),
145.5 (C-6), 148.7 (C-8a), 156.2 (C-1’).
3
3H, H-8b), 2.13 (s, 3H, H-7a), 2.69 (t, 2H, JH,H =6.8 Hz, H-4), 4.36 (s,
1
1H, OH), 5.77 (d, 1H, JC,H = 125 Hz), 7.17–7.36 (m, 10H, ArÀ H) 13C
NMR: δ=12.1 (C-7a), 12.2 (C-8b), 21.3 (C-4), 26.6 (C-2a), 33.2 (C-3),
49.1 (C-5a), 72.3 (C-2), 116.7 (C-8), 124.2 (C-5), 124.3 (C-4a), 125.2 (C-
7), 126.9 (C-4’), 128.9 (C-2’, C-6’), 129.0 (C-3’, C-5’), 141.6 (C-1’), 145.7
(C-8a), 145.9 (C-6).
EI-MS (70 eV): 135 (100%), 388 (73%), 190 (65%), 207 (26%), 197
(25%), 293 (22%), 370 (21%), 181 (21%), 77 (20%), 389 (19%), 105
(19%), 91 (18%), 372 (16%), 165 (16%), 121 (16%), 191 (15%), 313
(15%), 175 (14%), 69 (13%), 136 (11%), 301 (11%), 79 (11%), 152
(10%), 314 (10%), 134 (10%).
EI-MS (70 eV): 373 (100%), 240 (44%), 239 (36%), 374 (27%), 225
(21%), 226 (18%), 316 (17%), 302 (15%), 166 (14%), 317 (10%), 179
(10%). Rf (n-hexane/ethyl acetate, v/v=5:1)=0.58.
Rf (n-hexane/ethyl acetate, v/v=5:1)=0.33.
3,3,5,6-Tetramethyl-12-phenyl-1,2,3,12-tetrahydropyrano
[3,2-a]xanthene (10)
3,3,5,6-Tetramethyl-12-phenyl-1,2,3,12-tetrahydropyrano
[3,2-a]xanthene (10)
The reference compound for the final oxidation product of the
biphenyl model compound was prepared in three steps.
The intermediate carbinol obtained according to the above
protocol (10 mg) was dissolved in dry THF (2 mL) under argon and
°
cooled to 0 C. Concentrated sulfuric acid (5 μl) was added. The
2-(2,2,7,8-tetramethyl-chroman-6-yl-oxy)-benzaldehyde
solution was diluted with EE (10 mL), neutralized with saturated
NaHCO3-solution, dried over MgSO4, filtered, and evaporated in
vacuo. 9 mg of 3,3,5,6-tetramethyl-12-phenyl-1,2,3,12-tetrahydro-
pyrano[3,2-a]xanthene (10) were obtained as colorless solid (95%
yield).
2,2,7,8-Tetramethylchroman-6-ol (241 mg, 1.17 mmol, 1.0 eq.), 2-
formylphenylboronic acid (350 mg, 2.33 mmol, 2.0 eq.), copper(II)
acetate (350 mg, 1.75 mmol, 1.50 eq.), triethylamine (354 mg,
3.50 mmol, 3.0 eq.) and 4 Å molecular sieve (0.50 g) were mixed
with DCM (10 mL) under argon and stirred at room temperature.
After 17 hours, distilled water was added and the mixture was
extracted three times with DCM. The combined organic extracts
were washed with saturated NaHCO3-solution, dried over Na2SO4,
filtered, and evaporated in vacuo. The crude product was used
further without purification.
1H NMR: δ=1.08 (s, 3H, H-3a), 1.19 (s, 3H, H-3a), 1.52-1.70 (m, 1H, H-
2), 2.09 (s, 3H, H-5a/H-6b), 2.21-2.32 (m, 1H, H-1), 2.30 (s, 3H, H-6b/
H-5a), 2.60-2.70 (m, 1H, H-1), 5.09 (s, 1H, H-12), 6.87 (t, 1H, J=
7.2 Hz, H-4’), 6.98-7.14 (m, 6H, H-8, H-9, H-10, H-11, H-2’, H-6’), 7.19
(2 H, d, J=7.8 Hz, H-3’, H-5’). 13C NMR: δ=11.9 (C-5a/C-6b), 12.1 (C-
6b/C-5a), 19.8 (C-1), 26.6 (C-3a), 26.7 (C-3a), 32.6 (C-2), 42.8 (C-12),
72.8 (C-3), 115.5 (c-12b), 116.7 (C-8), 119.3 (C-11a), 122.7 (C-4’),
123.1 (C-5), 124.9 (C-6), 125.7 (C-12a), 126.3 (C-10), 127.3 (C-9, C-2’,
C-6’), 128.6 (C-3’, C-5’), 128.7 (C-11), 143.6 (C-6a), 145.7 (C-1’), 147.5
(C-4a), 151.5 (C-7a). EI-MS (70 eV): 370 (100%), 293 (88%), 313
(68%), 314 (41%), 237 (29%), 371 (28%), 315 (25%), 294 (19%), 299
(17%), 209 (25%), 194 (11%), 298 (10%), 195 (10%), 249 (10%). Rf
(n-hexane/ethyl acetate, v/v=5:1)=0.61.
3
1H NMR: δ=1.36 (s, 6H, 2a), 1.80 (t, 2H, JH,H =6.7 Hz, H-3), 2.09 (s,
3
3H, N-7a), 2.17 (s, 3H, H-8b), 2.74 (t, 2H, JH,H =6.7 Hz, H-4), 6.62 (s,
1H, H-5), 6.65 (ddd, 1H, J1 =8.43 Hz, J2 =1.00 Hz, J3 =0.46 Hz, H-6’),
7.06 (dddd, 1H, J1 =7.75 Hz, J2 =7.25 Hz, J3 =0.96 Hz, J4 =0.84 Hz, H-
4’), 7.42 (ddd, 1H, J1 =8.46 Hz, J2 =7.25 Hz, J3 =1.85 Hz, H-5’), 7.91
(ddd, 1H, J1 =7.74 Hz, J2 =1.84 Hz, J3 =0.45 Hz, H-3’), 10.67 (d, 1H,
J1 =0.87 Hz, CHO).13C NMR: δ=12.0 (C-7a), 12.6 (C-8b), 23.0 (C4),
27.0 (C-2a), 33.2 (C-3), 74.4 (C2), 115.6 (C-6’), 118.4 (C-5), 119.3 (C-
4a), 121.5 (C-4’), 125.4 (C-8), 126.9 (C-7), 128.1 (C-2’), 128.1 (C-3’),
135.7 (C-5’), 145.6 (C-6), 149.5 (C-8a), 161.7 (C-1’), 189.8 (CHO). EI-MS
(70 eV): 310 (100%), 121 (30%), 255 (27%), 135 (23%), 311 (22%),
211 (16%), 239 (13%), 91 (12%), 134 (11%), 77 (10%). Rf (n-hexane/
ethyl acetate, v/v=5:1)=0.48.
Acknowledgement
The financial support by the Austrian Biorefinery Center Tulln
(ABCT) is gratefully acknowledged.
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Revised manuscript received: January 12, 2021
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