# A Novel Dimer ofα-Tocopherol

Authors: Anjan Patel; Francesco Mazzini; Thomas Netscher; Thomas Rosenau
Journal: Research Letters in Organic Chemistry
 (2008)

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## Abstract

Decomposition of the complex4, formed between the  α-tocopherol ortho-quinone methide (2) and NMMO, by fast heating from −78∘C to 70∘C in inert solvents produces a novel α-tocopherol dimer with 6H,12H-dibenzo[b,f][1,5]dioxocine structure (5) which—in contrast to the well-known spiro-dimer of α-tocopherol (3)—is symmetrical. This is the first example of a direct reaction of the highly transient zwitterionic, aromatic precursor 2a in the formation of the ortho-quinone
methide 2.


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## Body

## 1. Introduction

Oxidation  ofα-tocopherol (1) [1, 2]
in aprotic media affords an ortho-quinone
methide (oQM, 2) which is formed
quite selectively at position C-5a [3]. If no coreactants or trapping
agents, such as electron-rich dienophiles, are present, the oQM undergoes
dimerization to the so-called spiro-dimer of α-tocopherol (3) [4, 5]
(see Scheme 1, path A), one of the major tocopherol oxidation products both in
vitro and in vivo. It was shown that a zwitterionic, aromatic species (2a)—carrying a
perpendicular benzyl cation and a phenolate group—was an
intermediate on the way from the phenol to the ortho-quinone methide. In-plane rotation of the exocyclic methylene
group then enables the system to assume the energetically more favorable
quinoid form (2) [3]. Recently, a
method was found to stabilize the zwitterionic intermediate at low temperature
with amine N-oxides [6]
which also carry a zwitterionic moiety (see Scheme 1, path B). Recently, the
structure of such complexes between zwitterionic oQM precursor 2a and stabilizing zwitterionic species—in this case
sulfonium ylide species derived from 2,5-dihydroxy-[1, 2, 6] benzoquinone—was proven by
X-ray and NMR data [7].Scheme 1
Oxidation ofα-tocopherol (1) conventionally leads to its
spiro-dimer (3) via ortho-quinone methide 2 (path A). The zwitterionic oQM precursor 2a is stabilized by NMMO in complex 4,
which upon rapid heating produces small amounts of the new dioxocine dimer 5 (path B). Acid treatment of 5 causes quantitative conversion into
spiro-dimer 3, via oQM 2 (path C).


## 2. Results and Discussion

Composition
of complex4, formed from the
zwitterionic intermediate 2a and N-methylmorpholine-N-oxide (NMMO), by fast heating from −78C° to temperatures of 70C° produced
a single minor product in reproducible yields of 3.5% besides spiro-dimer 3 (see Scheme 1, path B). Analytics of
this compound were somewhat surprising as microanalysis and the molpeak in mass
spectrometry were clearly indicative of spiro-dimer 3, but the chromatographic behavior evidently proved the substance
to be a different compound. The mass-spectrometric fragmentation pattern
indicated a highly symmetric compound, and NMR finally proved the compound to
be benzyl ether 5, a “dioxocine dimer” of α-tocopherol.
In the next step, the α-tocopherol model compound 2,2,5,7,8-pentamethyl-chroman-6-ol
(PMC, 6) was used for complex
formation and subsequent thermal degradation of the complex. Unfortunately, all
attempts to obtain crystals of the corresponding dioxocine dimer (7) in qualities sufficient for X-ray
analysis failed; the substance precipitated in an amorphous form throughout.Strictly
speaking, dibenzodioxocine dimer5 is not a reaction product of ortho-quinone
methide 2, but of its more transient
precursor 2a (see Scheme 1). As soon
as the out-of-plane methylene group in 2a rotates into the ring plane, the oQM 2 is formed, no reverse rotation is possible, and the spiro-dimer 3 results inevitably (see Scheme 1,
path A). The formation of the dibenzodioxocine dimer 5 from complex 4 (see Scheme
1, path B), which consists actually of two simultaneous etherifications driven
by charge recombination, is thus competing with this bond rotation and must be
the faster of the two processes for the dioxocine dimer to form, thus  rendering
the yield of 5 naturally limited,
according to the rate constants of the two processes. (Bond rotations have  kinetic rate constants krot of 10−12s−1 to 10−14s−1, the recombination
rate of the two zwitterions ions in solution krec cannot be faster than diffusion-controlled and
is limited to about 10−7lmol−1s−1 to 10−9lmol−1s−1.)Correctness
of the structure of5 was finally
proven by using a mixture of 5a-trideuterated α-tocopherol  (5-trideuteromethyl-γ-tocopherol, 9)
and β-tocopherol model compound (10) in the process of oxidation and NMMO-complexation. As expected,
the respective spiro-dimers  were obtained as the major products. (Three spiro-dimers were obtained, the spiro-dimer of 9, the spiro-dimer of 10, and the
mixed spiro-dimer. Structures and analytical data will be reported elsewhere in due course.)
Besides those spiro-dimers, also the dioxocine-dimers 11, 12 formed from the deuterated α-tocopherol (9)
and from β-tocopherol model (10),
respectively, were found. (The choice of the starting materials with regard to the presence of side chains was
performed in view of the chromatographic separability of the dioxocine products. With both of
them having one (none) side chain, all dioxocine dimers would have two (none) side chains,
and would be inseparable due to their nearly identical structure. Using 9 and 10 as the starting
materials, one dimer has two side C16H33 side chains (11), one has none (12), and one has one
(13), which renders the products sufficiently different to be chromatographically separated.)
These two dimers 11 and 12 were symmetrical, similar to 5, and the two “halves” of the molecules cannot be distinguished by
NMR. However, also dioxocine dimer 13—containing an α- and a β-tocopherol “half”—was found, which
was crucial for definite structure confirmation of the dioxocine dimers.
Through the different substitution pattern at the aromatic rings—β-tocopherol lacks the 7a-methyl group in comparison to α-tocopherol—the corresponding
carbons in these moieties were rendered magnetically inequivalent (albeit only
slightly by less than 1 ppm in the C13 domain.). The two aromatic systems in 13 thus became distinguishable in contrast to the symmetric dimer 5. Furthermore, the resonances of the
two benzyl ether carbons became inequivalent due to deuteration in the α-part. This way, direct HMBC connectivities as indicated in
Scheme 2 became observable, and the general dioxocine
structure was thus considered as confirmed. (The J5 long range coupling can only be observed due to the presence of the eightmembered
ring system making two “coupling paths” along the ring system available, which
add to each other.)Scheme 2
Oxidation of
a mixture of deuteratedα-tocopherol (9) and β-tocopherol (10). The corresponding NMMO-complexes
produce the symmetric dioxocine dimers 11 and 12 (symmetry indicated by
the dashed lines) and the “mixed” dimer 13 in which the two parts can be distinguished by NMR spectroscopy. The bent
arrows indicate the long range HMBC connectivities that prove the presence of
the dibenzodioxocine structure.Treatment of5 with acid at 50C° causes its
decomposition and clean formation of spiro-dimer 3 (see Scheme 1, path C). Evidently, the two benzyl ether functions
are cleaved, the resulting methylene groups immediately rotate into the plane
forming oQM 2, and this intermediate
dimerizes according to the “conventional” pathway into 3.The value of
the preparation of5 lies in its
contribution to general vitamin E chemistry and in affording further
experimental proof of the occurrence of zwitterionic intermediates in the
formation of oQMs from the parent ortho-methylphenols
and the first reaction of such an intermediate in vitamin E chemistry.


## 3. Experimental

(All-R)-tocopherols (1, 10) were used as the
starting materials. The deuterated α-tocopherol (9)
was available from previous work [8, 9], as was β-tocopherol model 10 [10]. H1 NMR spectra were recorded at 400.13 MHz for H1 and at
100 MHz for C13 NMR in CDCl3 if not otherwise stated.
Chemical shifts, relative to TMS as internal standard, are given in δ values, coupling
constants in Hz. C13 peaks were assigned by means of APT, HMQC, and
HMBC spectra. Resonances of the isoprenoid side chain are not listed as they
are only negligibly affected (<0.1 ppm for C13) by modifications
of the chroman skeleton [14].


### 3.1.α-Tocopherol Dioxocine Dimer (5)

Freshly prepared silver oxide
(25 mmol, 5.8 g) was suspended in chloroform (10 mL) at−78C° (acetone/dry ice colling), maintaining this temperature throughout. A r.t. solution of N-methylmorpholine-N-oxide (5.5 mmol, 0.64 g) in chloroform (5 mL) was added at once.
The slurry was stirred vigorously and a solution of α-tocopherol (5 mmol, 2.15 g) in
chloroform (3 ml) was added dropwise over about 3 minutes. After 1 minute (not
longer as the formed complex 4 tends
to decompose!), the slurry was quickly vacuum-filtered into a cooled vessel (−78C°). The
solution was added dropwise into toluene (10 mL) heated to 70C°. Care must be
taken that the temperature of the added solution is as close to −78C° as
possible, and the heating (oil bath) must be sufficiently effective to
guarantee maintenance of the temperature (70C°) also during addition of the
cooled solution. After completion of the addition, the mixture was stirred for
another 10 minutes, cooled to r.t., and concentrated to a volume of about 2 mL.
The remainder was
purified by column chromatography on silica gel (TEA/EtOAc/n-hexane, v/v/v =
0.01:1:20) to give spiro-dimer 3 (92.4%)
and dibenzodioxocine dimer 5 as
ivory wax (6.2%, 133 mg), mp: 25–28C°, TLC:
Rf=0.84 (n-hexane/diethyl
ether, v/v = 9:1). H1 NMR: δ 1.83 (m, 4H,
2×3-CH2), 2.09 (s, 6H, 2×8b-CH3); 2.13 (s, 6H, 2×7a-CH3),
2.66 (t, 4H, J3=7.0Hz,
2×4-CH2), 5.10 (s, 4H, 5a-CH2). C13 NMR: δ 11.6 (7a-CH3),
13.0 (8b-CH3), 21.0 (4-CH2), 23.8 (2a-CH3),
31.4 (3-CH2), 71.6 (5a-CH2), 74.7 (2-C), 115.9 (5-C),
117.8 (4a-C), 121.3 (7-C), 123.2 (8-C), 142.0 (6-C), 147.9 (8a-C). Anal. calcd
for C58H96O4 (857.41gmol−1): C
81.25, H 11.29; found: C 81.15, H 11.41.


### 3.2. PMC Dioxocine
Dimer (7)

The compound was prepared according to the above
procedure employing PMC (6, 5 mmol, 1.10 g). Chromatographic
purification was performed on silica gel (TEA/EtOAc/n-hexane, v/v/v =
0.01:1:10) to give spiro-dimer 8 (88.4%)
and dibenzodioxocine dimer 7 as
white powder (8.1%, 89 mg), mp: 74–78C°, TLC: Rf=0.44 (n-hexane/diethyl
ether, v/v = 9:1). H1 NMR: δ 1.28 (s,
12H, 4×2a-CH3), 1.78 (t, 4H, J3=7.1Hz, 2×3-CH2), 2.11 (s, 6H, 2×8b-CH3);
2.15 (s, 6H, 2×7a-CH3), 2.64 (t, 4H, J3=7.1Hz, 2×4-CH2), 5.04
(s, 4H, 5a-CH2). C13 NMR: δ 11.7; 11.9 (7a-CH3; 8b-CH3),
20.4 (4-CH2), 26.6 (2a-CH3), 32.8 (3-CH2),
71.8 (5a-CH2), 72.5 (2-C), 115.5 (5-C), 117.9 (4a-C), 121.3 (7-C),
123.5 (8-C), 142.3 (6-C), 148.0 (8a-C). Anal. calcd for  C28H36O4 (436.60gmol−1): C 77.03, H 8.31; found: C 76.91, H 8.37.


### 3.3. Mixed Dioxocine Dimer (13)

The compound
was prepared according to the above procedure employing 5,5,5-trideutero-α-tocopherol (9, 2.5 mmol, 1.10 g) and β-tocopherol model 10 (2.5 mmol, 0.52 g) simultaneously. Chromatographic purification was
performed on gel (TEA/EtOAc/n-hexane, v/v/v = 0.01:1:20) to give the
spiro-dimer of 9, dioxocine 11, the mixed spiro-dimer of 9 and 10, dioxocine 13,
spiro-dimer of 10, and dioxocine 12, in the order of elution. The
fraction rich in dioxocine 13 was
rechromatographed under similar conditions to provide neat 13 as a yellow wax (1.6% rel. to 9, 17 mg), mp: 32-33C°, TLC:
Rf=0.64 (n-hexane/diethyl
ether, v/v = 9:1). H1 NMR: δH1 NMR: δ 1.28 (s, 6H, 2a-CH3,
β, superimposed by resonances of the isoprenoid side chain of α), 1.79 (t, 2H, J3=6.8Hz, 2-CH2, β), 1.81 (m, 2H, 3-CH2, α), 2.08; 2.09; 2.11; 2.14 (4×s, 4×3H, 8b-CH3 and
7a-CH3, each α and β), 2.61 (t, 2H, J3=6.8Hz, 4-CH2, β), 2.64 (t, 2H, J3=7.0Hz, 4-CH2, α), 5.06 (s, 2H, 5a-CH2, β). 6.47 (s, 1H, H-7). C13 NMR: δ 11.8 (7a-CH3,
α), 13.0 (8b-CH3, α), 16.0 (8b-CH3, β), 21.0 (4-CH2, α), 21.5 (4-CH2, β), 23.8 (2a-CH3, α), 27.1 (2a-CH3, ß),
31.2 (3-CH2,
α),
33.0 (3-CH2,
ß),
70.8 (pent, 5a-CD2, JC-D=21Hz,
α),
71.6 (5a-CH2,
ß),
72.3 (2-C, ß),
74.6 (2-C, α),
115.20 (7-CH, ß),
115.9 (5-C, α),
117.8 (4a-C, α),
119.57 (5-C, ß),
120.52 (4a-C, ß),
121.3 (7-C, α),
123.2 (8-C, α),
124.45 (8-C, ß),
142.0 (6-C, α),
146.2 (6-C, ß),
146.8 (8a-C, ß),
147.5 (8a-C, α).
Anal. calcd for C42H64O4
(632.98gmol-1):
C 79.70, H 10.19; found: C 79.74, H 10.08.


## 3.1.α-Tocopherol Dioxocine Dimer (5)

Freshly prepared silver oxide
(25 mmol, 5.8 g) was suspended in chloroform (10 mL) at−78C° (acetone/dry ice colling), maintaining this temperature throughout. A r.t. solution of N-methylmorpholine-N-oxide (5.5 mmol, 0.64 g) in chloroform (5 mL) was added at once.
The slurry was stirred vigorously and a solution of α-tocopherol (5 mmol, 2.15 g) in
chloroform (3 ml) was added dropwise over about 3 minutes. After 1 minute (not
longer as the formed complex 4 tends
to decompose!), the slurry was quickly vacuum-filtered into a cooled vessel (−78C°). The
solution was added dropwise into toluene (10 mL) heated to 70C°. Care must be
taken that the temperature of the added solution is as close to −78C° as
possible, and the heating (oil bath) must be sufficiently effective to
guarantee maintenance of the temperature (70C°) also during addition of the
cooled solution. After completion of the addition, the mixture was stirred for
another 10 minutes, cooled to r.t., and concentrated to a volume of about 2 mL.
The remainder was
purified by column chromatography on silica gel (TEA/EtOAc/n-hexane, v/v/v =
0.01:1:20) to give spiro-dimer 3 (92.4%)
and dibenzodioxocine dimer 5 as
ivory wax (6.2%, 133 mg), mp: 25–28C°, TLC:
Rf=0.84 (n-hexane/diethyl
ether, v/v = 9:1). H1 NMR: δ 1.83 (m, 4H,
2×3-CH2), 2.09 (s, 6H, 2×8b-CH3); 2.13 (s, 6H, 2×7a-CH3),
2.66 (t, 4H, J3=7.0Hz,
2×4-CH2), 5.10 (s, 4H, 5a-CH2). C13 NMR: δ 11.6 (7a-CH3),
13.0 (8b-CH3), 21.0 (4-CH2), 23.8 (2a-CH3),
31.4 (3-CH2), 71.6 (5a-CH2), 74.7 (2-C), 115.9 (5-C),
117.8 (4a-C), 121.3 (7-C), 123.2 (8-C), 142.0 (6-C), 147.9 (8a-C). Anal. calcd
for C58H96O4 (857.41gmol−1): C
81.25, H 11.29; found: C 81.15, H 11.41.


## 3.2. PMC Dioxocine
Dimer (7)

The compound was prepared according to the above
procedure employing PMC (6, 5 mmol, 1.10 g). Chromatographic
purification was performed on silica gel (TEA/EtOAc/n-hexane, v/v/v =
0.01:1:10) to give spiro-dimer 8 (88.4%)
and dibenzodioxocine dimer 7 as
white powder (8.1%, 89 mg), mp: 74–78C°, TLC: Rf=0.44 (n-hexane/diethyl
ether, v/v = 9:1). H1 NMR: δ 1.28 (s,
12H, 4×2a-CH3), 1.78 (t, 4H, J3=7.1Hz, 2×3-CH2), 2.11 (s, 6H, 2×8b-CH3);
2.15 (s, 6H, 2×7a-CH3), 2.64 (t, 4H, J3=7.1Hz, 2×4-CH2), 5.04
(s, 4H, 5a-CH2). C13 NMR: δ 11.7; 11.9 (7a-CH3; 8b-CH3),
20.4 (4-CH2), 26.6 (2a-CH3), 32.8 (3-CH2),
71.8 (5a-CH2), 72.5 (2-C), 115.5 (5-C), 117.9 (4a-C), 121.3 (7-C),
123.5 (8-C), 142.3 (6-C), 148.0 (8a-C). Anal. calcd for  C28H36O4 (436.60gmol−1): C 77.03, H 8.31; found: C 76.91, H 8.37.


## 3.3. Mixed Dioxocine Dimer (13)

The compound
was prepared according to the above procedure employing 5,5,5-trideutero-α-tocopherol (9, 2.5 mmol, 1.10 g) and β-tocopherol model 10 (2.5 mmol, 0.52 g) simultaneously. Chromatographic purification was
performed on gel (TEA/EtOAc/n-hexane, v/v/v = 0.01:1:20) to give the
spiro-dimer of 9, dioxocine 11, the mixed spiro-dimer of 9 and 10, dioxocine 13,
spiro-dimer of 10, and dioxocine 12, in the order of elution. The
fraction rich in dioxocine 13 was
rechromatographed under similar conditions to provide neat 13 as a yellow wax (1.6% rel. to 9, 17 mg), mp: 32-33C°, TLC:
Rf=0.64 (n-hexane/diethyl
ether, v/v = 9:1). H1 NMR: δH1 NMR: δ 1.28 (s, 6H, 2a-CH3,
β, superimposed by resonances of the isoprenoid side chain of α), 1.79 (t, 2H, J3=6.8Hz, 2-CH2, β), 1.81 (m, 2H, 3-CH2, α), 2.08; 2.09; 2.11; 2.14 (4×s, 4×3H, 8b-CH3 and
7a-CH3, each α and β), 2.61 (t, 2H, J3=6.8Hz, 4-CH2, β), 2.64 (t, 2H, J3=7.0Hz, 4-CH2, α), 5.06 (s, 2H, 5a-CH2, β). 6.47 (s, 1H, H-7). C13 NMR: δ 11.8 (7a-CH3,
α), 13.0 (8b-CH3, α), 16.0 (8b-CH3, β), 21.0 (4-CH2, α), 21.5 (4-CH2, β), 23.8 (2a-CH3, α), 27.1 (2a-CH3, ß),
31.2 (3-CH2,
α),
33.0 (3-CH2,
ß),
70.8 (pent, 5a-CD2, JC-D=21Hz,
α),
71.6 (5a-CH2,
ß),
72.3 (2-C, ß),
74.6 (2-C, α),
115.20 (7-CH, ß),
115.9 (5-C, α),
117.8 (4a-C, α),
119.57 (5-C, ß),
120.52 (4a-C, ß),
121.3 (7-C, α),
123.2 (8-C, α),
124.45 (8-C, ß),
142.0 (6-C, α),
146.2 (6-C, ß),
146.8 (8a-C, ß),
147.5 (8a-C, α).
Anal. calcd for C42H64O4
(632.98gmol-1):
C 79.70, H 10.19; found: C 79.74, H 10.08.



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*Source: 742590-2008-09-21.xml*