Perfluorinated bronsted 'superacids': Powerful catalysts for the preparation of vitamin E

Article abstract of DOI:10.2533/000942904777678181

The key-step in the industrial synthesis of (all-rac)-α-tocopherol (synthetic vitamin E) is the condensation reaction of trimethylhydroquinone with the C₂₀ building block isophytol. For this Friedel-Crafts-type reaction, perfluorinated NH- and CH-acidic compounds (perfluoroalkyl(aryl) sulfonyl imides and methides) have been applied as excellent catalysts, preferably in biphasic solvent systems.

Full text of DOI:10.2533/000942904777678181

FLUORINE IN THE LIFE SCIENCE INDUSTRY
153
CHIMIA 2004, 58, No. 3
Chimia 58 (2004) 153–155
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
Perfluorinated Brønsted ‘Superacids’:
Powerful Catalysts for the Preparation
of Vitamin E
Thomas Netschera*, Werner Bonratha, Alois Haasb, Eike Hoppmannb, and Horst Paulinga
Abstract: The key-step in the industrial synthesis of (all-rac)-α-tocopherol (synthetic vitamin E) is the condensation
reaction of trimethylhydroquinone with the C20 building block isophytol. For this Friedel-Crafts-type reaction, per-
fluorinated NH- and CH-acidic compounds (perfluoroalkyl(aryl)sulfonyl imides and methides) have been applied as
excellent catalysts, preferably in biphasic solvent systems.
Keywords: Biphasic catalysis · Friedel-Crafts alkylation · Perfluorinated NH-acidic imides · α-Tocopherol ·
Tris(perfluoroalkylsulfonyl) methanes
Introduction
development of more selective and environ- catalysts of type 4 and CH-acidic com-
mentally friendly processes [2]. Polyfluori- pounds 5 for the efficient synthesis of 3
Vitamin E is the biologically most im- nated
compounds
were
already from 1 and 2. Starting from commercially
portant fat-soluble antioxidant. The form of involved in various approaches to accom- available sulfonyl halides (accessible by
highest commercial value is synthetic (all- plish this Friedel-Crafts-type alkylation re- electrochemical fluorination), the highly
rac)-α-tocopherol (3), which is produced in action. Examples are scandium triflate [3] air-sensitive bis[perfluoroalkyl(aryl)sul-
a scale of over 25’000 tons per year world- and the imide (CF3SO2)2NH [4], as well as fonyl] imides 4 have been obtained via the
wide.
heterogeneous solid perfluoro-alkanesul- sulfonamides and silyl derivatives (Scheme
All industrial syntheses of (all-rac)-α- fonic acids (i.e. their ‘microencapsulated’ 2). Literature procedures [6–8] had to be
tocopherol (3) use the reaction of trimethyl- variants and Nafion NR 50) [5].
hydroquinone (1) with (all-rac)-isophytol
adapted slightly to the individual com-
pounds. The products were usually ob-
tained after high-vacuum sublimation or
short-path distillation from conc. H2SO4, or
were isolated (e.g. aryl derivative 4g) from
(2) or a C20 equivalent thereof (Scheme 1).
Several classical Lewis and Brønsted acids Synthesis of Catalysts
have been applied as catalysts in this reac-
tion. Typical examples are zinc chloride and
In this communication we describe our the water-insoluble ammonium salt after
a mineral acid, BF3, AlCl3, Fe/HCl, or the findings when using fluorinated NH-acidic use of cation exchange resin. Some of the
combination of boric acid and carboxylic
acids [1]. Such known catalysts, however,
cause often serious corrosion and waste-
water problems in large-scale production.
HO
In order to avoid the disadvantages of
the known syntheses of (all-rac)-α-toco-
+
pherol (3), we focused our research on the
OH
HO
1
2
- H2O catalyst
*Correspondence: Dr. T. Netschera
Tel.: +41 61 688 67 55
Fax: +41 61 687 22 01
HO
E-Mail: thomas.netscher@dsm.com
aResearch and Development
DSM Nutritional Products
P. O. Box 3255
O
CH-4002 Basel
(former company name: Roche Vitamins Ltd,
CH-4070 Basel)
3
bRuhr-Universität Bochum
Fakultät für Chemie
D-44780 Bochum
Scheme 1. Industrial synthesis of (all-rac)-α-tocopherol (3)

FLUORINE IN THE LIFE SCIENCE INDUSTRY
154
CHIMIA 2004, 58, No. 3
NH3
1) MeONa, MeOH
2) HN(SiMe3)2
Rf1SO2X
Rf1SO2NH2
1) Rf2SO2X
Rf1 SO2
Rf1SO2N(Na)SiMe3
X = Cl, F
NH
Rf2 SO2
2) H2SO4 conc.
4
Rf1, Rf2, Rf3 = perfluoroalkyl or pentafluorophenyl
Scheme 2. Preparation of perfluorinated imide
catalysts 4
1) LiC(CH3)3 or CH3MgCl
SO2
Rf1
Rf1
2) Rf3SO2X
SO2
CH2
Rf2 SO2
Rf2 SO2 CH
Rf3 SO2
5
3) H2SO4 or HCl
4) sublimation
X = Cl, F
Rf1, Rf2, Rf3 = perfluoroalkyl or pentafluorophenyl
Scheme 3. Preparation of perfluorinated methide
catalysts 5
Table. Results of the condensation reaction of 1 and 2 in various solvents using NH-acidic com-
pounds of the type (Rf1SO2)(Rf2SO2)NH (4)
imides 4 were commercially available [2].
Sulfonylation of bis(perfluoroalkylsul-
fonyl) methanes (Scheme 3) delivered the
strongly acidic methides [tris(perfluo-
roalkylsulfonyl) methanes] 5 [9].
4
a
Rf1
Rf2
Solvent systema
Crude yield 3 [%]b
CF3
CF3
A
B
A
B
A
C
D
E
B
B
B
E
89.5
91.0
89.6
94.0
90.2
83.8
87.4
92.6
93.6
94.5
87.2
84.9
Results of the Condensation
Reactions
b
CF3
C4F9
Imides 4 as well as methides 5, used in
really low catalyst amounts, yielded highly
satisfying results in the condensation reac-
tion. This applied to mildness of conditions,
selectivity, and yield, which is remarkable
when considering the mechanistic pathway
of this transformation. In the preparation of
α-tocopherol (3) from 1 and 2 according to
Scheme 1, the Friedel-Crafts alkylation re-
action is followed by the chroman ring-clo-
sure step. It is of common knowledge that
tertiary allylic alcohols like 2 easily dehy-
drate in the presence of acids [10] to form
highly reactive carbocations. Therefore, the
formation of considerable amounts of
olefinic by-products is unavoidable in such
reactions.
c
d
C2F5
CF3
C4F9
C6F5
e
f
C2F5
C2F5
n/iso-C3F7
C6F5
n/iso-C3F7
C6F5
g
h
i
CF2CF2CF2
B
94.5
C4F9
C4F9
CF3
C4F9
E
E
E
E
E
94.0
93.3
86.4
85.6
91.1
k
m
n
o
C6F5
We were, however, pleased to find only
small amounts (generally less than 4%) of
phytadienes (several C20-dienes) when 2
was reacted with 1 in the presence of cat-
alytic amounts of perfluoroalkyl/aryl sub-
stituted imides 4 (0.1 mol% based on 2).
The conversion of 2 was around 99%, and
yields of up to 94% (all-rac)-α-tocopherol
(3) were obtained (Table) [2][11]. Trissul-
fonyl methides 5 or selected metal salts
thereof gave 3 in up to 96% yield [12]. In
general, two-phase solvent systems like
C8F17
C8F17
C8F17
C8F17
C4F9
aA = toluene; B = ethylene carbonate/heptane (4:5 v/v); C = diethyl ketone; D = γ-butyrolactone;
E = propylene carbonate/heptane (4:5 v/v). bYields based on 2 (GC analysis of crude product
with internal standard). Conditions: 50 mmol 1, 0.1 mol% 4 (based on 2), 50 ml (one-phase) or
40 + 50 ml (two-phase) solvent, addition of 33 mmol 2 during 20 min, 100 °C, additional heating
for 30 min [2].

FLUORINE IN THE LIFE SCIENCE INDUSTRY
155
CHIMIA 2004, 58, No. 3
A1, 2001 (Chem. Abstr. 2002, 136,
ethylene carbonate/heptane proved to be
most effective.
183967).
[12] W. Bonrath, A. Haas, E. Hoppmann, T.
Netscher, H. Pauling (F. Hoffmann-La
Roche), EP 1134218A1, 2001 (Chem. Ab-
str. 2001, 135, 257368).
In conclusion, perfluorinated NH-acidic
imides 4 and CH-acidic methides 5 are ex-
cellent catalysts for the synthesis of (all-
rac)-α-tocopherol (3) from trimethylhydro-
quinone (1) and isophytol (2). Best results
were achieved by the application of bipha-
sic solvent systems, i.e. combining the ac-
tivity and selectivity of homogeneous cata-
lysts with heterogeneous reaction media.
Received: January 8, 2004
[1] K.U. Baldenius, L. von dem Bussche-
Hünnefeld, E. Hilgemann, P. Hoppe, R.
Stürmer, in ‘Ullmans Encylopedia of In-
dustrial Chemistry’, VCH Verlagsge-
sellschaft, Weinheim, 1996, pp. 478–488;
T. Netscher, ‘Synthesis and production of
vitamin E’, in ‘Lipid Synthesis and Manu-
facture’, Ed.: F.D. Gunstone, Sheffield
Academic Press Ltd, Sheffield, UK, 1999,
pp. 250–267.
[2] W. Bonrath, A. Haas, E. Hoppmann, Th.
Netscher, H. Pauling, F. Schager, A. Wil-
dermann, Adv. Synth. Catal. 2002, 344, 37.
[3] M. Matsui, N. Karibe, K. Hayashi, H. Ya-
mamoto, Bull. Chem. Soc. Jpn. 1995, 68,
3569.
[4] K. Ishihara, M. Kubota, H. Yamamoto,
Synlett 1996, 1045; M. Baak, W. Bonrath,
H. Pauling (F. Hoffmann-La Roche), WO
Patent Application 9821197, 1997 (Chem.
Abstr. 1998, 129, 28106).
[5] F. Schager, W. Bonrath, Appl. Catal. A:
General 2000, 202, 117; F. Schager, W.
Bonrath, J. Catal. 1999, 182, 282; W. Bon-
rath (F. Hoffmann-La Roche), EP 782993
A1, 1996 (Chem. Abstr. 1997, 127,
109079).
[6] J.N. Meussdoerfer, H. Niederprüm, Chem.
Ztg. 1972, 96, 582; H. Niederprüm, J.N.
Meussdoerfer (Bayer AG), Deutsche Of-
fenlegungsschrift 2239817, 1972 (Chem.
Abstr. 1974, 80, 120260).
[7] J. Foropoulos Jr., D.D. Desmarteau, Inorg.
Chem. 1984, 23, 3720; D.D. Desmarteau,
M. Witz, J. Fluorine Chem. 1991, 52, 7.
[8] Alternative preparation via ammonium or
metal salts: K. Pohmer, R. Weber, C.
Dörzbach-Lange, K. Stachulla, H.-H.
Moretto, M. Wienand (BayerAG), DE Of-
fenlegungsschrift 4217366 A1, 1992
(Chem. Abstr. 1994, 120, 301651); H.
Sakaguchi, K. Fujii, S. Sakai, Y.
Kobayashi, Y. Kita (Central Glass Co.),
DE Offenlegungsschrift 19533711 A1,
1995 (Chem. Abstr. 1996, 124, 342658).
[9] L. Turowsky, K. Seppelt, Inorg. Chem.
1988, 27, 2135; A.G.M. Barrett, N.
Bouloc, D.C. Braddock, D. Catterick, D.
Chadwick, A.J.P. White, D.J. Williams,
Tetrahedron 2002, 58, 3835; J. Nishikido,
F. Yamamoto, H. Nakajima, Y. Mikami, Y.
Matsumoto, K. Mikami, Synlett 1999,
1990.
[10] J. March, ‘Advanced Organic Chemistry’,
4th Edition, John Wiley & Sons, NewYork,
1992, p. 1011.
[11] W. Bonrath, A. Haas, E. Hoppmann, H.
Pauling, (Roche Vitamins), EP 1180517