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Formation and Reactivity of Phosphonium Salts in the Vitamin A Series.

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metric electric field produced at the halide nucleus by the
metal ion. Rates of reactions such as
+ Br- +
+ H,O
can be evaluated.
Finally, it is of interest to mention that rates of rapid
exchange reactions can also be measured by using the
line broadefiing in EPR or ESR spectra [25]. Since the
time scale of EPR is some 103 times larger than that of
NMR (the frequency used is of the order 1010 cps rather
than lo7 cps) only very rapid reactions can be studied.
Half-lives of 10-6- 10-9 seconds are most convenient.
It has been possible to study rates of outer-sphere complex formation between paramagnetic cations and a para[?5] R . G. Pearson and T. Buch, J. chern. Physics 36, 1277 (1962).
magnetic anion, the nitrosyldisulfonate ion. Such outersphere reactions are very rapid, being diffusion controlled [26]. It is also possible to study rates of innersphere complex conversions by selecting a cation the complexes of which are very labile, for example Mn(II), and
going to high temperatures where the rates become sufficiently rapid [271.
We are indebted to Prof. A. L. Allrzd for much help in the
theory and practice of nuclear magnetic resonance spectroscopy.
Received: July24th, 1964. Supplemented: October 19th, 1964[A440/2041E]
German version: Angew. Chem. 77, 361 (1965)
1261 M . Eigen and K.Tamm, 2. Elektrochem., Ber. Bunsenges.
physik. Chern. 66, 93, 107 (1962).
[27] R . G. Hayes and R . J . Myers, J. chem. Physics 40,877 (1964).
Formation and Reactivity of Phosphonium Salts in the Vitamin A Series
Pubhhed on the occasion of the 100th nnnivcvmry of the establishment of Badische Anilin& Soda-Fabrik AG., on April 6th, 1965.
For syntheses in the carotenoid j e l d using the Wittig reaction, particularly on the technical
scale, it was necessary to ccrry out extensive studies on the preparation and properties of
the intermediates. Here the part of this work is discussed which dealt with quaternary
phosphoniunz compounds of triniethylcyclohexene derivatives.
1. Formation of Phosphonium Salts
The well-known reaction of tertiary phosphines with
organic halides to form quaternary phosphonium compounds [l] is unsatisfactory in the vitamin A series, since
here the halogen compounds are extremely unstable.
However, this difficulty has been overcome by a new
method for the preparation of quaternary phosphonium
salts [2].
When alcohols are treated simultaneously with tertiary
phosphines and acids, they give high yields of quaternary phosphonium salts [3]:
+ PR; + HX
+ [R-PR;]@ XO
+ HzO
Suitable starting materials include primary and secondary alcohols; substituted ally1 alcohols react particularly smoothly.
[ I ] G. M . Kosolapof Organophosphorus Compounds. Wiley,
New York 1950.
L21 H . Pommer, Angew. Chem. 72, 811, 911 (1960).
131 German Patent 1046046 (June 29th, 1956), BASF; inventors:
W. Sarnecki and H . Pommer; Chem. Zbl. 1959, 13003.
Angew. Chem. internat. Edit. 1 Vo1. 4 (1965)
1 No. 4
Thus, p-ionol (I) reacts with triphenylphosphine [*] and
an acid HX to give the @-ionyltriphenylphosphonium
salt (2) ; similarly (3-ionylidene-ethanol (3) gives the Pionylidene-ethyltriphenylphosphoniurn salt (6).
We assume an ionic mechanism for the formation of the
quaternary phosphonium salt from alcohol, phosphine,
and acid. Under the action of the proton, the alcohol
R-OH forms the carbonium ion Re, which then alkylates the tertiary phosphine to yield the quaternary salt.
In support of this mechanism, replacement of p-ionylidene-ethanol (3) by its isomer 9-vinyl-P-ion01 (4) leads
to the s a m e P-ionylidene-ethyltriphenylphosphonium
salt (6) [4].
[ * ] The tertiary phosphine used here and throughout this work
is triphenylphosphine, the preferred reagent for the Wittig
olefination. The components (C&&P and HX'can be replaced
by the quaternary phosphoniurn salt [(C,jH&PH]@XQ.
[4] German Patent 1060386 (Sept. 3rd, 1957), BASF; inventors:
W . Sarnecki and H . Pommer; Chem. Zbl. 1960, 13171.
Compounds (3) and (4) apparently react with the acid
to give the same carbonium ion (S), which has a number
of resonance structures (5a) -(Sd). This carbonium ion
is normally stabilized by loss of a proton with formation
which then reacts with the triphenylphosphine to give
the (3-ionylidene-ethyltriphenylphosphoniumsalt (6).
This reaction occurs with all retro-hydrocarbons in the
carotenoid series.
[ c b _
of the hydrocarbon (7), which exists in the so-called retro-configuration. The “retro-ionylidene rearrangement”, which was first described by Oroshnik et al. [ 5 ]
and by Huisman et al. [6], always takes place when a
carbonium ion is formed in the wposition relative to a
ring double bond or in a position vinylogous thereto.
However, if a tertiary phosphine is present. the cation ( 5 )
reacts preferentially with this nucleophile, instead of
assuming the retro-configuration.
In the vitamin A series, this method is an excellent alternative
to the formation of phosphonium salts from alcohols. It
proceeds more slowly than the formation of phosphonium
salts by direct alkylation of the tertiary phosphine; consequently, the phosphonium salt is always accompanied by a
small quantity of retro-hydrocarbon, which disappears only
after very long reaction times.
The reaction mechanism discussed above can be applied
to the formation of the vinylogous salts (9), (lo), and
The retro-configuration (8b) is energetically more favorable than the trimethylcyclohexene configuration (8a).
With a few exceptions, the retro-ionylidene rearrangement is irreversible. Thus, one of the major tasks in
carotenoid chemistry is the search for synthetic routes
and reaction conditions under which the retro-ionylidene rearrangement either does not take place at all, or
can be suppressed.
(60): n = 0
(6): n = 1
(10): n = 2
(11): n = 3
(11) from the corresponding alcohols; competing reactions again lead to the formation of small amounts of
the retro-hydrocarbon.
3. Other Syntheses of Phosphonium Salts
2. Reconversion of the Retro-Form into the
Trimethylcyclohexane Configuration
We found that the “reto-hydrocarbon’’ (7) could be
transformed to the trimethylcyclohexene configuration
by the combined action of phosphines and acids. For
example, a proton from the acid and the phosphorus
atom of the phosphine yield the phosphonium salt (6)
by 1,s-addition to the conjugated system of the retrohydrocarbon (7) [7]. First, the proton adds onto the
retro-hydrocarbon (7) to reform the carbonium ion (51,
[S] W. Oroslznik, G. Karmas, and A . D . Mebane, J. Amer. chem.
Sac. 74, 295, 3807 (1952).
161 H. 0. Huisman, A . Smit, S . Vromen, and L. G . M . Fischer,
Recueil Trav. chim. Pays-Bas 71, 899 (1952); 75, 977 (1956).
[7] German Patent 1046612 (Oct. 23rd, 1957), BASF; inventors:
H . Pommer and W. Surnecki; Chem. Zbl. 1960, 6928.
Quaternary phosphonium salts can also be synthesized
by the combined action of triphenylphosphine and an
acid on esters of alcohols in the vitamin A series. Thus,
the P-ionylidene-ethyltriphenylphosphoniumsalt (6) can
be obtained from P-ionylidene-ethyl acetate (12), and
the axerophthyltriphenylphosphonium salt (10) from
vitamin A acetate (13) [ 8 ] . The ester can be replaced by
(12): n = 0
(13): n = 1
[8] German Patent I 155 126 (May 23rd, 1962), BASF; inventors:
W . Surnecki, A. Niirrenbach, and W. Re$.
Angew. Chem. internat. Edit.
Vof.4 (1965)
1 No. 4
the ether with equal success. These results are again explained by the formation of a carbonium ion by the
action of a proton o n the ester or ether.
The main product in all our experiments was the
t e r m i n a l phosphonium salt. Salts derived from the resonance structures (56)-(5d), i.e. with the phosphorus
attached to non-terminal carbon atoms, could be detected either only in traces or not at all. It is obvious that
salts derived from structures (56) or (5c), in which the
conjugation is interrupted, are energetically less favored
than the terminal phosphonium salt (6). On the other
hand, energy considerations suggest that (5d) should
take part in the reaction as well as ( 5 4 , since the resulting systems have an equal number of conjugated
double bonds. Thus, the nucleophilic reagent must be
partly responsible for the fact that only (6) is formed. It
can be shown with Stuart models that (6) is the only
isomer with an unstrained structure. The molecule becomes strained, if the triphenylphosphine is attached to
carbons 9, 7, or 5 .
4. Quasi-Phosphonium Salts a n d Phosphonates
During attempts to synthesize phosphonates (15) instead of the quaternary phosphonium salts of type ( 6 ) ,
we found that the resonance forms (Sa) and (56) of the
carbonium ion intermediate react with the nucleophile.
Like the Michaelis-Arbusow reaction [2,9], the synthesis proceeds via a quasi-phosphonium salt (14), which
differs from the “normal” phosphonium salts in that
three alkyl or aryl residues have been replaced by RO
Despite their low stability - they readily lose a cation
R‘” with formation of the phosphonate grouping (15)
[lo] - the quasi-phosphonium salts are formed by the
same mechanism as normal phosphonium salts.
We then attempted to synthesize the phosphonates, in
which we were interested, using the Michaelis-Arbusow
reaction. However, the reaction of P-ionyl bromide (16)
with triethyl phosphite did not yield the desired product
(17). Instead, the retro-hydrocarbon (18) was formed
[9] Cf. H . Freysrhlag, W . Reif, and H . Ponimer, Communication
to the IUPAC Symposium on Organic Phosphorus Compounds,
Heidelberg (Germany), May 20th, 1964.
[lo] K . Dimroth and A. Niirrenbach, Chem. Ber. 93, 1649 (1960).
Angew. Chem. internat. Edit.
Vol. 4 (1965)
1 No. 4
by elimination of HBr, even at temperatures much
lower than those required for the Michaelis-Arbusow
reaction, i.r. a quasi-phosphonium salt is not formed.
Addition of hydrogen phosphites onto retro -hydrocarbons was also unsuccessful.
In contrast to tertiary phosphines, tertiary phosphites
are not stable toward acids, being rapidly decomposed,
even in the absence of water. We were therefore surprised to find that the desired phosphonates could be
prepared from alcohols and a phosphite in the presence
of p r o t o n d o n o r s ; we assume the mechanism to be
as follows: The phosphite reacts with carbonium ion R @
formed first to yield the quasi-phosphonium salt (14),
- -[ z:l
which is stabilized by elimination of a carbonium ion
R‘O and formation of the phosphonate grouping.
The yield of phosphonate is high only when the
phosphite is used in an excess of at least one
mole. Diethyl 3-ionylphosphonate (17) could be obtained in this way from p-ionol ( I ) and triethyl phosphite.
For the preparation of the vinylogous phosphonate by
the same method, it should be immaterial wheter the
starting material is P-ionylidene-ethanol (3) or 9-vinylp-ionol (4). With either compound, the first step leads
to the cation ( 5 ) , which can react further either by elimination of a proton t o form the retro-hydrocarbon (7),
or by alkylation of the phosphorus atom.
In contrast to the reaction leading to the phosphonium
salts (6), however, the formation of the retro-hydrocarbon during the preparation of the phosphonate is
irreversible. Probably reformation of the carbonium ion
(5) from the retro-hydrocarbon (7) is relatively slow in
comparison with the decomposition of the phosphite by
acid. The competing reaction leading to the retro-hydrocarbon must therefore be suppressed here by the use of
excess phosphite. In this way, the carbonium ion ( 5 )
formed as the first intermediate is intercepted as the
quasi-phosphonium salt.
Another difference between this reaction and formation of phosphonium salts is the occurrence of two
isomers: a primary phosphonate (19a) formed by reaction of the carbonium ion (5u) with the phosphite,
and a tertiary phosphonate (196) derived from the reso-
28 9
nance structure (5b). Phosphonates derived from resonance structures (Sc) and (5d) could not be detected. It
can be shown with Stuart models that triethyl phosphite,
unlike triphenylphosphine, can be attached to carbon 9
without steric hindrance, but not to carbons 7 or 5.
and (3-ionylidene-ethanol derivatives after protonation
more easily than acetoxy or alkoxy groups. This also
explains the lability of the halogen derivatives in this
series, and the difficulty encountered in preparing them
from the alcohols.
5. Rearrangement Mechanisms
The mechanism proposed for the formation of the retrohydrocarbon by elimination of a proton from a carbonium ion intermediate also explains why attempts to rearrange 9-vinyl-p-ionol (4) to p-ionylidene-ethanol (3)
have so far met with failure [5,6,11,12]. Evidently, the
rearranged compound is converted into the cationic intermediate as easily as the starting material, under the
reaction conditions used. Since the conversion of the
cation into the retro-compound is the only reaction
involved which is almost irreversible [*I, the most stable
product is the retro-compound. During the formation
of phosphonium salts, on the other hand, an allylic
r e a r r a n g e m e n t becomes possible (see Scheme 1) because of the stability of the new P-C bond.
Scheme 1
Thus, the normal allylic rearrangement should always
take place when the reaction of the carbonium ion intermediate with the nucleophile is favored over the reverse
reaction. The retro-hydrocarbon can be formed if the
carbonium ion intermediate arises equally readily from
both allylic isomers. However, if none of these steps is
particularly favored, the reaction should lead to a mixture of the products of the allylic rearrangement and of
the retro-rearrangement.
Thus, if 9-vinyl-P-ion01 (4) is treated with glacial acetic
acid, the product contains P-ionylidene-ethyl acetate
(12), together with the retro-hydrocarbon (7). If the
reaction is carried out in an acetic acid/ethanol mixture,
on the other hand, it is ethyl fi-ionylidene-ethyl ether
(20) that is formed together with the retro-compound
(7), although traces of the acetate (12) are also found.
These results disagree with the findings of earlier workers [5,6,11,12] but can be readily explained by assuming
that the hydroxy group is removed from 9-vinyl-P-ionol
I l l ] J. G . Baxter, Fortschr. Chem. org. Naturstoffe 9, 41 (1952).
I121 P . Kurrer and J. Kebrle, Helv. chim. Acta 35, 2570 (1952).
[*I The reverse reaction, i.e. the addition of a proton onto the
retro-hydrocarbon, is so slow that the formation of the retroconfiguration can be regarded as being “almost irreversible” in
this case.
(12) = 40%
+ (7) = 60%
(20) = 40%
+ (7) = 60%
6. Reactivity of the Phosphonium Salts
After we had succeeded in synthesizing all the desired
phosphonium salts of the vitamin A series, using the
methods described above, we proceeded to study their
stability and reactivity [13]. Among the isoprenologous
phosphonium salts [cyclogeranyl- (6a), P-ionylideneethyl- (6), axerophthyl- (lo), and homoisoprenoaxerophthyl-triphenylphosphonium salts (II)], (6a) reacts
d y sluggishly with carbonyl compounds when an alkali metal hydroxide is used for ylide formation or when
water is present. Elevated temperatures are required for
carbonyl olefination, even in absolutely anhydrous solvents and when sodium methoxide is used. On the other
hand, the isoprenologous salts (6), (lo), and (11) react
with carbonyl groups even in aqueous solution and with
only alkali metal hydroxide as proton acceptor. It was
surprising to find that these salts react in aqueous solution, since the Wittig reaction generally proceeds only
in the absence of water. The phosphonium ion (21) gives
up a proton to the base, in accordance with a reaction
scheme formulated by Wittig (Scheme 2). The resulting
ylide (22) readily adds on polar substances: addition of
carbonyl compounds leads to the betaine (23) by the
normal olefination reaction, while addition of water
leads to the phosphonium hydroxide (24) as a hydrolysis intermediate [14,15].
Scheme 2.
[13] Cf. W. Sarnecki and A . Niirrenbach, Communication to the
IUPAC Symposium o n Organic Phosphorus Compounds, Heideiberg (Germany), May 20th, 1964.
[I41 D. D. Coffmann and C. S. Marvel, J . Amer. chem. SOC. 51,
3496 (1929).
[I51G. W.FenfonandC. K.ZngoZd,J.chem.Soc.(London)Z929,2342.
Angew. Chem. internat. Edit. / Vol. 4(1965)
1 No. 4
Addition of water onto, and hence hydrolysis of, the isoprenologous salts should be more difficult owing to the
increased stabilization by resonance of the corresponding
ylides; this enhancement of the ylide stability can be
detected experimentally. If the phosphonium ion (21)
and its ylide (22) are regarded as a conjugate acid-base
pair, the equilibrium established between an ylide and
the phosphonium ion of a second compound will always
be displaced towards the weaker acid and the weaker
base [16]. Thus, a mixture of the ylide (6') and a stoichiometric quantity of phosphonium salt (10) react with
ethyl P-formylcrotonate to form only the ethyl heptaenoate (26) ; no ester of vitamin A acid (25) is formed.
It follows, therefore, that the ylide (10') must be a
weaker base than the ylide (6'), i.e. the phosphonium
ion (6) is a weaker acid than the phosphonium ion (10).
Thus, any increase in the number of double bonds is
accompanied by an increase in the acidity of the phosphonium ions, and a decrease in the basicity of the ylides.
However, measurement of the rates of hydrolysis of the
ylides [*] showed that hydrolysis is by no means retarded by the increasing resonance stabilization. Contrary to our original assumption, the rate of hydrolysis
actually increases with the number of conjugated double
bonds. The cyclogeranyltriphenylphosphonium salt (6a)
undergoes practically no hydrolysis at room temperature, whereas the salt (11) is hydrolysed fairly rapidly.
The hydrolysis is strongly dependent on temperature;
with the p-ionylidene-ethyltriphenylphosphonium salt
(6), for example, it ceases at about 0 "C (cf. Fig. 1).
Thus, olefination in the presence of water can proceed in
high yield only when the reaction is carried out below the
temperature at which hydrolysis ceases.
[I61 H . Besfmann, Chem. Ber. 95, 58 (1962).
[*1 The hydrolysis to (C6Hs)-,PO is accompanied by a corresponding consumption of base. Thus, after reaction of the
phosphonium salts with sodium methoxide in methanol to form
the ylides, followed by addition of water, determination of the
sodium methoxide consumption provides a simple titrimetric
method of determining the rate of hydrolysis (Fig. 1).
Angew. Cfiem. internrrt. Edit.1 V d . 4(1965)
No. 4
k==-9=t-, L
Fig. 1. Hydrolysis of CIO,Cis, Czo, and Czs ylides (c = 275x10-2.
moleil) in a 4:5 methanol/water mixture at a) 26°C; b) 4%.
Ordinate: Moles of base consumed per mole of phosphonium salt.
Abscissa: Hydrolysis time Irninl.
No decomposition of phosphonium salts in anhydrous
alcohols in the presence of alkoxides was observed in the
vitamin A series. This is in contrast to the thermal decomposition of phosphonium alkoxides [17,18]. Cleavage occurred only on addition of water, and the leaving
group was always that which was able to form the most
stable anion, i. e. the trimethylcyclohexene group [*I.
The attachment of these groups becomes less firm with
increasing chain length, owing to resonance stabilization. The ease of cleavage can be used to advantage in
preparative work. For example, axerophthene (27) is
obtained in a smooth reaction from the axerophthyltriphenylphosphonium salt (10). Other carotenoid hydrocarbons can also be obtained in good yields by a similar
Received: November 26th, 1964 [A 4331206 IE]
German version: Angew. Chem. 77, 277 (1965)
Translated by Express Translation Service, London
[I71 L. Hey and C. K . Ingold, J. chem. SOC.(London) 1933, 531.
[I81 M . Grayson and P . T . Keough, J. Amer. chem. SOC.82, 3919
[*I Horner 1191, Zanger [20], and Schlosser 1211 have reported
similar results in the cleavage of quaternary phosphonium salts.
[I91 L. Horner, H. Hoffmann, H . G. Wippel, and G . Hassei, Chem.
Ber. 91, 52 (1958).
[20] M . Zanger, C. A . van der Werf, and W . E. McEwen, J. Amer.
Chem. SOC.81, 3806 (1959).
[21] M . Schlosser, Angew. Chem. 74, 291 (1962); Angew. Chem.
internat. Edit. I, 266 (1962).
29 1
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salt, phosphonium, vitamins, series, formation, reactivity
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