1,1,3,3-Tetratriflylpropene (TTP): A Strong, Allylic C–H Acid for Br?nsted and Lewis Acid Catalysis

Article abstract of DOI:10.1002/anie.201609923

Tetratrifylpropene (TTP) has been developed as a highly acidic, allylic C–H acid for Br?nsted and Lewis acid catalysis. It can readily be obtained in two steps and consistently shows exceptional catalytic activities for Mukaiyama aldol, Hosomi–Sakurai, an

Full text of DOI:10.1002/anie.201609923

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International Edition: DOI: 10.1002/anie.201609923
German Edition: DOI: 10.1002/ange.201609923
Strong Acids
1,1,3,3-Tetratriflylpropene (TTP): A Strong, Allylic C–H Acid for
Brønsted and Lewis Acid Catalysis
Denis Hçfler, Manuel van Gemmeren, Petra Wedemann, Karl Kaupmees, Ivo Leito,
Markus Leutzsch, Julia B. Lingnau, and Benjamin List*
Abstract: Tetratrifylpropene (TTP) has been developed as
a highly acidic, allylic C–H acid for Brønsted and Lewis acid
catalysis. It can readily be obtained in two steps and
consistently shows exceptional catalytic activities for
Mukaiyama aldol, Hosomi–Sakurai, and Friedel–Crafts acy-
lation reactions. X-ray analyses of TTP and its salts confirm its
designed, allylic structure, in which the negative charge is
delocalized over four triflyl groups. NMR experiments, acidity
measurements, and theoretical investigations provide further
insights to rationalize the remarkable reactivity of TTP.
carbon allows the introduction of up to three electron-
withdrawing groups, the negative charge can be more
extensively delocalized in C–H acids than in O–H and N–H
acids, resulting in higher acidity of the former.
To increase the number of electron-withdrawing groups
beyond three, vinylogous acids can be designed and synthe-
sized. Inspired by the work of R. Kuhn and others,[9,10] we
were intrigued in assessing an allylic C–H acid carrying four
triflyl groups. This resulted in the design and development of
tetratriflylpropene (TTP, Scheme 1), which we present herein.
Strong organic acids and their salts are of fundamental
importance as charge carriers in fuel cells (e.g. electrolytes),
as stabilizers of highly reactive species, and as reagents or
catalysts in chemical synthesis.[1] Developing a strong organic
acid fundamentally means designing the corresponding
anion: its negative charge should be as delocalized as possible
to reduce its basicity. The most successful strategy to reducing
anion basicity involves the utilization of strongly electron-
withdrawing groups,[1a,2] among which the trifluoromethane-
sulfonyl (triflyl or Tf) group is particularly powerful and
frequently used.[3] Introducing triflyl groups to organic
molecules increases the acidity of the neighboring a-hydro-
gens, an effect that rises with the number of triflyl groups. As
a result, the maximum possible number of triflyl groups often
confers highest acidity to a molecule.[3b,4] Examples for strong
acids containing triflyl moieties are triflic acid (TfOH),[5]
triflimide (Tf2NH),[6] and tris(triflyl)methane (Tf3CH)[7] with
pKa values (in dichloroethane, relative to picric acid) of À11.4
(TfOH), À11.9 (Tf2NH), and an estimated À16.4 (Tf3CH).[1b]
Triflimide and to a lesser extent also tris(triflyl)methane have
been employed in Lewis and Brønsted acid catalysis, either in
their protonated form, silylated, or as salts.[8] The observed
Scheme 1. Design of tetratriflylpropene (TTP).
The anion of TTP was designed to be highly symmetric
and such that the negative charge can be delocalized over four
triflyl groups, each containing two oxygens (leading to a total
of eight conjugated oxygen atoms). In comparison to Tf3CH,
the scaffold of our allylic C–H acid is expanded by two carbon
atoms. The four CF3 groups of TTP are also presumed to
stabilize the anion through their field-inductive properties.
The high stabilization of the anion should minimize its Lewis
basicity thereby limiting protonation and coordination to
Lewis acids and increasing the Brønsted acidity of TTP.
In analogy to our previous synthesis of chiral allyltetra-
sulfones,[11] TTP can readily be obtained via a two-step
synthesis (Scheme 2) starting from commercially available
bistriflylmethane (1). Disulfone 1 is first converted essentially
quantitatively to enol ether 2,[11] which is then treated with
bistriflylmethane (1) and TMP base (solution of 2,2,6,6-
tetramethylpiperidinylmagnesium chloride lithium chloride
complex) to give the TMP·TTP salt 3. While ammonium salt 3
could be conveniently isolated, finding suitably acidic con-
ditions to obtain pure and reasonable quantities of TTP
proved to be rather challenging. All tested aqueous acids and
many organic acid solutions gave none or only traces of TTP.
Finally, we found that satisfying amounts of clean TTP could
be obtained upon workup with pure concentrated sulfuric
acid. Isolated in pure form, TTP is very hygroscopic and
readily decomposes in the presence of water. Both salt 3 and
TTP could be crystallized successfully and their crystal
structures are shown as ORTEP drawings (Scheme 2).
À
pKa trend is remarkable, as C H bonds are often intrinsically
unpolarized and proton dissociation is usually less facile than
À
À
that of O H and N H bonds. However, as the tetravalency of
[*] D. Hçfler, P. Wedemann, Dr. M. Leutzsch, J. B. Lingnau,
Prof. Dr. B. List
Max-Planck Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: list@kofo.mpg.de
Dr. M. van Gemmeren
Westfꢁlische Wilhelms-Universitꢁt Mꢀnster
Correnstrasse 40, 48149 Mꢀnster (Germany)
Dr. K. Kaupmees, Prof. Dr. I. Leito
University of Tartu, Institute of Chemistry
Ravila 14a, Tartu 50411 (Estonia)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609923.
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Scheme 2. Synthesis of TTP and X-ray structure analysis.
Remarkably, TTP has an intramolecular hydrogen bond
between the acidic proton and a neighboring sulfonyl group
with an average length of 2.13 ꢀ. The average angle between
C, H, and O is 1338. Both values lie within the expected range
for typical hydrogen bonds.[12] The crystal structure of
TTP·TMP (3) shows that not all four triflyl groups are in
the same plane. This structural property may reduce the
stability of the anion, potentially compromising the acidity of
TTP. Besides this, the triflyl groups in the 1,3 positions are
slightly bent away from each other as the angles between S3,
C3, and C2 and C2, C1, and S1 have an average value of 1248
(instead of 1208). This bending might be caused by the charge
repulsion between partially negatively charged oxygens.
When the tetraethylammonium salt of TTP was crystallized
and analyzed via X-ray structural analysis (see Figure S3 in
the Supporting Information) an average angle of 1308 was
measured for the same atoms indicating an even stronger
bending.
To evaluate the catalytic properties of TTP in silylium-
based Lewis acid catalysis, the Mukaiyama aldol reaction of
tert-butyldimethylsilyl (TBS)-protected silyl ketene acetal 5
with benzophenone (4) was chosen as a model reaction
(Figure 1).[13] This aldol reaction is challenging as ketones are
generally less reactive than aldehydes and possibly also due to
the required transfer of the rather bulky TBS group to give
silyl ether 6. Triflimide (8), tris(triflyl)methane (7), and the
structurally related carbon acid 9,[14] which can be viewed as
an unconjugated/hydrogenated version of TTP, were chosen
as benchmark acids. The reaction was monitored by ReactIR
in order to compare product formation at different time
points.
Figure 1. Comparing catalytic Mukaiyama aldol reactions using Reac-
tIR. For all reactions 1 mmol of ketone 4 was employed and the
reaction was halted by the addition of MeOH and Et3N.[15] The reaction
was carried out three times for each catalyst and product formation
was measured in situ by ReactIR. Triphenylmethane was added as an
internal standard and full product formation was verified by 1H NMR
analysis. A representative plot for each catalyst is shown which is
closest to the average of the three ReactIR measurements.
activity in Lewis and Brønsted acid catalysis (Figure 2). For
the previously undescribed Mukaiyama aldol addition of
ketene acetal 5 to the sterically more demanding ketone 10,
TTP again proved to be the most active catalyst (Figure 2a).
Catalyst 9 also displayed a relatively high activity when
compared to catalysts 7 and 8, which performed similarly. The
high reactivity of bis-C–H acid 9 is somewhat unexpected, as
it displayed lower activity than tris(triflyl)methane (7) in the
Mukaiyama aldol reaction of nucleophile 5 with benzophe-
none (Figure 1). Reports from the Taguchi group[14b,c] already
described carbon acid 9 as a more effective catalyst for
vinylogous Mukaiyama–Michael reactions than Tf2NH (8).
These experimental findings may be partially rationalized by
the fact that 9 is a diacid, which could in principle lead to
a
doubly silylated, catalytically active species.[14c] The
reported crystal structure of diacid 9 showed two intra-
molecular hydrogen bonds between the acidic protons and
oxygen atoms of the opposing triflyl groups.[14c] These hydro-
gen bonds may be strengthened upon deprotonation suggest-
ing the alternative possibility of a Brønsted acid assisted
Lewis acid mechanism of acid 9.
Remarkably, TTP showed the highest reaction rate with
90% product formation after only 7 min, followed by C–H
acid 7 with 28 min. Catalysts 8 and 9 showed almost identical
reaction rates with an average of 50–52 min to reach 90%
product formation.
The Hosomi–Sakurai reaction[16] of electron-poor p-nitro-
benzaldehyde (12) with allylsilane 13 was chosen as a chal-
À
lenging example of another class of synthetically useful C C
bond-forming reactions (Figure 2b).[17] Due to the nitro group
in the para position of 12, the Lewis basicity of the aldehyde is
reduced rendering the activation via the coordination of
a Lewis acid to the carbonyl lone pair of aldehyde 12
After these promising initial results for TTP catalysis,
other reactions were chosen for further evaluation of its
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Table 1: Fluoride ion affinities (FIA) of silyl Lewis acids and 29Si NMR
shifts.
Entry
X
Me3SiX
FIA [H in
FIA [U in
[d(29Si)] [ppm]
kcalmolÀ1 [a]
]
kcalmolÀ1 [b]
]
1
2
3
4
TTP
7
8
67.2
66.6
65.7
52.5
118.1
108.7
96.2[14a]
106.0
89.5
85.2
76.2[14a]
80.9
9
[a] BP86/SVP, 298.15 K, 1 bar. [b] kcalmolÀ1, BP86/SVP, in CH2Cl2. 29Si
NMR shifts were determined in a mixture of CDCl3 and [D]Et2O (4:1).
catalyst 7 as the second most active species. The two
computationally predicted, least active catalysts 8 and 9,
although structurally very different, were found to have very
similar activities in our experimental studies. The Mukaiyama
aldol reaction of 10 with 11 (Figure 2a) constitutes a notable
exception to this good agreement between theoretical and
experimental results, as a remarkably high activity of carbon
acid 9 was observed in this case, presumably due to the
different mode of action of this bifunctional catalyst in this
specific case.
Figure 2. Application of TTP and comparison with other catalysts.
Reactions (a–c) were run on a 1 mmol scale (with regard to starting
material 10, 12, and 15); reaction (d) was run on a 10 mmol scale.
Reaction (a) was quenched via the addition of MeOH and Et3N and
reaction (b) was quenched via the addition of Et3N. For reactions (b)
and (c) yields refer to isolated products. Product 14 was isolated as
free alcohol by flash chromatography. [a] Triphenylmethane was added
to reactions (a) and (d) and the yield was determined by 1H NMR
analysis. n.d.=not detected. For reaction (a) a previously reported
chiral binaphthylallyltetrasulfones (BALT) C–H acid (substituted with
a phenanthrenyl moiety)[12] was also tested but no product could be
obtained.
In order to complement our theoretical data, 29Si NMR
shift experiments were conducted next. Although this
approach was reported to have limited correlation with
Lewis acidities and catalytic activities,[20d] we attempted to
corroborate our theoretical data with these studies. Each
catalyst was treated with allyltrimethylsilane (13) in a deu-
1
terated solvent mixture and H as well as 29Si NMR spectra
unfavorable. Remarkably, only TTP was found to be active
and gave the corresponding silyl ether 14 in almost quanti-
tative yield, while all other tested catalysts gave no reaction
under these conditions.[18]
In addition, the difficult Brønsted acid catalyzed Friedel–
Crafts acylation reaction of electron-poor chlorobenzene (16)
with benzoylchloride 15 was carried out in the presence of the
different catalysts (Figure 2c).[19] When catalysts 8 and 9 were
employed, no desired product could be isolated. Carbon acid
7 provided the product in 17% yield, while TTP gave
a satisfying 59% yield, illustrating its potential in Brønsted
acid catalysis.
were acquired. Different chemical shifts for the 29Si NMR
signal were recorded for each catalyst. A less Lewis basic
catalyst anion should provide a more Lewis acidic and
deshielded silylium ion equivalent, resulting in a more down-
field signal in the 29Si NMR spectrum. TTP provided the
furthest downfield signal, thereby confirming its exceptional
Lewis acidity. However, the absolute differences (in ppm) to
acids 7 and 8 were relatively small. Surprisingly, diacid 9
provided by far the least downfield signal which may once
again hint at a different activation mode for this catalyst. The
small differences between TTP and acids 7 and 8 can be
explained by the leveling effect of the Lewis basic diethyl
ether solvent, which may coordinate to the silylium ion,
decreasing its overall Lewis acidity and resulting in a less
downfield chemical shift in the 29Si NMR spectra for all
catalysts.
Remarkably, ammonium salt 3 was also able to catalyze
the Mukaiyama aldol reaction of silyl ketene acetal 5 with
benzophenone (4) at a very low catalyst loading of 50 ppm
(0.005 mol%) at room temperature (Figure 2d).
During the application of TTP to acid-catalyzed reactions,
we became more and more interested in determining its
acidity. The well-established concept of fluoride ion affinity
(FIA) to computationally access Lewis acidities already
proved to be insightful for other strong organic acids.[13a,20]
Therefore, we used this approach to calculate the FIA values
of the catalytically employed silicon-centered Lewis acids
(Table 1). The FIA calculations suggest silylated TTP to be
the strongest Lewis acid. Our calculations also confirm
In addition, the pKa of TTP (relative to picric acid) was
determined in dichloroethane as À15.4 and the estimated pKa
in acetonitrile (on the basis of correlation)[1b] is À2.8. Overall,
the obtained results are in good agreement with our
experimental findings: the acidity of triflimide (8) is more
than 3 orders of magnitude lower and the acidity of carbon
acid 9 (pKa = À5.2) is at least 9 (approximate) orders of
magnitude lower than that of TTP. However, the acidity order
of TTP and Tf3CH (7), when compared to the previously
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In conclusion, we report the synthesis, structure, applica-
tion, and experimental and theoretical evaluation of TTP,
which is a novel, allylic C–H acid showing exceptionally high
reactivity in Lewis and Brønsted acid catalyzed reactions. Our
acid can be readily obtained in two steps from commercially
available bistriflylmethane. The structures of its protonated
form as well as its salts were solved using X-ray analysis. In
comparison to the prominent, very active, organic acids 7, 8,
and 9, TTP consistently displays the highest activity. This
outstanding activity of TTP could be corroborated through
FIA calculations, relative pKa measurements, and 29Si shift
experiments. We anticipate that TTP as a strongly acidic,
allylic C-H acid will enable the catalysis of a variety of
challenging reactions, which are currently being studied in our
laboratories. We furthermore envisage that TTP may be
useful for applications beyond organocatalysis, such as in
electrolytes and ionic liquids, and as a weakly coordinating
anion.
CCDC 1509165, 1509166, and 1509167 contain the sup-
plementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Acknowledgements
Generous support by the Max-Planck-Society and the Euro-
pean Research Council (Advanced Grant “C-H Acids for
Organic Synthesis, CHAOS”) is gratefully acknowledged. We
thank the members of our NMR, MS, GC, X-ray, and HPLC
departments for their excellent service. We gratefully
acknowledge the excellent service of H. Schucht, N. Nçthling,
and Dr. R. Goddard in determining the structure of TTP via
X-ray analysis. We also thank A. Deege and H. Hinrichs for
providing a very thorough HPLC analysis of our products, J.
Arlt for her technical support, and Dr. M. Klußmann for his
assistance regarding the ReactIR experiments. M.v.G. thanks
the Alexander von Humboldt Foundation (Feodor Lynen
Return Fellowship) and the Fonds der Chemischen Industrie
(Liebig Fellowship) for their generous support. The work of
K.K. and I.L. was supported by the institutional research
grant from the Ministry of Education and Research of Estonia
IUT20-14 (TLOKT14014I). Furthermore, we would like to
acknowledge helpful discussions with L. Schreyer and P. S. J.
Kaib.
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[18] The reaction could also be catalyzed with triflimide (8) and
tristriflylmethane (7) but not with carbon acid 9 when CH2Cl2
was chosen as solvent instead of diethyl ether.
Conflict of interest
The authors declare no conflict of interest.
Keywords: allylic C–H acids · Brønsted acids · Lewis acids ·
strong acids · tetratriflylpropene
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Manuscript received: October 10, 2016
Final Article published: && &&, &&&&
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Communications
Strong Acids
D. Hçfler, M. van Gemmeren,
P. Wedemann, K. Kaupmees, I. Leito,
M. Leutzsch, J. B. Lingnau,
B. List*
&&&& — &&&&
1,1,3,3-Tetratriflylpropene (TTP): A
Strong, Allylic C–H Acid for Brønsted and
Lewis Acid Catalysis
Acid strength by design: Tetratrifyl-
propene (TTP) has been developed as
a highly acidic, allylic C–H acid for
Brønsted and Lewis acid catalysis and
was tested in Mukaiyama aldol, Hosomi–
Sakurai, and Friedel–Crafts acylation
reactions. X-ray analyses, NMR experi-
ments, acidity measurements, and theo-
retical studies provide further insights to
rationalize the remarkable reactivity of
TTP.
6
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