The correlation of Lewis acidities of silyl triflates with reaction rates of catalyzed diels-alder reactions

Article abstract of DOI:10.1002/ejoc.201101307

The Lewis acidity of various silyl triflates was quantified by utilizing [D₅]pyridine as a ²H NMR spectroscopy probe. The chemical shifts of the ²H NMR signals for pyridine-silyl adducts are reported. The rate constants of silyl triflate catalyzed Diels-Alder reactions were determined by using UV/Vis spectroscopy. A correlation of the magnitude of the ²H NMR chemical shifts with the rate constants for most silyl triflates investigated was observed, but Me₃SiOTf exhibits a surprisingly large deviation. Control experiments indicate that proton catalysis of the Diels-Alder reaction can be excluded.

Full text of DOI:10.1002/ejoc.201101307

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101307
The Correlation of Lewis Acidities of Silyl Triflates with Reaction Rates of
Catalyzed Diels–Alder Reactions
Gerhard Hilt*[a] and Alexander Nödling[a]
Keywords: Lewis acids / Cycloaddition / Kinetics / NMR spectroscopy
The Lewis acidity of various silyl triflates was quantified by
utilizing [D5]pyridine as a 2H NMR spectroscopy probe. The
chemical shifts of the 2H NMR signals for pyridine–silyl ad-
ducts are reported. The rate constants of silyl triflate cata-
lyzed Diels–Alder reactions were determined by using UV/
Vis spectroscopy. A correlation of the magnitude of the
2H NMR chemical shifts with the rate constants for most silyl
triflates investigated was observed, but Me3SiOTf exhibits a
surprisingly large deviation. Control experiments indicate
that proton catalysis of the Diels–Alder reaction can be ex-
cluded.
vents and the NMR spectra are simplified because, in prin-
ciple, only the shift of one signal has to be observed.[3] We
then determined the effectiveness of Lewis acids in cata-
lyzed organic reactions in terms of their catalytic activity
by measuring the rate constants of the reactions. We could
show a good relation of the rate constants with the magni-
tude of the H NMR chemical shifts, proving that catalytic
activity of the Lewis acid relates well with the spectroscopi-
cally determined Lewis acidity.
Having shown this relation between both variables for
common traditional Lewis acids, we became interested in
further expanding the scope of this approach. Because silyl
triflates have gained more attention in the last years as ver-
satile Lewis acids[5] and due to their synthetic potential, we
were inspired to incorporate these still-unusual Lewis acids
in our classification.
Introduction
Lewis acids have found various applications as catalysts
in (asymmetric) organic and inorganic transformations.[1]
Their definition as electron-deficient compounds by Gilbert
Lewis is a fundamental concept in chemistry, covering
many classes of substances.[2] However, despite a large
number of approaches to quantify the strength of Lewis
acids by spectroscopic and thermodynamic methods, there
are few reports relating such scales to the effectiveness of
organic reactions. This, indeed, would help synthetic chem-
ists pondering which Lewis acid to choose for a reaction.
Trying to fill this gap, we recently developed quinolizidine
2
2
probe 1, which was used in H NMR spectroscopy for the
quantification of Lewis acidities.[3] Upon complexation of 1
2
with Lewis acids (LA), the H NMR signal was shifted to
a lower field. The chemical shift differences of the Lewis
acid adducts of type 2 were used as measures for the Lewis
acidities (Scheme 1).[4]
Results and Discussion
Quinolizidine probe 1 was treated with commercially
available silyl triflates in dichloromethane as solvent to gen-
erate adducts of type 2. Unfortunately, we found in NMR
titration experiments that even with a large excess of up to
20 equivalents of the silyl triflates complete complexation
could not be detected. As a simple alternative probe,
[D5]pyridine (3) was chosen to determine the NMR shifts
2
Scheme 1. Quinolizidine probe 1 for the quantification of Lewis
acidities.
of adduct 4 by H NMR measurements (Scheme 2). With a
The advantages of such a probe over others are that the
NMR experiments can be conducted in non-deuterated sol-
[a] Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein-Straße, 35043 Marburg, Germany
Fax: +49-6421-2825677
E-mail: Hilt@chemie.uni-marburg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101307.
Scheme 2. [D5]Pyridine (3) for the quantification of Lewis acidities.
Eur. J. Org. Chem. 2011, 7071–7075
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G. Hilt, A. Nödling
SHORT COMMUNICATION
10-fold excess of the Lewis acid, adducts of type 4 were tions with respect to 5 (Scheme 3). We used this approach
formed quantitatively, so that the quantification could be successfully in our previous work,[3] but it became apparent
2
realized.[6] Also, H NMR shift values for trifluorometh- that a large excess of isoprene results in the formation of
anesulfonic acid and HBF4·OEt2 were determined. The re- polymeric side products when silyl triflates are applied. On
2
sults of these H NMR measurements are summarized in the other hand, the formation of polymeric side products
Table 1.
was not encountered utilizing equimolar amounts of naph-
thoquinone, isoprene (5/6 = 1:1), and 5 mol-% of the silyl
triflates at 0 °C in dichloromethane but still led to reactions
following first-order kinetics as monitored by UV/Vis spec-
troscopy (Scheme 3). This can be rationalized in the follow-
ing way: At the beginning of the reaction, the Lewis acid
quantitatively forms an adduct with starting material 5. The
rate-determining step of the reaction is the cycloaddition of
Lewis acid adduct 5·LA and isoprene (6). The rate of the
reaction is therefore proportional to [5·LA][6]. During the
initial phase of the reaction, [5·LA] is proposed to be con-
stant, resulting in a reaction rate with a first-order depen-
dence on [6]. The stoichiometry of the reaction (5/6 = 1:1)
results also in an exponential decrease in [5], as shown in
the UV/Vis spectra (Figure 1). Product 7 of the reaction is
also a Lewis base that can form an adduct with the Lewis
acid [7·LA] so that the concentration of [5·LA] cannot be
assumed to be constant over the course of the whole reac-
tion. This circumstance was taken into consideration, and
Table 1. Results of 2H NMR measurements of pyridine–silyl triflate
adducts 4.
Entry
Lewis acid
Δδ(2H)position / ppm[a]
ortho
meta
para
1
2
3
4
5
6
7
8
9
none[a,b]
Me3SiOTf
Et3SiOTf
–
–
–
0.35
0.26
0.19
0.08
0.26
0.24
0.10
0.18
0.85
0.85
0.79
0.49
0.87
0.89
0.86
0.82
0.88
0.93
0.79
0.56
0.92
0.92
1.01
0.98
iPr3SiOTf
tBuPh2SiOTf
tBuMe2SiOTf
Et2iPrSiOTf
HOTf
HBF4·OEt2
[a] The naturally occurring deuterium content of dichloromethane
was used as an internal standard (δ = 5.30 ppm). [b] The H NMR
chemical shifts of [D5]pyridine are 8.60 (ortho), 7.69 (para), and
7.30 ppm (meta).
2
Regardless of whether a Lewis acid or a Brønsted acid the reactions were investigated until 40–50% conversions
was used, a downfield shift of every 2H NMR signal of were reached and the corresponding kinetic plots exhibited
[D5]pyridine was observed. Because the shift differences excellent fits for first-order dependencies (see the Support-
Δδ(2H)ortho of the silyl triflates, except for tBuPh2SiOTf, are ing Information).
larger than those of both Brønsted acids, falsification of
the measured shift differences due to hydrolysis of the silyl
triflates can be excluded.
Regarding only the NMR spectroscopic measurements
so far, some conclusions can be drawn to evaluate a scale
of the Lewis acidity of the applied silyl triflates. Inducing
the lowest shift differences in every case, tBuPh2SiOTf was
Scheme 3. Lewis acid catalyzed Diels–Alder reaction of 5.
revealed to be the weakest Lewis acidic silyl triflate, fol-
lowed by iPr3SiOTf as the second weakest. Et3SiOTf,
tBuMe2SiOTf, and Et2iPrSiOTf are all more acidic than
iPr3SiOTf and seem to be fairly equally strong. Interest-
ingly, Me3SiOTf exhibits the strongest influence on the or-
tho shifts and has comparable effects to the former three
silyl triflates regarding the meta position. Nevertheless, the
Lewis acidity of Me3SiOTf appears weaker when one con-
siders the shift differences for the para position. The appar-
ent order of the silyl triflates is tBuPh2SiOTf Ͻ iPr3SiOTf
Ͻ Me3SiOTf Յ Et3SiOTf ≈ tBuMe2SiOTf ≈ Et2iPrSiOTf.
Another interesting observation is that both Brønsted acids
HOTf and HBF4·OEt2 behave in an opposite manner to
that of Me3SiOTf, showing the smallest differences for the
chemical shift at the ortho position and the largest shift at
the para position compared with the silyl triflates. To pro-
vide this scale as a useful tool for organic chemists, we now
Figure 1. Overlay of UV/Vis spectra measured in 4-min time inter-
vals of a triethylsilyl triflate catalyzed Diels–Alder reaction of 5
with 6.
related the Lewis acidity of the silyl triflates to their cata-
lytic activity.
For the evaluation of the catalytic activities of the silyl
triflates, we chose the Diels–Alder reaction between 1,4-
The time-dependent decay of the absorption of 5 at
naphthoquinone (5) and an excess amount of isoprene (6) λmax = 335 nm (Figure 1) was used to determine the rate
to determine the rate constants kDA under first-order condi- constants kDA for the silyl triflate catalyzed reactions. The
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Correlation of Lewis Acidities with Reaction Rates in DA Reactions
rate constants determined by this method are sufficiently tivity. As the deviation is very small, there is yet no need to
accurate and give a proper impression of the activity of the jump to premature explanations concerning steric reasons
silyl triflates as catalysts in this organic transformation. As or different mechanisms for coordination to Lewis base 5.
expected, at higher conversions deviations from an ex- To address this issue in further detail, additional investi-
ponential decay were observed, resulting in a reduced reac- gations with a wide range of alkyl substituents will be
tion rate, most likely based on the formation of the adduct needed.
[7·LA].
For the determination of the average value of kDA at least
An exception to the catalytic effectiveness is Me3SiOTf,
which exceedingly accelerates the rate of the Diels–Alder
reaction despite a smaller NMR shift difference. A rationale
for this observation could be the small steric demand of the
methyl substituents, which makes the 5·LA adduct easier to
access for 6 in the rate-determining cycloaddition. Interest-
ingly, the Brønsted acid HOTf gave the highest catalytic
activity, which relates well to the highest-induced NMR
shift difference, whereas HBF4·OEt2, despite inducing a
higher shift difference than the silyl triflates, is only as
active as Et3SiOTf, tBuMe2SiOTf, or Et2iPrSiOTf.
four measurements per Lewis acid were carried out, which
are compiled in Table 2 together with the 29Si NMR chemi-
cal shifts of the silicon-containing Lewis acid precursors.
The correlation of the rate constants kDA with the 2H NMR
chemical shift values Δδ(2H)para for the para-deuterium
atom of the pyridine ring are shown in Figure 2 [for
Δδ(2H)ortho and Δδ(2H)meta, see the Supporting Information,
Figures S19–S23].
Table 2. Results of the 29Si NMR measurements of the pure silyl
triflates and rate constants.[7]
The results obtained by this investigation indicate that
the herein presented scale of Lewis acidities can be related
to some extend to kinetic experiments. However, exceptions
such as that of Me3SiOTf, which is a much more efficient
catalyst in the Diels–Alder reaction than Et3SiOTf, indicate
that a complete understanding of the chemistry involved in
the catalytic process is not at hand. To evaluate the Lewis
Entry
Lewis Acid
δ(29Si) / ppm[a]
kDA / 10–3 s–1
1
2
3
4
5
6
7
8
Me3SiOTf
Et3SiOTf
iPr3SiOTf
tBuPh2SiOTf
tBuMe2SiOTf
Et2iPrSiOTf
HOTf
43.9
45.4
41.5
12.9
43.3
43.4
–
2.82Ϯ0.75
0.62Ϯ0.26
0.42Ϯ0.11
0.35[b] Ϯ0.05
0.57Ϯ0.19
0.59Ϯ0.20
14.55Ϯ3.17
0.61Ϯ0.01
2
acidity order of silyl triflates obtained by H NMR spec-
troscopy by utilizing [D5]pyridine, a comparison to the 29Si
NMR chemical shifts of the silyl triflates, which is often
used as an indicator for Lewis acidity, is of interest. There-
fore, the rate constants of the silyl triflate catalyzed Diels–
Alder reaction are plotted versus the 29Si NMR chemical
shift values δ(29Si), as shown in Figure 3.
HBF4·OEt2
–
[a] Tetramethylsilane was used as an external standard. [b] Esti-
mated rate constant, see ref.[8]
The results presented in Figure 2 show that the rate con-
stants kDA for five of the six silyl triflates relate fairly well
One can easily see that for the silyl triflates, except
to the shift difference of the para position Δδ(2H)para. A Me3SiOTf, there is indeed a very good relation between the
higher NMR shift translates to a higher catalytic activity. rate constants kDA and the δ(29Si) values. Again, Me3SiOTf
The three Lewis acidic silyl triflates Et3SiOTf, tBuMe2Si- represents an exception, as its catalytic activity exceeds the
OTf, and Et2iPrSiOTf exhibit a nearly even catalytic ac- anticipated one based on the δ(29Si) value.
Figure 2. Plot of the kDA values of the silyl triflate catalyzed Diels–Alder reactions of 5 with 6 and relation to the Δδ(2H)para values.
TBDPS = tert-butyldiphenylsilyl; TIPS = triisopropylsilyl; TMS = trimethylsilyl; TBDMS = tert-butyldimethylsilyl; DEIPS = diethyliso-
propylsilyl; TES = triethylsilyl.
Figure 3. Plot of the kDA values of the silyl triflate catalyzed Diels–Alder reactions of 5 with 6 in relation to the δ(29Si) values of the pure
silyl triflates. TBDPS = tert-butyldiphenylsilyl; TIPS = triisopropylsilyl; TMS = trimethylsilyl; TBDMS = tert-butyldimethylsilyl; DEIPS
= diethylisopropylsilyl; TES = triethylsilyl.
Eur. J. Org. Chem. 2011, 7071–7075
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G. Hilt, A. Nödling
SHORT COMMUNICATION
Finally, an often-asked key question in silyl triflate cata-
lyzed processes regarding the influence of water leading to
proton-catalyzed reactions was addressed. In principle, the
hydrolysis side reaction should result in different reaction
kinetics. To prevent the influence of protons as concurring
catalysts, tetramethylsilane was added in a proof-of-prin-
ciple reaction as a proton scavenger when using Me3SiOTf
as catalyst (Scheme 4).[9]
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
and this support is gratefully acknowledged. The donation of oc-
tahydroquinolizidinium tetrafluoroborate for the synthesis of 1 by
Millennium Pharmaceuticals, Inc., Cambridge, USA is gratefully
acknowledged.
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[3] G. Hilt, F. Pünner, J. Möbus, V. Naseri, M. A. Bohn, Eur. J.
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Scheme 4. Trimethylsilyl-catalyzed vs. proton-catalyzed Diels–Al-
der reaction of 5. The triflate (OTf–) ion was omitted for clarity.
If HOTf is formed by hydrolysis then it should react with
tetramethylsilane to form methane and Me3SiOTf.[5,10] If
the HOTf is proposed as the sole active species in the Diels–
Alder reaction, the addition of tetramethylsilane should re-
duce the rate of the reaction considerably or even result in
no conversion. The addition of up to 2 equiv. of tetrameth-
ylsilane with respect to the Me3SiOTf catalyst did not result
in any change in the rate of the reaction. Therefore, the
catalytically active species in the Me3SiOTf-catalyzed Di-
els–Alder reaction is proposed to be the trimethylsilyl cat-
ion rather than the protons. Therefore, we extrapolate that
other Diels–Alder reactions catalyzed by silyl triflates are
also silyl cation catalyzed processes.
Conclusions
In conclusion, we have shown that [D5]pyridine is a cap-
able test system for the quantitative prediction of the Lewis
acidity of silyl cations derived from the respective triflates.
A good relation between the rate constants kDA and the
2H NMR shift differences as well as the 29Si NMR shifts
was found. The Lewis acidities correlate with the reactivities
of the silyl triflates as catalysts in a Diels–Alder reaction.
Also, we could identify the only deviating silyl triflate,
namely, Me3SiOTf, as the most catalytically active Lewis
acid. Although deviating from the acidity–reactivity rela-
tionship, this finding is in accordance with the observed
decrease in reactivity with an increase in the steric demand
of the alkyl substituents. Only by these investigations did
the special role of Me3SiOTf as a Lewis acid catalyst be-
come obvious. Accordingly, investigations to rationalize the
unexpectedly high activity of Me3SiOTf were initiated in
our group for a detailed understanding of the decisive pa-
rameters.
[5] For silicon-based Lewis acids in catalysis, see: A. D. Dilman,
S. L. Ioffe, Chem. Rev. 2003, 103, 733; S. Rendler, M. Oestreich,
Synthesis 2005, 1727; H. F. T. Klare, M. Oestreich, Dalton
Trans. 2010, 39, 9176; O. Sereda, S. Tabassum, R. Wilhelm,
Top. Curr. Chem. 2010, 291, 349; B. Mathieu, L. Ghosez, Tetra-
hedron 2002, 58, 8219; K. Hara, R. Akiyama, M. Sawamura,
Org. Lett. 2005, 7, 5621.
[6] G. A. Olah, D. A. Klumpp, Synthesis 1997, 744; A. R. Bassind-
ale, T. Stout, Tetrahedron Lett. 1985, 26, 3403.
[7] For 29Si NMR chemical shifts of silyl triflates, see: G. A. Olah,
K. Laall, O. Farooq, Organometallics 1984, 3, 1337; A. R. Bas-
sindale, T. Stout, J. Organomet. Chem. 1984, 271, C1.
[8] tBuPh2SiOTf shows a slightly different kinetic behavior, show-
ing a short induction phase at the beginning. Because this can
indicate a more complex reaction mechanism, we estimated the
rate constant by determining the reaction half lifetimes as the
time at 50% conversion and converting them into the rate con-
stants.
[9] The addition of 2,6-di-tert-butylpyridine as a hindered non-
nucleophilic base and proton scavenger in the Me3SiOTf- and
Et3SiOTf-catalyzed Diels–Alder reaction resulted in no conver-
sion after 24 h at room temperature. This could indicate that
protons are the catalytically active species. However, investi-
gations by others have shown that 2,6-di-tert-butylpyridine is
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and plots for the determination of
reaction rate constants.
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Correlation of Lewis Acidities with Reaction Rates in DA Reactions
able to interact with sterically hindered Lewis acids such as
triphenylcarbenium ions and trialkylsilyl cations, which would
also explain the absence of catalytic activity (see: M. J. Therien,
C.-L. Ni, F. C. Anson, J. G. Osteryoung, W. C. Trogler, J. Am.
Chem. Soc. 1986, 108, 4037; E. M. Arnett, S. Venimadhavan,
J. Org. Chem. 1991, 56, 2742; T. J. Barton, C. R. Tully, J. Org.
Chem. 1978, 43, 3649). Therefore, an inhibition of the silyl tri-
flates by 2,6-di-tert-butylpyridine cannot be excluded.
[10] H. C. Brown, B. Kanner, J. Am. Chem. Soc. 1953, 75, 3865; M.
Demuth, G. Mikhail, Synthesis 1982, 827.
Received: September 8, 2011
Published Online: November 8, 2011
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7075