On the acidity and reactivity of highly effective chiral Bronsted acid catalysts: Establishment of an acidity scale

Article abstract of DOI:10.1002/anie.201303605

Stronger acid, higher speed: The pK_a values of a range of binol-derived Bronsted acids of three different types were measured and found to correlate directly with the catalytic properties of the acids: higher rate constants k_I were observed for more acidic Bronsted acid catalysts (see plot; binol=1,1′-bi-2-naphthol). Copyright

Full text of DOI:10.1002/anie.201303605

Angewandte
Chemie
DOI: 10.1002/anie.201303605
Brønsted Acids
On the Acidity and Reactivity of Highly Effective Chiral Brønsted Acid
Catalysts: Establishment of an Acidity Scale**
Karl Kaupmees, Nikita Tolstoluzhsky, Sadiya Raja, Magnus Rueping,* and Ivo Leito*
Chiral phosphoric acid diesters derived from 1,1’-bi-2-naph-
thol (binol) and their analogues are a highly efficient class of
metal-free Brønsted acid organocatalysts.[1,2] Transfer hydro-
genation as well as various addition reactions to aldimines and
ketimines are among the most important reactions that can be
carried out efficiently with these catalysts. The moderate
acidity of these catalysts[3a] renders them ideal for the
activation of basic imines by hydrogen bonding or ion
pairing[3b] in a dual or bifunctional fashion. However, the
activation of less basic carbonyl functionalities is more
demanding, and only few enantioselective applications have
been reported so far.[4] Therefore, the more acidic chiral
binol-derived N-triflylphosphoramides (NTPAs)[5,6] were
introduced and proved suitable for the activation of more
challenging substrates.[4,7] Asymmetric C C and C X bond-
forming transformations, such as Diels–Alder and [3+2]
cycloaddition reactions, the Nazarov cyclization, asymmetric
protonation, and Mukaiyama aldol reactions, have been
carried out efficiently with chiral N-triflylphosphoramides in
a variety of organic solvents, including halogenated as well as
aromatic solvents, and more recently also in aqueous media.
Furthermore, Brønsted acid organocatalysts based on bis-
(sulfonyl)imides were introduced by Berkessel et al.
(JINGLE, Scheme 1)[8a] and Giernoth and co-workers (BIN-
BAM).[8b]
À
À
Scheme 1. Types of chiral Brønsted acid organocatalysts. [H8] denotes
5,6,7,8-tetrahydronaphthyl rings.
On the basis of reported data for achiral Brønsted acids, it
was proposed that the acidity of these classes of compounds
increases in the order: binol-derived phosphoric acid diesters
(BPAs) < NTPAs < JINGLEs (Scheme 1). However, the
pKa values of these catalysts are not known. Furthermore,
to date no correlation between the acidity and catalytic
activity of the different Brønsted acids has been reported, in
spite of their wide application in catalysis.
to obtain an acidity and reactivity scale that would help users
in Brønsted acid catalysis to choose the appropriate catalyst
for a given transformation. Herein we present our results on
the determination of the pKa values in acetonitrile (AN) of
a range of chiral Brønsted acids (Scheme 1) and discuss the
relation between the acidity and catalytic properties of these
compounds. Furthermore, we compare the results with
a recent report,[9] which appeared during our studies.
The pKa measurements were carried out by the previously
described spectrophotometric titration method.[10] All experi-
ments were performed in a glove box under an atmosphere of
argon in AN with a water content below 10 ppm to avoid the
distorting effect of water on pKa values. The results of the pKa
measurements are summarized in Table 1. The acids can be
divided according to their acidity centers into three groups:
A) binol-derived phosphoric acid diesters (BPAs), with
pKa values in the range of 12–14, B) mixed imides of
phosphoric and triflic acid (NTPAs), with pKa values in the
range of 6–7, and C) imides of sulfonic acids (JINGLEs), with
pKa values around 5.
We therefore decided to determine the pKa values of
binol-derived phosphoric acid diesters and their analogues
and correlate them with the catalytic activity of the catalysts
[*] K. Kaupmees, Prof. Dr. I. Leito
Institute of Chemistry, University of Tartu
14a Ravila Street, 50411 Tartu (Estonia)
E-mail: Ivo.Leito@ut.ee
N. Tolstoluzhsky, Dr. S. Raja, Prof. Dr. M. Rueping
RWTH Aachen University, Institute of Organic Chemistry
Landoltweg 1, 52074 Aachen (Germany)
E-mail: Magnus.Rueping@rwth-aachen.de
[**] Financial support by the DFG is gratefully acknowledged. The
research of K.K. and I.L. was supported by Grant 9105 from the
Estonian Science Foundation. We thank Prof. A. C. O’Donoghue for
helpful discussions.
As expected, the nature of the acidity center had the
strongest influence on the acidity of the catalysts studied: the
catalyst acidity increased in the order
(NTPAs) < C (JINGLEs). The next important influencing
A (BPAs) < B
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303605.
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Table 1: Results of the pKa measurements in AN in order of decreasing
acidity.
Compound[a]
Assigned pKa[b]
Àlog(kI)
LLS[c] NLS[d]
5-[H8] (R1 =9-phenanthrene)
3 (R1 =2,4,6-iPr3-C6H2)
4 (R1 =9-phenanthrene)
1 (R1 =Ph)
14.0
13.6
13.3
12.7
12.5
6.9
6.8
6.7
6.7
6.4
5.55
5.35
3.73
5.55
5.36
3.72
2 (R1 =4-F-C6H4)
11-[H8] (R1 =4-MeO-C6H4, R2 =CF3)
9-[H8] (R1 =Ph, R2 =C8F17)
7-[H8] (R1 =Ph, R2 =CF3)
8-[H8] (R1 =Ph, R2 =C4F9)
10 (R1 =4-MeO-C6H4, R2 =CF3)
6 (R1 =Ph, R2 =CF3)
3.60
3.33
3.60
3.32
6.4
6.3
5.2
12-[H8] (R1 =4-F-C6H4, R2 =CF3)
13 (R3 =3,5-(CF3)2-C6H3)
2.85
2.89
[a] References describing the synthesis of the compounds are given in
the Supporting Information. [b] The pKa scale in AN is anchored to the
value for picric acid (pKa =11.0).[11] [c] Values were obtained by the
linearized least squares method. [d] Values were obtained by the
nonlinear least squares method.
factor was the aromatic or aliphatic nature of the outer
binaphthalene rings. This influence can be seen in the pairs 4
and 5-[H8], 10 and 11-[H8], and 6 and 7-[H8], in which the
average influence of the second aromatic ring is equivalent to
0.5pKa units. The acidity increase observed in the series 11-
[H8], 7-[H8], 12-[H8] as well as in the series 3, 4, 1, 2
corresponds to that expected from the electronic properties of
the substituents R1 (Scheme 1). The greater influence of
substituent R1 in group A than in group B can be explained by
the delocalization of the negative charge in the anionic form
of the acid: the higher the concentration of the negative
charge at the acidity center, the more effect the substituent
has. In group B, the charge is largely delocalized on the
perfluoroalkanesulfonyl group. This phenomenon is also
responsible for the much larger pKa difference between
1 and 4-toluenesulfonic acid (4.2 pKa units) than between 6
Figure 1. Comparison of pKa data (values for the compounds in
AN).[10,11] Tf =trifluoromethanesulfonyl, Tos=p-toluenesulfonyl.
near unity and an intercept in the range of 10–13 pKa units
(pKa values in DMSO are lower).[11] However, in contrast to
our findings, three compounds belonging to groups B and C
(compounds 5, 7a, and 7b in Ref. [9]) have pKa values that
are very similar to those of compounds in group A. The
pKa range for groups A–C in Ref. [9] is between 1.7 and 4.2, in
stark contrast with the range of close to 9 pKa units found for
our pKa values in AN. Christ et al. conclude that the acidity
differences between the different catalysts are not large and
that the relative acidity of the catalysts may not be the only
factor that influences their catalytic performance.[9] In fact,
these three acids from groups B and C should have negative
or near-zero pKa values in DMSO. At first sight, it is
astonishing that groups of acids which differ by 6–7 pKa
units in AN (differences that are fully rationalizable in
terms of their structures) have almost identical pKa values in
DMSO. However, our past experience suggests that measure-
ments of highly acidic acids in DMSO can provide pKa values
of 1–3 (even though the true pKa value can be negative) if the
ionization ratio of the measured species is not monitored.[12]
To investigate this discrepancy, we carried out some
experiments in DMSO. Compound 6 was dissolved in DMSO,
and the UV/Vis spectrum of its anion was observed because of
and
N-trifluoromethanesulfonyl-p-toluenesulfonamide
(TosNHTf; 0.5 pKa units). The members of group B that
differ only in the length of the perfluoroalkyl chain have
almost equal acidities. Although the perfluoroalkyl chain is
closer to the acid center than the R1 substituent, it influences
the negative charge of the anions only through an inductive
effect. The type C catalyst 13 is the most acidic and differs in
acidity from the type B catalysts by one order of magnitude.
For a better comparison, we compiled an acidity scale
(Figure 1), in which we included the values of other known
acids together with those of the chiral Brønsted acids. This
scale will be useful for reaction planning and the further
development of the field of asymmetric Brønsted acid
catalysis.
Recently, Christ et al. reported pKa values for similar
acids in dimethyl sulfoxide (DMSO).[9] Only one of our acids
(compound 3) is included in their dataset, but all three groups
of acids (A–C) are described. Most of the pKa values in
Ref. [9]—those for the weaker acids—agree well with our
data and show a good correlation of the pKa values of neutral
OH, NH, and CH acids between AN and DMSO with a slope
2
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complete ionization. A large excess of an acidic titrant
(trifluoromethanesulfonic acid) was added to protonate the
anion. However, it was impossible to detect any neutral acid
form of the acid from the spectra. In contrast, the anion of 3
was readily protonated, as indicated by changes in the
spectrum. These experiments demonstrate that the pKa values
of these two compounds are very different, and that the
pKa value of 6 in DMSO is most likely below zero (see the
Supporting Information for details).
To evaluate the catalytic activity of the compounds
studied and correlate it with the assigned pKa values, we
investigated the Nazarov cyclization[13,14] of a dienone (see
Scheme 1 in the Supporting Information) according to
a previously reported procedure.[14] This reaction is partic-
ularly suitable, as the corresponding product, a neutral cyclo-
pentenone, does not contain basic sites that would bind the
Brønsted acid or form ion pairs and thus lead to different
catalyst concentrations or catalyst inhibition and hence
unreliable measurements and statements. We monitored the
performance of six catalysts by NMR spectroscopy to
determine the conversion of the substrate (see the Supporting
Information for full details).
On the basis of the recorded data, we calculated rate
constants kI for a first-order reaction by using two methods:
linearized least squares (LLS) and nonlinear least squares
(NLS; Table 1). The catalysts were chosen in such a way that
all three groups were represented and the full range of
measured pKa values was covered. A plot of Àlog(kI) values
against the pKa values revealed that the catalytic activity of
the investigated Brønsted acids correlates with their acidity
(Figure 2). The higher the acidity is (lower pKa value), the
In conclusion, we have determined pKa values for a series
of chiral Brønsted acids in AN on the basis of a UV/Vis
spectrophotometric method. For the three groups of catalysts
investigated, we can conclude that the binol-derived phos-
phoric acids that make up group A have a pKa range of 12–14,
the fluorinated N-sulfonylphosphoramides in group B have
acidity values around 6–7 on the pKa scale, and bis-
(sulfuryl)imides (group C) have pKa values of approximately
5 in AN. For comparison, we compiled an acidity scale
(Figure 1) that includes various other known acids as well as
the chiral Brønsted acids and will be useful for the further
development of the field of asymmetric Brønsted acid
catalysis. Furthermore, our experiments clearly indicate
a direct correlation of the catalytic properties of these acids
with their pKa values, whereby higher rate constants are
observed for more acidic Brønsted acid catalysts. It is also
evident from the present study that the big gap in acidity
between N-triflylphosphoramides and phosphoric acids calls
for the development of new chiral catalysts with adjusted
catalytic properties.
Received: April 28, 2013
Revised: August 9, 2013
Published online: && &&, &&&&
Keywords: acidity · Nazarov cyclization ·
N-triflylphosphoramides · organocatalysis · phosphoric acids
.
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acids have pKa values 6–8 units higher and rate-constant
values two orders of magnitude smaller than those of their
triflamide analogues. Whereas the ability to promote enan-
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Brønsted Acids
Stronger acid, higher speed: The
pKa values of a range of binol-derived
Brønsted acids of three different types
were measured and found to correlate
directly with the catalytic properties of the
acids: higher rate constants kI were
observed for more acidic Brønsted acid
catalysts (see plot; binol=1,1’-bi-2-
naphthol).
K. Kaupmees, N. Tolstoluzhsky, S. Raja,
M. Rueping,* I. Leito*
&&&& — &&&&
On the Acidity and Reactivity of Highly
Effective Chiral Brønsted Acid Catalysts:
Establishment of an Acidity Scale
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!