Oxygen superbases as polar binding pockets in nonpolar solvents

Article abstract of DOI:10.1021/ja103744f

A novel class of chiral superbases derived from the 2,2′-bipyridyl-N, N′-dioxide skeleton are presented. Combined experimental and theoretical data reveal that their proton affinities are on the order of 1050 kJ mol ^-1, with protonation occurring at the oxygen atoms in a chelating manner. In the free bases, the oxygen atoms form a strongly polar binding site hidden in a hydrophobic envelope formed by the hydrocarbon backbone of the superbases. This chiral molecular structure can entrap polar intermediates or polarized transition structures and stabilize them in nonpolar solvents. Specifically, this mode of catalysis is shown for the coupling of benzaldehyde and allyltrichlorosilane.

Full text of DOI:10.1021/ja103744f

Published on Web 08/19/2010
Oxygen Superbases as Polar Binding Pockets in Nonpolar
Solvents
Lucie Ducha´cˇkova´, Aneta Kadlcˇ´ıkova´, Martin Kotora, and Jana Roithova´*
Department of Organic Chemistry, Charles UniVersity in Prague, HlaVoVa 8,
12843 Prague 2, Czech Republic
Received May 2, 2010; E-mail: roithova@natur.cuni.cz
Abstract: A novel class of chiral superbases derived from the 2,2′-bipyridyl-N,N′-dioxide skeleton are
presented. Combined experimental and theoretical data reveal that their proton affinities are on the order
of 1050 kJ mol-1, with protonation occurring at the oxygen atoms in a chelating manner. In the free bases,
the oxygen atoms form a strongly polar binding site hidden in a hydrophobic envelope formed by the
hydrocarbon backbone of the superbases. This chiral molecular structure can entrap polar intermediates
or polarized transition structures and stabilize them in nonpolar solvents. Specifically, this mode of catalysis
is shown for the coupling of benzaldehyde and allyltrichlorosilane.
Scheme 1. Investigated Derivatives of 2,2′-Bipyridyl-N,N′-dioxide
(1) (Ph ) Phenyl, Me ) Methyl, Cy ) Cyclohexyl)
Introduction
The rapidly developing field of organocatalysis provides
a whole array of attractive organic molecules that are capable
of activating substrates either by specific coordination to their
reactive sites1-4 or by transforming them to more reactive
forms.5-9 Many of the present organocatalysts can be
understood as small organic analogues to natural enzymes
in that their skeletons are optimized to bind a specific
substrate and provide the necessary activation at the correct
position. Since activation of the substrate is usually achieved
by electrophilic or nucleophilic attack, the catalyst molecules
usually bear strongly polar functional groups or the reactive
forms may even be charged.10
the nucleophile so formed then reacts with the other components
in the reaction mixture. For chiral induction during the reaction, it
is necessary for the protonated base to remain in the vicinity of
the reactants or for the reverse transfer of a proton to the product
to proceed enantioselectively. These reactions are usually mediated
by very strong bases derived from guanidine12-15 or even
superbases.16,17
One of the attractive topics in organocatalysis from the
mechanistic point of view is enantioselective catalysis with
Brønsted bases.11-15 The reactions are usually initiated by
hydrogen abstraction from one of the reactant molecules, and
In this work, we investigated the properties and catalytic
activity of organocatalysts based on the skeleton of 1,1′-
bis(5,6,7,8-tetrahydroisoquinolyl)-N,N′-dioxide (1) (Scheme 1).18
A key structural feature of 1 is the N-oxide groups, which can
act together in a chelating manner. Consequently, coordination
of 1 with protons or metal cations is expected to involve binding
to both N-oxide groups. With respect to protonation, this
deduction leads to the expectation of a strong basicity of 1 and
its derivatives. Hence, as a first step in understanding the
coordination features of the title compound, we have determined
the experimental as well as theoretical proton affinities of 1a-c
and described the electronic structures of the free bases.
Besides the potential applications of derivatives of 1 as
Brønsted bases, the arrangement of the N-oxide groups also
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Chem., Int. Ed. 2008, 47, 6798.
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therein.
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C.-H. J. Am. Chem. Soc. 2006, 128, 13692. (b) Terada, M.; Nakano,
M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044.
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2010, 1, and references therein.
9
12660 J. AM. CHEM. SOC. 2010, 132, 12660–12667
10.1021/ja103744f  2010 American Chemical Society

Oxygen Superbases as Polar Binding Pockets
A R T I C L E S
Scheme 2. Mechanistic Dichotomy in the Coupling of Allyltrichlorosilane with Benzaldehyde Catalyzed By (S)-1b20
and a QOQ configuration of the manifold (Q stands for
quadrupole and O for octopole).21 The proton-bound dimers
(A-H-B)+, where A stands for 1a-c and B corresponds to a
reference base with known proton affinity [tripropylamine (TPA),
tributylamine (TBA), diisopropylethylamine (DIPEA), or 1,8-
bis(dimethylamino)naphthalene (DMAN)], were mass-selected
by Q1 and collided with xenon at a typical pressure of 7 × 10-5
mbar. The collision energy was adjusted by changing the offset
between Q1 and O, while the offset of Q2 was locked to the
sum of the offsets of Q1 and O. The zero point of the kinetic
energy scale as well as the width of the kinetic energy
distribution (fwhm ) 1.1 ( 0.1 eV) were determined by means
of retarding-potential analysis. The ionic fragments (AH+ and
BH+) that emerged from the octopole were detected by Q2, and
the respective abundances were determined using a Daly-type
detector operating in counting mode. The collision energy was
changed in steps of 0.25 eV (in the laboratory frame), and 15
scans were accumulated to achieve a good signal-to-noise ratio
in the resulting branching ratio. The proton affinities (PAs) given
belowwerederivedasaveragesofthreeindependentmeasurements.
The complementary calculations of PAs were performed using
the DFT method B3LYP22-25 together with the 6-311+G(2d,p)
triple-ꢁ basis set as implemented in the Gaussian 09 suite.26
Computation of the Hessian matrix was performed for all of the
optimized structures at the same level of theory in order to ensure
that the structures corresponded to genuine minima as well as
to calculate the thermochemical data. In the coupling of
allyltrichlorosilane with benzaldehyde catalyzed by 1b, the
interactions between the phenyl substituents of 1b and the two
reactants play an important stabilization role. Therefore, the
inclusion of dispersion interactions might be decisive for the
promises their interesting applications as chiral auxiliaries.
Currently, the derivatives of 1 have been employed in a Lewis
base-type activation of allyl silanes, in which it was assumed
that the N-oxide groups coordinate to the silicon atom.19 In
particular, these catalysts can be applied in an asymmetric
allylation of aromatic as well as R,ꢀ-unsaturated aldehydes18
using allyltrichlorosilane as a reagent. Interestingly, the
activation of allyltrichlorosilane by the derivatives of 1 very
much depends on the solvent used (Scheme 2). Polar solvents
(e.g., acetonitrile and dichloromethane) induce formation of
the ionized reactant [1 · SiCl2(C3H5)]+, whereas nonpolar
solvents (e.g., toluene and chlorobenzene) support the oc-
currence of the reaction in the neutral state.20 The change in
the mechanism is not only formal but also inverts the chirality
of the product alcohols; for example, the reaction between
benzaldehyde and SiCl3(C3H5) catalyzed by (S)-1b in polar
solvents proceeds toward (R)-1-phenylbut-3-en-1-ol, whereas
(S)-1-phenylbut-3-en-1-ol is formed in nonpolar solvents.18
While the reactions in the polar solvents are directed by the
interaction of the ionized silicon with the N-oxide group(s),
the reactions in nonpolar solvents are much more sensitive
to the overall electronic structure of the catalyst. Accordingly,
larger enantioselectivities also were observed in nonpolar
solvents. As our intention was to address the essence of the
catalytic activity of derivatives of 1, we used density
functional theory (DFT) to investigate the interaction of 1b
with allyltrichlorosilane and the mechanism of the coupling
of the reaction intermediates with benzaldehyde in the
nonpolar solvent toluene.
Experimental and Computational Details
(21) Ducha´cˇkova´, L.; Roithova´, J. Chem.sEur. J. 2009, 15, 13399.
(22) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200.
(23) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785.
(24) Becke, A. D. Phys. ReV. A 1988, 38, 3098.
The experiments were performed with a TSQ Classic mass
spectrometer equipped with an electrospray ionization source
(25) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989,
157, 200.
(19) Orito, Y.; Nakajima, M. Synthesis 2006, 1391.
(20) Hrdina, R.; Opekar, F.; Roithova´, J.; Kotora, M. Chem. Commun. 2009,
2314.
(26) Frisch, M. J.; et al. Gaussian 09, revision A.02; Gaussian, Inc.:
Wallingford, CT, 2009.
9
J. AM. CHEM. SOC. VOL. 132, NO. 36, 2010 12661

A R T I C L E S
Ducha´cˇkova´ et al.
Table 1. Theoretical and Experimental Proton Affinities (kJ mol-1
of 1a-c and Selected Reference Bases at 0 and 298 K
)
basea
PA
PA
PA
PA
exp
0K
theor
298K
theor
0K
exp
298K
1a
1b
1c
DMAN
TBA
DIPEA
TPA
1036
1046
1046
1024
992
1042
1053
1053
1030
998
1047 ( 7b
1057 ( 7b
1061 ( 10b
1053 ( 7
1064 ( 7
1068 ( 10
1028.2c
998.5c
Figure 1. Electrostatic potential maps (in atomic units) for 1c and its
protonated form 1c · H+ color-coded at the isodensity surface F ) 0.02
994
985
1001
991
994.3c
991.0c
e Å-3
.
a For abbreviations of compound names, see the text. b The reported
0K
values of PA are averages of three measurements. The error margins
exp
form. The electrostatic potential of the protonated base reveals
that the positive charge is delocalized over the whole hydro-
carbon backbone of the base.
are set to the maximum errors evaluated in the individual experiments,
as estimated by linear fits over different ranges of the experimental data
(for details, see the SI). c Data from ref 36.
In comparison with those for the bases 1a-c, the proton
affinity of the parent compound 2,2′-bipyridyl-N,N′-dioxide (2)
is much smaller (1016 kJ mol-1). The effect of the substituents
at the 3- and 3′-positions as well as that of the annelated
saturated rings can be assessed by means of isodesmic reactions
(Scheme 3).37 Clearly, the inductive effects of the alkyl
substituents in the positions ortho to the nitrogen atoms provide
the major contributions to the increase in the proton affinity of
the derivatives of 1. The introduction of the methyl groups
increases the proton affinity of 2 by 21.5 kJ mol-1, whereas the
annelation of the saturated ring results in an increase of only
correct description of the entire system with regard to possible
mechanistic implications.27 With respect to the size of the studied
system, we chose to employ DFT with a functional that includes
a semiempirical correction for dispersion interaction (DFT-D),
namely, the B97D method.28,29 The geometry optimizations and
thermochemistry calculations were performed at the B97D/6-
31G* level of theory. The final energies were determined by
single-point calculations at the B97D/cc-pVTZ level with
corrections for basis-set superposition error (BSSE).30 It should
be noted that the BSSE can be extremely large for the title
compounds when small basis sets are used; the errors were on
the order of 10 kJ mol-1 using the cc-pVTZ basis set. As the
last step, solvation energies were determined by single-point
calculations using the polarized continuum model at the B97D/
cc-pVTZ level.31 We note in passing that the DFT-D method
has been successfully used in the investigation of the reaction
mechanism of the same coupling reaction catalyzed by QUINOX,
which is an analogous catalyst bearing only a single N-oxide
site.32
16.4 kJ mol-1
.
Experimentally, the proton affinities of the title compounds
were approached using the kinetic method.38 To this end, we
generated mixed proton-bound dimers (A-H-B)+ of 1a-c (A)
with several reference bases (B) and investigated the fragmenta-
tions of the mass-selected dimers in a triple-quadrupole mass
spectrometer. The ratio of the abundances of the fragments AH+
and BH+ upon collisional activation reflects the ratio of
dissociation rates of (A-H-B)+ to AH+ and BH+, respectively
Results and Discussion
(eq 1; GB ) gas-phase basicity, PA ) proton affinity, Teff
)
In order to show the mode of action of the derivatives of 1
in organocatalysis, we first determined their gas-phase proton
affinities and electronic structures. The computational results
suggest PAs of ∼1050 kJ mol-1 (Table 1), which are close to
those of prototypical nitrogen superbases such as the proton
sponge DMAN (PA ) 1028 kJ mol-1).33-35 The large basicities
arise from the concentration of negative charge at the oxygen
atoms and the fact that both oxygen atoms can coordinate to
the proton because of the geometries of 1a-c. Figure 1 shows
the electrostatic potentials of the derivative 1c and its protonated
effective temperature reflecting the internal energy of the
fragmenting ion).
IAH
IBH
kA
GBA - GBB PAA - PAB
+
+
ln
≈ ln
≈
≈
(1)
(
)
( )
kB
RTeff
RTeff
The rather large proton affinities of the title compounds
predicted by theory limited our selection of reference bases to
some of the most basic nitrogen compounds available, namely,
proton sponge (DMAN), Hu¨nig base (DIPEA), TBA, and TPA.
The significantly diverse structures of the title compounds and
the reference bases most probably led to different entropic
changes upon their protonation. Thus, the conversion from gas-
phase basicities (determined from Gibbs free energies) and
proton affinities (determined from enthalpies) was not as
straightforward as suggested by eq 1, so we used the extended
kinetic method (Figure 2).39,40
(27) Hobza, P.; Mu¨ller-Dethlefs, K. Non-coValent Interactions: Theory and
Experiment; RSC Theoretical and Computational Chemistry Series,
No. 2; Royal Society of Chemistry: Cambridge, U.K., 2010.
(28) Grimme, S. J. Comput. Chem. 2006, 27, 1787.
(29) Pevarati, R.; Baldridge, K. K. J. Chem. Theory Comput. 2008, 4, 2030.
(30) Boys, S. F.; Bernardi, F. Mol. Phys. 1970, 19, 553.
(31) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. ReV. 2005, 105, 2999.
(32) Malkov, A. V.; Ram´ırez-Lo´pez, P.; Biedermannova´, L.; Rul´ısˇek, L.;
Dufkova´, L.; Kotora, M.; Zhu, F.; Kocˇovsky´, P. J. Am. Chem. Soc.
2008, 130, 5341.
(33) Roithova´, J.; Schro¨der, D.; M´ısˇek, J.; Stara´, I.; Stary´, I. J. Mass
Spectrom. 2007, 42, 1233.
(36) Hunter, E. P.; Lias, S. G. J. Phys. Chem. Ref. Data 1998, 27, 413.
(37) Exner, O. J. Phys. Org. Chem. 1999, 12, 265.
(34) (a) Eckert-Maksic, M.; Glasovac, Z.; Troselj, P.; Kutt, A.; Rodima,
T.; Koppel, I.; Koppel, I. A. Eur. J. Org. Chem. 2008, 5176. (b) Coles,
M. P.; Aragon-Saez, P. J.; Oakley, S. H.; Hitchcock, P. B.; Davidson,
M. G.; Maksic, Z. B.; Vianello, R.; Leito, I.; Kaljurand, I.; Apperley,
D. C. J. Am. Chem. Soc. 2009, 131, 16858.
(38) (a) Cooks, R. G.; Wong, P. S. H. Acc. Chem. Res. 1998, 31, 379. (b)
Cooks, R. G.; Koskinen, J. T.; Thomas, P. D. J. Mass Spectrom. 1999,
34, 85.
(39) Drahos, L.; Vekey, K. J. Mass Spectrom. 2003, 38, 1025.
(40) For insightful essays about the performance and inherent problems of
the kinetic method, see: (a) Bouchoux, G.; Sablier, M.; Berruyer-
Penaud, F. J. Mass Spectrom. 2004, 39, 986. (b) Wesdemiotis, C. J.
Mass Spectrom. 2004, 39, 998. (c) Ervin, K. M.; Armentrout, P. B. J.
Mass Spectrom. 2004, 39, 1004. (d) Drahos, L.; Peltz, C.; Vekey, K.
J. Mass Spectrom. 2004, 39, 1016.
(35) (a) Verkade, J. G. Top. Curr. Chem. 2003, 223, 1. (b) Kolomeitsev,
A. A.; Koppel, I. A.; Rodima, T.; Barten, J.; Lork, E.; Roschenthaler,
G. V.; Kaljurand, I.; Kutt, A.; Koppel, I.; Maemets, V.; Leito, I. J. Am.
Chem. Soc. 2005, 127, 17656. (c) Tailefer, M.; Rahier, N.; Hameau,
A.; Volle, J. N. Chem. Commun. 2006, 3238.
9
12662 J. AM. CHEM. SOC. VOL. 132, NO. 36, 2010

Oxygen Superbases as Polar Binding Pockets
A R T I C L E S
Scheme 3. Isodesmic Reactions Used To Evaluate the Effect of the Substituents on the Basicity Of 2
The effect of entropy on the gas-phase basicity depends on
the temperature and can be approached experimentally by
performing the dissociation experiment with (A-H-B)+ at
different collision energies. Figure 2a shows the determination
of the so-called apparent gas-phase basicity (GBapp) of 1b at
collision energies of 2.4 and 3.6 eV, respectively. At a given
affinities, which are listed in Table 1 [for all of the experimental
0K
data and the detailed evaluation of PA
values, see the
exp
Supporting Information (SI)]. With respect to the large experi-
mental errors in the determination of the entropies,40 the final
0K
proton affinities were obtained as a sum of PA and the
exp
298K
theoretical correction for the temperature effect (PA
-
theor
PA ) (Table 1).42
0K
collision energy, the intersection of the linear fit of ln(I1bH+
/
theor
I
BH+) as a function of PAB (B ) DMAN, DIPEA, TBA, TPA)
The experimental proton affinities of the studied derivatives
of 1 exceed 1050 kJ mol-1, and the results thus fully support
the calculations and demonstrate that the derivatives of 1
are exceptionally strong oxygen bases whose basicities exceed
even that of DMAN. We note in passing that in the collision
experiments, which were performed at rather high effective
temperatures (∼900 K), DMAN showed larger basicity than
any of the derivatives of 1. The seeming conflict can be easily
explained by considering entropy effects: If we calculate the
basicity differences (determined from ∆∆G) between DMAN
and 1a at 298, 1000, and 2000 K, we obtain differences of
-12, -3, and +5 kJ/mol, respectively. Thus, DMAN is more
basic than the derivatives of 1 at large internal energies, at
which we performed our experiments. This result can be
attributed to the changes in geometry upon protonation of 1
and locking of the dihedral angle between the two tetrahy-
droisoquinoline rings.
with the horizontal axis reveals GBapp(1b) and the slope of the
linear fit is equal to (RTeff)-1 (see eq 1).41 The value of GBapp(1b)
does not correspond to any observable thermodynamic property,
as it contains entropy contributions from all of the processes
involved in its determination. In an ideal case, however, the
linear extrapolation of the dependence of GBapp to the effective
temperature Teff ) 0 K would lead to the elimination of all
entropy effects and directly yield the proton affinity of the
studied compound at 0 K. Such a treatment of our experimental
data from three independent measurements gave the proton
The most basic organic oxygen bases known to date are based
on pyrone-like structures, whose large basicity is a result of
delocalization of the charge over the aromatic backbone (Scheme
4).43,44 The charge of the incoming proton is either delocalized
over the aromatic ring (structure A) or transferred to the nitrogen
substituents in the base (structure B). It should be also noted
that all of these oxygen superbases have been studied only
theoretically. Apart from these neutral bases, there is a series
of anionic oxygen bases (e.g., alkoxides) whose extreme basicity
(41) (a) Drahos, L.; Vekey, K. J. Mass Spectrom. 1999, 34, 79. (b) Ervin,
K. M. Int. J. Mass Spectrom. 2000, 195/196, 271. (c) Laskin, J.; Futrell,
J. J. Phys. Chem. A 2000, 104, 8829. (d) Armentrout, P. B. J. Am.
Soc. Mass Spectrom. 2000, 11, 371.
(42) We also probed the collisional experiments using argon as a collision
gas and using an ion-trap instrument in order to obtain data at different
effective temperatures. In contrast to the exclusive dissociations of
the proton-bound dimers to the protonated bases obtained in the
experiments with xenon (see the SI for the spectra), the experiments
with argon and in the ion trap also led to other dissociation channels,
such as oxygen transfers from the N-oxide bases, so we did not include
those data here.
Figure 2. Determination of the proton affinity of 1b using the extended
kinetic method. (a) Determination of the gas-phase basicity of 1b at collision
energies of 2.4 (2) and 3.6 eV (b) by linear fits of the dependences of
ln(IAH+/IBH+) as a function of the PA of the reference base B. The
intersection of a given linear fit with the horizontal axis gives GBapp(1b).
The effective temperature corresponding to a given collision energy is
determined from the slope of the linear fit. (b) Dependence of GBapp(1b)
on the effective temperature (results of three measurements). The extrapola-
(43) Suarez, D.; Menendez, J. A.; Fuente, E.; Montes-Moran, M. A. Angew.
Chem., Int. Ed. 2000, 39, 1320.
tions of the linear fits of the data obtained in the ECM range 2.0-4.4 eV to
0K
Teff ) 0 K gives the estimates of PA (the linear fits for the three
(44) Despotovic, I.; Maksic, Z. B.; Vianello, R. Eur. J. Org. Chem. 2007,
3402.
exp
measurements are given by their equations in the respective colors).
9
J. AM. CHEM. SOC. VOL. 132, NO. 36, 2010 12663

A R T I C L E S
Ducha´cˇkova´ et al.
Scheme 4. Theoretically Predicted Oxygen Superbases A and B
(Only the Most Basic Representatives of the Corresponding
Classes of Compounds Are Shown) and Experimentally
Investigated Superbase Ca
Table 2. B97D/cc-pVTZa Energetics of Intermediates and
Transition States (kJ mol-1) for the Formation of (S)- and
(R)-4-Phenylbut-1-en-4-oxytrichlorosilane Catalyzed by (S)-1ba
gas-phase
in toluene
b
b
c
b
c
∆H0K
∆H298K
∆G298K
∆H298K
∆G298K
TS1
TS2
3a
3b
82
74
43
5
-34
-32
34
48
30
53
12
137
108
59
13
14
162
175
160
179
128
131
137
128
130
47
14
-41
-40
39
55
35
58
9
3c
a The proton affinities amount to PAA ) 1054 kJ mol-1 and PAB
43
)
46
(S)-TS3_a
(S)-TS3_b
(R)-TS3_a
(R)-TS3_b
(S)-TS4_a
(S)-TS4_b
(S)-TS4_c
(R)-TS4_a
(R)-TS4_b
36
52
33
56
8
7
9
2
10
164
179
162
182
125
126
132
119
126
44
1138 kJ mol-1
,
and the gas-phase basicity of C is 1028 kJ mol-1
.
is a result of neutralization of their negative charge.45 A similar
situation is also found for zwitterionic compounds such as
species C in Scheme 4, where the negatively charged group is
protonated, resulting in localization of the positive charge on
the ammonium group.46 The experimental gas-phase basicity
of this zwitterion amounts to 1028 kJ mol-1, and it was also
determined by the kinetic method as applied here. The deriva-
tives 1a-c of 2,2′-bipyridyl-N,N′-dioxide are derived from a
family of pyridine N-oxide compounds,47 and their special
backbone arrangement makes them a new class of chiral oxygen
superbases that can easily be synthetically prepared and used
in catalysis.18,48
8
10
3
13
13
12
15
11
a Geometry optimizations and thermochemistry calculations were
performed at the B97D/6-31G* level of theory. The total energies were
refined by single-point calculations including the BSSE correction, and
the solvation free energies were obtained by single-point PCM
calculations, both at the B97D/cc-pVTZ level. b Energies are given
relative to the sum of the enthalpies of the reactants (for more details,
see the SI). c Energies are given relative to the sum of the Gibbs free
energies of the reactants (see the SI).
Having determined the exceptionally large basicities of the
derivatives of 1, which are associated with strongly polar sites
constituted by two N-oxide functions, we then investigated the
mode of action of one of the catalysts, 1b, in allylations of
benzaldehyde proceeding in toluene, as mentioned in the
Introduction.
the special catalytic activity of 1b, we addressed its mode
of action toward allyltrichlorosilane and benzaldehyde in
toluene using DFT calculations with an empirical correction
for the dispersion energy (i.e., we used the B97D functional).
According to our computational investigations of com-
plexes of 1b with allyltrichlorosilane, the coordination of 1b
via the oxygen atom(s) to the silicon atom of allyltrichlo-
rosilane is endothermic (complex 3a, Figure 3). In contrast,
the coordination of 1b via the hydrogen atoms of the allyl
group is energetically favored (complexes 3b and 3c). These
results suggest that the oxygen atoms of 1b do not interact
directly with the sterically hindered silicon atom of allyl-
trichlorosilane; instead, the catalyst 1b forms a polar pocket
that interacts with the whole polarized backbone of allyl-
trichlorosilane.
The reaction in polar solvents proceeds in the ionized
state,20 in which the catalyst coordinates to the silicon atom
of the allyldichlorosilicenium ion. According to the previ-
ously suggested mechanism, the oxygen atom of benzalde-
hyde coordinates to the silicon atom of the cationic complex,
and the C-C coupling can proceed via a six-membered
transition structure (Scheme 1).32 An analogous mechanism
in the neutral state would involve either seven-coordinate
silicon, which appears to be rather improbable, or coordina-
tion to silicon by only one of the oxygen atoms of the
organocatalyst (Scheme 1). However, both scenarios impose
large steric demands on the approach of benzaldehyde to the
primary complex of 1b and allyltrichlorosilane. On the other
hand, however, 1b is a very efficient catalyst, and the
coupling proceeds faster than with other catalysts bearing a
less sterically demanding structure.49 In order to understand
The noncatalyzed coupling between benzaldehyde and
allyltrichlorosilane in toluene proceeds via an energy barrier
of 74 kJ mol-1 (TS1 in Table 2 and Figure 4).32,50 We have
further considered possible catalysis by a chloride ion, which
might be present in the reaction mixture as a result of partial
Figure 3. Different modes of coordination between 1b and allyltrichlorosilane. Energies refer to the sum of the energies of 1b and (C3H5)SiCl3 at 0 K in
the gas phase.
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12664 J. AM. CHEM. SOC. VOL. 132, NO. 36, 2010

Oxygen Superbases as Polar Binding Pockets
A R T I C L E S
Figure 4. B97D/cc-pVTZ//B97D/6-31G* potential energy surface for the coupling of allyltrichlorosilane (C3H5SiCl3) with benzaldehyde (PhCHO) in toluene.
The structures show the optimized geometries of the transition states. Energies are given relative to the sum of the enthalpies of the reactants at 298 K in
-
toluene (for details, see the SI). It should be noted that reactants are C3H5SiCl3 + PhCHO for the uncatalyzed reaction (black), C3H5SiCl4 + PhCHO for
the anionic reaction (green), and C3H5SiCl3 + PhCHO + (S)-1b for the organocatalytic reaction (blue and red).
Scheme 5. Hydrolysis of Allyltrichlorosilane and Removal of HCl
from the Reaction Mixture
First, it removes from the solution protons that would
otherwise be bound to the strongly basic catalyst 1b and thus
deactivate it for the coupling step. Second, the precipitation
of ammonium chloride from the toluene solution removes
the free chloride ions from the reaction mixture, which would
otherwise promote the nonenantioselective coupling (Scheme
5).
In the next step, we investigated the effect of the catalyst
1b on the barrier height for the coupling reaction. First, the
hydrolysis of allyltrichlorosilane with traces of moisture
(Scheme 5). The coordination of a chloro ligand to the silicon
decreases the reaction barrier by ∼30 kJ mol-1 (TS2). Such
a reaction represents an undesired pathway, however, because
it leads to a racemic mixture of products. It has been reported
that the addition of Hu¨nig base to the reaction mixture is
essential for the high enantiomeric excess obtained in the
reaction.51,52 According to the above results, we hence
suggest that the role of the added base is to generate the
ammonium chloride salt, which brings two effects at once.
activation of allyltrichlorosilane by coordination of the
catalyst via the oxygen atom was considered. Two types of
transition structures were localized. The lower-energy path-
ways proceed via the transition structures (S)-TS3_a and (R)-
TS3_a, which are stabilized by the stacking interaction of
the benzene rings of the catalyst and benzaldehyde [Figure
5; the prefixes (S) and (R) denote the chirality of the product
formed].53 The corresponding reaction barriers are slightly
lower than that for the reaction catalyzed by chloride and
amount to 34 kJ mol-1 for the formation of the S product
and 30 kJ mol-1 for the formation of the R product (blue
pathway in Figure 4). With inclusion of the entropy effects
(see the Gibbs free energies in Table 2), the reaction pathways
proceeding via the two TS3_a structures are much less
favored than the reaction catalyzed by chloride; moreover,
they are less favored than the noncatalyzed reaction. The
geometries of the transition structures (S)-TS3_b and (R)-
TS3_b do not suggest any major stabilization by the backbone
of the catalyst; accordingly, they lie more than 10 kJ mol-1
higher in energy than both of the TS3_a structures and
therefore were not considered further.
(45) (a) Arnett, E. M.; Moe, K. D. J. Am. Chem. Soc. 1991, 113, 7288. (b)
Majumdar, T. K.; Clairet, F.; Tabet, J.-C.; Cooks, R. G. J. Am. Chem.
Soc. 1992, 114, 2897.
(46) Strittmatter, E. F.; Wong, R. L.; Williams, E. R. J. Am. Chem. Soc.
2000, 122, 1247.
(47) (a) Makowski, M.; Tomaszewski, R.; Kozak, A.; Chmurzynski, L. J.
Phys. Chem. A 2001, 105, 7381. (b) Berdys, J.; Makowski, M.;
Makowska, M.; Puszko, A.; Chmurzynski, L. J. Phys. Chem. A 2003,
107, 6293.
(48) Formally, the diatomic neutral alkaline-earth oxides (particularly CaO,
SrO, and BaO) are the strongest oxygen superbases known, but they
are not comparable with the organocatalysts studied here.
(49) The allylation of benzaldehyde with allyltrichlorosilane catalyzed by
1b (0.1 mol %) in chlorobenzene at -40 °C gives 100% yield with
80% ee in 1 h.18a For comparison, the same reaction catalyzed by
QUINOX [1-(2-methoxynaphth-1-yl)isoquinoline N-oxide) (5 mol %)
in CH2Cl2 at -40 °C gives 68% yield with 87% ee in 12 h, and only
<5% yield is observed after 12 h when the reaction is conducted at
-40 °C in toluene.32
As an alternative, different reaction pathways were dis-
covered for the approach of benzaldehyde to the complexes
derived from 3b and 3c (red pathway in Figure 4). Such
interactions lead to transition structures that are very low in
energy relative to the separated reactants (Figure 5 and Table
2). The transition structures are stabilized by a number of
interactions within the polar pocket formed by the catalyst
(50) Sakata, K.; Fujimoto, H. Organometallics 2010, 29, 1004.
(51) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem. Soc.
1998, 120, 6419.
(52) The allylation of benzaldehyde with allyltrichlorosilane catalyzed by
(R)-1b (10 mol %) in PhCl (-40 °C, 1 h) without Hu¨nig base (DIPEA)
yielded only racemic product (50%). No asymmetric induction was
observed.
(53) Lee, E. C.; Kim, D.; Jurecˇka, P.; Tarakeshwar, P.; Hobza, P.; Kim,
K. S. J. Phys. Chem. A 2007, 111, 3446.
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J. AM. CHEM. SOC. VOL. 132, NO. 36, 2010 12665

A R T I C L E S
Ducha´cˇkova´ et al.
substituents of 1b and the reactants as well as dipole
interactions between the chlorine atoms and the C-H bonds
of the annelated saturated rings of 1b. We localized several
transition structures that lie very close in energy. The lowest
energy barriers for the formation of the S and R products
both amount to 12 kJ mol-1. Also, when entropic factors are
taken into account, the “pocket” mechanism remains clearly
favored over the mechanism proceeding via six-coordinate
silicon as well as over the noncatalyzed coupling.
As far as the enantioselectivity of the coupling is con-
cerned, our results do not reproduce the experimentally
observed preference for the formation of the S product. We
are aware of the limitations of the theoretical approach
chosen, and therefore, we do not dwell upon the small energy
differences between (S)- and (R)-TS4 but rather point to the
large structural and energetic differences between TS3 and
TS4. The intention is thus to show the modes of action of
the catalysts derived from 1 rather than to deliver ultimately
exact energy barriers. We note in passing that for the correct
description of the chiral preferences in the reaction, correlated
ab initio calculations with BSSE corrections would have to
be applied; however, this would be extremely computationally
demanding, particularly because in a strict sense this level
would also be required in the geometry optimizations.
Moreover, our inclusion of solvation as an a posteriori
correction is a fair compromise but has its limits.
In a more general sense, we can say that the catalyst 1b
behaves similar to an enzyme in that it provides a well-
structured, strongly polar pocket for stabilization of a polarized
molecular structure in otherwise nonpolar environment. How-
ever, it should be noted that in comparison to most enzymes,
the pocket and the medium have reversed phases in 1b. Figure
6 illustrates the mode of action of 1b in the coupling reaction
and the role of the polar pocket in particular. In the most stable
conformation of 1b, the N-oxide binding sites point to the
opposite sides of the plane tentatively formed by the phenyl
substituents. Notably, this conformation is operative in the TS3-
type transition structures. The “pocket” conformation of 1b lies
3 kJ mol-1 higher in energy, and the illustration shows a putative
interaction mode of 1b with the transition structure TS1 for the
coupling reaction.
Such a mode of reactivity can be very promising for other
electrocyclic reactions proceeding in nonpolar solvents, such
as Diels-Alder reactions.15 In principle, many axially chiral
guanidine bases currently used for an increasing number of
organocatalytic reactions have a similar structure. They are often
derived from 1,1′-biaryls that are connected to guanidine via
methylene bridges at the 2 and 2′ positions and have large
aromatic substituents at the 3 and 3′ positions. Thus, these bases
may in fact form similar chiral pockets in the active steps of
catalysis of a variety of reactions with high enantioselectivities.
The concept of chiral pockets itself might thus have implications
beyond the range of the title compounds, and we will explore
this aspect in forthcoming work.
Conclusions
Figure 5. Transition structures for the reaction of allyltrichlorosilane
with benzaldehyde catalyzed by (S)-1b. The energies refer to the gas
phase at 0 K and to toluene at 298 K and are given relative to the
separated reactants.
Using a mass-spectrometric kinetic method and theoretical
calculations, we have studied a new class of organic chiral
oxygen superbases whose proton affinities exceed 1050 kJ
mol-1. In contrast to other theoretically predicted oxygen
superbases, the basicity of 1a-c stems from a strongly polar
binding site consisting of two N-oxide functions. The positive
charge formed upon protonation is mostly stabilized by the
1b. In addition to the dipole interactions between the N-oxide
groups and various C-H bonds, the structures are also
stabilized by dispersion interactions between the phenyl
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12666 J. AM. CHEM. SOC. VOL. 132, NO. 36, 2010

Oxygen Superbases as Polar Binding Pockets
A R T I C L E S
Figure 6. Illustration of the “polar pocket” stabilization of the transition structure for the coupling of allyltrichlorosilane with benzaldehyde by (S)-1b.
Molecules are depicted by their electrostatic potential (in atomic units) color-coded at the isodensity surface F ) 0.02 e Å-3. The different scales for TS1
and (S)-1b should be noted. The reaction enthalpy refers to 298 K and toluene solvation.
inductive effect of the hydrocarbon backbone of the super-
bases. The congested and very polar molecular structure of
these compounds provides a specific chiral binding pocket
that can entrap polar intermediates or polarized transition
structures and hence stabilize them in nonpolar environments.
In particular, we have investigated the coupling between
allyltrichlorosilane and benzaldehyde catalyzed by 1b in the
nonpolar medium toluene. By analogy to the previously
described catalysis by N,N-dimethylformamide or the struc-
turally related catalyst QUINOX, we have found reaction
pathways in which allyltrichlorosilane is coordinated to one
of the N-oxide functions of 1b. In addition, however, we have
discovered an alternative, energetically favored mechanism
that is based on stabilization of the transition structure by
dipole and weak interactions within the polar pocket of the
catalyst. This special catalytic mode may offer new perspec-
tives for reactions that proceed via polarized transition
structures and are performed in nonpolar solvents.
Acknowledgment. Support by the Ministry of Education of the
Czech Republic (MSM0021620857) and the Charles University
Grant Agency (259029) is acknowledged.
Supporting Information Available: Detailed evaluation of the
proton affinities, details of the theoretical approach chosen, total
energies, optimized geometries, and complete ref 26. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA103744F
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