Edge-to-face CH/π aromatic interaction and molecular self-recognition in epi-cinchona-based bifunctional thiourea organocatalysis

Article abstract of DOI:10.1002/chem.200800197

The impact of cooperativity between intermolecular interactions is demonstrated by the molecular self-recognition properties of highly enantioselective epi-cinchona bifunctional thiourea organocatalysts. Low-temperature NMR experiments in inert solvents have revealed two sets of nonequivalent resonances in equal population for thiourea-modified members of the epi-quinine and epi-quinidine families. In solution, the predominance of an asymmetric (C₁) dimeric self-assembly with noteworthy structural motifs became evident: simultaneous intra-and intermolecular thiourea hydrogen bonding and a CH/π interaction were observed. Both the stereochemical and the diverse conformational features of the system favor the observed quinoline T-shaped aromatic π-π stacking interaction. The structure findings are supported by quantitative protonproton distance data that were available from NOE buildup curves. The 3D structure of the dimeric assembly has been modeled in agreement with the H-H distance restraints. Owing to the geometrical preference associated with the dimerization process, the self-assembled bifunctional system is interpreted as a charge-transfer complex with the potential for catalyst self-activation.

Full text of DOI:10.1002/chem.200800197

DOI: 10.1002/chem.200800197
Edge-to-Face CH/p Aromatic Interaction and Molecular Self-Recognition in
epi-Cinchona-Based BifunctionalThiourea Organocatayl sis
Gµbor Tµrkµnyi,*[a] PØter Kirµly,[a] Szilµrd Varga,[b] Benedek Vakulya,[b] and
Tibor Soós*[b]
Dedicated to Professor Csaba Szµntay on the occasion of his 80th birthday
Abstract: The impact of cooperativity
between intermolecular interactions is
demonstrated by the molecular self-
recognition properties of highly enan-
tioselective epi-cinchona bifunctional
thiourea organocatalysts. Low-temper-
ature NMR experiments in inert sol-
vents have revealed two sets of none-
quivalent resonances in equal popula-
tion for thiourea-modified members of
the epi-quinine and epi-quinidine fami-
lies. In solution, the predominance of
an asymmetric (C1) dimeric self-assem-
bly with noteworthy structural motifs
became evident: simultaneous intra-
and intermolecular thiourea hydrogen
bonding and a CH/p interaction were
observed. Both the stereochemical and
the diverse conformational features of
the system favor the observed quino-
line T-shaped aromatic p–p stacking in-
teraction. The structure findings are
supported by quantitative proton–
proton distance data that were avail-
able from NOE buildup curves. The
3D structure of the dimeric assembly
has been modeled in agreement with
the H–H distance restraints. Owing to
the geometrical preference associated
with the dimerization process, the self-
assembled bifunctional system is inter-
preted as a charge-transfer complex
with the potential for catalyst self-acti-
vation.
Keywords:
hydrogen bonds
·
molecular recognition
·
organo-
AHCTREUNG
Introduction
Among them, the bifunctional thiourea organocatalysts[3]
excel as remarkably general and highly enantioselective cat-
alysts for a broad range of chemical reactions, including Mi-
chael additions,[4] Strecker reactions,[5] and Mannich reac-
tions.[6] The mechanism of these catalytic processes is the
subject of intensive research with experimental methods and
theoretical calculations.[5d,7] Despite these advances and the
broad interest in bifunctional organocatalysis, several issues
remain unsettled. One major problem that seems to hamper
the in-depth knowledge of the mechanism and further cata-
lyst design is the lackof structural information, including
conformational states and dynamics, about the catalysts in
solution. Furthermore, the fact that bifunctionality is also a
potential source of self-recognition of the catalysts has not
received much attention.[8] However, there appear to be nu-
merous practically and theoretically important aspects of
this phenomenon. First, the accessibility of active catalytic
sites may be influenced. Second, if noncovalent interactions
favor geometrically very specific assemblies, a different level
of structure study becomes attainable: the main structural
features of a catalyst can be studied under equilibrium con-
ditions. This allows one to identify conformational features
Asymmetric organocatalysis has emerged as a frontier in the
field of organic chemistry.[1] As might be expected for this
biomimetic approach, much of the inspiration and origins in
organocatalyst design comes from the chemistry found in
enzymes,[1b,2] for example, the well-arranged multifunctional-
ity and the importance of H-bonds in the catalytic cleft.
Awareness of these key design elements led to the develop-
ment of several useful bifunctional organocatalyst systems.
[a] Dr. G. Tµrkµnyi, P. Kirµly
Laboratory for NMR Spectroscopy
Chemical Research Center of the Hungarian Academy of Sciences
Pusztaszeri fflt 59–67, 1025, Budapest (Hungary)
Fax : (+36)1325-7554
E-mail: gtarkanyi@chemres.hu
[b] Sz. Varga, B. Vakulya, Dr. T. Soós
Laboratory for Organometallic Chemistry
Chemical Research Center of the Hungarian Academy of Sciences
Pusztaszeri fflt 59–67, 1025, Budapest (Hungary)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
that can model the active site of the catalyst. Finally, any
rare instance of a homochiral self-assembly discovered for
an enantiopure alkaloid derivative is likely to initiate further
research towards applications based on chiral molecular rec-
ognition in supramolecular chemistry.[8a,9]
arrays can be further complicated by the presence of the
quinoline ring as a possible basic and p-donor site in cincho-
na derivatives 1a–c and 2a. Despite the several possible in-
teraction sites owing to this multifunctionality, the low-tem-
1
perature solution H NMR experiments revealed spectra of
With these aims in mind, we initiated a program to inves-
tigate this neglected aspect of organocatalysis by using de-
tailed NMR studies to obtain accurate structural informa-
tion about potential conformers and possible self-assemblies.
In this paper, we present NMR studies of four cinchona-
based bifunctional thiourea organocatalysts, 1a–c and 2a
(Scheme 1), developed in our group recently.[10] These cata-
highly organized structures for 1a–c and 2a (Figure 1.).
Figure 1. The low-temperature 1H NMR spectra of 1a–c (ꢀ808C) and 2a
(ꢀ948C) in CD2Cl2 (599.9 MHz, 30 mmol).
A common feature of these spectra is the appearance of
two sets of resonances in equal (1:1) population, which is in
contrast with the results of the room-temperature experi-
ments (see Figure S1 in the Supporting Information). Both
the aromatic and the aliphatic signals are doubled and there
appear to be two sharp highly deshielded protons at
dꢁ12 ppm, a feature that may indicate twofold thiourea hy-
drogen bonding. Signal doubling of this kind is rationalized
by the formation of an asymmetric self-assembled dimeric
system. Alternatively, the simplest interpretation would be a
balanced conformational equilibrium within the monomeric
species, but this option will be ruled out by the complete
1H-NOESY NMR spectra (see below). Qualitatively, the re-
semblance of the proton spectra in Figure 1, as well as the
cross-peakpatterns of the 1H-NOESY spectra for 1a–c (see
the Supporting Information), suggests that the three epi-qui-
nine derivatives adopt structurally very similar assemblies.
The self-assemblies are held together by intermolecular
forces, among which hydrogen bonding is predicted to be
the strongest. The “pseudoenantiomer” 2a also forms a di-
meric assembly, although it assembles at a lower tempera-
ture (ꢀ948C). This indicates that the nature of the assem-
blies is such that the stereochemical difference between 1a
and 2a does not induce the breakdown of self-recognition.
As expected, signal doubling diminished completely in the
oxygen-donor [D8]tetrahydrofuran ([D8]THF; ꢀ808C) due
to the competition for hydrogen bonding. Experiments in
the p-donor [D8]toluene (ꢀ808C) resulted in more broad-
ened resonances than those in CD2Cl2, a result that antici-
Scheme 1. Bifunctional epi-cinchona-based thiourea organocatalysts.
lysts have been exploited successfully in various homogene-
ous enantioselective catalytic reactions,[10,11] which makes
them popular members of a “privileged” catalyst family.[12]
These studies unequivocally proved a significant level of as-
sociation of the catalysts in nonpolar media, even at room
temperature. We explored further the molecular basis of this
self-recognition phenomenon through low-temperature
NOESY experiments. It appeared that the prominent struc-
tural features of the self-associate are unique cooperative in-
termolecular H-bonding and CH/p interactions.
Results and Discussion
Self-association of the catalyst: It is generally agreed that
the role of thiourea in organocatalytic reactions is related to
its hydrogen-bond-donor properties,[5,13] for which the two
ꢀ
N H bonds of thiourea concurrently interact with oxygen
donors such as nitrones[14] or chalcones.[15] It is also known
that basic amines (DNR3) increase the solubility of thioureas
in nonpolar solvents by promoting hydrogen bonding be-
tween the amino group and the NH groups of the thiour-
ea.[16] When the amine is introduced as part of the thiourea
catalyst to afford bifunctionality, the possibility of intra- and
intermolecular hydrogen bonds is introduced. These H-bond
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G. Tµrkµnyi et al.
pates a certain role for p–p interactions in the assembly for-
mation. It follows from the thermodynamics of self-associa-
tion that the monomeric 1a species should be in equilibrium
with the dimeric [1a···1a*] form over a broad temperature
range. At room temperature, however, the 1H NMR spec-
trum shows only one resonance set with broadening effects
that suggest the presence of the underlying self-association
phenomenon. The most affected resonances are those of
H2’, H9, and H5’. At intermediate temperatures (ꢀ50 to
an asymmetric (C1) object. The inversion center or the
planar symmetry, which may be valid symmetry operations
for characterizing the shape of some achiral hydrogen-
bonded[19] and predesigned[20] self-assemblies in solution, are
not applicable for the given case. The two sets of chemically
nonequivalent proton resonances seen for the enantiopure
compound strongly suggest a conformational difference be-
tween the two halves of the dimer. For practical reasons, in
the treatment of this conformational asymmetry, an asterisk
(*) will be used to distinguish the “south” molecular unit
from the “north” one in Figure 2.
Another particularly important characteristic of the T-
shaped aromatic-stacking motif is that it unravels the organ-
izational role of the methoxyquinoline moiety that occurs in
cinchona alkaloids. The importance of this p-donor system
in enantioselective reactions has been well described.[21] In
our case, the quinoline unit that has the hydrogen-bond-ac-
ceptor nitrogen atom N1’* is oriented towards the relatively
electron-dense area beneath the second quinoline ring. A
self-assembled charge-transfer complex with an aromatic
CH/p interaction[22] is formed, in which the H-bond acceptor
(in the “south” unit) is partially positive whereas the H-
bond-donor part of the dimer (in the “north” unit) is partial-
ly negative (Figure 3). The weakattractive and charge-trans-
fer nature of the CH/p interaction has been anticipated by
theoretical studies for small-sized p systems,[23] benzene,[24]
and other aromatics.[25] These weakT-shaped aromatic inter-
actions, however, may significantly control the conformation
and molecular-recognition properties of larger molecular
systems.[26] Numerous instances of CH/p interactions have
been found in the solid state by X-ray crystallography and a
pivotal organizing role has been assigned to this interaction
in supramolecular chemistry.[27]
1
08C), broad H resonances are observed due to the superpo-
sition of both intra- and intermolecular exchange processes
(see the Supporting Information). The appropriate tempera-
ture range for the investigation of the self-assembly struc-
ture is in the slow-exchange regime at around ꢀ808C. To es-
tablish a 3D model of the self-assembly, we have undertaken
a NOESY study of 1a–c by low-temperature two-dimension-
al NMR methods.
Structural features of the self-assembly: The above prelimi-
nary NMR experiments encouraged us to explore the 3D
structure of the self-assembly [1a···1a*] by exploiting H–H
distance information from NOESY experiments at ꢀ808C.
Figure 2 shows the structure model, which is fully consistent
with the set of low-temperature 2D NMR data (see the Sup-
porting Information). It is a self-assembled dimer held to-
gether by cooperative intermolecular forces. There are a few
interesting features of this dimeric geometry that make it
unique. First of all, it exhibits asymmetric thiourea hydrogen
bonds, namely one intra- and one intermolecular NBH···DN-
type contact. Furthermore, the assembly is stabilized by a
T-shaped p–p stacking interaction[17] occurring between the
two methoxyquinoline rings. Unlike many homochiral self-
assemblies with axial symmetry (C2, C3, etc.),[18] [1a···1a*] is
In solution, the interaction is often referred to as T-
shaped or edge-to-face p–p stacking if it occurs between
Figure 2. The dimeric structure of 1a. The characteristic NOE contacts
are indicated by dashed lines. The asterisk(*) is used to distinguish as-
signments in the “south” part of the dimeric assembly. For H–H distance
details, see Table 1.
Figure 3. A side view of the dimeric assembly [1a···1a*] with the CH/p
interaction clearly shown.
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Self-Assembled Organocatalysts
FULL PAPER
aromatic systems. According to NMR studies, intramolecu-
lar T-shaped p–p stacking interactions exist in various pre-
designed model systems,[28] whereas intermolecular occur-
rences have mainly been reported for heterogeneous sys-
tems, such as mixtures of solvents[29] and multicomponent
self-assemblies.[30] The cooperation of hydrogen bonds is fre-
quent for cavitands and their inclusion complexes.[31] The
emergence of aromatic CH/p interactions in enantiopure
chiral organocatalysts is not commonplace. In the following
section, we present proof of the structure of the dimeric
self-assembly in which the coincidence of asymmetric thiour-
ea hydrogen bonding, a T-shaped p–p interaction, and steric
effects lead to an unprecedented molecular self-recognition
phenomenon.
terunit NOEs, we searched for alterations in the NOESY
cross-peakpatterns. The two hydrogen-bonded thiourea
proton resonances (NBH and NBH*) at dꢁ12 ppm give rise
to two markedly different NOE patterns (see the Supporting
Information). The downfield-shifted NBH* proton signal
shows intraunit H–H contacts only. Its major NOE enhance-
ments involve correlations to the aliphatic protons (H2*,
H6*, H8*) neighboring the N1* nitrogen atom. In sharp con-
trast to this, NBH has short interunit contacts to the quino-
line H2’* and H8’* hydrogen atoms surrounding the N1’* ni-
trogen atom and no proximity to its “own” quinuclidine ni-
trogen atom (N1) and the corresponding neighbors (H2, H6,
H8). This is a strong indication that only those structural
models that exhibit asymmetric hydrogen bonding are valid.
The nature of hydrogen bonding was explored in more
detail for 1b, because we introduced selective 15N isotope la-
beling at positions NB (and NB*) to verify that hydrogen
bonding is established through the thiourea NBH forms. The
Proof of the structure: The geometry of the dimeric self-as-
sembly [1a···1a*] in Figure 2 was constructed solely by in-
voking experimental proton–proton distance (NOE) re-
straints in molecular modeling[32] (Table 1). In this section,
pertinent resonances of the labeled compound [15NB]-1b in
1
both the H and 15N spectra became doublets (1J
(1H,15N)=
15
ꢀ
ꢀ
80 Hz), which is characteristic of S=C N H moieties and
rules out presence of the tautomeric forms (H S C=N).
Slow molecular reorientation at ꢀ808C induced the TROSY
effect[34] on the selectively labeled 15N–1H doublets of [15NB]-
1b (see the Supporting Information), which manifested in
the differential line widths of the J-coupled doublets.
ꢀ
Table 1. The measured H H distances that were applied as NOE re-
straints.
ꢀ ꢀ
ꢀ
ꢀ
Proton pairs
H H [Š]
Proton pairs
H H [Š]
H8*, H3’*
H9*, H5’*
NBH*,H2exo
NBH*, H8*
NBH*, H6b*
H8, H3’
2.2
2.1
2.5
2.8
2.5
2.5
2.0
4.3
NBH, H2’*
NBH, H8’*
H8’, H2’*
H8’, H3’*
H8’, H7b*
H8’, =CH*
H7’, =CH*
H9, H2’*
3.0
2.6
4.3
3.8
2.9
3.1
2.9
4.3
*
To satisfy the condition of intermolecular NBH···N1’* hy-
drogen bonding, as well as the conformation preference of
ꢀ
the C C bonds around the C9 and C9* atoms, the two quin-
H9, H5’
H9, H2’*
oline moieties adopted the T-shaped p–p stacking. The
emergence of the H2’* resonance in the aromatic region of
1
the H NMR spectra has provided a fascinating proof of this
concept. The unusually shielded H2’* proton signal in
Figure 4 (almost 2 ppm upfield relative to the H2’ reso-
nance) is unequivocally due to the ring-current effect of the
“north” quinoline ring in the T-shaped geometry (Figure 3).
We note that the chemical-shift information in this particu-
lar case is compelling evidence because constitutionally
identical hydrogen atoms are being compared. Similar
shielding effects have been described recently for the intra-
molecular case.[28f] Independently, the T-shaped motif of the
assembly is also supported by further interunit H–H NOE
contacts between the CH=CH2* group and the H7’/H8’ pro-
we show that the refined structure is also in agreement with
important torsional-angle (from J coupling) and chemical-
shift data. Owing to the slow molecular tumbling of the
[1a···1a*] complex at ꢀ808C, the system was found to be
deep in the negative NOE regime, where cross-relaxation
for protons is highly effective[33] while chemical exchange is
negligible. We utilized this to perform the quantitative H–H
distance determination by constructing NOE buildup curves
from a series of NOESY experiments recorded with short
incremented mixing times (see the Supporting Information).
The H–H distances that were applied as NOE restraints are
listed in Table 1. To facilitate understanding of the proof of
the dimeric assembly, the most conclusive NMR facts will
be summarized in the following paragraph.
ꢀ
tons. These H–H* contacts persisted with the CH2 CH3*
moiety of 1b as well, but were never detected in the oppo-
site direction (that is, between CH=CH2 and H7’*/H8’*).
Most of these important NOE contacts are depicted in
Figure 2.
In the low-temperature experiments (ꢀ808C), 1a ap-
peared to be conformationally rigid in both molecular units
Finally, the appearance of the H9 and H9* multiplets
merit some further comment because the different multiplic-
ities of these resonances are also indicative of the geometry
of the self-assembly. As delineated by the modified Karplus
equation,[35] the vicinal couplings are torsional-angle depen-
dent and the maximum coupling (Jꢁ9 Hz) is expected in
the trans conformations, whereas smaller (J<3 Hz) cou-
plings are predicted for the gauche conformers.[36] Being
trans to the neighboring H8 and H8* hydrogen atoms, the
ꢀ
of the assembly with respect to rotation about the C4’ C9
ꢀ
and C9 C8 bonds. The H9–H5’ and H8–H3’ distances are
rather short (<2.5 Š) and the H9 and H8 protons are in a
trans conformation in both units of the dimer. These intrau-
nit NOEs also established the connection between resonan-
ces in the two sets of quinoline/quinuclidine pairs. Several
intramolecular NOE patterns ran parallel within the rigid
quinuclidine moieties of the system. To extract important in-
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G. Tµrkµnyi et al.
tional preferences. It seems to be a condition of the molecu-
lar self-recognition process to have the above-demonstrated
conformation alteration for the thiourea part.
Thermodynamic parameters of the assembly formation: Our
efforts to determine the enthalpy and entropy changes (DH,
DS, respectively) of the self-assembly process through deter-
mination of the temperature dependence of the dimerization
equilibrium constants, K, over a sufficiently broad tempera-
ture range, failed in dichloromethane. Both line-shape anal-
ysis and magnetization-transfer experiments[37] were not ap-
plicable to the system owing to excessive monomer/dimer
signal overlap, as well as the rapid transverse relaxation
(T2 =10–30 ms) in 1H NMR spectroscopy. 19F NMR spectros-
copy suffered strong signal overlap in CD2Cl2 and sensitivity
problems occurred in 13C NMR spectroscopy. The only
viable method proved to be 19F NMR detection in
[D8]toluene for 1b.
Fortunately, the CF3 resonances of the dimeric and the
monomeric species appeared sufficiently separated to afford
calculation of the K value through integration of the perti-
nent resonances (Figure 6). The Eyring plot (lnK versus
Figure 4. Partial 1H–13C-gHSQC experiment showing proton–carbon one-
bond correlations for the complex [1a···1a*] (599.9 MHz, ꢀ808C,
30 mmol, CD2Cl2). The chemical shift of the H2’* resonance is indicative
of the CH/p interaction.
H9 and H9* protons both carry one large (Jꢁ8 Hz) cou-
pling each. Whereas the H9 signal has a doublet appearance
because of this, H9* has a second large coupling (Jꢁ8 Hz
ꢀ
ꢀ
ꢀ
for H C9* NA* H) and the signal is therefore a triplet.
This effect is best viewed with compound 1b where the per-
tinent spectral region is well resolved (Figure 5). It follows
that H9* is trans to NAH*, whereas H9 should be gauche to
NAH. The additional trans coupling is also manifested in the
extra cross-peakbetween the signals for H9* and N AH* in
1
the H–1H-COSY spectrum of 1a (see the Supporting Infor-
mation) while there no similar correlation can be found for
H9. The model in Figure 2 built primarily on the basis of H–
H distance restraints successfully returns these conforma-
Figure 6. Temperature-dependent 19F NMR (564.2 MHz) spectrum of 1b
(0.3 mmol) in [D8]toluene.
Tꢀ1) yielded the values of DH=(ꢀ36.4ꢂ1.5) kJmolꢀ1 and
DS=(ꢀ87ꢂ7) Jmolꢀ1 Kꢀ1 for the dimerization process (for
details, see the Supporting Information). The extrapolated
DG values indicate that the dimeric self-assembly should be
abundant near room temperature, although fast exchange
determines the appearance of the proton spectra. The pro-
ductivity of organocatalytic reactions is reported to be high-
est in nonpolar solvents (for example, dichloromethane or
toluene) so one may conclude that the self-assembled spe-
cies plays an important role in catalyst self-activation
through a protonation/deprotonation[38] mechanism. This
notion is in complete agreement with the recent observation
made for proline catalysis that the self-assembly of organo-
Figure 5. Partial 1H NMR (599.9 MHz, ꢀ808C, 30 mmol, CD2Cl2) spec-
trum for the complex [1b···1b*], which shows the different multiplicities
for protons H9 and H9*.
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Self-Assembled Organocatalysts
FULL PAPER
catalysts increases the productivity and enantioselectivity of
the reactions.[39]
Conclusion
Unique self-association equilibria have been identified for
recently developed epi-quinine (1a–c) and epi-quinidine
(2a) based thiourea bifunctional organocatalysts. Low-tem-
perature solution NMR experiments unraveled an asymmet-
ric dimeric self-assembly with the coincidence of the notable
structural features of aromatic edge-to-face (T-shaped) p–p
stacking and asymmetric thiourea hydrogen bonding. In ad-
dition to these interactions, the molecular self-recognition of
the enantiopure catalysts is brought about by the conforma-
tion diversity of the thiourea part. Although simultaneous
hydrogen bonding and p–p stacking are the most fundamen-
tal intermolecular interactions in nature,[40] their relevance
for small-sized organic molecules arises from the role played
in spontaneously induced enantioselective chemical reac-
tions. The focus of future research will be to explore wheth-
er the successful bifunctionality and enantioselectivity of the
catalysts is embedded in the conformational features of the
proposed noncovalent dimer.[41] The estimated enthalpy and
entropy changes of the self-association process suggest that
the charge-transfer assembly is also abundant at room tem-
perature. The results indicate that bifunctionality is a poten-
tial source of molecular self-recognition, and extensive work
needs to be done to recognize the influence of this on the
productivity of reactions. The unraveled structural features
of the dimeric assembly will influence our thinking on the
mechanism of organocatalytic reactions and, in particular,
on preferences in the capture and activation of reactants
(the finding of active sites). When it is observed that
oxygen-donor solvents suppress both the amount of self-as-
sembly and the productivity of the organocatalytic reactions,
it is likely that the cooperation between intermolecular
forces significantly helps in promoting the reactions. Com-
plexation studies with 6-methoxyquinoline indicated that the
molecular-recognition phenomenon can also be extended to
host–guest systems. This can be utilized in several fields of
chemistry and chemical analysis, like heterogeneous cataly-
sis[42] or the separation sciences.[21c–e]
Molecular recognition in a host–guest system: An important
salient feature of the assemblies of 1a–c is that they are the
subject of intermolecular exchange and the monomeric
halves should have a high tendency to act as recognition ele-
ments. In order to further verify the structural reasons for
the cooperation between the thiourea hydrogen bonding
and the CH/p interaction, we tested systems 1a–c for their
ability to bind 6-methoxyquinoline (MeOQ). According to
the model in Figure 2, the T-shaped aromatic p–p interac-
tion between the two methoxyquinoline rings is specifically
assisted by the NBH···DN hydrogen bond. As expected, when
MeOQ was added to 1b, all of the sharp 1H resonances
became broader; this indicates interaction between 1b and
MeOQ (three-site exchange for 1b). An additional hydro-
gen-bonded thiourea NBH proton signal, related to the
[1b···MeOQ] heterodimer, appeared at dꢁ11.6 ppm
(Figure 7). Although an excess of MeOQ did not completely
1
Figure 7. Partial H NMR (599.9 MHz) spectra of pure 1b (lower) and 1b
ExperimentalSection
doped with 6-methoxyquinoline (1b+MeOQ, upper) in CD2Cl2 at
ꢀ808C.
Compounds 1a–b and 2a were prepared by following the synthetic route
described previously.[10,11v] Hydroquinine, quinine, quinidine, and diiso-
propylazodicarboxylate were purchased from Fluka. Diphenylphosphoryl-
azide and 6-methoxyquinoline were purchased from Aldrich. 9-amino-9-
deoxy-epi-hydroquinine was prepared as described in the literature.[10]
THF was distilled from sodium/benzophenone prior to use. Exact-mass
(HRMS) spectra were recorded on a VG ZAB2-SEQ tandem mass spec-
trometer. For thin-layer chromatography, Mercksilica gel 60 (F254,
2 mm, 20”20 cm) was employed. Procedures have not been optimized
and yields are low due to hydrolysis of the CF3 groups in the acidic aque-
ous medium. The NMR experiments were carried out on 400 MHz (for
suppress the formation of the dimeric species, it is likely
that the thiourea-modified epi-cinchona systems possess the
ability to recognize heteroaromatic p systems. Their catalyt-
ic sites for capturing intermediates of enantioselective reac-
tions may equally be around the basic quinuclidine nitrogen
atom or below the electron-dense p system of the quinoline
ring owing to the conformational flexibility of the thiourea
part.
1
1H) Varian Inova and 600 MHz (for H) Varian NMR System spectrome-
ters by using 5 mm direct detection 15N–31P/
A
1
with a Z pulse field gradient. H chemical shifts are referenced to residu-
al solvent signals (CD2Cl2: d=5.32 ppm; [D8]toluene: d=2.09 ppm
(Me)). Deuterated (99.98 atom%) solvents were purchased from Merck
GmBH (Germany). 15N NMR spectra were recorded by using a 5 s recy-
Chem. Eur. J. 2008, 14, 6078 – 6086
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6083

G. Tµrkµnyi et al.
cle delay and Waltz gated proton decoupling during acquisition. The 15N
7.03 (s, 2H, CH-Ar), 7.21 ppm (s, 1H, CH-Ar); 15N NMR (40.5 MHz,
and 19F NMR chemical shifts are referenced to nitromethane (dCH NO
=
CDCl3, 308C): d=ꢀ320.4 ppm.
A
3
2
0.0 ppm) and CFCl3 (dCFCl =0.0 ppm), respectively. Spectra were pro-
isothiocyanate:
Thiophosgene
3
cessed with the VnmrJ 2.1B software. All two-dimensional spectra were
by using the Varian standard spectrometer pulse-sequence library. In
(100 mg, 0.87 mmol) was suspended in distilled water (1 mL) and cooled
to 158C. [15N]-3,5-bis(trifluoromethyl)aniline (90 mg, 0.39 mmol) in
chloroform (0.5 mL) was added to this mixture. The mixture was then
stirred for 4 h. The reaction mixture was added to 10% HCl solution
(10 mL) and the whole mixture was washed with CH2Cl2 (4”10 mL). The
combined organic phases were washed with brine, dried over Na2SO4,
and concentrated in vacuo. The isothiocyanate was obtained without fur-
ther purification as a yellow oil (50.0 mg, 0.18 mmol; yield: 47.0%):
HRMS (EI): m/z calcd for C8H3F615NS [M]+: 271.9861; found: 271.9865;
1H NMR (399.9 MHz, CDCl3, 308C): d=7.64 (s, 2H, CH-Ar), 7.76 ppm
(s, 1H, CH-Ar); 15N NMR (40.5 MHz, CDCl3, 308C): d=ꢀ271.8 ppm.
1
low-temperature H-NOESY experiments, solvent presaturation was used
during the recycle delay. 6012 complex data points were acquired in the
F2 dimension and 320 complex data points in the F1 dimension. Spectral
widths of 16 kHz were used in both dimensions and the relaxation delay
time was 1.2 s. NOESY mixing times of 5, 10, and 20 to 150 ms were
used. Data were multiplied by Gaussian weighting functions and zero
filled to a 8192”4096 matrix. Digital resolution in the F1 dimension was
doubled by twofold linear prediction. An automated polynomial baseline
correction was used. All spectra were referenced to residual solvent sig-
nals in both dimensions. NOESY peakpicking and volume integration
was performed with the VnmrJ 2.1B software. The assignment of the
NMR resonances of 1a at ꢀ808C followed the regular procedure: collec-
tion and analysis of through-bond (1H–1H- and 1H–13C-COSY) and
AHCTREUNG
[15N]-(3’’,5’’-bis(trifluormethyl)phenyl-N’-(9-deoxy-epi-quinin-9-yl)thiour-
ea ([15NB]-1b): A solution of [15N]-3,5-bis(trifluoromethyl)phenyl isothio-
cyanate (50 mg, 0.18 mmol) in dry THF (2 mL) was slowly added to a so-
lution of 9-amino-(9-deoxy)-epi-hydroquinine (65 mg, 0.2 mmol) in dry
THF (5 mL) at ambient temperature. The mixture was stirred overnight
and the solvent was removed in vacuo. The residue was purified by prep-
arative thin-layer chromatography on silica gel (with EtOAc/MeOH/
concd aq NH4OH (300:5:1) as the eluent) to afford the 15N-labeled thio-
urea catalyst as an off-white amorphous solid (39.1 mg, 0.07 mmol; yield:
36.4%): HRMS (EI): m/z calcd for C29H30F6N315NOS [M]+: 597.2015;
found: 597.2012; 15N NMR (60.8 MHz, CD2Cl2, ꢀ808C): d=ꢀ246.6,
ꢀ247.2 ppm.
1
through-space (1H-NOESY) correlations. The H NMR chemical-shift in-
dexing used to evaluate the NOESY spectra is listed in Table S1 in the
Supporting Information. A total number of 514 cross-peaks was assigned
in the NOESY spectra of 1a. Parallel experiments performed on the two
other derivatives 1b and 1c helped to verify the proposed model by un-
raveling analogous H–H contacts in the close structural analogues. The
cross-relaxation rates, sij, between protons i and j were determined by
using the initial linear buildup of the NOE contacts. Typical buildup
curves are shown in the Supporting Information. To obtain the interpro-
ton distances (rij), we determined the molecular reorientational correla-
tion time (tc =3.35 Eꢀ7 s) according to an invariant interproton distance
(rH2’ H3’ =2.5 Š) by using Equation (1), in which m0 is the vacuum permea-
ꢀ
bility, ꢀh is the Planckconstant divided by 2 p, g is the gyromagnetic con-
stant of protons, and w is the Larmor frequency for protons.
Acknowledgement
ꢀ
ꢁ
ꢂ
ꢃ
m0 ꢀh2g4
6tc
The support of the Hungarian GVOP-3.2.1.-2004-04-0210/3.0 project and
grants 1/A/005/2004 NKFP MediChem2 and OTKA K-69086 is gratefully
acknowledged.
ꢀ6
ð1Þ
sij
¼
2 ꢀtc rij
4p 10 1þ4w2tc
The relevant NOE-based intra- and interunit rij values were introduced
as H–H distance restraints in molecular modeling to allow refinement of
the structure model. Molecular modeling was performed at the AM1
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level by using HyperChem 8.0 Professional.[32] Distance restraints of
ꢀ2
1 kcalmolꢀ1
optimization.
[15N]-1-Nitro-3,5-bis(trifluoromethyl)benzene: Concentrated sulfuric acid
Š
were applied for each H–H contact in AM1 geometry
A
(20 mL) was cooled to 08C. Oleum (65%; 5 mL) was then slowly added
dropwise at 08C. Afterwards, K15NO3 (1.91 g, 18.7 mmol) was added to
this mixture. 1,3-Bis(trifluoromethyl)benzene (2.00 g, 9.35 mmol) was
poured into the acidic mixture. The mixture was allowed to warm to
room temperature and was stirred overnight. The reaction mixture was
poured onto ice and washed with CH2Cl2 (3”20 mL). The combined or-
ganic phases were dried over Na2SO4 and concentrated in vacuo. The
nitro compound was obtained without further purification as a yellow oil
(0.30 mg, 1.15 mmol; yield: 12.3%): HRMS (EI): m/z calcd for
C8H3F615NO2 [M]+: 260.0038; found: 260.0037; 1H NMR (399.9 MHz,
CDCl3, 308C): d=8.23 (s, 1H, CH-Ar), 8.71 ppm (s, 2H, CH-Ar);
15N NMR (40.5 MHz, CDCl3, 308C): d=ꢀ17.0 ppm.
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A
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(0.26 g, 1.00 mmol) was dissolved in concentrated hydrochloride acid and
cooled to 08C. SnCl2·2H2O (2.26 g, 10.0 mmol) was then added. The mix-
ture was allowed to warm to room temperature and was stirred over-
night. The reaction mixture was poured onto ice and made alkaline with
10% NaOH solution while being kept at 08C. At first, Sn(OH)2 precipi-
tated from the solution but this dissolved again upon addition of further
amounts of the NaOH solution. This mixture was washed with CH2Cl2
(4”20 mL). The combined organic phases were dried over Na2SO4 and
concentrated in vacuo. The aniline was obtained without further purifica-
tion as a yellow oil (90.0 mg, 0.39 mmol; yield: 39.1%): HRMS (EI): m/z
calcd for C8H5F615N [M]+: 230.0297; found: 230.0296; 1H NMR
(399.9 MHz, CDCl3, 308C): d=4.06 (d, 2H, 1J(1H,15N)=82.9 Hz, 15NH2),
ACHTREUNG
6084
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6078 – 6086

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Received: January 31, 2008
Published online: May 26, 2008
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