A chiral frozen hydrogen bonding in C4-symmetric inherently chiral resorcin[4]arenes: NMR, X-ray, circular dichroism, and theoretical study

Article abstract of DOI:10.1002/ejoc.200800247

Chiral C₄-symmetric resorcinarenes, substituted with L-amino acid derivatives at upper rims, were synthesized by the modified Mannich reaction and subsequent N-substitution reactions. Compounds of that type (5a-e) can exist in two relatively stable inherently chiral C₄-symmetric conformations, (M) and (P), stabilized by the formation of seams of hydrogen bonds. However, because of diastereomeric preferences the amino acid substituted resorcinarenes exhibit considerable diastereomeric excesses for the induced conformational inherent chirality (up to ≥95%). The relatively slow exchange allowed the determination of the directions of the hydrogen bond ring closures through the combined application of NMR (ROESY) and X-ray analysis. It was also possible to correlate the absolute conformation with the sign of the Cotton effects observed for the transitions within the resorcinol chromophore in the CD spectra (solution and solid state). The ab initio calculations (TDDFT/B3LYP/DZVP and TDDFT/CAMB3LYP/6-31++G*) for model compounds showed that the chiral arrangement of the hydrogen bonding in resorcinarenes can produce substantial CD effects, which are amplified by exciton coupling. However, it was also shown that the neighboring urea, amide, or phenyl groups have crucial effects on the direction of electric transition dipoles and, as the result, on the signs of the exciton-coupled bands.

Full text of DOI:10.1002/ejoc.200800247

FULL PAPER
DOI: 10.1002/ejoc.200800247
A Chiral “Frozen” Hydrogen Bonding in C4-Symmetric Inherently Chiral
Resorcin[4]arenes: NMR, X-ray, Circular Dichroism, and Theoretical Study
Bogumił Kuberski,[a] Magdalena Pecul,[b] and Agnieszka Szumna*[a]
Keywords: Calixarenes / Amino acids / Atropisomerism / Conformation analysis / Receptors
Chiral C4-symmetric resorcinarenes, substituted with L-
amino acid derivatives at upper rims, were synthesized by
the modified Mannich reaction and subsequent N-substitu-
tion reactions. Compounds of that type (5a–e) can exist in
Cotton effects observed for the transitions within the resor-
cinol chromophore in the CD spectra (solution and solid
state). The ab initio calculations (TDDFT/B3LYP/DZVP and
TDDFT/CAMB3LYP/6-31++G*) for model compounds
two relatively stable inherently chiral C4-symmetric confor- showed that the chiral arrangement of the hydrogen bonding
mations, (M) and (P), stabilized by the formation of seams of in resorcinarenes can produce substantial CD effects, which
hydrogen bonds. However, because of diastereomeric prefer- are amplified by exciton coupling. However, it was also
ences the amino acid substituted resorcinarenes exhibit con-
siderable diastereomeric excesses for the induced conforma-
tional inherent chirality (up to Ն95%). The relatively slow
exchange allowed the determination of the directions of the
hydrogen bond ring closures through the combined applica-
tion of NMR (ROESY) and X-ray analysis. It was also possible
to correlate the absolute conformation with the sign of the
shown that the neighboring urea, amide, or phenyl groups
have crucial effects on the direction of electric transition di-
poles and, as the result, on the signs of the exciton-coupled
bands.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
exhibiting inherent chirality.[5] Recently, our group[6] and
others[7] reported chiral C4-symmetric organization of the
arms of resorcin[4]arenes by means of the cooperative belts
of hydrogen bonds. Compounds of type 1 (Scheme 1) can
exist in two C4-symmetric enantio/diastereomeric confor-
mations, (M) and (P), and can switch between those two
forms with the concerted rupture of eight stabilizing hydro-
gen bonds (and thus exhibiting considerable energetic barri-
ers).[6] The examples of the determination of the stereo-
chemistry of covalently inherently chiral resorcinarenes are
limited[5a,8] and for the conformationally inherently chiral
compounds the task was so far not feasible due to the time-
scale of the relatively fast dynamic processes. In the current
paper we show the effective synthesis of C4-symmetric con-
formationally inherently chiral resorcinarenes 5a–e, substi-
tuted with -amino acid derivatives, and for the first time,
we address the question of their stereochemistry. We hoped
that by using amino acids as upper rim substituents, in ad-
dition to providing the source of chirality to promote differ-
entiation of diastereomeric conformers, may provide ad-
ditional stabilizing interactions (hydrogen bonding and/or
steric overcrowding) to slow down the dynamic processes
and thus allow the determination of the direction of the
hydrogen bond ring closures.
Introduction
The majority of large proteins in cells are symmetrical
oligomeric complexes with two or more subunits. Such sym-
metrical arrangements have many advantages that justify
their evolutionary selection.[1] The advantages involve error
control in synthesis, coding efficiency, and cooperative func-
tions such as allosteric binding, assembly, and amplification
of the molecular response to external stimuli.[2] Symmetri-
cal synthetic molecules also have similar advantages that
include simplified synthesis and the possibility of amplifi-
cation of molecular properties through symmetrical supra-
molecular organization. These features make them useful in
many areas including catalysis, molecular recognition, and
material science. Of special interest are molecules pos-
sessing only rotational symmetry, which proved to be effec-
tive as asymmetric catalysts[3] or chiral materials.[4] Exam-
ples are widely known for C2- and C3-symmetric mole-
cules,[3] whereas there is comparatively less known about
chiral systems possessing higher rotational symmetry.
The promising but still relatively poorly explored class
of chiral molecules having rotational symmetry are those
[a] Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax: +48-22-632-6681
Additionally, we would like to discuss the correlation be-
tween asymmetry of the hydrogen bonding system and the
chiroptical spectra. We previously noted interesting circular
dichroism spectra for the compounds of type 1, which have
E-mail: szumnaa@icho.edu.pl
[b] Department of Chemistry, Warsaw University,
Pasteura 1, 02-093 Warsaw, Poland
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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B. Kuberski, M. Pecul, A. Szumna
FULL PAPER
Scheme 1. Structure and stereochemical notation of conformationally inherently chiral resorcin[4]arenes.
shown considerable Cotton effects in the region of the ab- the N,O-acetal bridge of 3 had to be removed. Recently, we
sorption of the resorcinarene skeleton Ϫ quite remote from reported mild conditions for N,O-acetal removal by using
the chiral centers, but involved in the conformationally chi- ethyl nitroacetate.[6] That procedure was very efficient and
ral pattern.[6] The question arises as to whether the Cotton worked also for amino acid derivatives 3a and 3b. However,
effects can be ascribed to the “frozen” chiral hydrogen the simplification of the procedure by applying the direct
bonding system involving the resorcinarene chromophore route (Scheme 2, route c) would be desirable. A little puz-
or to other more elusive factors. In order to shed light on zling is that examples of the isolation of intermediate sec-
these questions we preformed ab initio calculations for the ondary amines of type 4 from the direct route are not
model compounds and discussed the application of the exci- known. To check the possibility of formation of amine 4b
ton chirality method for the current systems.
through the direct route we initially modified the known
“benzoxazine” procedure by simply changing the ratio of
the reagents from 1:5:10 to 1:4:4 (2/amine/HCHO) in
MeOH/AcOH. The reaction gave a complicated mixture of
differently substituted amines and benzoxazines, which
were very difficult to separate. As a result, we obtained
amine 4b in low yield (≈20%). During the course of the
optimization we found that substantial modification of the
original procedure by (1) changing the solvent from meth-
anol to dichloromethane (the reaction is then two phase),
(2) changing the ratio of the reagents to 1:5:4 (2/amine/
Results and Discussion
Synthesis
The Mannich reaction between resorcin[4]arene 2, form-
aldehyde, and primary amines in methanol is known to give
tetrabenzoxazines of type 3 (Scheme 2).[5c] Application of
such a procedure for -amino acid methylamides gave benz-
oxazines 3a and 3b. In order to obtain secondary amines 4
Scheme 2. Synthesis of 5a–e. Reagents and conditions: (a) aq. HCHO, -amino acid methylamide, AcOH, MeOH; (b) ethyl nitroacetate,
MeOH; (c) aq. HCHO, -amino acid methylamide, CH2Cl2; (d) see Experimental Section.
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Chiral “Frozen” Hydrogen Bonding in C4-Symmetric Resorcin[4]arenes
HCHO), and (3) using no acid allowed the synthesis of
amines 4a and 4b in high yields (64–76%). Moreover, the
mixtures were much easier to separate, in the case of 4b just
by filtration.
The subsequent N-substitution reactions resulting in fi-
nal products 5a–e were carried out in analogy to the pre-
viously described procedures[6] by using di-tert-butyl dicar-
bonate (for 5a, 5c), tert-butyl isocyanate (for 5b, 5d), or tri-
methylsilyl isocyanate (for 5e). The reaction of trimethylsilyl
isocyanate with amine 4a gave the analogous product to 5e;
however, its solubility in common organic solvents was too
low for further studies.
Figure 1. The most relevant ROESY contacts for 5a and 5b.
The Stereochemistry of tert-Butylaminocarbonyl (Bac)
Derivatives 5b and 5d
The Dynamics and Stereochemistry of tert-Butoxycarbonyl
(Boc) Derivatives 5a and 5c
1
The H NMR spectra of tert-butylaminocarbonyl (Bac)
derivatives 5b and 5d in CDCl3 contained multiple con-
siderably broadened signals indicating the existence of nu-
merous conformations. Although signals for one dominant
conformation could be distinguished (having the features of
C4-symmetric conformation) the 2D spectra were unin-
formative due to overlapping signals. We have tried to influ-
ence the conformational equilibria by changing the solvent
and the temperature. [D8]Toluene spectra were even more
complicated, and they simplified only at high temperatures
(Ͼ363 K) showing C4 symmetry. The [D6]DMSO spectra of
5b and 5d showed single C4-symmetric forms; however, the
important signals were highly broadened (due to faster dy-
namic processes). Raising the temperature sharpened the
signals, but the compounds appeared to be unstable (de-
composition).
The reasonably sharp spectra at 303 K with one C4-sym-
metric dominating form (Ͼ90%) was obtained for 5b in
1,1,2,2-[D2]tetrachloroethane ([D2]TCE). The minor con-
former was most probably an unsymmetrical form with one
leucine side chain self-encapsulated in the cavity (interpre-
ted from signals of leucine methyl groups at –0.4 and
–1.9 ppm showing exchange peaks with each other and with
analogous signals of the main conformer). The ROESY
spectrum of 5b (τmix = 200 ms, [D2]TCE) revealed charac-
teristic structural features of the main conformer. The most
important cross peak is between the leucine methyl groups
Hj and the aliphatic Hc and Hb protons from the aliphatic
lower rim of the resorcinarene skeleton (Figure 1). This sug-
1H and 13C NMR spectra in CDCl3 for both -Leu/Boc
5a and -Phe/Boc 5c derivatives are relatively sharp and
simplified by fourfold symmetry with the characteristic pat-
terns for C4-symmetric chiral conformations, namely, two
distinct signals for the phenolic OH groups with a large
chemical shift difference (see Supporting Information).
It was shown that the two diastereomeric conformations
of the compounds of this type, being in the regime of slow
exchange (NMR timescale), can be easily distinguished, as
they have separate signals that exhibit chemical exchange
cross peaks in the 2D EXSY experiments (moderate mixing
time ca. 300 ms).[6] To probe the dynamics of 5a and 5c, we
recorded 2D EXSY spectra in CDCl3 by using various mix-
ing times (ranging from 300 ms up to 1.5 s). In all cases
no exchange was observed at 300 ms. Some exchange was
observed at 1.5 s, but the integrals of the exchange cross
peaks with respect to diagonal peaks are very small (and
probably also biased by spin diffusion). This indicates that
for amino acid derivatives 5a and 5c the isomerization is
considerably slower than that of the previously reported de-
rivatives of the simple aliphatic amines.
Because the dynamics of the system is slow (from EXSY
1
experiments and the relatively sharp H and 13C spectra)
and the second possible diastereomeric conformation is ex-
pected to have a considerably different spectrum, we postu-
late that Boc derivatives 5a and 5c exist in the solution as
single diastereoconformers (de Ͼ95%).
The stereochemistry of 5a and 5c was probed by using gests that, contrary to the previous cases, it is the leucine
ROESY spectra (τmix = 200 ms). For both derivatives, cross side chain and not the backbone (as in the case of 5a, 5c,
peaks were observed between methyl protons from the and 5e) that is directed towards the lower rim of the resor-
amino acid methylamide Hl and the methyl protons from cinarene. This implies that the aliphatic chains interact with
the aliphatic lower rim of the resorcinarene skeleton Ha the aromatic walls of the resorcinarene. Such a conclusion
(Figure 1). This indicates that the molecule is highly bent is also supported by the chemical shift of the leucine methyl
with the backbone of the amino acid part pointing towards protons Hj, which are high-field shifted and appear at δ =
the bottom of the molecule. Such a bent structure implies 0.4 ppm. Other important stereochemical information
that an amide moiety has to reside in close proximity to comes from the presence of a NHn···Hh1 contact in the ab-
the aromatic walls, most probably by forming some kind of sence of a NHn···Hg contact, which indicates the proximity
stabilizing amide···π[9] or amide···OH interactions.
of the leucine side chain and the urea-type amide NHn.
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B. Kuberski, M. Pecul, A. Szumna
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The molecular structure of 5b in the solid state (X-ray, in positions remote from the rest of the molecule, and this
Figure 2) confirms the conclusions that were deduced from explains the absence of any ROESY cross peaks between
NMR spectroscopy. The molecule of 5b is held in the in- them and other protons, except for trivial 1,3-contacts.
herently chiral conformation by means of 12 intramolecular
While analyzing the crystal structure it is worth noting
hydrogen bonds (3 per unit). Analogous to the previously the extensive interactions of molecule 5b with acetonitrile
reported inherently chiral structures,[6,5d] the seam of hydro- molecules. In the crystal structure, one acetonitrile molecule
gen bonds is formed between the phenolic hydrogen atoms is hosted inside the molecular cavity and four others inter-
and the carbonyl groups (eight H-bonds). However, in the act with the side chains through hydrogen bonding with the
current structure, an additional four intramolecular hydro- sixth molecule (occupancy 82%) found in the intermo-
gen bonds are formed between urea-type NHn groups and lecular voids. Another important feature is the slightly dis-
the carbonyl groups of the amino acid backbone (forming torted cone conformation of the resorcinarene skeleton,
seven-membered rings). Another important intramolecular which has an approximate noncrystallographic C2 sym-
interaction is the CH···π interaction of the leucine methyl metry (distances between centroids of the opposite aromatic
groups, which are directed towards the lower rim of the rings are 7.22 and 6.40 Å).
molecule and located in close proximity to the aromatic
Because the configuration of -leucine is known, it is
walls of the resorcinarene skeleton (Figure 2b, blue lines, possible to determine unambiguously the absolute structure
C···aromatic plane distances ca. 3.7 Å). This explains the of 5b (and thus the conformation). We used the notation
unusually low chemical shift for the methyl Hj protons in proposed by Heaney and coworkers[10] for chiral Cn-sym-
the 1H NMR spectrum and justifies the Hj···Hc cross peaks metric molecules with a slight modification for this nonco-
in the ROESY spectrum. Also, the presence of NHn–Hh1 valent case (Scheme 1).[6] Thus, when looking from a posi-
cross peaks (NHn–Hh1 distance is 2.0 Å) in the absence of tion above the polar rim and by assuming that the doubly
NHn···Hg contacts (distance 3.5 Å and spatial separation by hydrogen bonded oxygen atom takes priority over the singly
a carbon atom) can be explained by the geometry of the hydrogen-bonded oxygen atom, the stereochemistry of 5b
molecule in the solid state. The methylamide Hl protons are in the solid state can be described as (P). On the basis of
the similarities, we postulate that the solution-state struc-
ture resembles the solid-state structure, and thus, the domi-
nant conformation of 5b in solution is also (P).
UV/CD Spectra
UV and circular dichroism (CD) spectra of the inherently
chiral conformers 5a–e are presented in Figure 3. For the
current study, the spectral range 280–320 nm is of particular
significance, as it is attributed to the transitions within the
substituted resorcinol chromophore. The UV spectra of all
products 5a–e in chloroform exhibited absorption bands
with similar wavelength maxima of 290 nm with pro-
nounced low-energy shoulders at 309 nm. The band energy
is not dependent on the type of amino acid (aromatic or
aliphatic) or N-substituent (Bac, Boc, or CON). It was ear-
lier postulated that these spectral characteristics come from
the rigid C4-cone conformation of the resorcinarene, which
result in pronounced excitonic splitting of the individual
1Lb electronic transitions.[11]
All CD spectra of compounds 5a–e in CHCl3 show the
bisignate Cotton effects centered at almost identical wave-
lengths of 290 and 309 nm (Figure 3). In the case of the -
leucine derivatives, both Boc 5a and Bac 5b exhibited a
negative CD couplet in the range of interest. The similar
negative couplet was also observed for -Phe/Boc 5c. In
contrast, -Phe/Bac 5d and -Phe/CON 5e exhibited a posi-
tive sign of the CD couplet.
Owing to the noncovalent nature of supramolecular in-
teractions that are responsible for the inherently chiral ar-
Figure 2. The crystal structure of 5b: (a) top view; lower-rim alkyl
rangements, the medium and solvent interactions with the
chains were removed for clarity, MeCN solvent molecules are col-
molecular components of the whole system can play a key
role in such processes, thus influencing the degree of in-
ored in green; b) side view; solvent molecules were removed for
clarity, blue dotted lines represent close CH–π interactions.
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Chiral “Frozen” Hydrogen Bonding in C4-Symmetric Resorcin[4]arenes
Figure 4. CD and UV spectra of 5b in various solvents and in the
solid state.
Figure 3. CD and UV spectra of 5a–e (CHCl3, 303 K).
duced inherent chirality. To probe the solvent effects, we
chose compound 5b, for which the crystal structure is
known. We recorded the CD spectra in various solvents and
in a KBr matrix (Figure 4). The CD spectra revealed the
strongest Cotton effects in TCE, which is in agreement with
the NMR spectroscopic data, and showed that in that sol-
vent the C4-symmetric structure existed in the highest
amount (for other derivatives there was no substantial dif-
ference between spectra in CHCl3 and TCE). The spectra in
more polar solvents (DMSO, MeCN, and MeOH) showed
considerably smaller Cotton effects in the range of interest.
It is also worth noting that the low-energy band (at 309 nm)
is much more affected than the higher energy band
(290 nm). This observation is in agreement with the pre-
vious observations for covalently inherently chiral resor-
cin[4]arenes, which also showed the decay of the low-energy
band (309 nm) with increasing solvent polarity.[11] Surpris-
ingly, the solid-state spectrum of 5b exhibited only a mono-
signate negative Cotton effect at 309 nm. Although some
flattening of the absorption bands is known for solid-state
CD spectra,[12] it has a more unified character, so it can not
be a reason for the selective one-band disappearance. We
attribute this phenomenon to the lower symmetry of the
resorcinarene skeleton in the solid state (C2 flattened-cone
conformation) than in the solution (C4-cone). Such an in-
terpretation is also supported by our previous observation
of chiral resorcinarenes conformationally locked in boat
(positive bisignate Cotton effects) as in the CHCl3 solution
(Figure 5). Such an observation speaks in favor of our pre-
vious interpretation that the presence of excitonic splitting
is strictly connected with the symmetry. The previously re-
ported crystal structure of 5f revealed an exact C4-symmet-
ric molecule (also crystallographic symmetry). The similari-
ties of the spectra also allowed the assumption that a solid-
state sample of 5f exhibits the same conformation as those
of the dominant form in solution.
Figure 5. CD spectra of previously reported 5f[6] (CHCl3 solution
and crystals in KBr).
On the basis of the NMR spectra and a crystal structure
conformations, which also showed monosignate Cotton ef- of 5b (see previous section), we attribute the negative cou-
fects.[13]
plet in the 280–320 nm range to the structure with (P) ar-
In order to gather more data for the current discussion, rangement of the hydrogen-bonding system. Surprisingly,
we recorded spectra of the crystals of the previously re- for compound 5f, the (P) arrangement of the hydrogen-
ported chiral resorcinarene 5f.[6] In this case, the KBr sam- bonding system (as in the crystal structure) is attributed to
ple exhibits the same sign and shape of the CD spectrum the positive couplet.
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B. Kuberski, M. Pecul, A. Szumna
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Discussion and the Ab Initio Calculations
We were particularly interested whether the chiral C4-
symmetrical arrangement of the hydrogen-bonding system
is able to induce substantial CD signals for the transitions
of the resorcinol chromophore. The subsequent question
was if this arrangement is responsible for the sign of the
experimentally observed Cotton effects for compounds 5a–
e. Those two questions are treated separately, because it is
known that Cotton effects are sensitive to many factors
(small conformational variations,[14] noncovalent interac-
tions with nearby environment[15]) and thus the CD spec-
trum can be also influenced by those factors (very difficult
to consider for such a large structure).
The simple but still accurate approach to the interpret-
ation of CD spectra of multichromophoric systems consists
in application of the exciton coupling theory.[16] Although
the CD spectra are almost routinely recorded for inherently
chiral compounds as a proof of their chirality, the examples
of data interpretation by application of excitonic coupling
are very limited.[11,5a] In order to consider the applicability
of that theory to the C4-symmetric resorcin[4]arenes, we fo-
cus on the influence of structural features on the direction
of electric dipoles.
1
For the resorcinol chromophore, the lowest Lb state is
of interest. For C2v-symmetric resorcinol, the electric-tran-
sition dipole is polarized in the plane of the aromatic ring
(Figure 6a). Its direction can be turned by differentiation of
the OH groups, by substitution (like in the case of coval-
ently inherently chiral resorcinarenes)[5,17] or by asymmetric
positions of the hydrogens (like in the present “noncoval-
ent” case, Figure 6b,c). In order to predict the direction of
1
the electric dipole of the lowest Lb electronic transition,
the ab initio calculation of the simple resorcinol chromo-
phore with an asymmetric OH geometry was preformed
(Figure 6b). The TDDFT calculations at the B3LYP/DZVP
level indicate that the lowest-energy transition at 247 nm
has HOMOǞLUMO and HOMO–1ǞLUMO+1 compo-
nents. The electric dipole connected with that transition is
Figure 6. Model compounds for the ab initio calculations. Arrows
indicate the directions of the electric dipole moments for the low-
est-energy transitions as calculated by TDDFT/B3LYP/DZVP.
polarized in the plane of the resorcinol ring (xy). In ad- electric-transition dipoles are characterized by the positive
dition to the relatively large y component, the asymmetry torsion angles (See Supporting Information). This, accord-
of the OH groups is responsible for the small x component ing to the exciton chirality rule, should result in a positive
of that electrical moment. This causes the turn of the elec- CD couplet.
tric dipole (the angle is +4°, Figure 6b). The magnetic di-
To check those predictions, we also preformed the ab ini-
pole of that transition is perpendicular to the resorcinol tio calculations by using TDDFT/CAMB3LYP/6-31++G*
ring exhibiting only z contribution. The additional calcula- and TDDFT/B3LYP/DZVP for the model tetramers (P)-
tions using the B3LYP functional and 6-31+(d,p) basis set 6 and (P)-7 [both having formal (P) arrangement of the
gave a UV spectrum almost identical to that generated by hydrogen-bonding system, in analogy to 5b, Figure 6d]. In
using the DZVP basis set. In this case, the lowest-energy the case of (P)-6, geometry optimization resulted in the C4-
transition (also at 247 nm) had HOMOǞLUMO and symmetric cone conformation being the energy minimum.
HOMO–1ǞLUMO+3 components. Although the orbital Interestingly, in the case of (P)-7, the C4-cone conformation
numbering (and order) is different, the shape of the orbitals appeared to be a “saddle” point, indicating a transition
involved in the transition at 247 nm is identical. Thus, the state. However, because both structures are only models to
orientation of the electric-transition dipoles is the same as evaluate the influence of the inherent chirality of the hydro-
that calculated by using the DZVP basis set.
gen-bonding system, we calculated the CD spectra for both
For the spatial arrangement of the four asymmetric res- structures. The comparison of the results for those two ba-
orcinol rings like in (P)-6 and (P)-7 (Figure 6d) and with sis sets with experimental data leads to the conclusion that
relatively small α angles, all possible combinations of two the DZVP basis set reproduces the band energy better than
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Chiral “Frozen” Hydrogen Bonding in C4-Symmetric Resorcin[4]arenes
6-31++G*. However, both calculations gave the same CD noteworthy that the turn angle is the largest in the current
qualitative result: the strong positive CD couplet for the case (α = –20.3°). Thus, for such an orientation of the elec-
lowest-energy bands for both (P)-6 and (P)-7 (Figure 7).
tric-transition dipole, the exciton chirality rule predicts the
negative sign of the couplet Ϫ in agreement with the experi-
mental observation.
For the monomer “(P)”-11, which is the fragment of the
previously reported crystal structure of (P)-5f,[6] the poten-
tial disturbance of the transition of interest can also come
from a phenyl ring residing in close proximity to the resor-
cinol. Indeed, the TDDFT/B3LYP/DZVP calculations indi-
cated the crucial contribution of the neighboring phenyl
ring in the lowest-energy transitions. The resulting electric-
transition dipole has the same turn as that of the simple
resorcinol with asymmetric OH groups. Thus, the exciton
chirality rule predicts a positive couplet for the (P) arrange-
ment of the hydrogen-bonding system Ϫ as it is indeed ob-
served for the solution and solid sample [crystals of (P)-5f
Figure 7. Calculated CD spectra for (P)-6 and (P)-7.
Although the ab initio calculations and the exciton coup- in KBr].
ling theory produced consistent results and indicated that a
Although our experimental UV and CD spectra were
chiral hydrogen-bonding system can produce a considerable very similar for aromatic versus aliphatic amino acids, es-
CD signal, these predictions are in contradiction to our ex- ters versus amides, and even amino acid derivatives versus
perimental observations for 5b with respect to the sign of simple amines, the ab initio calculations indicated that ad-
the couplet. Although, it is known that the theoretical cal- ditional chromophores have crucial influence on the transi-
culations with approximate models as those we employed tions in the resorcin[4]arene skeleton. Determination of
may give erroneous results for the ECD spectra, we believe those contributions combined with the exciton coupling
that in our case the difference comes from the additional theory allowed the correct prediction of the sign of the cou-
interactions with the remaining part of the molecule or sol- plets for 5b and 5f. However, it should be noted that as a
vent molecules that were not taken into account during the result of symmetry reasons, the magnetic-transition dipole,
calculations.
neglected by exciton chirality methods, may also need atten-
In order to evaluate the influence of additional groups tion.
and chromophores on the transitions under discussion, we
preformed ab initio calculations for monomeric fragments
Conclusions
“(P)”-8 and “(P)”-9, which are the simplest monomers con-
taining additional chromophores. Their starting geometries
were derived from the crystal structures (previously re-
ported[6] or current). Upon geometry optimization, the mo-
lecular shape of those fragments underwent only minor
changes in relation to their crystal structures. The TDDFT/
B3LYP/DZVP calculations for monomers “(P)”-8 and
“(P)”-9 showed a well-separated low-energy transition at
263 nm (next transition ca. 226 nm), which had
HOMOǞLUMO and HOMO–1ǞLUMO+1 components.
The analysis of the orbitals involved in those transitions
(see Supporting Information) indicates that the urea chro-
mophore also has a slight contribution to those orbitals. As
a result, the electric-transition dipole has the opposite turn
in comparison to that of a simple resorcinol with the same
asymmetric position of the OH groups.
Monomer “(P)”-10 is the monomeric fragment of the
crystal structure (P)-5b. In addition to the urea-type chro-
mophore, it contains yet another chromophore that can in-
terfere with the transition of interest Ϫ an amide group
from the amino acid backbone. The TDDFT/B3LYP/
DZVP calculations showed that all chromophores have
some contributions to the lowest-energy transition at
263 nm. In this case, the electric-transition dipole is also
polarized in the plane of the resorcinol ring, having the
We prepared amino acid substituted conformationally
chiral resorcinarenes in an efficient two-step synthesis.
Compounds 5a–e fold into C4-symmetric conformations
due to the formation of chiral seams of hydrogen bonds.
The seams can be directed in one particular direction be-
cause of diastereomeric conformational preferences (de Ͼ
95%). The formation of such chiral arrangements is respon-
sible for pronounced effects in the chiroptical spectra. De-
tailed NMR spectroscopic and X-ray studies allowed the
determination of the absolute conformation for 5b and thus
the correlation between the direction of the hydrogen-bond-
ing seam and CD spectra. Thus, with 5b having a (P) ar-
rangement of the hydrogen-bonding system, we observed
a negative couplet in the range 280–310 nm. The ab initio
calculations for model compounds showed that the chiral
arrangement of the hydrogen bonding in resorcinarenes can
produce substantial CD effects, which are amplified by exci-
ton coupling. However, it was also shown that the neigh-
boring urea, amide, or phenyl groups have crucial effects on
the direction of the electric-transition dipole and, as the re-
sult, on the sign of the exciton coupled band.
Experimental Section
General: All chemicals were used as received unless otherwise
same turn as the cases with urea-type chromophores. It is noted. Reagent-grade solvents (CH2Cl2, hexanes) were distilled
Eur. J. Org. Chem. 2008, 3069–3078
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3075

B. Kuberski, M. Pecul, A. Szumna
FULL PAPER
prior to use. All reported NMR spectra were collected with a
Bruker spectrometer at 500 (1H) and 125 (13C) MHz. Chemical
shifts are reported as δ values relative to the TMS signal defined
at δ = 0.00 ppm (1H) or relative to the CDCl3 signal defined at δ
= 77.00 ppm (13C). Mass spectra were obtained with a Mariner
PerSeptive Biosystem instrument by using the ESI technique. Col-
umn chromatography was performed on silica gel (Kieselgel 60,
200–400 mesh).
22.63, 23.55, 25.00, 26.03, 26.39, 27.40, 28.17, 31.70, 38.44, 42.79,
61.65, 82.90, 85.13, 112.30, 124.06, 124.95, 125.08, 149.78, 151.35,
158.13, 171.89 ppm. MS (ESI): m/z = 1736.2 [C96H152N8O20
–
H]–; isotope profile agrees. C96H152N8O20·2MeOH (1802.36): calcd.
C 65.30, H 8.95, N 6.21; found C 65.34, H 8.96, N 6.00.
5b: To a solution of amine 4a (267 mg, 0.2 mmol) in THF (2 mL)
was added tert-butyl isocyanate (242 µL, 2 mmol). The reaction
mixture was stirred overnight and evaporated to dryness. The crude
product was purified by column chromatography (CH2Cl2/MeOH,
4a: Resorcinarene 2 (712 mg, 1 mmol) and -leucine methylamide
(720 mg, 5 mmol) were dissolved in CH2Cl2 (5 mL). Aqueous
HCHO was then added (37%, 300 µL, 4.0 mmol). The reaction
mixture was vigorously stirred overnight at room temperature. The
reaction mixture was evaporated to dryness, and the crude product
was purified by column chromatography (CH2Cl2/MeOH, 97:3 to
95:5). Subsequent crystallization from CH2Cl2 gave 4a as a white
crystalline material (856 mg, 64%). [α]D = –4.0 (c = 1.0, MeOH).
1H NMR (400 MHz, DMSO, TMS, 303 K): δ = 0.83 (d, J = 6.6 Hz
12 H), 0.85 (d, J = 6.5 Hz 12 H), 0.89 (d, J = 6.8 Hz 12 H), 0.91
(d, J = 6.9 Hz 12 H), 1.36 (m, 12 H), 1.55 (m, 4 H), 1.98 (m, 4 H),
2.13 (m, 4 H), 2.60 (d, J = 4.6 Hz, 12 H, Hl), 3.09 (t, J = 7.1 Hz,
4 H, Hg), 3.54 (d, J = 15.0 Hz, 4 H, Hf), 3.87 (d, J = 15.0 Hz, 4
H, Hf), 4.25 (t, J = 7.6 Hz, 4 H, Hd), 7.19 (s, 4 H, He), 8.02 (br. q,
J = 4.8 Hz, 4 H, Hk) ppm. 13C NMR (100 MHz, DMSO, 303 K):
δ = 22.26, 22.65, 22.78, 22.96, 24.21, 25.40, 25.80, 30.76, 41.47,
41.65, 43.69, 58.53, 108.02, 122.37, 123.37, 123.60, 151.23, 151.72,
172.31 ppm. MS (ESI): m/z = 1335.9 [C88H112N8O12 – H]–; isotope
profile agrees. C76H120N8O12·0.9CH2Cl2 (1414.25, solvent visible
also in NMR): calcd. C 65.31, H 8.68, N 7.92; found C 65.30, H
8.85, N 8.02.
99:1) to give 5b as an off-white powder (180 mg, 52%). [α]2D5
=
+81.5 (c = 0.99, CHCl3). 1H NMR (500 MHz, [D2]TCE, 303 K)
main conformer: δ = 0.40 (br. s, 12 H, Hj), 0.73 (br. s, 12 H, Hj),
0.93 (br. s, 12 H, Ha), 0.99 (d, J = 5.5 Hz, 12 H, Ha), 1.07 (br. m,
4 H, Hi), 1.40 (s, 40 H, Hm, Hh), 1.47 (m, 4 H, Hb), 1.71 (s, 4 H,
Hh), 1.76 (br. m, 4 H, Hc), 2.25 (br. m, 4 H, Hc), 2.94 (br. s, 12 H,
Hl), 3.74 (br. s, 4 H, Hg), 4.31 (br. d, Hf2), 4.44 (br. d, 4 H, Hf1),
4.53 (br. t, 4 H, Hd), 6.37 (br. t, 4 H, Hk), 7.18 (s, 4 H, He), 7.86
(br. s, 4 H, Hn), 8.60 (br. s, 4 H, OH2), 12.13 (br. s, 4 H, OH1)
ppm. 13C NMR (125 MHz, [D2]TCE, 303 K): δ = 25.40, 26.13,
26.60, 26.95, 27.26, 28.14, 29.82, 30.71, 33.31, 33.58, 35.43, 42.06,
46.45, 46.76, 54.53, 63.0 (broad), 115.31, 127.65, 128.18, 128.81,
154.26, 154.80, 163.45, 177.12 ppm. MS (ESI): m/z = 1732.1
[C96H156N12O16 – H]–; isotope profile agrees. C96H156N12O16
(1734.34): calcd. C 66.48, H 9.07, N 9.69; found C 66.24, H 9.03,
N 9.53.
5c: According to the procedure described for 5a. Yield 281 mg,
75%. [α]2D5 = –124.1 (c = 1.00, CHCl3). H NMR (500 MHz, [D2]-
1
TCE, 303 K): δ = 0.94 (br. d, 24 H, Ha), 1.35 (m, 4 H, Hb), 1.50
(s, 36 H, Hm), 2.01 (br. s, 8 H, Hc), 2.58 (br. s, 12 H, Hl), 3.21 (m,
4 H, Hh1), 3.39 (m, 4 H, Hh2), 3.46 (br. s, 4 H, Hf2), 4.05 (d, J =
14.0 Hz, 4 H, Hf1), 4.45 (br. t, 4 H, Hd), 4.59 (m, 4 H, Hg), 5.29
(br. s, 4 H, Hk), 7.08 (s, 4 H, He), 7.18 (br. m, 20 H, Hi-ar), 8.22 (s,
4 H, OH2), 10.53 (s, 4 H, OH1) ppm. 13C NMR (125 MHz, CDCl3,
303 K): δ = 22.50, 22.63, 26.07, 26.37, 28.29, 31.56, 35.07, 42.79,
45.50, 65.07, 83.11, 112.35, 123.83, 124.86, 125.08, 126.41, 128.55,
129.22, 138.46, 149.47, 151.11, 157.89, 171.13 ppm. 15N NMR
(50.7 MHz, CDCl3): δ = –289.1 (NH) ppm. MS (ESI): m/z = 1896.2
[C108H144N8O20 + Na]+, 1872.3 [C108H144N8O20 – H]–; isotope pro-
file agrees. C108H144N8O20 (1874.34): calcd. C 69.21, H 7.74, N
5.98; found C 68.90, H 7.69, N 6.13.
4b: To a solution of resorcinarene 2 (712 mg, 1 mmol) and -phen-
ylalanine methylamide (890 mg, 5 mmol) in CH2Cl2 (5 mL) was
added aqueous HCHO (37%, 300 µL, 4.0 mmol). The reaction
mixture was vigorously stirred overnight at room temperature. The
resulting precipitate was filtered, washed with CH2Cl2 and water,
and then vacuum dried to give analytically pure 4b as a pinkish
1
powder (1.120 g, 76%). [α]D = +2.5 (c = 1.16, MeOH). H NMR
(400 MHz, DMSO, TMS, 303 K): δ = 0.89 (m, 24 H, Ha), 1.31 (m,
4 H, Hb), 1.95 (m, 4 H, Hc), 2.03 (m, 4 H, Hc), 2.55 (d, J = 4.6 Hz,
12 H, Hl), 2.70 (dd, J = 13.4 Hz, J = 8.1 Hz, 4 H, Hh1), 2.83 (dd,
J = 13.4 Hz, J = 5.7 Hz, 4 H, Hh2), 3.28 (t, J = 6.9 Hz, 4 H, Hg),
3.52 (d, J = 14.7 Hz, 4 H, Hf2), 3.88 (d, J = 14.7 Hz, 4 H, Hf1),
4.09 (t, J = 7.6 Hz, 4 H, Hd), 7.12–7.28 (m, 24 H, He, Hi), 7.95 (br.
q, J = 4.7 Hz, 4 H, Hk) ppm. 13C NMR (100 MHz, DMSO, 303 K):
δ = 22.72, 22.85, 25.34, 25.79, 30.61, 41.52, 43.48, 54.52, 61.86,
108.45, 122.37, 123.33, 123.50, 126.22, 128.12, 129.14, 137.58,
5d: According to the procedure described for 5b. Yield 221 mg,
59%. [α]2D5 = –42.5 (c = 1.00, CHCl3). 1H and 13C NMR spectra
were too broad for interpretation. MS (ESI): m/z = 1869.1
[C108H148N12O16 – H]–, 1893.2 [C108H148N12O16 + Na]+; isotope
profile agrees. C108H148N12O16·2H2O (1906.43): calcd. C 68.04, H
8.04, N 8.81; found C 68.08, H 8.03, N 9.05.
150.99, 171.91 ppm. MS (ESI): m/z = 1472.6 [C88H112N8O12
–
H]–; isotope profile agrees. C88H112N8O12·0.8CH2Cl2 (1541.8, sol-
vent visible also in NMR): calcd. C 69.17, H 7.42, N 7.27; found
C 69.10, H 7.38, N 7.15.
5e: To a solution of amine 4a (267 mg, 0.2 mmol) in THF (2 mL)
was added trimethylsilyl isocyanate (280 µL, 2 mmol). The reaction
was stirred for 3 d and then evaporated to dryness and suspended
in acetone (2 mL). The mixture was heated at reflux for 5 min and
then left for 2 h to precipitate. The analytically pure 5e (as a pinkish
powder) was obtained by filtration (217 mg, 66%). An alternative
procedure involves solvent change from THF to methanol. It al-
5a: To a solution of amine 4a (267 mg, 0.2 mmol) in dioxane/water
(2:1, 3 mL) was added Boc2O (348 mg, 1.6 mmol). The reaction
mixture was stirred overnight and evaporated to dryness. The crude
product was purified by column chromatography (CH2Cl2/MeOH,
99:1) to give 5a as an off-white powder (220 mg, 63%). [α]2D5
=
lows shortening of the reaction time to 1 d (216 mg, 66%). [α]2D5
=
–111.3 (c = 1.20, CHCl3). 1H NMR (500 MHz, CDCl3, TMS,
303 K): δ = 0.93 (m, 24 H, Hj), 0.96 (d, J = 2.2 Hz, 12 H, Ha), 0.98
–86.8 (c = 1.00, CHCl3). 1H NMR (500 MHz, CDCl3, TMS,
303 K): δ = 0.91 (d, J = 6.6 Hz, 12 H, Ha), 0.96 (d, J = 6.4 Hz, 12
(d, J = 2.2 Hz, 12 H, Ha), 1.42 (br. s, 40 H, Hb, Hm), 1.56 (m, 4 H, H, Ha), 1.44 (br. m, 4 H, Hb), 1.85 (br. m, 4 H, Hc1), 2.17 (br. m,
Hi), 1.82–1.98 (m, 8 H, Hh), 2.09 (m, 8 H, Hc), 2.53 (br. s, 12 H, 4 H, Hc2), 2.70 (br. d, J = 4.5 Hz, 12 H, Hl), 3.14 (dd, J = 5.7 Hz,
Hl), 4.26 (d, J = 14.8 Hz, 4 H, Hf2), 4.31 (m, 4 H, Hg), 4.56 (t, J J = 13.8 Hz, 4 H, Hh1), 3.41 (dd, J = 13.0 Hz, J = 10.5 Hz, 4 H,
= 7.5 Hz, 4 H, Hd), 4.57 (d, J = 14.8 Hz, 4 H, Hf1), 5.34 (br. s, 4
H, Hk), 7.21 (s, 4 H, He), 8.55 (br. s, 4 H, OH2), 10.77 (br. s, 4 H,
OH1) ppm. 13C NMR (125 MHz, CDCl3, 303 K): δ = 22.16, 22.57,
Hh2), 3.47 (d, J = 15.5 Hz, 4 H, Hf2), 4.24 (d, J = 15.2 Hz, 4 H,
Hf1), 4.47 (br. t, J = 7.8 Hz, 4 H, Hd), 4.52 (m, 4 H, Hg), 6.00 (br.
s, 8 H, Hn), 7.06 (s, 4 H, He), 7.26–7.37 (m, 20 H, Hi), 7.47 (br. q,
3076
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3069–3078

Chiral “Frozen” Hydrogen Bonding in C4-Symmetric Resorcin[4]arenes
4 H, Hk), 9.19 (s, 4 H, OH2), 11.77 (s, 4 H, OH1) ppm. 13C NMR
Acknowledgments
(125 MHz, CDCl3, 303 K): δ = 22.51, 23.39, 25.99, 26.30, 31.93,
34.25, 42.35, 48.43, 66.43, 114.49, 123.39, 125.26, 126.67, 126.94,
128.79, 129.28, 136.95, 149.45, 150.08, 160.79, 171.24 ppm. MS
(ESI): m/z = 1644.9 [C92H116N12O16 – H]–, 1668.0 [C92H11N12O16
+ Na]+; isotope profile agrees. C92H116N12O16·2H2O (1682.01):
calcd. C 65.69, H 7.19, N 9.99; found C 65.68, H 6.95, N 10.07.
This work was supported by the Ministry of Science and Higher
Education (Project # N20408631/2028 and 1TO9A07130). We are
grateful to Prof. Jadwiga Frelek and her group members for kind
assistance with the CD measurements. The X-ray data collection
was undertaken at the Crystallographic Unit of the Physical Chem-
istry Laboratory, Chemistry Department, University of Warsaw.
UV/Vis and CD Spectroscopy: CD spectra were measured at room
temperature with solutions (solvents UV grade) at concentrations
of ca. 10–4  with a Jasco 715 spectrophotometer by using cells
with path length 0.1 to 1 cm (spectral band width 2 nm, sensitivity
5ϫ10–6 or 10ϫ10–6 [∆A unit nm–1], where ∆A = AL–AR is the
difference in the absorbance). ∆ε is expressed in [Lmol–1 cm–1]. So-
lid-state samples were obtained by grinding of the respective crys-
tals (the same as used for X-ray structure determination) in a KBr
matrix. The measurements for solid state samples were qualitative.
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X-ray Crystallographic Structure Determination of 5b: The diffrac-
tion quality crystals of 5c were grown from CH2Cl2/MeCN solu-
tion. After removal from the mother liquid the crystal was immedi-
ately covered with an immersion oil and frozen at 153 K. The mea-
surement was performed with a KM4CCD j-axis diffractometer
with graphite-monochromated Mo-Kα radiation. The crystal was
positioned at 62 mm from the CCD camera. 1500 Frames were
measured at 0.5° intervals with a counting time of 30 s. The data
were corrected for Lorentz and polarization effects. Data reduction
and analysis were carried out with the Oxford Diffraction pro-
grams. The structure was solved with DIRDIF by using the resor-
cinarene skeleton as a starting structure for ORIENT.[18] The crys-
tal was twinned by merohedry (twinning matrix 1 0 0 0 –1 0 –1 0
–1, occupancy 0.67: 0.33). The structure was refined by using
SHELXL (X-Seed interface)[19] against twinned data. The refine-
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negative F2. Weighted R factors wR and all goodness-of-fit S values
are based on F2.The non-hydrogen atoms were refined with aniso-
tropic thermal parameters, and all H atoms were positioned geo-
metrically. The geometrical restraints were applied for disordered
atoms. C108H174N18O16, M = 1980.65, monoclinic, space group P21
(No. 4), a = 9.0772(6) Å, b = 35.982(2) Å, c = 18.555(1) Å, β =
103.712(5)°, V = 5887.7(6) Å3, Z = 2, Dcalcd. = 1.117 g/cm3, F(000)
= 2152, Mo-Kα radiation, λ = 0.71073 Å, T = 173(2) K, 2θmax
=
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on 19958 reflections with IϾ2σ(I) (refinement on F2), 1369 param-
eters, 1 restraint. Lp and absorption corrections applied, µ =
0.076 mm–1.
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Computational Details: The structures of model compounds were
optimized by means of DFT with the B3LYP functional and 6-
31G* basis set. The CD spectra were calculated by using time-
dependent DFT[20] with B3LYP (or CAMPB3LYP) functional and
DZVP (or 6-31++G*) basis set. Both the length gauge formulation
with London orbitals and velocity gauge formulation were used,
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Supporting Information (see footnote on the first page of this arti-
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sentation of vectors for (P)-6 and molecular orbitals for (P)-8.
Eur. J. Org. Chem. 2008, 3069–3078
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3077

B. Kuberski, M. Pecul, A. Szumna
FULL PAPER
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