Effect of substituents on the molecular shapes of π-basic macrotricyclic receptors

Article abstract of DOI:10.1002/ejoc.200901398

Molecular recognition between receptor and substrate is optimized when these compounds show complementary shapes, sizes, and interacting moieties. A family of C_3v-symmetric macrotricycles 1-4 is presented that incorporate resorcinol- and mesity

Full text of DOI:10.1002/ejoc.200901398

FULL PAPER
DOI: 10.1002/ejoc.200901398
Effect of Substituents on the Molecular Shapes of π-Basic Macrotricyclic
Receptors
Anne Lélias-Vanderperre,[a] Emmanuel Aubert,[b] Jean-Claude Chambron,*[a] and
Enrique Espinosa*[b]
Keywords: Cyclophanes / Receptors / Conformation analysis / Steric hindrance / Substituent effects
Molecular recognition between receptor and substrate is op-
timized when these compounds show complementary
shapes, sizes, and interacting moieties. A family of C3v-sym-
the “walls” and the “cap” on the shapes of the macrotricy-
cles in solution (1H NMR), the solid state (X-ray diffraction),
and gas phase (calculations). Substitution of the lower posi-
metric macrotricycles 1–4 is presented that incorporate resor- tion of the “walls” by Br (in 3) or MeS (in 4) has the same
cinol- and mesitylene-derived “walls” and “cap”, respec-
tively. These compounds feature, in principle, a tetrahedral
π-basic cavity. This paper reports the effect of substituents in
effect as ethyl substitution of the “cap” (in 2), that is, im-
parting high rigidity to the molecules and deforming their
expected spherical shape to a cylindrical one.
feature π-electron-rich tetrahedral cavities and were shown
Introduction
+
(ESI-MS) to complex NH4 selectively over alkali metal
The specificity and selectivity of molecular recognition
events between receptor and substrate are optimized when
these compounds are complementary in terms of shape,
size, and interacting moieties.[1–3] These observations have
ultimately led to the concept of preorganization between
host and guest, which was originally illustrated by the
spherands of Cram.[4] These alkali-metal-cation receptors
are rigid analogues of Pedersen’s crown ethers and Lehn’s
cryptands.[1,2] They owe this property to the fact that they
are made only from aromatic subunits that are directly con-
nected to each other. The design of receptors that are preor-
ganized for optimum substrate recognition has been a chal-
lenge since then. For example, genuine calixarenes, which
can be considered as deriving from spherands by the incor-
poration of methylene connectors between the aryl sub-
units, are flexible molecules that exist in several conforma-
tions.[5] The problem of fixing either one has been solved
by intramolecular bridging or by substituting the phenolic
oxygen atoms with appropriate groups (e.g., nPr).[6]
+
cations and the bulky primary ammonium tBuNH3 in the
gas phase, presumably through cation–π interactions. This
report introduces analogues of macrotricycle 1 that carry a
substituent at the C-h position of the resorcinol subunits
(Br for 3, CH3S for 4, Figure 1). Macrotricycle 4 combines
a cavity and a tripod thioether chelate.[9] It was designed
for the CuI-directed encapsulation[10] of ethylene in order to
model the biological receptor of this natural hormone in
analogy with previous work involving the [9]aneS3 macro-
cycle.[11] Macrotricycle 3 was considered a direct precursor
of 4. The synthetic aspects are first presented followed by a
study of the effect of substituents on either the “cap” (Et
for 2) or the “walls” (Br and CH3S for 3 and 4, respectively)
on the shapes of these molecules in solution (1H NMR), in
the solid state (X-ray crystallography), and in the gas phase
(calculations). Finally, the implications of the structural dif-
ferences are discussed with regard to the preorganization of
receptors 1 and 2 for gas-phase π-complexation properties
studied in a previous investigation.[7]
We recently reported the synthesis and properties of
macrotricyclic molecules 1 and 2[7] incorporating resorcin-
ol- and mesitylene-derived “walls” and “cap”, respectively
(Figure 1), and complementing molecular cages derived
from hexahomotrioxacalix[3]arene.[8] These compounds
[a] ICMUB (UMR no. 5260 of the CNRS), Université de Bour-
gogne,
9, avenue Alain Savary, BP 47870, 21078 Dijon, France
Fax: +33-3-80396117
E-mail: Jean-Claude.Chambron@u-bourgogne.fr
[b] CRM2 (UMR no. 7036 of the CNRS), Nancy Université,
Boulevard des Aiguillettes, BP 239, 54506 Vandœuvre-lès-
Nancy, France
Figure 1. Chemical structures of macrotricycles 1–4. Atom labels
are shown in grey.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901398.
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FULL PAPER
Results and Discussion
The macrotricycles 1–4 used in this study were obtained
by intramolecular cyclization of tripod precursors (a rela-
tively common strategy for the synthesis of basket-shaped,
C3v-symmetric macrotricycles[12]) bearing pendant resor-
cinol functionalities that are connected by formaldehyde
acetal bridges in analogy with the formation of cavitands
from resorcinarenes.[13] The synthesis of macrotricycles 1
and 2 has been reported previously.[7] The synthesis of the
tripod precursors 5 and 6 of the macrotricycles 3 and 4,
respectively, started with functional-group transformations
of the resorcinol derivatives 7 and 10 (Scheme 1 and
Scheme 2). Accordingly, methyl 4-bromo-3,5-dihydroxyben-
zoate (7) was treated with MOMCl in the presence of
HünigЈs base (iPr2NEt) to afford ester 8 in 85% yield. The
latter was subsequently reduced to 4-bromobenzyl alcohol
9 by DIBAL-H in 96% yield.[14] The corresponding 4-meth-
Scheme 3. Syntheses of benzyl thiols 15 and 16. Reagents and con-
ditions: a) AcSH, DIAD, PPh3, 49% for 13, 70% for 14; b) K2CO3/
CH3OH, 92% for 15; LiAlH4/THF, 96% for 16.
MOM protecting groups (aqueous HCl) induces cleavage
of the benzylic thioether bridges and thus non-hydrolytic
conditions were examined.[16] Accordingly, tripods 18, 19
were treated with p-toluenesulfonic acid in CH2Cl2/
CH3OH, which produced the target tripods 5, 6 in 87 and
100% yield, respectively.
ylthio derivative was prepared by
a different route
(Scheme 2). Ortho-lithiation of 10[15] by nBuLi in the pres-
ence of TMEDA followed by quenching with elemental sul-
fur and in situ reaction of the resulting thiophenolate with
CH3I afforded methyl thioether 11 in 66% yield. The TBS
protection was cleaved by reaction of 11 with TBAF and 4-
methylthiobenzyl alcohol 12 was obtained in 99% yield.
The benzyl thiol analogues 15 and 16 of the benzyl alcohols
9 and 12, respectively, were prepared in two steps from the
latter compounds (Scheme 3). First, 9 (resp. 12) was treated
with AcSH under Mitsunobu conditions (DIAD, PPh3,
0 °C) to produce thioacetate derivatives 13 (resp. 14) in 49%
(resp. 70%) yield. Methanolysis (K2CO3, CH3OH) of 13
and reduction (LiAlH4) of 14 followed by quenching of the
reaction mixture with dilute aqueous HCl afforded benzyl
thiols 15 (92%) and 16 (96%), respectively.
Scheme 4. Preparation of tripods 5 and 6. Reagents and conditions:
a) NaH, THF, 79% for 18, 100% for 19; b) pTsOH, CH2Cl2/
CH3OH, 87% for 5, 100% for 6.
Macrotricycles 3 and 4 were prepared by three-fold ring-
closure condensation reaction of tripods 5 and 6, respec-
tively, with dibromomethane in the presence of Cs2CO3 as
base in high dilution conditions (9ϫ10–4  in DMF at
60 °C), as shown in Scheme 5. They were obtained in 4.8
and 6% yields, respectively, which is very much lower than
the 18% yield of 1 obtained under the same reaction condi-
tions.[7] This indicates that the cyclization reactions are
hampered by the presence of the bulky Br (for 3) and CH3S
(for 4) substituents. In support of this assertion, the inter-
mediate macrobicyclic product of two-fold ring closure (4a)
was isolated in trace amounts in the course of the chroma-
tographic purification of macrotricycle 4. As a result of the
poor yields obtained from the macrotricyclization reactions,
the direct preparation of 4 from 3 was not attempted.
The first evidence that the polycyclic structures 3, 4a, and
Scheme 1. Synthesis of benzyl alcohol 9. Reagents and conditions:
a) MOMCl, iPrNEt, THF, 85%; b) DIBAL-H, THF/CH2Cl2, 96%.
Scheme 2. Synthesis of benzyl alcohol 12. Reagents and conditions:
a) i. nBuLi, TMEDA; ii. S8; iii. CH3I, 66%; b) (nBu4N)F, THF,
99%.
Tripods 5 and 6 were synthesized in two steps from ben-
zyl thiols 15 and 16, respectively (Scheme 4). Deprotonation 4 had indeed been formed was provided by electrospray
of 15 and 16 with NaH followed by a triple condensation mass spectrometry. In all three cases the signal correspond-
reaction with 1,3,5-tris(bromomethyl)benzene (17) afforded ing to the sodium adduct of the species investigated was
the MOM-protected tripods 18 and 19 in 79 and 100% observed and the corresponding isotope peak cluster was in
yields, respectively. Standard conditions for cleavage of the agreement with the calculated one (Figures S15–S17 of the
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Molecular Shapes of π-Basic Macrotricyclic Receptors
2. The largest energy differences are obtained for com-
pounds 3 and 4 in spite of short S···S (3.47 and 3.38 Å,
respectively) and Br···Br (3.55 and 3.54 Å, respectively) in-
teratomic contacts in the collapsed form (Figures S21 and
S22). As shown in Figure 3, the most stable optimized
structures (elongated forms) of macrotricycles 3 and 4 are
very similar to that of 2 even though their substituents are
in positions that differ from those of the latter macrotricy-
cle.
Scheme 5. Preparation of macrotricycles 3 and 4. Reagents and
conditions: a) CH2Br2, Cs2CO3, DMF, 60 °C, 4.8% for 3, 6% for
4. In the case of the latter, the intermediate macrobicycle 4a was
isolated in minor amounts by chromatography.
Supporting Information). That the sodium rather than the
proton adduct was observed is not surprising in the light of
previous studies involving macrotricycles 1 and 2.
An ORTEP view of the X-ray crystal structure of macro-
tricycle 1 is shown in Figure 2 together with the already
known one of macrotricycle 2.[7] Unlike 2, which shows a
well-defined but elongated (cylindrical) cavity in the solid
state, 1 has a collapsed structure because the mesitylene
“cap” has a weak interaction (ring-to-ring distance of
3.981 Å) with one of the resorcinol-derived aromatic
“walls”.
Figure 3. Representation (sticks) of the molecular structures opti-
mized at the DFT PBE1PBE 6-311G** level of theory (distances
between centroids or heteroatoms in Å) for the macrotricycles a)
1, b) 2, c) 3, and d) 4.
Table 1. Gas-phase calculated standard free energy differences (∆G0
= ∆G0
– ∆G0coll.) between the elongated and collapsed forms
elong.
of macrotricyles 1–4.
Macrotricycle
1
2
3
4
∆G0 [kJmol–1]
20.09
–33.44
–51.93
–56.41
The solution structures of macrotricycles 1–4 were eluci-
1
dated by H NMR spectroscopy. The spectra were fully as-
Figure 2. Comparison of the X-ray crystal structures of macrotricy-
cles (a) 1 and (b) 2.[7] Hydrogen atoms have been omitted for clarity.
Thermal ellipsoids are drawn at the 50% probability level.
1
1
signed through 2D H/13C HSQC and HMBC, and H/1H
NOESY experiments (Figures S1–S7 of the Supporting In-
formation). The chemical shifts of the protons relevant to
Gas-phase DFT calculations were performed at the this study are collected in Table 2. Careful examination of
PBE1PBE 6-311G** level of theory using the X-ray molec- the data shows that the protons of macrotricycles 3 and 4
ular structures of 1 and 2 as the starting points. All four and, to a lesser extent, of macrotricycle 2 have similar
compounds 1–4 showed stable collapsed and elongated con- chemical shifts, which suggests that the conformations of
formations (Figures S19–S22 and Figure 3) with large en- these molecules are similar and are controlled by the bulky
ergy differences between them (Table 1). Macrotricycle 1 is substituent on the C-h atoms, that is, Br (for 3) and CH3S
more stable in the collapsed conformation, which is in (for 4), or the ethyl substitution of C-a for 2. In contrast,
1
agreement with the experimental solid-state structure. In the H NMR spectrum of macrotricycle 1, which lacks any
contrast, macrotricycles 2–4 are significantly more stable in substituent at these positions, is significantly different to
the elongated form, as is also observed in the solid state for those of 2–4, the most striking features being the relatively
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A. Lélias-Vanderperre, E. Aubert, J.-C. Chambron, E. Espinosa
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high-field shift of the signal of proton a-H in the former, the molecule has a cylindrical rather than a spherical shape.
1
and the inversion of the relative values of the chemical shifts On the basis of the H NMR spectroscopic data, it is likely
of protons c-H and d-H (Table 2).
that macrotricycles 3 and 4 adopt similar structures.
Another stereochemical feature of the macrotricycles in
solution is the conformation of the formaldehyde acetal
bridges. Careful examination of Figure 3 shows three types
of orientations for protons i-H and j-H in the gas phase:
Axial-up j-H and equatorial i-H, axial-down i-H and equa-
torial j-H (Figure 3, a), and both i-H and j-H pointing
down towards the inside (inside-down) and the outside
(outside-down) of the macrotricycle, respectively (Figure 3,
b–d). The latter could explain the relative shielding of i-
H in comparison with j-H. All four macrotricycles show a
correlation between j-H and f-H in the 1H/1H NOESY
NMR spectra, which results from axial-up j-H. In addition,
the spectra of 1 and 2 show a correlation between i-H and
h-H due to axial-down or inside-down i-H, which of course
is lacking in the case of 3. In the case of 4, the correlation
i-H/CH3S is observed, which is presumably due to equato-
rial i-H, as outside-down j-H and inside-down i-H should
both interact with CH3S. Protons i-H and j-H form a dia-
stereotopic pair at room temperature. Variable-temperature
1H NMR experiments on macrotricycles 1 and 3 up to
408 K in C2D2Cl4 did not show any coalescence phenom-
ena, which indicates that the macrotricycles do not invert
on the NMR timescale (Figures S11 and S12 of the Sup-
porting Information). In addition, most of the protons, in
particular a-H and c-H of the mesitylene “cap” of 1, show
downfield shifts upon increasing the temperature from 298
to 408 K (Table 3).
1
Table 2. H NMR chemical shifts for macrotricycles 1–4.
Compd. δ [ppm]
a
c
d
f
h
i
j
1[a,b]
2[a,b]
3[c]
6.47
–
7.11
7.13
3.24
3.69
3.25
3.15
3.11
6.50
6.80
6.33
–
5.60
5.72
3.86
3.78
3.80
6.40
6.54
6.60
5.50
5.53
5.48
5.65
6.07
5.97
4[b]
–
[a] Data from ref.[7]. [b] Determined in CDCl3. [c] Determined in
CD2Cl2.
Examination of these data and of the NOE correlations
observed in compounds 1–4 (Figure 4) shows that the me-
sitylene “cap” has a different conformation in 1 in compari-
son with 2–4. In the case of the unsubstituted macrotricycle
1 it is squeezed by twisting towards the cage inside, hence
the shielding of the a-H and c-H protons by the resorcinol
“walls” and the NOE correlation c-H/f-H, which is absent
in the spectra of the macrotricycles 2–4. In the case of the
macrotricycles 3 and 4, a-H has a quasi-normal δ value for
an aromatic proton, whereas d-H is shielded relative to c-
H and a NOE correlation between a-H and d-H is ob-
served. This suggests that the mesitylene “cap” is fully un-
twisted, which places d-H in its shielding field. This confor-
mational difference is a result of the steric repulsion be-
tween the large substituents of C-h, Br in the case of 3,
CH3S in the case of 4. Therefore steric interactions at the
lower part of macrotricycles 3 and 4 are mechanically con-
veyed to the upper part of the molecules and translated
into an untwisting of the mesitylene “cap”. Macrotricycle 2
shows similar features to 3 and 4 (i.e., shielding of d-H,
deshielding of c-H, and an Et-H/d-H NOE correlation,
which parallels the a-H/d-H correlation seen in the latter
compounds). These observations indicate that the mesity-
lene “cap” is also untwisted in 2. In 2 this conformational
feature is not due to remote steric effects, but to the pres-
ence of the ethyl substituents. This is clearly apparent from
the X-ray crystal structure (Figure 2, b), which also shows
1
Table 3. Variations in the H NMR chemical shifts of macrotricy-
cles 1 and 3 upon temperature increase between 298 and 408 K[a]
and between 182 and 300 K.[b]
Compd. ∆δ [ppm]
a
c
d
f
h
i
j
1[a]
1[b]
3[a]
3[b]
0.14
0.14
0.02
0.01
0.06
0.02
–
0.06
0.04
0.08
0.01
0.02
–0.01
0.22
0.06
0.06
0.21
0.06
0.06
0.02
0.07
0.03
0.08
0.06
0.12
–
–0.03 –0.07
[a] Determined in C2D2Cl4 (298–408 K). [b] Determined in CD2Cl2
that, as a consequence of the stiffening of its upper part, (182–300 K).
Figure 4. NOE correlations observed in macrotricycles 1–4. Those conveying structural information are highlighted in black. The different
orientations adopted by protons i-H and j-H (from DFT optimizations, see Figure 3) are also shown. The arrow connecting i-H and R
concerns macrotricycle 4 (R = CH3S).
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Molecular Shapes of π-Basic Macrotricyclic Receptors
sieves before use. All commercially available products were reagent
grade and used without further purification. Flash column
chromatography was performed by using 35–70 mesh silica gel.
NMR spectra were recorded with Bruker Avance 300, 500, and
600 spectrometers with tetramethylsilane as the internal standard.
Melting points were determined with a Büchi Melting Point B-
545 apparatus. Elemental analyses were performed with an EA1108
CHNS Fisons Instrument. ESI-TOF mass spectra were recorded
with a Bruker Micro TOF mass spectrometer.
Cooling CD2Cl2 solutions of macrotricycle 1 from 300 to
182 K produces broadening of the signals and a significant
upfield shift of a-H by –0.22 ppm and c-H by –0.21 ppm at
182 K (Figures S13 and S14 of the Supporting Infor-
mation). This indicates again that the dynamics of the me-
sitylene “cap” are affected more than other parts of the
molecule by temperature changes. In short, motion within
the macrocycle is only slowed by decreasing the tempera-
ture. In the case of 3, the signals are lower in intensity and
broaden strongly, and, as in the high-temperature regime
when the temperature is decreased, they undergo small up-
field shifts. Maximum broadening is observed at 200 K at
which coalescence takes place; below this temperature there
are two sets of signals, one corresponding to a major species
and the other corresponding to a very minor species. The
Methyl 4-Bromo-3,5-bis(methoxymethoxy)benzoate (8): MOMCl
(3.9 mL, 50.8 mmol) was slowly added to a solution of 7 (13.2 g,
76.2 mmol) and iPr2NEt (10.9 mL, 61.0 mmol) in THF (100 mL)
at 0 °C and the reaction mixture was stirred at room temperature.
An additional portion of MOMCl (0.8 mL, 10.2 mmol) was added
after 5.5 h. After stirring for 20 h at room temperature and then at
reflux, the reaction mixture was poured into water (50 mL). The
major subspectrum is very similar to the room-temperature aqueous layer was extracted twice with CH2Cl2. The organic layer
was then washed twice with water, then 1% aqueous HCl, and fi-
nally brine. It was dried with MgSO4 and concentrated. The crude
product was crystallized from hot EtOAc to afford yellow needles
of 8 (5.81 g, 85% yield), m.p. 138.5–141.7 °C. 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 3.53 (s, 6 H, CH3O), 3.89 (s, 3 H, CH3O), 5.29
(s, 4 H, CH2O), 7.48 (s, 2 H, CH) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 52.6 (CH3O), 56.7 (CH3OCH2), 95.2 (CH2O),
109.5 (CBr), 110.1 (CH), 130.5 (CO), 154.9 (CC=O), 166.3
(C=O) ppm. C12H15O6Br (335.15): calcd. C 43.00, H 4.51; found
C 42.79, H, 4.83.
spectrum, which indicates that the corresponding species
has a conformation that is very close to that of the starting
system (virtually no temperature-induced shifts). The minor
subspectrum, which corresponds to a highly unsymmetrical
conformation, is very different. Upon decreasing the tem-
perature further, the signals sharpen again, which confirms
the occurrence of dynamic phenomena.
Conclusions
[4-Bromo-3,5-bis(methoxymethoxy)phenyl]methanol (9): DIBAL-H
(22.4 mL, 22.4 mmol, 1  in hexane) was added dropwise to a solu-
tion of 8 (3.00 g, 8.95 mmol) in THF (30 mL) and CH2Cl2 (50 mL)
at 0 °C. After stirring for 2 h at room temperature, water (10 mL)
and then 10% aqueous NaOH (5 mL) were slowly added at 0 °C.
The precipitate was removed by filtration and washed with CH2Cl2
and EtOAc. The solution was concentrated to afford 9 as a color-
less solid (2.65 g, 96% yield), m.p. 57.4 °C. 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 3.51 (s, 6 H, CH3O), 4.64 (s, 2 H, CH2OH),
5.26 (s, 4 H, CH2O), 6.85 (s, 2 H, CH) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 56.6 (CH3O), 65.0 (CH2OH), 95.2 (CH2O),
102.7 (CBr), 107.8 (CH), 141.9 (CCH2), 155.1 (CO) ppm.
C11H15O5Br (307.14): calcd. C 43.02, H 4.92; found C 42.96, H
5.28.
This study has shown that the experimental structures of
macrotricycles 1 and 2 are very different in the solid state
as well as in solution. These observations have been con-
firmed by theoretical calculations at the PBE1PBE 6-
311G** level of theory. Macrotricycle 1, being highly flexi-
ble, has an average spherical tetrahedral shape, whereas
macrotricycle 2, being stiffened by persubstitution of the
mesitylene “cap”, takes up an elongated tetrahedral
shape.[17] In addition, as shown by 1H NMR studies, substi-
tution of the 2-position (C-h) of the resorcinol-derived sub-
units by relatively large heteroatom-bearing groups (Br in
3, CH3S in 4) has the same effect as persubstitution of the
mesitylene “cap”. Interestingly, in spite of important struc-
tural differences, macrotricycles 1 and 2 both show selective
3,5-Bis(methoxymethoxy)-4-methylthiobenzyl tert-Butyldimethylsi-
lyl Ether (11): A solution of n-BuLi (4.4 mL, 11.1 mmol, 2.5  in
hexane) was added to a mixture of 10 (2.71 g, 7.9 mmol) and
TMEDA (7.7 mL, 11.1 mmol) in THF (50 mL) at –40 °C. After
stirring for 9 h, sulfur (0.31 g, 9.5 mmol) followed by MeI (0.6 mL,
9.5 mmol) were added to the reaction mixture. Stirring was contin-
ued overnight at room temperature. Subsequent addition of water
(40 mL) was followed by extraction of the aqueous layer with
CH2Cl2 (twice). The organic layer was then washed twice with
water and brine, dried with MgSO4, and concentrated. The residue
was purified by flash column chromatography (SiO2, CH2Cl2/n-
heptane, 90:10 to 98:2) to afford 11 as a colorless oil (2.02 g, 66%
yield). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 0.09 (s, 6 H,
SiCH3), 0.94 (s, 9 H, CCH3), 3.51 (s, 6 H, CH3O), 4.67 (s, 3 H,
CH3S), 4.67 (s, 2 H, CH2OSi), 5.24 (s, 4 H, CH2O), 6.84 (s, 2 H,
CH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = –5.2 (CH3Si),
18.3 (CH3S), 18.5 (CCH3), 26.0 (CCH3), 56.4 (CH3O), 64.7
(CH2OSi), 95.2 (CH2O), 106.7 (CH), 113.1 (CS), 143.8 (CCH2),
+
affinity for NH4 over K+ in the gas phase (ESI-MS).[7]
+
This suggests either that NH4 forms NH+···π interactions
only with the more electron-rich resorcinol-derived aro-
+
matic walls or that the energy of interaction of NH4 with
macrotricycle 2 is large enough to change the structure of
the latter to a spherical conformation.
Experimental Section
General: Macrotricycles 1 and 2 were obtained from a previous
study.[7] 3,5-Bis(methoxymethoxy)benzyl tert-butyldimethylsilyl
ether (10)[15] and 1,3,5-tris(bromomethyl)benzene (17)[18] were syn-
thesized according to procedures reported in the literature. All reac-
tions were performed under dinitrogen using standard Schlenk
techniques unless otherwise stated. THF, CH2Cl2, and TMEDA
were distilled from Na/benzophenone, CaH2, and Na, respectively.
DMF was purified by filtration through standardized aluminium
oxide 90. They were stored under dinitrogen over 4 Å molecular
158.5 (CO) ppm. 29Si NMR (99 MHz, CDCl3, 25 °C):
δ =
21.20 ppm. C18H32O5SSi (388.60): calcd. C 55.64, H 8.30; found C
55.43, H 8.42.
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FULL PAPER
[3,5-Bis(methoxymethoxy)-4-methylthiophenyl]methanol
(12): Then 5% aqueous HCl (4.3 mL) was carefully added to the reac-
TBAF (9.02 mL, 9.02 mmol, 1  in THF) was added to a solution
of 11 (1.75 g, 4.51 mmol) in THF (20 mL) at 0 °C and the reaction
mixture was stirred for 5 h. It was subsequently quenched by ad-
dition of a saturated solution of aqueous NH4Cl (9 mL). The aque-
ous layer was extracted with ethyl acetate. The organic layer was
washed twice with water and brine, dried with MgSO4, and concen-
trated. The residue was purified by flash column chromatography
(SiO2, CH2Cl2/CH3OH, 96:4) to give 12 as a colorless oil (1.23 g,
tion mixture at 0 °C. The aqueous layer was extracted twice with
ethyl acetate and CH2Cl2. The organic layer was then washed twice
with water and brine, dried with MgSO4, concentrated, and dried
to afford 16 as an oil (0.81 g, 96% yield). 1H NMR (300 MHz,
3
CDCl3, 25 °C): δ = 1.80 (t, JH,H = 7.8 Hz, 1 H, SH), 2.39 (s, 3 H,
3
CH3S), 3.53 (s, 6 H, CH3O), 3.68 (d, JH,H = 7.8 Hz, 2 H, CH2S),
5.27 (s, 4 H, CH2O), 6.82 (s, 2 H, CH) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 18.2 (CH3S), 29.4 (CH2S), 56.6 (CH3O), 95.2
(CH2O), 108.9 (CH), 113.8 (CS), 143.0 (CCH2), 158.6 (CO) ppm.
C12H18O4S2·0.25C4H8O2 (312.43): calcd. C 49.97, H 6.45, S 20.53;
1
99% yield). H NMR (300 MHz, CDCl3, 25 °C): δ = 2.39 (s, 3 H,
CH3S), 3.52 (s, 6 H, CH3O), 4.65 (s, 2 H, CH2OH), 5.27 (s, 4 H,
CH2O), 6.86 (s, 2 H, CH) ppm. 13C NMR (75 MHz, CDCl3, found C 50.24, H 6.41, S 21.16.
25 °C): δ = 18.2 (CH3S), 56.5 (CH3O), 65.2 (CH2OH), 95.2
(CH2O), 107.4 (CH), 114.1 (CS), 142.9 (CCH2), 158.7 (CO) ppm.
Tripod 18: A solution of 17 (0.29 g, 0.82 mmol) in THF (15 mL)
was added portionwise to a mixture of NaH (60% in oil, 0.10 g,
2.55 mmol) and 15 (0.82 g, 2.54 mmol) in THF (20 mL) at 0 °C.
The reaction mixture was stirred for 2 h at room temperature. A
saturated aqueous solution of NH4Cl was added at 0 °C until pH 6.
The aqueous layer was extracted with EtOAc. The organic layer
was washed twice with brine, dried with MgSO4, and concentrated.
The residue was purified by column chromatography (SiO2, n-hep-
tane/EtOAc, 68:32) to give 18 as a colorless oil (0.70 g, 79% yield).
1H NMR (500 MHz, [D6]acetone): δ = 3.43 (s, 18 H, CH3), 3.56
(s, 6 H, d-H), 3.63 (s, 6 H, c-H), 5.23 (s, 12 H, CH2O), 6.82 (s, 6
H, f-H), 7.13 (s, 3 H, a-H) ppm. 13C NMR (75 MHz, [D6]acetone):
δ = 35.8 (C-c), 36.1 (C-d), 56.6 (CH3O), 95.8 (CH2O), 102.3 (C-h),
110.7 (C-f), 129.3 (C-a), 139.8 (C-b), 140.5 (C-e), 155.7 (C-g) ppm.
C42H51O12Br3S3 (1083.75): calcd. C 46.55, H 4.74, S 8.87; found C
46.26, H 4.99, S 8.88.
C12H18O5S (274.33): calcd. C 52.53, H 6.61; found C 52.76, H 6.98.
4-Bromo-3,5-bis(methoxymethoxy)benzyl Thioacetate (13): A mix-
ture of thioacetic acid (0.95 mL, 13.02 mmol) and 9 (2.0 g,
6.51 mmol) in THF (20 mL) was added slowly to a mixture of
DIAD (1.72 mL, 8.14 mmol) and triphenylphosphane (2.16 g,
8.14 mmol) in THF (30 mL) at 0 °C. After stirring overnight at
room temperature, the solvent was removed in vacuo. The residue
was purified by repeated column chromatography on silica eluting
with EtOAc/n-heptane (88:12) to afford 13 as a colorless oil (1.17 g,
1
49% yield). H NMR (500 MHz, CDCl3, 25 °C): δ = 2.35 (s, 3 H,
COCH3), 3.52 (s, 6 H, CH3O), 4.04 (s, 2 H, CH2S), 5.22 (s, 4 H,
CH2O), 6.77 (s, 2 H, CH) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 30.5 (CH3C=O), 33.7 (CH2S), 56.7 (CH3O), 95.3
(CH2O), 102.8 (CBr), 110.2 (CH), 138.5 (CCH2), 155.0 (CO), 195.0
(C=O) ppm. C13H17O5BrS (365.25): calcd. C 42.75, H 4.69, S 8.78;
found C 42.92, H 4.82, S 8.69.
Tripod 19: Synthesized following the procedure used for 18 from
16 (0.61 g, 2.10 mmol), NaH (60% in oil, 85 mg, 2.13 mmol), and
17 (0.25 g, 0.69 mmol) in THF (50 mL). Tripod 19 was obtained in
100% yield (0.77 g) as colorless needles after purification by
crystallization from CH2Cl2/Et2O (6:4), m.p. 62.2–64.2 °C. 1H
NMR (300 MHz, CD2Cl2, 25 °C): δ = 2.35 (s, 9 H, CH3S), 3.48 (s,
18 H, CH3O), 3.53 (s, 6 H, d-H), 3.61 (s, 6 H, c-H), 5.21 (s, 12 H,
CH2O), 6.75 (s, 6 H, f-H), 7.14 (s, 3 H, a-H) ppm. 13C NMR
(75 MHz, CD2Cl2, 25 °C): δ = 18.1 (CH3S), 35.9 (C-c), 36.2 (C-d),
56.6 (CH3O), 95.5 (CH2O), 110.0 (C-f), 114.3 (C-h), 128.8 (C-a),
139.2 (C-b), 140.3 (C-e), 158.7 (C-g) ppm. C45H60O12S6 (985.36):
calcd. C 54.85, H 6.14, S 19.53; found C 55.17, H 6.39, S 19.68.
3,5-Bis(methoxymethoxy)-4-methylthiobenzyl Thioacetate (14): Syn-
thesized following the procedure used for 13 from 12 (1.15 g,
4.17 mmol), thioacetic acid (0.61 mL, 8.35 mmol), DIAD
(1.01 mL, 3.05 mmol), and triphenylphosphane (1.27 g, 4.80 mmol)
in THF (40 mL). Thioacetate 14 was obtained in 70% yield (0.97 g)
as a yellow oil after purification by flash column chromatography
(SiO2, CH2Cl2/n-heptane, 90:10 followed by n-heptane/ethyl acet-
1
ate, 75:25). H NMR (300 MHz, CDCl3, 25 °C): δ = 2.35 (s, 3 H,
COCH3), 2.37 (s, 3 H, CH3S), 3.52 (s, 6 H, CH3O), 4.06 (s, 2 H,
CH2S), 5.24 (s, 4 H, CH2O), 6.77 (s, 2 H, CH) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 18.1 (CH3S), 30.5 (CH3C=O), 33.8
(CH2S), 56.6 (CH3O), 95.3 (CH2O), 109.7 (CH), 114.2 (CS), 139.3
(CCH2), 158.6 (CO), 195.0 (C=O) ppm. C14H20O5S2 (332.44):
calcd. C 50.58, H 6.06, S 19.29; found C 50.61, H 6.18, S 19.92.
Tripod 5: A mixture of 4-toluenesulfonic acid (3.03 g, 15.04 mmol)
and 18 (0.68 g, 0.63 mmol) in MeOH (15 mL) and CH2Cl2 (15 mL)
was stirred overnight at 25 °C. An aqueous solution of NaHCO3
was added subsequently until pH 6. The aqueous layer was ex-
tracted twice with EtOAc. The organic layer was then washed twice
with brine, dried with MgSO4, and concentrated to give 5 as a foam
[4-Bromo-3,5-bis(methoxymethoxy)phenyl]methanethiol
(15):
K2CO3 (1.33 g, 9.64 mmol) was added portionwise to a solution of
13 (1.17 g, 3.21 mmol) in methanol (15 mL). After stirring over-
night at room temperature, 1% aqueous HCl (70 mL, 19.3 mmol)
was added dropwise at 0 °C. The aqueous layer was extracted twice
with ethyl acetate and CH2Cl2. The organic layer was washed twice
with brine, dried with MgSO4, and concentrated to give 15 as an
oil (0.96 g, 92% yield). 1H NMR (500 MHz, CDCl3, 25 °C): δ =
1.79 (t, 3JH,H = 8 Hz, 1 H, SH), 3.52 (s, 6 H, CH3O), 3.67 (d, 3JH,H
= 8 Hz, 2 H, CH2S), 5.25 (s, 4 H, CH2O), 6.82 (s, 2 H, CH) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 29.2 (CH2S), 56.6 (CH3O),
95.3 (CH2O), 102.6 (CBr), 109.4 (CH), 142.1 (CCH2), 155.1
(CO) ppm. C11H15O4BrS·0.25C4H8O2 (345.23): calcd. C 41.75, H
4.96, S 9.29; found C 42.08, H 4.84, S 9.64.
1
(0.45 g, 87% yield). H NMR (500 MHz, [D6]acetone): δ = 3.52 (s,
6 H, d-H), 3.61 (s, 6 H, c-H), 6.53 (s, 6 H, f-H), 7.11 (s, 3 H, a-H),
8.56 (br. s, 6 H, OH) ppm. 13C NMR (75 MHz, [D6]acetone): δ =
36.0 (C-c), 36.1 (C-d), 103.7 (C-h), 108.8 (C-f), 129.1 (C-a), 139.7
(C-b), 140.1 (C-e), 155.9 (C-g) ppm. C30H27O6Br3S3·C4H8O2
(781.53): calcd. C 45.00, H 3.89, S 10.60; found C 45.54, H 4.14, S
10.89.
Tripod 6: Synthesized following the procedure used for 5 from 19
(0.18 g, 0.18 mmol) and 4-toluenesulfonic acid (0.84 g, 4.39 mmol).
Tripod 6 was obtained as a foam (0.15 g, 100% yield), m.p. 37 °C.
1H NMR (300 MHz, [D6]acetone): δ = 2.23 (s, 9 H, CH3S), 3.54
[4-Methylthio-3,5-bis(methoxymethoxy)phenyl]methanethiol (16): A (s, 6 H, d-H), 3.67 (s, 6 H, c-H), 6.48 (s, 6 H, f-H), 7.14 (s, 3 H, a-
solution of 14 (0.97 g, 2.91 mmol) in THF (20 mL) was added
dropwise to a suspension of LiAlH4 (0.23 g, 5.82 mmol) in THF
(40 mL) at 0 °C. The reaction mixture was stirred for 5 h at reflux.
H), 7.99 (br. s, 6 H, OH) ppm. 13C NMR (75 MHz, [D6]acetone):
δ = 18.1 (CH3S), 36.2 (C-c), 36.3 (C-d), 106.7 (C-h), 108.0 (C-f),
129.1 (C-a), 139.7 (C-b), 142.6 (C-e), 159.5 (C-g) ppm.
2706
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2701–2708

Molecular Shapes of π-Basic Macrotricyclic Receptors
C33H36O6S6·H2O (739.05): calcd. C 53.63, H 5.18; found C 53.59, gram.[21] Refinements were carried out by full-matrix least-squares
H 5.40.
on F2 using the SHELXL-97 program[22] and the complete set of
reflections. Anisotropic thermal parameters were used for non-hy-
drogen atoms. In the crystal structure determination, all hydrogen
atoms were located in the Fourier synthesis. They were placed at
calculated positions on their carrier atom X(-H) using the riding
model with an isotropic thermal factor fixed at Uiso(H) =
1.2Ueq(X). The structure was converged into the final statistical
agreement factors: R1 = 0.0413 and 0.0461 for IϾ2σ(I) and all
data, respectively. Further crystal data and structure refinement de-
tails are given in Table S1. Figure 2 was drawn using the ORTEP3
for Windows program.[23]
Macrotricycle 3: A solution of 5 (0.100 g, 0.122 mmol) and CH2Br2
(270 µL, 4.03 mmol) in DMF (50 mL) was added over 7.5 h to a
suspension of Cs2CO3 (0.26 g, 0.81 mmol) in DMF (150 mL) at
60 °C. After stirring overnight, the reaction mixture was concen-
trated under reduced pressure. The residue was taken up into
CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2.
The organic layer was then washed three times with water, dried
with MgSO4, and concentrated. The residue was purified by flash
column chromatography (Al2O3, CH2Cl2/n-heptane, 7:3 to 9:1, then
SiO2, n-heptane/EtOAc, 4:6) to afford 3 as a colorless powder
1
CCDC-754731 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(5 mg, 4.8% yield). H NMR (300 MHz, CD2Cl2, 25 °C): δ = 3.15
(s, 6 H, d-H), 3.78 (s, 6 H, c-H), 5.53 (d, JH,H = 7.7 Hz, 3 H, i-
H), 6.07 (d, JH,H = 7.7 Hz, 3 H, j-H), 6.54 (s, 6 H, f-H), 7.11 (s, 3
2
2
H, a-H) ppm. 13C NMR (151 MHz, CD2Cl2, 25 °C): δ = 33.9 (C-
d), 36.1 (C-c), 92.9 (CH2O), 105.8 (C-h), 112.7 (C-f), 129.5 (C-
a), 136.7 (C-e), 138.4 (C-b), 154.7 (C-g) ppm. HRMS: calcd. for
C33H27Br3NaO6S3 874.84121; found 874.84550.
Calculations: All calculations were performed in the gas phase with
the Gaussian03 program package[24] using density functional
theory (DFT) with the hybrid exchange-correlation PBE1PBE
functional.[25] The molecular structures of 1–4 were optimized
using the 6-311G** basis set for all elements except bromine for
which the LANL08d[26] effective core potential and basis set were
used.
Macrotricycle 4 and Macrobicycle 4a: A mixture of 6 (0.14 g,
0.19 mmol) and CH2Br2 (45.5 µL, 0.64 mmol) in DMF (50 mL)
was added over a period of 9 h to a suspension of Cs2CO3 (0.76 g,
2.33 mmol) in DMF (150 mL) at 60 °C. After stirring for 3 d at
60 °C, the solvent was removed under reduced pressure. The crude
product was taken up in CH2Cl2 and EtOAc and then filtered
through Celite. The Celite cake was washed with CH2Cl2. The fil-
trate was concentrated and purified by flash column chromatog-
raphy (SiO2, CH2Cl2) to afford 4 as a colorless powder (8 mg, 6%
yield). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 2.27 (s, 9 H, CH3S),
Experimental X-ray structures are only known for 1 and 2, which
display collapsed and elongated shapes, respectively. These molecu-
lar structures were used as the starting points for the theoretical
gas-phase structural optimizations. As shown in Figure S18, the
optimized molecular structures are very similar to the experimental
ones. To study the preference of these compounds for a given con-
formation (either elongated or collapsed), hypothetical 1-elongated
and 2-collapsed forms were created from the experimental struc-
tures using appropriate substitutions and then optimized in the gas
phase. For compounds 3 and 4, no crystal of suitable quality for
X-ray experiment could be obtained. Thus, initially collapsed and
elongated forms were created for both compounds from the experi-
mental structures of 1 and 2 by using appropriate substitutions and
then optimized (Figures S21 and S22).
2
3.11 (s, 6 H, d-H), 3.80 (s, 6 H, c-H), 5.48 (d, JH,H = 7.8 Hz, 3 H,
i-H), 5.97 (d, JH,H = 7.8 Hz, 3 H, j-H), 6.60 (s, 6 H, f-H), 7.13 (s,
2
3 H, a-H) ppm. 13C NMR (151 MHz, CDCl3, 25 °C): δ = 18.5
(CH3S), 34.5 (C-d), 36.4 (C-c), 96.5 (CH2O), 115.7 (C-f), 118.0 (C-
h), 129.7 (C-a), 137.1 (C-e), 138.5 (C-b), 159.2 (C-g) ppm. HRMS:
calcd. for C36H36NaO6S6 779.07383; found 779.07588.
4a: 1H NMR (500 MHz, CDCl3, 25 °C): δ = 2.06 (s, 3 H, CH3SЈЈ),
2.34 (s, 6 H, CH3S), 3.40 (AB, JAB = 14.0, ∆ν = 90 Hz, 4 H, d,dЈ-
H), 3.43 (AB, JAB = 14.5, ∆ν = 28 Hz, 4 H, c,cЈ-H), 3.77 (s, 2 H,
cЈЈ-H), 3.79 (s, 2 H, dЈЈ-H), 5.60 (d, JH,H = 5.8 Hz, 2 H, i-H or j-
H), 5.69 (d, JH,H = 5.8 Hz, 2 H, i-H or j-H), 6.10 (d, JH,H
0.9 Hz, 2 H, f-H), 6.51 (s, 2 H, a-H), 6.77 (d, JH,H = 0.9 Hz, 2 H,
fЈ-H), 6.97 (s, 2 H, OH), 7.02 (s, 2 H, fЈЈ-H), 7.19 (s, 1 H, aЈЈ-
H) ppm (see the Supporting Information for the atom numbering).
HRMS: calcd. for C35H36NaO6S6 767.07283; found 767.07713.
To check that all the calculated structures corresponded to true
energy minima and also to compute zero-point energy corrections,
frequency calculations were finally performed at the same level of
theory on each optimized cage.
2
2
4
=
4
Supporting Information (see also the footnote on the first page of
this article): 1H/1H NOESY NMR spectra of macrotricycles 1 and
1
4 and macrobicycle 4a, H/13C HSQC and HMBC NMR spectra
of macrotricycles 1 and 4, 13C NMR spectra of tripod 6 and macro-
X-ray Diffraction: Single crystals of 1 were grown by slow evapora-
tion of a CH2Cl2 solution. Compound 1 crystallizes in the triclinic
system (space group P1) with two molecules per unit cell (Z = 2).
1
tricycles 3 and 4, VT H NMR spectra of macrotricycles 1 and 3.
¯
ESI-HRMS of macrobicycle 4a and macrotricycles 3 and 4, details
of the calculations of the gas-phase structures of macrotricycles 1,
2, 3, and 4, and figures showing the calculated structures, table of
crystallographic data for macrotricycle 1.
Unit cell parameters at T = 100(2) K are a = 9.0838(11), b =
9.4446(13), c = 17.2029(19) Å, α = 101.302(6), β = 99.299(6), γ =
98.227(7)°. A colorless single-crystal specimen of prismatic shape
(0.2ϫ0.2ϫ0.2 mm3) was selected for the X-ray diffraction experi-
ment at T = 100(2) K. The X-ray source used was graphite-mono-
chromatized Mo-Kα radiation (λ = 0.71073 Å) from a sealed tube.
Data were collected with a Nonius–KappaCCD diffractometer
equipped with a nitrogen jet stream low-temperature system (Ox-
ford Cryosystems) and by using the COLLECT software.[19] Lattice
parameters were obtained by a least-squares fit to the optimized
setting angles of 6717 collected reflections in the full θ range data
collection 1.23ϽθϽ27.98°. Intensity data were recorded as φ and
ω scans with κ offsets. Data reduction was performed by using
DENZO software[20] and did not require absorption corrections.
Acknowledgments
The Centre National de la Recherche Scientifique (CNRS) and the
Conseil Régional de Bourgogne are acknowledged for a doctoral
fellowship (A. L.-V.). M.-J. Penouilh is thanked for ESI HRMS
measurements. E. Wenger and the “Plateforme de Mesures de Dif-
fraction X” of the CRM2 laboratory are acknowledged for sup-
porting the XRD experiment. The Institut Jean Barriol (Nancy
Université) and GENCI-CINES (Grant 2009-X2009085106) are
The structure was solved by direct methods using the SIR92 pro- thanked for providing access to computational facilities. We are
Eur. J. Org. Chem. 2010, 2701–2708
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2707

A. Lélias-Vanderperre, E. Aubert, J.-C. Chambron, E. Espinosa
FULL PAPER
[17] The shapes of the macrotricycles of this study refer to the poly-
hedron formed by the centers of the aromatic rings.
[18] a) W. P. Cochrane, P. L. Pauson, T. S. Sevens, J. Chem. Soc.
C 1968, 630–632; b) E. Díez-Barra, J. C. García-Martínez, S.
Merino, R. del Rey, J. Rodríguez-López, P. Sánchez-Verdú, J.
Tejeda, J. Org. Chem. 2001, 66, 5664–5670.
[19] B. Nonius, COLLECT, Data Collection Software, BV Nonius,
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[20] DENZO-SCALEPACK: Z. Otwinowski, W. Minor, Methods
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grateful to J. Ángyán for fruitful discussions and we thank F.
Hoffmann for help with the computational facility.
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Received: December 2, 2009
Published Online: April 7, 2010
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