Dimercuration of calix[4]arenes: Novel substitution pattern in calixarene chemistry

Article abstract of DOI:10.1021/ol403133b

A mercuration reaction of tetrapropoxycalix[4]arene immobilized in the cone conformation gave a mixture of two dimercurated products (meta,meta and meta,para) in approximately a 1:1 ratio. Both regioisomers represent inherently chiral compounds, which makes them very attractive for design of novel receptors. As demonstrated by Pd-catalyzed arylation, the different reactivity of HgCl functions in the meta,para-disubstituted isomer opens the door for regioselective introductions of two different functional groups to achieve a substitution pattern so far unknown in calixarene chemistry.

Full text of DOI:10.1021/ol403133b

Letter
pubs.acs.org/OrgLett
Dimercuration of Calix[4]arenes: Novel Substitution Pattern in
Calixarene Chemistry
Karolína Flídrova,† Stanislav Bohm,† Hana Dvorakova,‡ Vaclav Eigner,§,⊥ and Pavel Lhotak*,†
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†Department of Organic Chemistry, ‡Laboratory of NMR Spectroscopy, and §Department of Solid State Chemistry. Prague Institute
of Chemical Technology (PICT), Technicka 6, 166 28 Prague 6, Czech Republic
⊥Institute of Physics AS CR, v.v.i., Na Slovance 2, 182 21 Prague 8, Czech Republic
S
* Supporting Information
ABSTRACT: A mercuration reaction of tetrapropoxycalix[4]-
arene immobilized in the cone conformation gave a mixture of two
dimercurated products (meta,meta and meta,para) in approx-
imately a 1:1 ratio. Both regioisomers represent inherently chiral
compounds, which makes them very attractive for design of novel
receptors. As demonstrated by Pd-catalyzed arylation, the
different reactivity of HgCl functions in the meta,para-disubstituted isomer opens the door for regioselective introductions of
two different functional groups to achieve a substitution pattern so far unknown in calixarene chemistry.
lectrophilic substitution of classical calix[n]arenes1 repre-
trifluoroacetates cannot be purified on silica gel, the crude
Esents a straightforward way for the modification of reaction mixture was transformed into the chloromercurio
derivatives by reaction with brine. This transformation allowed
us to remove the unreacted starting compound 1 (4%) and
monoderivative 2 (10%) by column chromatography. Surpris-
ingly, the fraction containing dimercurated compounds consists
of only two main products, which were separated by repeated
chromatography and crystallization. As a result, compounds 3b
and 4b were isolated in 13% and 14% yields, respectively. Low
yields are caused by the affinity of the mercurated calixarenes to
sorbent during chromatographic separation. On the other hand,
the reaction is easily scalable up to a gram scale.
aromatic subunits (the so-called upper rim) of the parent
macrocyclic skeleton. All direct electrophilic substitutions of the
upper-rim-unsubstituted calixarenes known so far in calixarene
chemistry1,2 lead exclusively to the para-substituted (with
respect to phenolic function) products. These compounds are
then used as valuable intermediates in the design and
preparation of more sophisticated supramolecular systems.
Very recently, we described3 an unprecedented reaction of
classical calix[4]arene 1 with mercury(II) trifluoroacetate
leading exclusively to the meta-substituted organomercurial
product 2. This unexpected regioselectivity thus enables a
direct derivatization of calixarenes in this unusual position as
demonstrated by meta-arylation4 or by the formation of meta-
bridged calixarenes.5 As the meta-substituted6 calixarenes
represent inherently chiral compounds, these macrocyclic
systems are very attractive potential building blocks for the
construction of chiral receptors. In this paper we report on the
dimercuration reaction of calix[4]arene 1, which leads
regioselectively to a mixture of two isomers, 3 and 4. Although
organomercurial compounds are not very popular due to their
alleged toxicity, in this case they enable a direct way to
inherently chiral unique substitution pattern (meta,para)
inaccessible7 by other synthetic methods.
The regioselectivity of the dimercuration reaction was
studied using the cone conformer 1, which was reacted with 2
equiv of Hg(TFA)2 in CHCl3 at room temperature. As depicted
in Scheme 1, theoretically up to 10 different regioisomers A−J
could be obtained if we consider only monomercuration of
aromatic subsunits. It is known3 that monomercuration leads to
the meta-substituted compound 2, while the corresponding
para-isomer was never observed in the reaction mixture. This
excludes the formation of isomers I and J, which can be formed
only from a para-substituted intermediate. As the mercury
The assignment of structures is not a trivial task. Thus, the
1
splitting pattern and multiplicity of signals in the H NMR
spectrum of 3b (CDCl3) indicates a highly symmetrical
structure with both HgCl groups in the meta positions (A−
E). Two pairs of doublets at 4.70, 4.46, 3.22, and 3.03 ppm for
methylene bridges with typical geminal coupling constants (14
Hz), together with the signals of only two different propyl
groups, indicate the C2 symmetry of molecule corresponding to
structure B.
1
On the other hand, the H NMR spectrum of 4b exhibits
lower symmetry as demonstrated by four doublets for
equatorial C−H bonds. This excludes structures A, B, D, and
E and indicates that an unknown isomer possesses both meta
and para substitution. This assumption was further corrobo-
rated by 199Hg NMR spectra of both isomers (Figure 1). The
spectrum of 3b shows a doublet (J = 154 Hz) at −1029 ppm
(referenced to HgPh2, which was reported8 to have δ = −745
ppm toward HgMe2 as a standard). The spectrum of 4b shows
a similar doublet at −1031 ppm corresponding to the meta-
substitution) and a triplet at −1065 ppm (J = 188 Hz)
Received: October 31, 2013
Published: December 12, 2013
© 2013 American Chemical Society
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Organic Letters
Letter
Scheme 1. Dimercuration of Calix[4]arenes and
Theoretically Possible Regisomers (Asterisk Denotes
Inherent Chirality)
Figure 2. (a) X-ray structure of 3b showing the Hg···aromatic
interactions and (b) the same for isomer 4b. (c) Packing motif of 3b.
indicate that these interactions are much stronger if compared
with isomer 4b. An interesting motif can be found in crystal
packing of 3b where the intermolecular Hg···Cl interactions
(3.275 Å) lead to the formation of dimers (Figure 2c). This
kind of interaction is encountered also in 4b where the dimer is
formed via the intermolecular interactions between two -HgCl
groups in the meta positions (3.270 and 3.272 Å).
The formation of meta,para isomer G is rather unexpected as
we have never observed direct para-substitution during the
monomercuration of compound 1. To gain deeper insight into
the regioselectivity of dimercuration, we have carried out a
quantum-chemical calculation of the correspoding isomers A−
H. The combination of methods PBEPBE/LANL2DZ, which
was successfully applied in our previous paper,3 was used for
the evaluation of the thermodynamic stability of the
dimercuration products.
Calix[4]arene immobilized in the cone conformation is
known to exhibit so-called pinched cone-pinched cone equili-
brium.1 That is why we took into consideration two frontier
conformations with the Hg-substituted rings pointing outside
the cavity (“ring out”) or inside the cavity (“ring in”). As can be
seen from Table 1, the meta,para substitution in isomer G is
thermodynamically the most favored arrangement. This is in
good agreement with our experiments and indicates that
regioselectivity can be thermodynamically driven. On the other
hand, the energy of second isolated isomer B (11.26 kcal·
mol−1) is visibly higher than that of product A (8.11 kcal·
mol−1) and C (3.04 kcal·mol−1), which were never observed in
the reaction mixture.
In this context, a dimercuration reaction was carried out at
three different temperatures to evaluate the influence of
reaction temperature on the regioselectivity. Reaction carried
out at 0 and 30 °C gave the identical mixture of isomers 3b and
4b as the main products.9 The same reaction conditions at 60
°C led to a very small amount of dimercurated products, while
probably higher mercurated compounds were formed (as
deduced from their TLC behavior).
Figure 1. 199Hg NMR spectra of (a) 3b and (b) 4b (CDCl3, 298 K, 89
MHz, HgPh2 as standard).
indicating the para-substitution pattern. The above results
clearly showed for the isomers F, G, or H, nevertheless, the
final assignment of this structure was enabled only by a single
crystal X-ray analysis.
Compound 4b crystallizes in the space group P-1 with both
enantiomers in the asymmetric unit. The calixarene moiety
adopts the pinched cone conformation (Figure 2b) with
chloromercurio groups in meta and para positions on the
opposite phenolic rings (isomer G) oriented inside (the
interplanar angle ∼27.15°). The unsubstituted phenolic units
are oriented outside the cavity with interplanar angle ∼112.3°.
Chloromercurio group in the meta position shows intra-
molecular Hg···π interactions with two neighbor aromatic
carbons (η2 interaction). The Hg···C distances are 3.194 and
3.462 Å, respectively. Similar Hg···π interactions can be also
seen in the X-ray structure of 3b (Figure 2a). The
corresponding Hg···C distances 3.072, 3.314 Å (for one
aromatic moiety) and 3.038, 3.080 Å (for the second one)
To demonstrate the synthetic usefulness of dimercurio
derivatives, we have carried out an arylation reaction using
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Organic Letters
Letter
Table 1. Comparison of Total and Relative Energies of the
Corresponding Dimercurated Isomers A−H (X = -OC(
O)CF3)
a
b
c
structure
total energy
relative energy
A (Hg in)
−2987.0679636
−2987.0467116
−2987.0629571
−2987.0475791
−2987.0601964
−2987.0703280
−2987.0547837
−2987.0502192
−2987.0601779
−2987.0808945
−2987.0467544
−2987.0487432
−2987.0543193
8.11
21.45
11.26
20.91
3.04
A (Hg out)
B (Hg in)
Figure 3. X-ray structure of 6 showing the Hg···aromatic interactions.
B (Hg out)
C
D
E
extends the synthetic possibilities, offered by organomercurial
chemistry of calix[4]arene, as it enables the introduction of two
different functional groups into the meta and para positions. To
validate this assumption, we have carried out a one-pot double-
arylation procedure of 4b. The first arylation with 1 equiv of p-
tolyl iodide was accomplished under standard conditions, and
then another equivalent of p-nitrophenyl iodide was added to
the same flask without any isolation of intermediate. The
expected derivative 8 bearing two different aryl moieties was
isolated in 26% yield after column chromatography.
21.53
16.38
19.25
13.00
0.00
F (para Hg in)
F (para Hg out)
G (para Hg in)
G (para Hg out)
H (para Hg in)
H (para Hg out)
21.42
20.18
16.68
a
b
c
PBEPBE/LANL2DZ method. In au. In kcal·mol−1.
In conclusion, a highly regioselective dimercuration of the
calix[4]arene skeleton leads to two different products 3b and
4b with distal meta,meta and meta,para arrangement of
functional groups, respectively. Both compounds represent a
unique substitution pattern in calixarene chemistry so far
inaccessible by other synthetic methods. As demonstrated by
Pd-catalyzed arylation reactions, different reactivity of meta and
para mercury groups open the way for the synthesis of
completely novel type of inherently chiral calixarenes.
conditions4 developed for monoderivative 2. Thus, the reaction
of 3b/4b with 2 equiv of p-nitrophenyl iodide using a
Pd(OAc)2/PPh3/NaI catalytic system in acetone/THF mixture
gave smoothly the corresponding diarylated compounds 5 or 7
in approximately 50% yields (Scheme 2). Both products
represent completely novel substitution pattern in calixarene
chemistry.
Scheme 2. Arylation of Dimercurycalix[4]arenes 3b and 4b
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, full characterization of compounds,
and the X-ray structures of 3b, 4b, and 6. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lhotakp@vscht.cz.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Czech Science Foundation
(Grant P207/12/2027) and by grant Praemium Academiae of
the Academy of Sciences of the Czech Republic. Financial
support from Specific University Research (MSMT No. 20/
2013) is also highly acknowledged.
Interestingly, when reacted with only 1 equiv of p-
nitrophenyl iodide, isomer 4b yielded monosubstituted product
6 (40%), indicating the higher reactivity of the HgCl group in
the para position. The structure of this intermediate was
unambiguously confirmed by X-ray crystallography. As shown
in Figure 3, the calixarene moiety adopts the pinched cone
conformation with Hg···π interactions between the iodomer-
curio group in meta position and neighbor aromatic unit (η2
interaction). The corresponding Hg···C distances are 3.253 and
3.081 Å, respectively. The formation of compound 6 even
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