Acid-catalyzed hydrogen-deuterium exchange in β-pyrrolic positions of calix[4]pyrrole at room temperature

Article abstract of DOI:10.1016/j.tetlet.2016.06.015

Calix[4]pyrrole was found to be high deuterium incorporation and easy-to-make hydrogen-deuterium exchange in β-pyrrolic positions with the 98% sulphuric acid as catalyst in D₂O/CH₃CN–D₂O/CHCl₃–D₂O. Co

Full text of DOI:10.1016/j.tetlet.2016.06.015

Accepted Manuscript
Acid-catalyzed hydrogen-deuterium exchange in β-pyrrolic positions of cal-
ix[4]pyrrole at room temperature
Ying-Chun He, Ji-Gang Pan, Dian-Sheng Liu
PII:
S0040-4039(16)30675-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.015
TETL 47742
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
4 April 2016
3 June 2016
3 June 2016
Please cite this article as: He, Y-C., Pan, J-G., Liu, D-S., Acid-catalyzed hydrogen-deuterium exchange in β-pyrrolic
positions of calix[4]pyrrole at room temperature, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.06.015
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Graphical Abstract
Acid-catalyzed hydrogen-deuterium exchange in
β-pyrrolic positions of calix[4]pyrrole at room
temperature
Ying-Chun He, Ji-Gang Pan, and Dian-Sheng Liu
1

Acid-catalyzed hydrogen-deuterium exchange in β-pyrrolic positions of
calix[4]pyrrole at room temperature
Ying-Chun Hea, Ji-Gang Pana*, and Dian-Sheng Liub
a College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
b Institute of Applied Chemistry, Shanxi University, Taiyuan 030006, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Calix[4]pyrrole in D2O/CH3CN-D2O/CHCl3-D2O using the 98 % sulphuric acid as catalyst
was found to high deuterium incorporation and easy-to-make hydrogen-deuterium
exchange in β-pyrrolic positions. Compounds 2a-d were obtained by acid-catalyzed
hydrogen-deuterium exchange in β-pyrrolic positions of calix[4]pyrroles 1a-d,
respectively. Deuterium labelling at the pyrrole-β-position for compounds 1b and 1c can
be achieved with nearly 100 % incorporation in D2O-H2SO4 and CH3CN-D2O-H2SO4
systems, and deuterium labelling at the pyrrole-β-position for 1a and 1d is more than 90 %
in CHCl3-D2O-H2SO4.
Received in revised form
Accepted
Available online
Keywords:
Calix[4]pyrrole
β-Pyrrolic Positions
Hydrogen-Deuterium Exchange
Crystal structure
Elsevier Ltd. All rights reserved
1. Introduction
Calix[4]pyrroles are macrocyclic species having an
array of four NHs that act as a binding site for anionic
and electron-rich neutral guests in organic solvents. In
nonpolar organic solvents, the 1,3-alternate conformer is
demonstrated to be the most stable for calix[4]pyrrole.
Upon the addition of bound neutral substrates, anions,
or perturbing substituents to the solution, the
calix[4]pyrrole core undergoes a conformational change
adopting the cone conformation. In this manner all four
pyrrole N–H groups of the calix[4]pyrrole core can
participate in hydrogen bonding interactions with the
bound guest.1 In order to qualify the binding affinity and
also to develop versatile applications, a large number of
the functionalized calix[4]pyrrole derivatives have been
designed.2 Recently, calix[4]pyrroles with potential
application as medicaments were reported.3 In addition,
tritiated compounds are of increasing importance for
radiolabeling of bioactive compounds in medicinal
chemistry applications.4 Hence, facile, fast, and efficient
protocols for the deuteration and tritiation of
calix[4]pyrroles are of great value. More recently, as the
make hydrogen-deuterium exchange in β-pyrrolic
positions in the appropriate system.
In fact, it was found that pyrrole and N-methylpyrrole
could make acid (deuterioacetic acid)-catalysed proton
exchange in a dioxan-D2O solution via the A-SE2
mechanism in which there is general acid catalysis in
1971 by Gerritt P. Bean.6 And David M. Muir and
co-workers measured the rate of exchange on both the
carbon and nitrogen atoms of the pyrrole and indole in
the D2O-acetonitrile-HClO4 system. In contrast to early
work by Koizumi and Titan, they found that in mixtures
of D2O and aprotic solvents, N-H exchange was much
7
slower than C-H exchange. Subsequently, a number of
tritiated compounds made by the deuteriopyrrole and
corresponding material were reported.8 Interestingly,
our preparation method for deuterated calix[4]pyrroles
avoided protiodedeuteriation of deuterated pyrrole as
starting material in the reaction and purification, and
found that 98 % sulphuric acid is a good catalyst of high
deuterium incorporation and easy-to-make hydrogen-
deuterium exchange. According to the mechanism of the
pyrrole, 6 we proposed the mechanism of this reaction
(Scheme 1).
result
of
our
work
with
meso-piperidine
calix[4]pyrrole,5 it has occurred to us that the
water-soluble calix[4]pyrrole 1b might serve as such
easy-to-make hydrogen-deuterium exchange in β-
pyrrolic positions in D2O at room temperature.
Simultaneously, we have found that other
calix[4]pyrroles, taking 1a, 1d (insoluble in water) and
1c (slightly soluble in water) as examples, could also
Herein, we now report acid-catalyzed hydrogen-
deuterium exchange of high deuterium incorporation in
β-pyrrolic positions of calix[4]pyrroles 1a-d.
Scheme 2-3 provides a summary of the synthesis of
calix[4]pyrrole. Briefly, compounds 1a-d are prepared
∗ Corresponding author. Tel.: 13700501929; E-mail:
panjigang_sxu@163.com
2

The first evidence that acid-catalysed proton
exchange occurs on calix[4]pyrrole came from 1H NMR
spectroscopic analyses carried out in D2O. Compound
1b displays a doublet peak for the β-CH proton signals
at 5.90-5.94 ppm. However, upon the addition of 98 %
sulphuric acid, the doublet peak for the β-CH proton
signals becomes disappearing after 6 h. When H2O was
added, the doublet peak for the β-CH proton signals
appears, which shows the reversibility of proton
exchange in the presence of the acid (Figure S18). And
the changing of the peak for the β-CH proton signals of
compounds 1a, 1c-d are consistent with 1b under acid
existing. It is worth mentioning that deuterium labelling
at the pyrrole-β-position for compounds 1b and 1c can
be achieved with nearly 100 % incorporation, and
deuterium labelling at the pyrrole-β-position for 1a and
1d is more than 90 %. Interstingly, early work by
Koizumi and Titani showed that N-H exchange was
much faster than C-H exchange, but David M. Muir and
Mark C. Whiting found that in mixtures of D2O and
aprotic solvents, N-H exchange is sufficiently slow to
Scheme 1. Proposed mechanism for Hydrogen-Deuterium
Exchange in β-pyrrolic positions of calix[4]pyrrole via Lewis acid
catalysis.
by the corresponding ketone with pyrrole (With
condensation reaction of 1b, Boc is removed
simultaneously).5,9-11 H-D exchange for compounds 1a
and 1d in CHCl3/D2O (10 : 1), compound 1b in D2O
and compound 1c in CD3CN/D2O (99:1) with 1 % (by
D2O weight) 98 % sulphuric acid, respectively, gave the
desired deuterated calix[4]pyrrole 2a-d.
Configurational assignment was performed by a com-
1
bination of H NMR spectroscopy and single-crystal
X-ray crystalographic analysis. The calix[4]pyrroles
1c-d display only one type of β-pyrrole resonance and
exhibit, in d6-DMSO and CDCl3 respectively, a sharp
and well-resolved proton spectrum indicative of a time-
averaged C4 symmetry, whereas β-pyrrole resonance of
Scheme 2. Synthesis of Compounds 1a-d.
-O3SH3C +H2N
NH2+ CH3SO3
-
D
ND
D
D
DN
D
D
ND
D
D
the calix[4]pyrrole 1b displays
a doublet. The
symmetries of the various isomers were reflected
directly in resonances. The αααα isomer has one type of
CH group, while the ααββ isomer has two types of
pyrrolic CH group.11 So, we can confirm that
calix[4]pyrroles 1c-d are the αααα isomers while
calix[4]pyrrole 1b is the ααββ isomer. The single
crystals of 2b suitable for X-ray diffraction was grown
from CH3CN/D2O (10/1). The resulting structure
revealed that calix[4]pyrrole 2b adopts the so-called
partial cone conformation in the solid state with one
N
D
N
D
D
D
D
D
D
D
D
DN
D
D
N
D
N
D
-
NH2+ CH3SO3
-O3SH3C +H2N
2b
2a
HO
OH H3CO
OCH3
D
D
D
D
N
D
N
D
D
D
D
D
D
D
D
D
-
DN
D
DN
D
ND
D
ND
D
CH3SO3 bound to the pyrrolic NH protons. The
-
included CH3SO3 is held within this cleft by a series of
D
N
D
N
N-H•••O hydrogen bonding interactions involving the
three N-H groups of the four pyrrole rings (Figure S20),
which is consistent with compound 1b.5 While the
single-crystal X-ray structure of 2c grown from CH3CN
confirmed that the calixpyrrole core is in a cone
conformation, with one solvent molecule included in the
aromatic cavity and hydrogen bonded to the four NH
groups. The X-ray structure of single crystal obtained
by slow evaporation of acetonitrile solutions containing
the tetraether 2d and an excess of N-oxide shows that
the receptor adopts a cone conformation with the
N-oxide included deep in the cavity (Figure S21 and
S22).
2c
2d
OH
OCH3
HO
H3CO
D
D
NH
D
R
R
R
R
R
R
N
N
D
D
D
D
H
H
H
HN
HN
NH
D2O
H
N
H
N
R
R
D
1
or
OMe
R = CH3;
;
OH
N
-
H2+ CH3SO3
Scheme 3. Synthesis of Compounds 2a-d.
3

1
and characterized by H NMR spectroscopic analyses,
be followed using the first overtone of the N-H
stretching mode.7 Now, we unambiguously prove that
N-H exchange is much slower than C-H exchange in
mixtures of D2O and aprotic solvents through H NMR
spectroscopic analyses with compound 1a in CDCl3
(Figure 1). Calix[4]pyrrole 1b was treated with H2O,
which doesn’t show a marked change except for the
pyrrole and piperidine NH signals. This suggests that
hydrogen-deuterium exchange in β-pyrrolic positions of
calix[4]pyrrole is very slow under neutral condition
(Figure S19).
1
Figure 1． 1H NMR (600 MHz) spectra of acid-catalyzed hydrogen- deuterium exchange in β-pyrrolic positions of 1a (1.28 mM) in CDCl3. A) 120 h;
B) 72 h; C) 39 h; D) 9 h E) 0 h
Figure 2. 13C-NMR (150 MHz) spectrum of 2a recorded in CDCl3.
To gain further understanding of acid-catalysed
proton exchange occurs on calix[4]pyrrole, we have
measured 13C NMR of 2a-d. Compounds 2a-d display
slipt for the β-C signals at 102.23-102.59 ppm,
103.65-104.10/104.82-105.22 ppm, 104.32-105.00 ppm
and 105.91-106.20 ppm, respectively (Figure 2, S7, S12
and S16). That is different from 13C NMR of
compounds 2a-d.5.11-12 Of course, the presence of the D
4

atom leads to splitting peaks for the β-C signals.
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In summary, we have prepared four novel deuterated
calix[4]pyrroles 2a-d, and the structure of compounds
2b-d unambiguously were characterized by X-ray
crystalography. In principal, the present results thus
highlight an approach to creat tritiated calix[4]pyrroles
and other macrocyclic species with pyrrole, which is
important for the synthesis of radiolabeled
calix[4]pyrroles for medicinal applications.
Acknowledgments
This work was supported by College of Chemistry
and Chemical Engineering, Shanxi University, Taiyuan,
Chao Jianbin (for NMR measurements) and Cao Wei
(for the X-ray diffractometer).
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8212.
Supplementary data
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NMR spectroscopic data and X-ray structural data
are available. Single crystal data for compounds 2b
(CCDC 1443139), 2c (CCDC 1443141) and 2d (CCDC
1443140) have been deposited in the Cambridge
Crystallographic Data Center. Supplementary data
related to this article can be found at
http://dx.doi.org/10.1016/j.tetlet.2016.03.027.
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5

Graphical Abstract
Acid-catalyzed hydrogen-deuterium exchange in
β-pyrrolic positions of calix[4]pyrrole at room
temperature
Ying-Chun He, Ji-Gang Pan, and Dian-Sheng Liu
6

Highlights:
1. Facile, fast, and efficient protocols for
the deuteration of calix[4]pyrroles.
2. There are no examples reported the
deuteration of calix[4]pyrroles.
3. Highlight an approach to create
tritiated macrocyclic species with
pyrrole.
7