Synthesis and structural analysis of 2,11-diaza[3.3](3,5)pyridinophane

Article abstract of DOI:10.1039/b200402j

A possible bidentate receptor with two kinds of nitrogen atoms, 2,11-diaza[3.3](3,5)pyridinophane 1, was synthesized. A VT ¹H NMR study and ab initio MO calculations indicated that the two conformers of 1, boat-boat and chair-boat, have almost

Full text of DOI:10.1039/b200402j

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Synthesis and structural analysis of 2,11-diaza[3.3](3,5)pyridino-
phane†
Teizi Satou*a and Teruo Shinmyozub
2
a Venture Business Laboratory, Kyushu University, Hakozaki, Fukuoka 812-8581, Japan.
E-mail: usasatou@ms.ifoc.kyushu-u.ac.jp
b Institute for Fundamental Research of Organic Chemistry (IFOC), Kyushu University,
Hakozaki, Fukuoka 812-8581, Japan. E-mail: shinmyo@ms.ifoc.kyushu-u.ac.jp
Received (in Cambridge, UK) 4th May 2001, Accepted 11th January 2002
First published as an Advance Article on the web 6th February 2002
A possible bidentate receptor with two kinds of nitrogen atoms, 2,11-diaza[3.3](3,5)pyridinophane 1, was
synthesized. A VT 1H NMR study and ab initio MO calculations indicated that the two conformers of 1, boat–boat
and chair–boat, have almost the same stabilities. The free energy barrier ∆G‡ for the conformational change is
estimated to be 10.4 kcal molϪ1 (T c = Ϫ55 ЊC). An X-ray crystallographic study revealed that 1 forms a hydrogen-
bonding network in the crystalline state.
Introduction
Results and discussion
Recently, we reported the synthesis and conformational studies
of 2,11-diaza[3.3](2,6)pyridinophane 2 and 2,11-diaza[3.3]-
metacyclophane 3, where the flipping of the –CH2NCH2–
bridges was studied by variable temperature (VT) NMR
spectroscopy and theoretical calculations.1
Synthesis
The title compound, 2,11-diaza[3.3](3,5)pyridinophane 1, was
synthesized in three steps from commercially available 3,5-
lutidine in a 6% total yield (Scheme 1). Chlorination of
Scheme 1 Reagents and conditions: i, TsNH2, NaH, DMF, 23%;
ii, H2SO4, 87%.
3,5-lutidine with N-chlorosuccinimide in CCl4 afforded 3,5-
bis(chloromethyl)pyridine 5 (32%).6 The coupling reaction of
5 with toluene-p-sulfonamide in the presence of NaH in
DMF7,8 afforded the dimer, N,NЈ-ditosyl-2,11-diaza[3.3](3,5)-
pyridinophane 6 (23%). Detosylation of 6 was accomplished
with conc. H2SO4 to give the desired product, 1 (87%).
A wide variety of pyridinophanes have been investigated so
far. In particular, 2,6- and 2,5-disubstituted pyridine derivatives
have been used predominantly with the aim of controlling the
orientation of the lone pair electrons. In fact, pyridinophanes
and macrocycles containing 2,6-disubstituted pyridine rings
have been used as ligands for transition metal complexes2
and as host molecules for the inclusion of metal cations3 and
organic molecules.4 In contrast, studies concerning cyclophanes
that incorporate 3,5-disubstituted pyridines are scarce and most
Conformational analysis
[3.3]Pyridinophanes are expected to have three stable con-
formers in solution with syn-geometry, i.e. syn(boat–boat) BB,
syn(chair–boat) CB, and syn(chair–chair) CC, as illustrated in
Scheme 2, which arise from the flipping of the –CH2NCH2–
bridges between the boat and the chair forms. A conform-
ational study of [3.3]metacyclophane 4 in solution revealed that
CC, which has the minimum steric hindrance, is the major con-
former, and the free energy barrier ∆G‡ for the flipping of
the bridges is 11.6 kcal molϪ1 (T c = Ϫ26 ЊC).9,10 In contrast, in
the case of 2,11-diaza[3.3](2,6)pyridinophane 21 the most stable
conformer is BB because the attractive interaction between the
lone pair electrons of the pyridine nitrogens and the amino
proton of the bridges decreases the energy of BB. For 2,11-
diaza[3.3]metacyclophane 3,1 the free energy difference between
the conformers becomes small. The population of the con-
formers at Ϫ71 ЊC is BB : CB = 3.8 : 1.0, and, therefore, the free
energy difference between BB and CB is only 0.5 kcal molϪ1 at
this temperature.
of the cyclophanes investigated were thiacyclophanes.5
A
reason for the lack of studies may be the low stability of 2,6-
unsubstituted 3,5-bis(halomethyl)pyridines, which are common
precursors.
In this paper, we describe the first synthesis of 3,5-
disubstituted diaza[3.3]pyridinophane 1, its conformational
analysis, and an X-ray crystallographic study.
† Electronic supplementary information (ESI) available: 3D coordin-
ates for compounds 1 and 6 and for the three calculated conformers of
compound 1 (1BB, 1CB and 1CC). See http://www.rsc.org/suppdata/
p2/b2/b200402j/
DOI: 10.1039/b200402j
J. Chem. Soc., Perkin Trans. 2, 2002, 393–397
This journal is © The Royal Society of Chemistry 2002
393

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1
1
Fig. 1 (a) VT H NMR spectra of the aromatic proton signals of 1 in CD2Cl2 (300 MHz). (b) VT H NMR spectra of the benzylic and amino
proton signals of 1 in CD2Cl2 (300 MHz). The inset is the spectrum at Ϫ90 ЊC after the addition of D2O. (c) Expanded 1H NMR spectrum (600 MHz)
of the benzylic protons of 1 at Ϫ90 ЊC in CD2Cl2. (d) H NMR spectra of the aromatic proton signals of 1 at Ϫ90 ЊC in CD2Cl2 (300 MHz). The
numbers indicate the integrations of peaks. Top: after deuteration, bottom: before deuteration.
1
600 MHz shows that the higher field signal splits into three
doublets (Fig. 1c), whereas, the lower field signal remains
incompletely resolved. The amino proton signals appear as
broad singlets (δ = 2.40, 1.94) at Ϫ90 ЊC. As indicated in the
inset of Fig. 1b, the signals disappeared when a small amount
of D2O was introduced. The aromatic proton signals also
broaden, and, eventually, are resolved into five singlets. The
three axial benzylic proton signals and the integrals of the five
aromatic proton signals (1 : 1 : 1 : 2 : 1) suggest that two kind of
conformers exist at Ϫ90 ЊC.
A detailed conformational study of the [3.3]metacyclophane
derivative9b established that the magnitude of the geminal
coupling constant Jgem of the benzylic protons depends on
the conformation of the trimethylene bridges (chair or boat);
the Jgem values are 14.6 and 13.8 Hz for the boat and chair
conformations, respectively. On the basis of these results, the
benzylic protons of 1 at Ϫ90 ЊC can be assigned as follows:
δ 3.63 (J = 13.6 Hz, Hax, CB, chair), 3.57 (J = 14.4 Hz, Hax,
boat), and 3.52 (J = 14.4 Hz, Hax, boat).
In order to assign the aromatic proton signals, partially deu-
terated 1 was prepared according to the literature procedure.11
As a result of hydrogen–deuterium exchange in the pyridine
moiety, the ratio of the integrals of Ha : Hb changed from 1.0 :
2.0 to 1.0 : 1.1 at rt in CDCl3. The integrals of the five aromatic
proton signals at Ϫ90 ЊC changed from 1.0 : 1.0 : 1.2 : 2.0 : 1.0
to 0.6 : 0.6 : 0.7 : 1.4 : 1.0 on deuteration (Fig. 1d). Therefore,
δ = 7.70 and 7.64 can be attributed to BB, and δ = 8.01, 7.93
and 7.74 to CB. Since the chemical shift at rt is the weighted
mean of all of these conformers, the Ha proton signal of CB is
δ = 8.01. Therefore, the aromatic protons can be assigned as
follows: δ 8.01 (Ha2, CB), 7.93 (Hb1Ј, CB), 7.74 (Hb2, CB), 7.70
(Hb1, BB), and 7.64 (Ha1, BB). The proportion of the two con-
formers is estimated to be BB : CB = 1 : 1 on the basis of the 1H
NMR integrals of these peaks. Therefore, the BB and CB
Scheme 2 The conformational equilibrium among the BB, CB, and
CC conformers of 2,11-diaza[3.3](3,5)pyridinophane 1 via chair–boat
flipping of the –CH2NCH2– bridges. Assignments and 1H chemical
shifts of the aromatic proton signals are also shown.
VT 1H NMR study in solution
The dynamic nature of azapyridinophane 1 was investigated by
means of the VT NMR technique. Figs. 1a and 1b show the
1
amino, benzylic and aromatic proton signals of the H NMR
spectra (300 MHz) at low temperatures in CD2Cl2. The sharp
singlets of the benzylic (δ = 3.90) and aromatic proton signals
(δ = 7.83, 7.81) at room temperature suggest rapid conform-
ational interconversion of the bridges on the NMR time-scale.
As the temperature is lowered, the benzylic proton signal begins
to broaden, and resolves into two broad signals. Observation at
394
J. Chem. Soc., Perkin Trans. 2, 2002, 393–397

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Table 1 Calculated relative thermodynamic stabilities (kcal molϪ1
25 ЊC)
,
1BB
1CB
1CC
B3LYP/6-311G*a
0.00
1.00
2.65
a A zero-point vibrational correction has been made. The calculated
absolute energies for 1BB, 1CB, and 1CC are Ϫ762.2570023,
Ϫ762.2551618 and Ϫ762.252581 Eh, respectively. The zero-point
vibrational energies for 1BB, 1CB, and 1CC are 751287.3, 750644.1
and 750762.8 J molϪ1, respectively. These energies are scaled by 0.9804.
conformers have the same stability. At the coalescence temper-
ature of Ϫ55 ЊC, the free energy of activation ∆G‡ is calculated
to be 10.4 kcal molϪ1
.
Theoretical calculations
It is known that theoretical MO calculations are effective
methods for predicting the relative thermodynamic stabilities
of conformers and their dynamic processes,1,12 particularly in
processes which are inaccessible to observation because of low
energy barriers on the NMR time-scale.
Geometry optimizations and calculations of the relative
thermodynamic stabilities (kcal molϪ1, 25 ЊC) of the three con-
formers of pyridinophane 1 (1BB, 1CB and 1CC) were per-
formed as ab initio (DFT)13 MO calculations in Gaussian 94.14
The basis set used was DFT/B3LYP/6-311G*. The zero-point
energy correction was applied for the calculated energy.
The resultant relative thermodynamic stabilities of three con-
formers are listed in Table 1. ab initio Calculation predicts the
stabilities to be in the following order: BB > CB > CC. The
estimated energy difference (1.00 kcal molϪ1) between the BB
and CB conformers by the DFT/B3LYP method is in good
agreement with the experimental result (ca. 0 kcal molϪ1).
X-Ray crystallographic analysis
The crystal structures of 1 and 6 were determined by X-ray
diffraction crystallographic study. Single crystals of 1 and 6
were obtained by the slow evaporation of their solutions in
MeOH. The crystallographic parameters of 1 and 6 are listed in
Table 2. The ORTEP drawing and crystal packing diagrams of
1 and 6 are shown in Figs. 2 and 3, respectively.
Fig. 2 (a) ORTEP drawing of 1 at 50% probability. One side of the
bridge is disordered, N(3), H(8) (chair) and N(4), H(9) (boat). The
population is estimated to be CC : CB = 67 : 33. (b) Packing diagram
of 1 viewed along the b axis. Three kinds of hydrogen bonds
[H(9) ؒ ؒ ؒ N(3) 2.42 Å, H(8) ؒ ؒ ؒ N(2) 2.31 Å and H(3) ؒ ؒ ؒ N(1) 2.64 Å]
are indicated by broken lines.
In the case of 1, three kinds of intermolecular hydrogen
bonds are formed, H(9) ؒ ؒ ؒ N(3) 2.42 Å, H(8) ؒ ؒ ؒ N(2) 2.31 Å
and H(3) ؒ ؒ ؒ N(1) 2.64 Å (Fig. 2b and Table 3). As a result, 1
forms pairs with the pyridine rings facing each other, and the
pairs are linked by the hydrogen bond between the bridging
amine nitrogen atom and the amine hydrogen atom. This
hydrogen-bonding network may lead to the relatively high melt-
ing point 254.0–256.5 ЊC. In order to form the latter hydrogen
bond, the –CH2NCH2– bridges must be disordered, because if
the all the bridges assume a chair conformation, no hydrogen
bonds can be formed. Therefore, compound 1 assumes CC and
CB conformations in the crystalline state at Ϫ180 ЊC, and the
population is estimated to be CC : CB = 67 : 33. This result
differs from that obtained by the VT NMR study and ab initio
calculations, presumably due to crystal lattice energy and the
above-mentioned hydrogen-bonding network.
6%. A VT 1H NMR study in CD2Cl2 indicated that the BB and
CB conformers have almost the same stabilities, and ab initio
MO calculations support this result. The free energy barrier
∆G‡ for the bridge flipping (BB
CB) is estimated to be
10.4 kcal molϪ1 (T c = Ϫ55 ЊC), and the value is comparable
to that of 2,11-diaza[3.3]metacyclophane 3 (10.8 kcal molϪ1
,
T c = Ϫ40 ЊC), but slightly higher than that of 2,11-diaza-
[3.3](2,6)pyridinophane 2 (9.9 kcal molϪ1, T c = Ϫ57 ЊC). In
contrast, 1 adopts CC and CB conformations in the solid state
at Ϫ180 ЊC, mainly as a result of a characteristic intermolecular
hydrogen-bonding network.
Four nitrogen lone pairs of electrons of 2,11-diaza[3.3]-
(2,6)pyridinophane 2 are convergently directed and form metal
complexes with Cu(),2a Ni(),2b Co(),2b and Fe()2c ions. In
contrast, [3.3](3,5)pyridinophane 1 has two types of nitrogen
donor atoms: the pyridine nitrogen and the amino nitrogen in
the bridge. Therefore, we can expect that this bireceptor
molecule should form transition metal complexes at two donor
sites, a study of which is in progress and the results will be
reported elsewhere.
The pyridinophane moiety of 6 adopts a CB conformation.
The intermolecular contacts fall within the van der Waals
radius at two positions: H(2) ؒ ؒ ؒ N(1) 2.59
Å
and
H(7) ؒ ؒ ؒ O(4) 2.48 Å (Fig. 3a and Table 3). Compound 6 aligns
in a head-to-tail manner to form a columnar structure in its
crystals.
Experimental
General
Conclusion
The title compound, 2,11-diaza[3.3](3,5)pyridinophane 1, was
synthesized in three steps from 3,5-lutidine in an overall yield of
1H NMR spectra were recorded on a JEOL JNM-EX270 (270
and 68 MHz for 1H and 13C, respectively), a JEOL JNM-AL300
J. Chem. Soc., Perkin Trans. 2, 2002, 393–397
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Table 2 Crystal data for 1 and 6a
1
6
Formula
C14H16N4
240.31
Orthorhombic
Pnma (no. 62)
8.1751(4)
12.6839(9)
11.4135(7)
1183.5(2)
93
4
1.349
0.84
C28H28N4O4S2
548.67
Formula weight
Crystal system
Space group
a/Å
Orthorhombic
P212121 (no. 19)
20.487(1)
20.6726(8)
6.1558(3)
2607.1(2)
296
b/Å
c/Å
Volume/Å3
Temperature/K
Z value
4
Dcalc/g cmϪ3
µ(Mo-Kα)/cmϪ1
Reflections measured
1.398
2.47
Total: 12704
3324 (Rint = 0.056)
344
Total: 10318
Unique: 1421 (Rint = 0.067)
91
Number of variables
R
Rw
GOF
0.056
0.131
0.85
0.044
0.141
1.02
Number of reflections used in refinement for I > 2.0σ(I ) data 637
1540
a All hydrogen atoms were placed by calculation but not refined.
Table 3 Hydrogen bond and intermolecular contact data for 1 and 6a
D–H ؒ ؒ ؒ Ab
D–H
H ؒ ؒ ؒ A
D ؒ ؒ ؒ A
ЄD–H ؒ ؒ ؒ A
Compound 1
N(4)–H(9) ؒ ؒ ؒ N(3)i
N(3)–H(8) ؒ ؒ ؒ N(2)ii
C(5)–H(3) ؒ ؒ ؒ N(1)iii
1.01
1.08
0.95
2.42
2.31
2.64
3.428(10)
3.367(5)
3.547(3)
177
164
160
Compound 6
C(3)–H(2) ؒ ؒ ؒ N(1)iv
0.95
0.97
2.59
2.48
3.483(8)
3.415(8)
155
163
C(7)–H(7) ؒ ؒ ؒ O(4)v
a Distances are given in Å; angles in deg. b D = donor, A = acceptor; i = x Ϫ ½, ½ Ϫ y, ½ Ϫ z; ii = 1 ϩ x, y, z; iii = x Ϫ ½, y, 32 Ϫ z; iv = x, y, 1 ϩ z;
v = x, y, z Ϫ 1.
Fig. 3 (a) ORTEP drawing of a pair of molecules of 6 at 50% probability. Intermolecular contacts are indicated by broken lines. (b) Crystal packing
diagram of 6 viewed along the c axis.
1
(300 and 75 MHz for H and 13C, respectively) and a Bruker
DRX600 (600 MHz for 1H) spectrometer in CDCl3 unless
otherwise noted, and chemical shifts are reported as δ values
in ppm relative to the internal standard of TMS. FAB mass
spectra were obtained with a JEOL JMS-SX/SX 102A with
m-nitrobenzyl alcohol as a matrix. Melting points were meas-
ured on a Yanaco micro melting point apparatus MP-S3, and
are uncorrected. Elemental analyses were carried out by the
396
J. Chem. Soc., Perkin Trans. 2, 2002, 393–397

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Service Centre of the Elementary Analysis of Organic Com-
pounds affiliated to the Faculty of Science, Kyushu University.
Analytical thin layer chromatography (TLC) and column
chromatography were performed using silica gel 60 F254
(Merck) and silica gel 60 (Merck, 40–63 mm or 60–200 mm),
respectively. DMF was dried with 4 Å molecular sieves. 3,5-
Bis(chloromethyl)pyridine 5 was obtained by chlorination of
3,5-lutidine in a procedure similar to a literature method.6
several times with CH2Cl2. The combined organic layer was
evaporated to give a white powder (2.3 mg). The ratios of the
1H NMR integrals of the aromatic and benzylic proton signals
varied from Ha : Hb : Hbz = 2.0 : 4.0 : 8.0 to 2.0 : 2.3 : 6.0.
Acknowledgements
This work is partially supported by a Priority Area (A) of the
Creation of Delocalized Electronic Systems (no. 12020241)
from the Ministry of Education, Science, Sports, and Culture,
Japan.
X-Ray crystallographic study‡
All measurements were made on a Rigaku R-AXIS RAPID
imaging plate area detector with graphite monochromated
Mo-Kα radiation. The crystal structure was solved by the direct
method SIR9215 and expanded using DIRDIF94.16 The non-
hydrogen atoms were refined anisotropically. All hydrogen
atoms were placed by calculation but not refined. All the
computations were performed using teXsan.17
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Synthesis of 2,11-diaza[3.3](3,5)pyridinophane (1)
To a 50 ml round-bottomed flask, which was placed in an ice
bath, were added successively 6 (569 mg, 1.04 mmol) and conc.
sulfuric acid (10 ml) slowly. The mixture was heated for 2 h at
110 ЊC with stirring. Then the reaction vessel was placed in an
ice bath and made alkaline by the addition of aqueous sodium
hydroxide solution. The resulting solution was continuously
extracted with CH2Cl2 for 24 h. The extracted CH2Cl2 solution
was evaporated under reduced pressure to give a pale yellow
solid (220 mg, 87%). Compound 1: mp 254.0–256.5 ЊC; an
analytical sample was recrystallized from EtOH (Found: C,
69.91; H, 6.68; N, 23.20%. C14H16N4 requires C, 69.97; H, 6.71;
N, 23.31%). 1H NMR (CDCl3, 270 MHz) 7.89 (d, J = 1.65 Hz,
4H), 7.83 (s, 2H), 3.93 (s, 8H); 13C NMR (CDCl3, 75 MHz)
148.1, 148.0, 134.4, 52.3; HRMS (FAB) m/z calcd for C14H17N4
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16 P. T. Beurskens, G. Admiraal, G. Beurskens, W. P. Bosman, R. de
Gelder, R. Israel and J. M. M. Smits, The DIRDIF-94 program
system, Technical Report of the Crystallography Laboratory,
University of Nijmegen, The Netherlands, 1994.
17 Crystal Structure Analysis Package, Molecular Structure
Corporation, 1985 and 1992.
Deuteration of 2,11-diaza[3.3](3,5)pyridinophane (1)
A mixture of 1 (8.4 mg, 0.03 mmol) and D2O (0.5 ml, 99.8% D)
was sealed in a glass tube, and the tube was heated at 200 ЊC for
4 days. The resultant solution was made alkaline with small
amounts of aqueous sodium hydroxide solution, and extracted
‡ CCDC reference numbers 173247 and 173248. See http://www.rsc.org/
suppdata/p2/b2/b200402j/ for crystallographic files in .cif or other
electronic format.
J. Chem. Soc., Perkin Trans. 2, 2002, 393–397
397