Pseudo-cyclic face-to-face rigid structure caused by the intramolecular ion pair effect

Article abstract of DOI:10.3390/molecules14041546

Six 3-methylpyridine zwitterions and six quinoline zwitterions were synthesized through the reaction of 4-hydroxycoumarins, p-benzoquinone and the corresponding Naromatics. The novel pseudo-cyclic face-to-face rigid structure of the zwitterion was elucida

Full text of DOI:10.3390/molecules14041546

Molecules 2009, 14, 1546-1560; doi:10.3390/molecules14041546
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Pseudo-cyclic Face-to-face Rigid Structure Caused by the
Intramolecular Ion Pair Effect
Sheng-Ling Zhang 1,*, Zhi-Shu Huang 2 and Lian-Quan Gu 2
1
Department of Chemistry, Shaoguan University, Shaoguan 512005, P. R. China
2
School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510275, People’s Republic
of China; E-mails: huangzhishu@hotmail.com (Z-S.H.), cesglq@mail.sysu.edu.cn (L-Q.G.)
* Author to whom correspondence should be addressed; E-mail: zhisland@yahoo.com.cn.
Received: 14 March 2009; in revised form: 9 April 2009 / Accepted: 10 April 2009 /
Published: 14 April 2009
Abstract: Six 3-methylpyridine zwitterions and six quinoline zwitterions were synthesized
through the reaction of 4-hydroxycoumarins, p-benzoquinone and the corresponding N-
aromatics. The novel pseudo-cyclic face-to-face rigid structure of the zwitterion was
1
elucidated by H-NMR at different temperatures, and assumed to be caused by both the
intramolecular ion pair attraction and the steric interaction.
Keywords: 4-Hydroxycoumarins; Zwitterion; Molecular structure.
1. Introduction
Recently, the compounds with cyclic structures derived from the [2.2] paracyclophane backbone 1
(Figure 1) have stimulated considerable interest due to their special properties and applications. 4,12-
Bis(diphenylphosphino)-[2.2]-paracyclophane was shown to be an excellent transition metal ligand for
the catalytic asymmetric hydrogenation of carbonyl groups [1-4]. The bridge-fluorinated
paracyclophanes display intriguing chemical reactivity [5-7] and commercial applications [8-9]. The
bridging ligands derived from paracyclophane have afforded the opportunity to investigate the role of
–stacking interactions in mediating electronic communication, as charge-transport was observed in
double-stranded DNA [10-12]. It is believed that the cyclic face-to-face rigid structure of the
paracyclophane moiety plays an important role in properties of these derivatives.

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Figure 1. The structure of [2.2] paracyclophane.
Cyclic structure
1
In a recent communication [13], we reported the synthesis of zwitterionic 4-hydroxycoumarin
derivatives. We now describe the novel pseudo-cyclic face-to-face rigid structures of these zwitterions
(Figure 2).
Figure 2. The zwitterion structures.
OH
N+
O-
OH
O
O
Pseudo-cyclic structure
R
2a: R = H
2b: R = CH3
2. Results and Discussion
The zwitterionic 4-hydroxycoumarin derivatives are composed of hydroquinone, pyridine and 4-
hydroxycoumarin planes. The pyridine and 4-hydroxycoumarin planes are joined to the hydroquinone
core to form the pseudo-cyclic face-to-face structure (Figure 2).
The different 1H-NMR shifts of the two -protons located on the pyridine ring of 2b [13] indicated
that the pyridine plane cannot rotate freely at room temperature, as it is known that if the pyridine ring
1
can rotate freely, the two -protons do not give separate H-NMR signals. Moreover, when N-
heterocyclic aromatics such as 3-methylpyridine and quinoline (which lack a C2-symmetric axis
through the nitrogen atom) were treated with 4-hydroxycoumarins and p-benzoquinone, both cis and
trans products were obtained, due to the restricted rotation about the C-N bond. The results of these
reactions are summarized in Tables 1 and 2.
These cis and trans products could not be separated by silica gel column chromatography. The
assignment of the respective stereochemistry and their isomer ratios could however be established
from the 1H-NMR spectra. For the 3-methylpyridinium zwitterion 3a, the -proton next to the methyl
group on the pyridine ring was predicted to only show a single peak in the aromatic region (Figure 3).
The appearance of the two aromatic singlets, at  8.92 and 8.51 ppm, respectively, implied that both
cis and trans isomers might be generated. Futhermore, the two aromatic singlets had a total integrated
area equal to 1H, consistent with a mixture of the two isomers. The peak at 8.92 was attributed to the
-proton (H2) adjacent to the methyl group of cis isomer, in which H2 was is further away from the
shielding region of the oxyanion, and came at low fields relative to H2’ of the trans isomer. Thus the
area ratio of 1.3:1 of the two aromatic singlets represents the cis and trans isomer ratio.

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Table 1. The synthesis of 3-methylpyridinium zwitterions.
O
OH
OH
OH
N+
O-
N+
O-
aqu. acetone
rt, 24hr, 39%
+
+
+
O
O
N
O
OH
OH
O
O
O
O
3a(cis)
3a'(trans)
cis : trans = 1.3:1
Yield(%)a
Cis/Transb
Entry
1
Product
4-HCs
OH
OH
OH
OH
N+
O-
N+
O-
1.3:1
35
29
42
O
O
OH
O
O
O
O
O
3b(cis)
3b'(trans)
OH
O
OH
OH
N+
O-
N+
O-
2
1.2:1
1.3:1
1.1:1
O
OH
OH
O
O
O
3c(cis)
3c'(trans)
OH
O
OH
OH
N+
O-
N+
O-
3
4
O
O
OH
OH
O
O
O
O
3d(cis)
3d'(trans)
OH
O
OH
OH
OH
N+
O-
N+
O-
37
OH
O
O
O
O
3e(cis)
3e'(trans)
OH
OH
OH
N+
OH
O
N+
O-
O-
1.1:1
5
31
O
OH
O
O
O
O
3f'(trans)
3f(cis)
aIsolated. bDetermined by 1H-NMR

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Table 2. The synthesis of quinolinium zwitterions.
O
O
OH
O
OH
OH
OH
OH
N+
O-
N+
O-
aqu. acetone
rt, 24hr, 15%
+
+
+
O
N
O
O
O
O
4a(cis)
4a'(trans)
cis : trans = 1:1.6
Yield(%)a
Cis/Transb
Entry
Product
4-HCs
OH
N+
OH
N+
O-
OH
O
O-
1:1.3
1
12
OH
O
4b(cis)
OH
O
O
O
O
O
O
4b'(trans)
OH
OH
N+
O-
N+
O-
OH
O
2
9
1:1.4
1:1.7
1:1.3
OH
OH
O
O
O
4c'(trans)
4c(cis)
OH
OH
N+
O-
OH
O
N+
O-
16
3
4
OH
OH
O
4d(cis)
O
O
O
O
O
4d'(trans)
OH
N+
O-
OH
OH
OH
O
N+
O-
13
OH
O
O
O
O
4e(cis)
4e'(trans)
OH
OH
OH
N+
O-
OH
O
N+
O-
1:1.5
5
12
OH
O
O
O
O
O
4f'(trans)
4f(cis)
aIsolated yield. bDetermined by 1H-NMR

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Figure 3. The 1H-NMR spectra of compounds 2a and 3a.
1
The chemical shifts and the integration of the peaks of the H-NMR spectrum did not change even
when the sample of 2b and 4a was warmed. (Figures 4 and 5.) This showed that the zwitterionic 4-
hydroxycoumarin derivatives were very stable. However, pyridium zwitterions are generally
considered to be reactive species and unstable [14]. The characteristic features of the 1H-NMR spectra
of the zwitterions at different temperatures indicated that the zwitterionic 4-hydroxycoumarin
derivatives possessed a rigid backbone containing two defined face-to-face planes, just likes [2.2]
paracyclophanes do. However, [2.2] paracyclophane is a macrocyclic ring, and the zwitterions just
were pseudo-cyclic.
Figure 4. The 1H-NMR spectra of compound 2b at 30 °C and 70 °C.

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Figure 4. Cont.
Figure 5. The 1H-NMR spectra of compound 4a at 30 °C and 80 °C.
Emadi et al. [15] have reported a trimeric compound 5 (Figure 6), with structural features similar to
those of zwitterionic 4-hydroxycoumarin derivatives. In compound 5 the presence of conjugation
between the naphthoquinone and the two (2-hydroxynaphthoquinone) subunits was suggested. This
conjugation implied that the subunit could rotate along the bond joining the subunit to the quinone
core and a rigid structure wasn’t generated.

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Figure 6. The structure of compound 5.
O
HO
O
O
O
O
O
HO
5
The face-to-face rigid backbone of the zwitterions was assumed to be caused by both the
intramolecular ion pair attraction and the steric interaction (Figure 7). The ion pair attraction made the
4-hydroxycoumarin ring tilt toward the pyridine ring until the equilibration between the ion pair
attraction and the steric interaction was reached and the rings could remain stable at a certain angle.
Conversely, the tilted 4-hydroxycoumarin ring constrained the pyridine from rotating freely through
steric interactions.
Figure 7. The intramolecular ion pair attraction and steric interaction of the zwitterion.
HO
OH
O
N+
-O
O
3. Experimental
3.1. General
1H-NMR spectra were measured at room temperature (except for the temperature dependence
studies) on a Varian UNITY INOVA 500 MHz spectrometer using TMS as an internal standard. For
the electrospray (ESI) MS analysis, a Finnigan LCQ Deca XP ion trap mass spectrometer equipped
with a Microsoft Windows NT data system and an ESI interface was used. Elementary analysis was
recorded on an Elementar Vario EL elementary analysis device. IR spectra were recorded on a Bruker
TENSOR 37 spectrophotometer.
3.2. General procedure: synthesis of 4-hydroxycoumarin zwitterions
A mixture of 4-hydroxycoumarin (5 mmol), p-benzoquinone (1.08 g, 10 mmol) and the appropriate
N-heterocyclic aromatic (10 mmol) was magnetically stirred in aqueous acetone (30 mL, v:v = 1:1) at
room temperature for 24 h. The reaction mixture was filtered to afford a brown crude product which

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was purified by column chromatography (silica gel, methanol-chloroform = 1:10) to give yellow
compounds.
Cis and trans 3-(3,6-Dihydroxy-2-(3-methylpyridinium-1-yl)phenyl)-2-oxo-2H-chromen-4-olate (3a
1
and 3a’): yield 39%; 3a:3a’ = 1.3:1; H-NMR (DMSO-d6) δ 2.25 (3H, s) ppm; IR: 3404, 3060, 1649,
1597, 1505, 1445 cm-1; ESI-MS (m/e): 360 (M-1)-; Anal. Calcd. for C21H15NO5: C, 69.80%; H, 4.18%;
N, 3.88%. Found: C, 69.47%; H, 4.35%; N, 4.02%.
Cis and trans 3-(3,6-dihydroxy-2-(3-methylpyridinium-1-yl)phenyl)-8-methyl-2-oxo-2H-chromen-4-
olate (3b and 3b’): yield 35%, 3b:3b’ = 1.3:1; 1H-NMR (DMSO-d6) δ 2.25 (3H, s), 2.21 (3H, s) ppm;
IR: 3062, 1620, 1504, 1424, 1335, 1278 cm-1; ESI-MS (m/e): 374 (M-1)-; Anal. Calcd. for C22H17NO5:
C, 70.39%; H, 4.56%; N, 3.73%. Found: C, 69.56%; H, 4.73%; N, 3.95%.
Cis and trans 3-(3,6-dihydroxy-2-(3-methylpyridinium-1-yl)phenyl)-7-methyl-2-oxo-2H-chromen-4-
olate (3c and 3c’): yield 29%; 3c:3c’ = 1.2:1; 1H-NMR (DMSO-d6) δ 2.67 (3H, s), 2.29 (3H, s) ppm;
IR: 2924, 1603, 1501, 1434, 1272 cm-1; ESI-MS (m/e): 374 (M-1)-; Anal. Calcd. for C22H17NO5: C,
70.39%; H, 4.56%; N, 3.73%. Found: C, 70.15%; H, 4.81%; N, 3.87%.

Molecules 2009, 14
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Cis and trans 3-(3,6-dihydroxy-2-(3-methylpyridinium-1-yl)phenyl)-6-methyl-2-oxo-2H-chromen-4-
olate (3d and 3d’): yield 42%; 3d:3d’ = 1.3:1; 1H-NMR (DMSO-d6) δ 2.32 (3H, s), 2.24 (3H, s) ppm;
IR: 3394, 1641, 1504, 1512, 1270 cm-1; ESI-MS (m/e): 374 (M-1)-; Anal. Calcd. for C22H17NO5: C,
70.39%; H, 4.56%; N, 3.73%. Found: C, 70.22%; H, 4.63%; N, 3.81%.
Cis and trans 3-(3,6-dihydroxy-2-(3-methylpyridinium-1-yl)phenyl)-2-oxo-2H-benzo[h]chromen-4-
1
olate (3e and 3e’): yield 37%; 3e:3e’= 1.1:1; H-NMR (DMSO-d6) δ 2.22 (3H, s) ppm; IR: 3068,
1638, 1478, 1271 cm-1; ESI-MS (m/e): 410 (M-1)-; Anal. Calcd. for C25H17NO5: C, 72.99%; H, 4.16%;
N, 3.40%. Found: C, 72.67%; H, 4.57%; N, 3.76%.

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Cis and trans 2-(3,6-dihydroxy-2-(3-methylpyridinium-1-yl)phenyl)-3-oxo-3H-benzo[f]chromen-1-
olate (3f and 3f’): yield 31%; 3f:3f’ = 1.1:1; 1H-NMR (DMSO-d6) δ 2.24 (3H, s) ppm; IR: 3059, 1632,
1507, 1266 cm-1; ESI-MS (m/e): 410 (M-1)-; Anal. Calcd for C25H17NO5: C, 72.99%; H, 4.16%; N,
3.40%. Found: C, 72.63%; H, 4.51%; N, 3.69%.
Cis and trans 3-(3,6-dihydroxy-2-(quinolinium-1-yl)phenyl)-2-oxo-2H-chromen-4-olate (4a and 4a’):
yield 15%, 4a(cis):4a’(trans) = 1:1.6; IR: 3093, 1639, 1513, 1274 cm-1; ESI-MS (m/e): 396 (M-1)-;
Anal. Calcd for C24H15NO5: C, 72.54%; H, 3.80%; N, 3.52%. Found: C, 72.55%; H, 3.91%; N, 3.65%.

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Cis and trans 3-(3,6-dihydroxy-2-(quinolinium-1-yl)phenyl)-8-methyl-2-oxo-2H-chromen-4-olate (4b
1
and 4b’): yield 12%; 4b(cis):4b’(trans) = 1:1.3; H-NMR (DMSO-d6) δ 9.39 (0.56H, s), 8.83 (0.44H,
br), 2.10 (3H, s) ppm; IR: 3391, 1635, 1516, 1274 cm-1; ESI-MS (m/e): 410 (M-1)-, Anal. Calcd for
C25H17NO5: C, 72.99%; H, 4.16%; N, 3.40%. Found: C, 72.74%; H, 4.32%; N, 3.55%.
Cis and trans 3-(3,6-dihydroxy-2-(quinolinium-1-yl)phenyl)-7-methyl-2-oxo-2H-chromen-4-olate (4c
1
and 4c’): yield 9%; 4c (cis):4c’(trans) = 1:1.4; H-NMR (DMSO-d6) δ 2.24 (3H, s) ppm, IR: 3432,
1605, 1508 cm-1; ESI-MS (m/e): 410 (M-1)-; Anal. Calcd. for C25H17NO5: C, 72.99%; H, 4.16%; N,
3.40%. Found: C, 72.77%; H, 4.33%; N, 3.46%.

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Cis and trans 3-(3,6-dihydroxy-2-(quinolinium-1-yl)phenyl)-6-methyl-2-oxo-2H-chromen-4-olate (4d
1
and 4d’): yield 16%, 4d:4d’= 1:1.7, H-NMR (DMSO-d6) δ 2.25 (3H, s) ppm; IR: 3366, 1641, 1512,
1277 cm-1; ESI-MS (m/e): 410 (M-1)-; Anal. Calcd. for C25H17NO5: C, 72.99%; H, 4.16%; N, 3.40%.
Found: C, 72.83%; H, 4.26%; N, 3.43%.
Cis and trans 3-(3,6-dihydroxy-2-(quinolinium-1-yl)phenyl)-2-oxo-2H-benzo[h]chromen-4-olate (4e
and 4e’): yield 13%; 4e:4e’= 1.3:1; IR: 3090, 1638, 1578, 1524, 1272 cm-1; ESI-MS (m/e): 410 (M-1)-;

Molecules 2009, 14
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Anal. Calcd. for C28H17NO5: C, 75.16%; H, 3.83%; N, 3.13%. Found: C, 75.06%; H, 3.93%; N,
3.28%.
Cis and trans 2-(3,6-dihydroxy-2-(quinolinium-1-yl)phenyl)-3-oxo-3H-benzo[f]chromen-1-olate (4f
and 4f’): yield 12%, 4f:4f’ = 1:1.5; IR: 3094, 1629, 1512, 1270 cm-1; ESI-MS (m/e): 410 (M-1)-; Anal.
Calcd for C28H17NO5: C, 75.16%; H, 3.83%; N, 3.13%. Found: C, 75.31%; H, 3.98%; N, 3.24%.

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Acknowledgements
We thank the National Nature Science Foundation of China (20672148), the Hong Kong
Polytechnic University ASD Fund for financial support of this study, and Jun-Ming Quan for technical
support.
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Sample Availability: Samples of the compounds are available from the authors.
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