An alternative to 'propylene/Leonard linker' for studying arene interactions in flexible pyrazolo[3,4-d]pyrimidine core based models both at molecular and supramolecular levels

Article abstract of DOI:10.1039/c0ce00336k

An alternative C-3 linker to 'propylene/Leonard linker' is proposed for studying arene interactions in face-to-face (offset) mode. The two new flexible symmetrical compounds with an electron deficient pyrazolo[3,4-d]pyrimidine core and biologically important isomeric purine systems and one dissymmetrical compound with a pyrazolo[3,4-d]pyrimidine core and electron-rich carbazole residue at the termini of the new linker show folding due to intramolecular π-π interactions by both ¹H NMR in solution and X-ray crystallography in the solid state. Surprisingly, the replacement of the 4-methylsulfanyl group of the dissymmetrical compound by an electron donating methoxy group shows open conformation in the solid state by X-ray crystallography. The fifth symmetrical compound with an electron-rich carbazole residue at the termini of new linker, however, shows the normally expected open conformation.

Full text of DOI:10.1039/c0ce00336k

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PAPER
An alternative to ‘propylene/Leonard linker’ for studying arene interactions in
flexible pyrazolo[3,4-d]pyrimidine core based models both at molecular and
supramolecular levels†
a
Kamlakar Avasthi, Amantullah Ansari,a Ruchir Kant,b Prakas R. Maulik,b Krishnan Ravikumar,c
*
Partha Chattopadhyayd and Nirmal D. Adhikaryd
Received 25th June 2010, Accepted 18th November 2010
DOI: 10.1039/c0ce00336k
An alternative C-3 linker to ‘propylene/Leonard linker’ is proposed for studying arene interactions in
face-to-face (offset) mode. The two new flexible symmetrical compounds with an electron deficient
pyrazolo[3,4-d]pyrimidine core and biologically important isomeric purine systems and one
dissymmetrical compound with a pyrazolo[3,4-d]pyrimidine core and electron-rich carbazole residue at
the termini of the new linker show folding due to intramolecular p–p interactions by both 1H NMR in
solution and X-ray crystallography in the solid state. Surprisingly, the replacement of the 4-
methylsulfanyl group of the dissymmetrical compound by an electron donating methoxy group shows
open conformation in the solid state by X-ray crystallography. The fifth symmetrical compound with
an electron-rich carbazole residue at the termini of new linker, however, shows the normally expected
open conformation.
development.12 Since Hunter and Sanders’ seminal paper13 this
area has witnessed increased activity.14
1. Introduction
Browne et al. showed in a pioneering study that intramolecular
In 1995 we demonstrated, for the first time, the use of a
interactions between different nucleic acid bases connected by
a propylene linker can be demonstrated in solution.1 Earlier
pyrazolo[3,4-d]pyrimidine (PP) core, which is isomeric with
the biologically important purine, as a novel system for
work on ‘trimethylene bridges’ as synthetic spacers for the
studying intramolecular arene interactions in truly flexible
detection of intramolecular interactions has been reviewed,
however, no X-ray crystallographic structures of a folded
compound with a single propylene linker was mentioned.2
Eventually, after about thirty years the structure of one of these,
namely 1,3-bis(Ad)propane was shown to have a folded structure
by X-ray crystallography in the solid state,3 as shown by earlier
studies in solution.1 In addition to the stabilization of DNA/
RNA structures,4 arene interactions are known to play an
increasingly important role in chemistry,5 and biology,6 partic-
ularly in molecular recognition,7 crystal engineering,8 cyclo-
phanes,9 foldamers,10 molecular tweezers/- clips11 and drug
aMedicinal and Process Chemistry Division, Central Drug Research
Institute, CSIR, Lucknow, 226001, India. E-mail: kavasthi@rediffmail.
com
bMolecular and Structural Biology Division, Central Drug Research
Institute, CSIR, Lucknow, 226001, India
cX-Ray Crystallography Division, Indian Institute of Chemical Technology,
Hyderabad, 500007, India
dChemistry Division, Indian Institute of Chemical Biology, Kolkata,
700032, India
† Electronic supplementary information (ESI) available: 1H and 13C
NMRs spectra, selected intramolecular and intermolecular interactions.
CCDC reference numbers 757990 (7a), 757991 (9a), 771296 (12),
771297 (13a) and 771298 (14). For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0ce00336k
Fig.
1 Pyrazolo[3,4-d]pyrimidine core based ‘‘propylene/Leonard
linker’’ compounds (1a–1l, 2–5).
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1,3-bis(4,6-dimethylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-1-
1
115.83ꢀ, we decided to go ahead with new linker as 120ꢀ is not
significantly different from the highest value 115.83 seen in model
compound (1h, Fig. 1).
yl)propane (1a, Fig. 1) by H NMR in solution15a and X-ray
crystallography in the solid state.15b Moreover, the robustness of
the unusual U-motif formed due to intramolecular p–p inter-
actions in 1a has been established in many more symmetrical
(115c–15h and 2,15i–15k Fig. 1) and two dissymmetrical compounds
To test this hypothesis a new compound 7a (N1–N1 isomer)
was prepared along with two other positional isomers (7b, N1–N2
and 7c, N2–N2, Scheme 1) following the same procedure as
described for the synthesis of 1a15a from 4,6-dimethylsulfany-1H-
pyrazolo[3,4-d]pyrimidine (6)17 except that methallyl dichloride
was used in place of 1,3-dibromo propane. The synthesis and
X-ray crystallographic structures of four more compounds (9a,
12, 13a and 14) with the butylidene linker are also reported.
1
(315l and 4,15m Fig. 1) by H NMR in solution and X-ray crys-
tallography in the solid state. The importance of the propylene
linker is further established by the fact that both the ethylene
linker compound 1B15c and the tetramethylene linker compound
2B15n do not show any intramolecular stacking by X-ray crys-
tallography in the solid state (Fig. 1). Surprisingly, the symmet-
rical chloro compound (1k) is actually folded due to
intramolecular S/S interaction and cyano compound (1l) is
open, in fact, both compounds are devoid of intramolecular p–p
interactions.15h Furthermore, the positional isomer 5a (N1–N2,
2. Experimental
2.1 General information
1
Fig. 1) of 1a (N1–N1, Fig. 1) is open both by H NMR in sol-
ution15a and X-ray crystallography15n in solid confirming addi-
tional importance of the position of propylene linker between
two arene residues.
Analytical grade reagents were used without any further purifi-
cation. Melting points are uncorrected and were measured on
a Buchi 530 melting point apparatus. Mass spectra were recorded
on a Jeol-JMS D-300 spectrophotometer. 1H NMR and 13C
NMR were recorded on a Bruker DRX-300 instrument at 300
MHz and 75 MHz, respectively, using TMS as an internal
standard. C, H and N microanalyses were carried out using
a Heraeus Vario EL III Carlo Erba 1108 elemental analyzer.
All these studies convincingly demonstrate the potential of the
PP core, for studying arene interactions in flexible compounds
both at molecular and supramolecular level. Vogtle refers to
singly linked molecules that adopt p–stacked conformations as
‘‘protophanes’’.16
Now, we report an alternative to propylene linker that is easily
accessible from commercial methallyl dichloride (3-chloro-2-
chloromethyl-1-propene). The main reason to look for a new
linker is the fact that during last fifteen years it was often
observed that even when the 1H NMR of several propylene linker
compounds, with two arene residues (same or different) at its
termini, show reasonable up-field shift for intramolecular folding
in solution, they failed to crystallize. This questioned the exact
nature of the interaction (e.g. p–p, C–H/p etc.). For example,
the dissymmetrical propylene linker compound 5b shows intra-
molecular folding by 1H NMR in solution which is actually due
to C–H/p interaction between protons of the 6-methylsulfanyl
group and the phenyl ring of the phthalimido moiety and not by
p–p interactions between two arene residues as shown by X-ray
crystallography.15o In other words, the success of the propylene
linker has been mainly confined to symmetrical compounds (1a–
1j, 2b–2d, Fig. 1) based on the PP core. Though compound 3
(Fig. 1) is dissymmetrical it can be considered as a hybrid of 1a
and 2b both containing arene residues derived from same PP
core. So far we have reported only one (4, Fig. 1) in which second
arene moiety is triazolo[4,5-d]pyrimidine (different from PP core)
as truly dissymmetrical compound forming unusual U-motif due
to intramolecular p–p interactions comparable to other
symmetrical compounds (1a–1j, 2b–2d, Fig. 1). The selection of
this linker is based on following observations. This new butyli-
dene linker is quite similar to propylene linker as far as carbon
atom in the linker is concerned but has an extra methylene
carbon attached to central C of earlier propylene linker through
a double bond. Net result of this additional methylene unit at
central C of propylene linker is a theoretical increase in earlier
angle of 109ꢀ (tetrahedral) to 120ꢀ (planar). Both 1,3-dibromo
propane for propylene linker and methallyl dichloride for new
linker, are commercially available. Since angle at central C in
propylene linker of our various models is in the range of 113.94–
Scheme 1 Synthesis of different diaryl butylidene compounds.
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2.2 Synthesis and characterization
The organic layer was collected and the aqueous layer was
washed two times with 200 mL of chloroform (2 ꢁ 100 mL).
Organic layers were combined, washed with 200 mL of water
(2 ꢁ 100 mL) and dried over anhydrous sodium sulfate. The
residue obtained by the removal of chloroform under reduced
pressure was purified by column chromatography on silica gel
using mixture of methanol–chloroform in increasing polarity to
give pure 9a, 9b, and 9c inꢀthe order mentioned.
Compounds 7a, 7b, 7c, 9a, 9b, 9c, 11, 12, 13a, 13b and 14 were
synthesized according to Scheme 1.
Synthesis and characterization of 1,3-bis(4,6-dimethylsulfanyl-
1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylenepropane (7a), 1-
(4,6-dimethylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-1yl)-3-(4,6-
dimethylsulfanyl-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-2-methyl-
enepropane (7b) and 1,3-bis(4,6-dimethylsulfanyl-2H-pyr-
azolo[3,4-d]pyrimidin-2-yl)-2-methylenepropane (7c). To a stirred
suspension of 6 (1 g, 4.71 mmol) in DMF (40 mL) at room
temperature was added K2CO3 (1 g, 7.24 mmol). After 30 min of
stirring, methallyl dichloride (263 mL, 2.50 mmol) was added and
stirring was continued for 24 h. DMF was removed under
reduced pressure and the residue was treated with 200 mL of
chloroform–water (1 : 1) mixture. The organic layer was
collected and the aqueous layer was washed two times with 100
mL of chloroform (2 ꢁ 50 mL). Organic layers were combined,
washed with 200 mL of water (2 ꢁ 100 mL) and dried over
anhydrous sodium sulfate. The residue obtained by the removal
of chloroform under reduced pressure was purified by column
chromatography on silica gel using mixture of ethyl acetate–
hexane in increasing polarity to give pure 7a, 7b, and 7c in the
order mentioned.
1
9a: Yield 53%; mp 184 C; MS (ESI) m/z 477 [M + H]+. H
NMR (300 MHz, CDCl3) d (ppm) 2.53 (s, 6 H, 2 ꢁ SMe), 2.70 (s,
6 H, 2 ꢁ SMe), 4.74 (s, 4 H, 2 ꢁ NCH2), 5.29 (s, 2 H, CH2), 7.83
(s, 2 H, ArH). 13C NMR (75 MHz, CDCl3) d (ppm) 11.77, 14.58,
45.25, 119.15, 128.30, 138.34, 140.69, 149.07, 161.57, 165.68.
Anal. calcd for C18H20N8S4: C 45.36, H 4.23, N 23.51. Found: C
45.08, H 3.98, N 23.74.
9b: Yield 23%; mp 222 C; MS (ESI) m/z 477 [M + H]+. H
NMR (300 MHz, CDCl3) d (ppm) 2.53 (s, 3 H, SMe), 2.59 (s, 3 H,
SMe), 2.63 (s, 3 H, SMe), 2.71 (s, 3 H, SMe), 4.71 (s, 1 H), 4.88 (s,
2 H, NCH2), 4.93 (s, 2 H, NCH2), 5.26 (s, 1 H), 7.84 (s, 1 H,
ArH), 7.97 (s, 1 H, ArH). 13C NMR (75 MHz, CDCl3) d (ppm)
11.78, 12.17, 14.54, 14.70, 45.66, 49.19, 117.13, 120.04, 128.33,
139.62, 141.00, 146.48, 149.31, 153.78, 159.41, 161.75, 165.78,
165.94. HRMS (ESI) calcd for C18H21N8S4 477.07720; found
477.07767 [M + H]+.
ꢀ
1
1
9c: Yield 4%; mp 226 ꢀC; MS (ESI) m/z 477 [M + H]+. H
7a: Yield 25%; mp 156–158 ꢀC; MS (ESI) m/z 477 [M + H]+. 1H
NMR (300 MHz, CDCl3) d (ppm) 2.35 (s, 6 H, 2 ꢁ SMe), 2.68 (s,
6 H, 2 ꢁ SMe), 4.81 (s, 4 H, 2 ꢁ NCH2), 5.41 (s, 2 H, CH2), 7.94
(s, 2 H, ArH). 13C NMR (75 MHz, CDCl3) d (ppm) 11.97, 14.04,
48.40, 109.02, 118.68, 132.31, 138.83, 151.66, 164.52, 168.52.
Anal. calcd for C18H20N8S4: C 45.36, H 4.23, N 23.51. Found: C
45.09, H 4.52, N 23.72.
NMR (300 MHz, CDCl3) d (ppm) 2.64 (s, 6 H, 2 ꢁ SMe), 2.65 (s,
6 H, 2 ꢁ SMe), 4.88 (s, 2 H, CH2), 5.04 (s, 4 H, 2 ꢁ NCH2), 7.98
(s, 2 H, ArH). 13C NMR (75 MHz, CDCl3) d (ppm) 12.22, 14.51,
49.30, 116.31, 120.22, 140.01, 146.59, 153.62, 159.47, 165.89.
HRMS (ESI) calcd for C18H21N8S4: 477.07720; found:
477.07736 [M + H]+.
7b: Yield 45%; mp 144–146 ꢀC; MS (ESI) m/z 477 [M + H]+. 1H
NMR (300 MHz, CDCl3) d (ppm) 2.49 (s, 3 H, SMe), 2.62 (s, 3 H,
SMe), 2.66 (s, 3 H, SMe), 2.68 (s, 3 H, SMe), 4.87 (s, 2 H, NCH2),
4.94 (s, 2 H, NCH2), 5.36 (s, 1 H), 5.39 (s, 1 H), 7.78 (s, 1 H,
ArH), 7.95 (s, 1 H, ArH). 13C NMR (75 MHz, CDCl3) d 11.86,
11.92, 14.20, 14.22, 48.92, 56.52, 108.99, 109.08, 120.52, 124.10,
132.36, 137.62, 151.89, 158.60, 165.00, 166.23, 168.59, 169.21.
Anal. calcd for C18H20N8S4: C 45.36, H 4.23, N 23.51. Found: C
45.13, H 4.52, N 23.76.
7c: Yield 15%; mp 196–198 ꢀC; MS (ESI) m/z 477 [M + H]+. 1H
NMR (300 MHz, CDCl3) d (ppm) 2.63 (s, 12 H, 4 ꢁ SMe), 4.95
(s, 4 H, 2 ꢁ NCH2), 5.53 (s, 2 H, CH2), 7.70 (s, 2 H, ArH). 13C
NMR (75 MHz, CDCl3) d (ppm) 12.01, 14.25, 56.79, 109.21,
122.89, 124.26, 136.74, 158.63, 166.40, 169.01. Anal. calcd for
C18H20N8S4: C 45.36, H 4.23, N 23.51. Found: C 45.18, H 4.37,
N 23.73.
Synthesis and characterization of 9-(2-chloromethyl-allyl)-9H-
carbazole (11) and 1,3-bis(-9H-carbazol-9-yl)-2-methylenepropane
(12). To a stirꢀred suspension of NaH (0.30 g, 7.5 mmol) in DMF
(20 mL) at 0 C was added 10 (1 g, 5.7 mmol). After 30 min of
stirring the mixture became transparent. This mixture was added
slowly within 1 h to a solution of methallyl dichloride (2.0 mL,
17.3 mmol) in DMF (20 mL) at room temperature and stirring
was continued for further 15 h. DMF was removed under
reduced pressure and the residue was treated with 300 mL of
chloroform–water (1 : 1) mixture. The organic layer was
collected and the aqueous layer was washed two times with 200
mL of chloroform (2 ꢁ 100 mL). Organic layers were combined,
washed with 200 mL of water (2 ꢁ 100 mL) and dried over
anhydrous sodium sulfate. The residue obtained by the removal
of chloroform under reduced pressure was purified by column
chromatography on silica gel using mixture of ethylacetate-
hexane in increasing polarity to give pure 11 and 12.
1
Synthesis and characterization of 1,3-bis(2,6-dimethylsulfanyl-
9H-purin-9-yl)-2-methylenepropane (9a), 1-(2,6-dimethylsulfanyl-
7H-purin-7-yl)-3-(2,6-dimethylsulfanyl-9H-purin-9-yl)-2-methyl-
enepropane (9b) and 1,3-bis(2,6-dimethylsulfanyl-7H-purin-7-yl)-
2-methylenepropane (9c). To a stirred suspension of 8 (1 g, 4.71
mmol) in DMF (40 mL) at room temperature was added K2CO3
(1 g, 7.24 mmol). After 30 min of stirring, methallyl dichloride
(263 mL, 2.50 mmol) was added and stirring was continued for 60
h. DMF was removed under reduced pressure and the residue
was treated with 300 mL of chloroform–water (1 : 1) mixture.
11: Yield 36%; viscous liquid; MS (FAB) m/z 255 [M]+; H
NMR (300 MHz, CDCl3) d (ppm) 4.01 (s, 2 H, CH2Cl), 4.92 (s, 1
H, CH), 5.01 (s, 2 H, NCH2), 5.20 (s, 1 H, CH), 7.17–7.31 (m, 2
H, ArH), 7.34–7.54 (m, 4 H, ArH), 8.10 (d, J ¼ 7.56 Hz, 2 H,
ArH). 13C NMR (75 MHz, CDCl3) d (ppm) 45.05, 45.71, 108.91,
117.03, 119.33, 120.33, 123.02, 125.85, 140.09, 140.51. Anal.
calcd for C16H14ClN: C 75.14, H 5.52, N 5.48. Found: C 75.32, H
5.34, N 5.62.
1
12: Yield 58.5%; mp 162 ꢀC; MS (FAB) m/z 386 [M]+. H
NMR (300 MHz, CDCl3) d (ppm) 4.74 (s, 4 H, 2 ꢁ NCH2), 4.82
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14: Yield 88%; mp 120 C; MS (ESI) m/z 416 [M + H]+. H
NMR (300 MHz, CDCl3) d (ppm) 2.32 (s, 3 H, SMe), 4.10 (s, 3 H,
OMe), 4.83 (s, 2 H, NCH2), 4.91 (s, 2 H, NCH2), 5.01 (s, 1 H,
CH), 5.18 (s, 1 H, CH), 7.06–7.14 (m, 2 H, ArH), 7.16–7.25 (m, 2
H, ArH), 7.26–7.39 (m, 2 H, ArH), 7.99 (s, 1 H, ArH), 8.05 (d,
J ¼ 7.68 Hz, 2 H, ArH). 13C NMR (75 MHz, CDCl3) d (ppm)
14.04, 45.72, 49.40, 54.18, 99.98, 108.66, 116.00, 119.17, 120.14,
122.94, 125.58, 132.11, 139.15, 140.40, 155.63, 162.68, 169.81.
Anal. calcd for C23H21N5OS: C 66.48, H 5.09, N 16.85. Found: C
66.38, H 5.28, N 16.68.
ꢀ
1
(s, 2 H, CH2), 7.03–7.14 (m, 4 H, ArH), 7.15–7.26 (m, 4 H, ArH),
7.27–7.42 (m, 4 H, ArH), 8.06 (d, J ¼ 7.21 Hz, 4 H, ArH). 13C
NMR (75 MHz, CDCl3) d (ppm) 45.65, 108.77, 113.69, 119.29,
120.33, 122.99, 125.78, 139.20, 140.46. Anal. calcd for C28H22N2:
C 87.01, H 5.74, N 7.25. Found: C 86.86, H 5.74, N 7.17.
Synthesis and characterization of 1-(9H-carbazol-9-yl)-3-(4,6-
dimethylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methyl-
enepropane
(13a)
and
1-(9H-carbazol-9-yl)-3-(4,6-dime-
thylsulfanyl-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-2-methylenepropane
(13b). To a stirred suspension of 6 (0.35 g, 1.7 mmol) in DMF (20
mL) at room temperature was added K2CO3 (0.35 g, 2.5 mmol).
After 30 min of stirring compound 11 (0.5 g, 1.9 mmol) was added
and stirring was continued for 15 h. DMF was removed under
reduced pressure and the residue was treated with 100 mL of
chloroform–water (1 : 1) mixture. The organic layer was collected
and the aqueous layer was washed two times with 100 mL of
chloroform (2 ꢁ 50 mL). Organic layers were combined, washed
with 200 mL of water (2 ꢁ 100 mL) and dried over anhydrous
sodium sulfate. The residue obtained by the removal of chloro-
form under reduced pressure was purified by column chromatog-
raphy on silica gel using mixture of ethyl acetate–hexane in
increasing polarity to give pꢀure 13a and 13b.
2.3 X-Ray crystallography
Unit cell determinations and intensity data collection were per-
formed on a Bruker SMART APEX CCD area-detector instru-
ments. The structures were solved by the direct method and
refined by full-matrix least-squares methods on F2 using SMART
(Bruker, 2001), SMART 32(Bruker), SAINT (Bruker, 2001),
SHELXTL-NT [Bruker AXS Inc., Madison, Wisconsin, USA
1997]. Crystallographic data for all five compounds are
summarized in Table 1.
1
13a: Yield 53%; mp 118 C; MS (ESI) m/z 432 [M + H]+. H
3. Results and discussion
NMR (300 MHz, CDCl3) d (ppm) 2.33 (s, 3 H, SMe), 2.67 (s, 3 H,
SMe), 4.83 (s, 2 H, NCH2), 4.90 (s, 2 H, NCH2), 5.02 (s, 1 H,
CH), 5.18 (s, 1 H, CH), 7.04–7.16 (m, 2 H, ArH), 7.16–7.25 (m, 2
H, ArH), 7.26–7.39 (m, 2 H, ArH), 7.99 (s, 1 H, ArH), 8.05 (d,
J ¼ 7.45 Hz, 2 H, ArH). 13C NMR (75 MHz, CDCl3) d (ppm)
11.81, 14.05, 45.75, 49.20, 108.63, 109.34, 116.18, 119.18, 120.14,
122.94, 125.57, 132.26, 139.07, 140.38, 152.01, 164.80, 168.99.
Anal. calcd for C23H21N5S2: C 64.01, H 4.90, N 16.23. Found: C
63.95, H 4.81, N 16.01.
Compound 7a shows an up-field shift for 6-methylsulfanyl
protons in its 1H NMR giving strong indication that the
compound is intramolecularly folded in CDCl3 solution (ESI,
Fig. S1, S12).† The first evidence that the butylidene linker is
behaving somewhat differently in comparison to the propylene
linker came from the fact that the yield of 7a was much less than
7b while the reverse was the case when the propylene linker was
used in place of methallyl dichloride.
13b: Yield 28%; mp 164 C; MS (ESI) m/z 432 [M + H]+. H
NMR (300 MHz, CDCl3) d (ppm) 2.63 (s, 3 H, SMe), 2.64 (s, 3 H,
SMe), 4.69 (s, 2 H, NCH2), 4.86 (s, 2 H, NCH2), 5.16 (s, 1 H,
CH), 5.24 (s, 1 H, CH), 7.05–7.15 (m, 2 H, ArH), 7.16–7.27 (m, 2
H, ArH), 7.30–7.38 (m, 2 H, ArH), 7.40 (s, 1 H, ArH), 8.05 (d,
J ¼ 7.65 Hz, 2 H, ArH). 13C NMR (75 MHz, CDCl3) d (ppm)
11.85, 14.22, 45.64, 56.12, 108.63, 108.91, 118.27, 119.36, 120.25,
122.82, 124.15, 125.77, 138.25, 140.09, 158.73, 166.32, 168.61.
Anal. calcd for C23H21N5S2: C 64.01, H 4.90, N 16.23. Found: C
64.18, H 4.99, N 16.15.
The solid state conformation of 7a as determined by X-ray
crystallography is shown in Fig. 2 with its atom-numbering
scheme. The four important distances namely N1/N1,
Cg(XA)/Cg(XA0), Cg(XC)/Cg(XC0) and Cg(XB)/Cg(XB0)
defining stacked conformation of 7a are 3.29, 4.53, 3.94 and 3.69
ꢀ
1
ꢀ
A, respectively. For comparison corresponding distances in
parent propylene linker compound 1a are 3.27, 4.48, 3.94 and
ꢀ
3.71 A, respectively (ESI, Fig. S15).† This comparison convinc-
ingly shows that important features of 1a and the new compound
7a with the new linker are quite comparable. The C–C–C angle of
the linker is 117ꢀ (ESI, Fig. S13).†
Synthesis and characterization of 1-(9H-carbazol-9-yl)-3-(4-
methoxy-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-
methylenepropane (14). To a stirred solution of 13a (0.5 g, 1.16
mmol) in THF–MeOH mixture (40 mL, 1 : 3) at room
temperature was added MeONa (500 mg, 9.3 mmol). The
reaction mixture was refluxed for 6 h. Removal of solvent
under reduced pressure gave a white residue, which was treated
with 100 mL of chloroform–water (1 : 1) mixture. The organic
layer was collected and the aqueous layer was washed two times
with 100 mL of chloroform (2 ꢁ 50 mL). Organic layers were
combined, washed with 200 mL of water (2 ꢁ 100 mL) and
dried over anhydrous sodium sulfate. The residue by the
removal of chloroform under reduced pressure was purified by
column chromatography on silica gel using mixture of ethyl
acetate–hexane to pure give 14.
Another figure shows part of an infinite vertical stack con-
sisting of three molecules attached to each other by intermolec-
ular p–p interactions (Fig. 3). On one side of the stack,
additional intermolecular CH/S dimerization also takes place.
In other words any molecule in the stack on one side is bound to
other molecule by intermolecular p–p interaction while on the
other side of the molecule it is held together with other molecule
by both p–p interaction and CH/S dimerization. Another
figure shows three such vertical stacks attached to each other on
sides by intermolecular CH/S interactions (ESI, Fig. S14).†
Three packing figures of 1a for comparison with 7a are also
shown (ESI, Fig. S16–S18).† The first depicts the tetramer
formed by CH/N interactions and the second shows another
tetramer formed by CH/N, CH/S and S/S interactions. Such
tetramers are not formed in 7a.
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Table 1 Crystallographic data and structural refinement summary
7a
9a
12
13a
14
Chemical formula
Formula weight
T/K
C18H20N8S4
476.66
294(2)
Triclinic
ꢁ
P1
9.122(5)
9.560(5)
14.181(5)
102.828(5)
102.183(5)
107.820(5)
1094.9(9)
2
1.446
0.46
27.97
9810
C18H20N8S4
476.66
293(2)
Orthorhombic
Pbcn
16.357(3)
10.062(2)
13.506(3)
90.00
90.00
90.00
2223.0(8)
4
1.424
0.45
27.69
23923
2669
2309
139
C28H22N2
386.48
100(2)
Monoclinic
P21
9.3786(17)
23.547(4)
18.543(3)
90.00
90.617(3)
90.00
4094.6(13)
8
1.254
0.07
26.39
26700
10348
7806
1081
C23 H21N5S2
431.57
296(2)
Monoclinic
P21/n
10.1518(10)
8.7585(9)
24.492(3)
90.00
101.961
90.00
2130.4(4)
4
1.346
0.27
26.96
20703
4931
3446
273
C23H21N5OS
415.51
293(2)
Triclinic
ꢁ
P1
8.5125(5)
10.6289(7)
11.9705(8)
70.965(3)
81.944(3)
86.356(3)
1013.56(11)
2
1.361
0.19
30.92
26405
Crystal system
Space group
ꢀ
a/A
ꢀ
b/A
ꢀ
c/A
a/ꢀ
b/ꢀ
g/ꢀ
V/A
Z
3
ꢀ
rcalcd/g cmꢂ1
m/mmꢂꢀ1
2qmax
/
Total reflections
Unique reflections
Reflections I > 2s(I)
Parameters
3490
3197
275
6438
5032
273
Rint
R [F, I > 2s(I)]
wR (F2, all data)
0.0161
0.0369
0.1017
0.022
0.0371
0.1066
0.0478
0.0627
0.2046
0.0553
0.0434
0.1224
0.0252
0.0437
0.1270
Fig. 2 ORTEP diagram of 7a (at 30% probability level) showing p–p
interactions with atomic labelling scheme.
Fig. 3 Part of the vertical columns of 7a formed as a result of p–p, and
C–H/S interactions.
Encouraged by this finding, next we decided to make an
important symmetrical compound, a purine analog (9a) of 7a,
having the 2,6-dimethylsulfanyl-9H-purinyl residue in place of
the pyrazolo[3,4-d]pyrimidine of 7a. The new compound 9a (N9–
N9 isomer, purine numbering) was prepared along with two other
positional isomers (9b, N7–N9 and 9c, N7–N7) following similar
procedure as described earlier for the synthesis of 7a except that
2,6-dimethylsulfanyl-9H-purine (8)18 was used in place of 4,6-
dimethylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (6). The new
compound 9a also shows up-field shift for one methylsulfanyl
Once again folding is due to intramolecular p–p stacking. The
four important distances defining the geometry of 9a are shown
in Fig. 4 and are very comparable with corresponding distances
of 7a confirming structural similarity of both compounds at
molecular level. Interestingly, this geometry is quite different
from that of 1,3-bis(Ad)propane,3 presumably due to different
substitution pattern in two compounds.
At a supramolecular level, the formation of infinite vertical
stacks due to intermolecular p–p interactions similar to pyr-
azolo[3,4-d]pyrimidine analogue 7a also takes place. In addition
to infinite vertical column due to p–p stacking infinite chain
formation due to CH/N also takes place. Both of these inter-
actions result in the formation of a + motif which is shown in
1
protons in its H NMR spectrum clearly indicating that new
compound 9a is also in folded conformation (ESI, Fig. S4, S12).†
Solid state structure determined by X-ray crystallography is
shown in Fig. 4. The compound has crystallographically imposed
twofold symmetry with the C11]C12 bond on the twofold axis.
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Fig. 4 ORTEP diagram of 9a (at 30% probability level) showing p–p
interactions with atomic labelling scheme. The additional ‘‘A’’ letters in
the atom labels indicates that these atoms are at equivalent position (1 ꢂ
x, y, 1/2 ꢂ z).
Fig. 6 ORTEP diagram of 12 (at 30% probability level) showing open
conformation stabilized by CH/p interactions with atomic labelling
scheme.
Fig. 5. As a chain motif is not present in 7a therefore the + motif
is also absent. It is important to mention here that our earlier
efforts in crystallizing corresponding propylene linker analogue
of new compound 9a were not successful. To the best of our
knowledge this is the first purine based compound with this
linker whose solid state structure is reported by X-ray crystal-
lography. It is important to emphasize that both compounds (7a
and 9a) are isomeric and show very comparable ORTEP
diagrams, however, their detailed packing shows that from
crystal engineering point of view they are quite different.
state open conformation for the compound 12 containing elec-
tron rich carbazole residue is not surprising as 1,3-bis(carbazol-9-
yl)propane (propylene linker analog of 12) is known to exist in
open conformation in solid state without intramolecular p–p
interactions by X-ray crystallography.19 The open conformation
of 12 is stabilized by intramolecular C–H/p interactions
(Fig. 6). In fact, The distance between two N atoms connecting
ꢀ
two carbazole units in 12 is much larger (4.29 A) as compared to
ꢀ
3.30 A seen in the two earlier folded compounds (7a and 9a).
More importantly, this also confirmed that the new linker like
propylene linker does not dictate intramolecular stacking but
merely facilitates folded conformation if arene moieties in
question have tendency for intramolecular p–p interactions.
Recently, open conformation in the solid state for one symmet-
rical compound with the same linker having hydroxy-quinoline
residue as an arene moiety has been reported by X-ray crystal-
lography.20 Though several compounds based on this linker have
been used as starting material for the synthesis of cyclophanes
X-ray crystallographic studies on starting mono linker
compounds were not reported.21
Satisfied with the results of these two butylidene linker
compounds (7a and 9a) we decided to extend the use of this linker
to dissymmetrical compounds in which one PP core of 7a is
replaced by electron-rich carbazole to give the dissymmetrical
compound. Thus, reaction of carbazole (10) with methallyl
dichloride in the presence of sodium hydride gave the desired
halide 11 along with symmetrical 12 in good yield (Scheme 1).
1
The H NMR shows the possibility of folded conformation in
solution for 12 (ESI, Fig. S8),† however, X-ray crystallography
shows open conformation (Fig. 6). There are four independent
molecules in the asymmetric unit and one of these (the one with
the central C15]C16 double bond) is shown in Fig. 6. The solid
Finally, the desired dissymmetrical compound was prepared in
which one pyrazolo[3,4-d]pyrimidine moiety of 7a has been
replaced by electron rich carbazole residue to give the dissym-
metrical compound 13a (Scheme 1). The new compound 13a
shows up-field shift for one methylsulfanyl protons in its 1H
NMR spectrum clearly indicating that it is in folded conforma-
tion (ESI, Fig. S9).† The solid-state structure of 13a, as deter-
mined by X-ray crystallography, is shown in Fig. 7. Once again
folding is due to intramolecular p–p interactions and the
distance between two N atoms connecting two arene units is
ꢀ
ꢀ
much smaller (3.08 A) as compared to 3.29 and 3.30 A seen in
two earlier folded compounds respectively. This result is signifi-
cant as dissymmetrical compounds like this may considerably
increase the scope of butylidene linker in comparison to earlier
propylene linker for studying arene interactions in dissym-
metrical compounds for their application to crystal engineering.
Interestingly, second phenyl ring of carbazole (whose centroid is
not shown in Fig. 7) does not show any favourable distance for
intramolecular p–p interactions from PP core. In fact, two
Fig. 5 Part of the + motif of 9a formed as a result of p–p, and C–H/N
interactions.
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important crystallographic data of three folded compounds (7a,
9a and 13a) along with reference compound (1a) is given in Table
2. Perusal of data in column two (Table 2) shows that distance
between two N atoms connecting butylidene linker of dissym-
ꢀ
metrical compound (13a) is much less (3.08 A) in comparison to
same distance in two other symmetrical compounds (7a: 3.29 and
ꢀ
9a: 3.30 A). Interestingly, distance between two N atoms con-
necting butylidene linker of symmetrical compounds (7a and 9a)
is very similar to corresponding distance in symmetrical
propylene linker compound (1a). We believe involvement of two
different ring systems of which one is electron rich carbazole and
other is electron deficient PP is responsible for smaller distance
between two N atoms in 13a as compared to corresponding
distance in three symmetrical compounds (1a, 7a and 9a). On the
other hand angle between the least-squares planes (last column of
Table 2) is quite comparable for all four compounds highlighting
the subtle role played by different linker/rings for intramolecular
folding.
Fig. 7 ORTEP diagram of 13a (at 30% probability level) showing p–p
interactions with atomic labelling scheme.
molecules of 13a dimerize via C–H/p interaction involving such
phenyl rings from two different molecule (ESI, Fig. S19).†
Lastly, to study substituent effect on arene interaction, the 4-
methylsulfanyl group of 13a was replaced by the common elec-
tron donating methoxy group. The new compound 14 also shows
an up-field shift for methylsulfanyl protons in its 1H NMR
spectrum clearly indicating that the new compound 14 is also in
a folded conformation in solution (ESI, Fig. S11).† The solid-
state structure of 14, as determined by X-ray crystallography, is
shown in Fig. 8. Surprisingly, 14 showed open conformation
while similar changes were well tolerated in symmetrical
compounds (1d, 1e and 1j, Fig. 1). The two compounds 13a and
14 constitute a unique pair where mere replacement of 4-methyl-
sulfanyl group by common electron donating methoxy group
opens the folded conformation of 13a. The distance between two
4. Conclusions
In conclusion, an alternative conformationally less mobile three
carbon linker (butylidene) for the established propylene/Leonard
linker, to study arene interaction in both symmetrical and dis-
symmetrical flexible compounds has been reported for the first
time. Two symmetrical compounds (7a and 9a) prepared with the
new linker with an electron deficient PP core and isomeric purine
system at its termini show intramolecular stacking due to p–p
1
interactions both by H NMR in solution and X-ray crystallog-
ꢀ
ꢀ
raphy in the solid. Thirdly, the symmetrical compound (12) with
the new butylidene linker and electron rich carbazole core shows
an open conformation by 1H NMR in solution without any
intramolecular stacking due to p–p interactions. Two new dis-
symmetrical flexible compounds (13a and 14) differing only in
one substituents (SMe/OMe) show intramolecular folding by 1H
NMR in solution, which carries over to the solid state only for
one with the SMe substituent as revealed by X-ray crystallog-
raphy. A first advantage of the butylidene linker over the
propylene linker in solution can be seen from Fig. S12 (ESI)†,
which clearly shows an increased up-field due to intramolecular
stacking. Second advantage is getting good diffraction quality
crystals presumably due to reduced freedom in butylidene linker
mobility which is significant from crystal engineering point of
view. We believe this butylidene linker together with propylene/
Leonard linker can provide easy access to variety of new ‘pro-
tophanes’ for better understanding of difficult to understand p–
p interactions and their application to crystal engineering.
Most importantly, the new butylidene linker opens access to
dissymmetrical compounds (13a and 14) having electron-rich
carbazole and electron poor PP cores, for the first time, thus
promising to be good linkers for a better understanding of
substituent effect in arene interactions in flexible models in
comparison to propylene linker and/or other biased models in
literature. Currently, work is in progress to determine the scope
and generality of the new butylidene linker for a better under-
standing of arene interactions so that they can be used efficiently
for crystal engineering and will be reported in the future.
N atoms connecting two arenes is 4.02 A as compared to 4.29 A
seen in earlier symmetrical open compound (12). This reduction
of distance between two N atoms, is presumably due to intra-
ꢀ
molecular CH/N interaction (2.80 A, Fig. 8). Most likely,
ꢀ
ꢀ
dimerization due to CH/O interactions (2.63, 3.42 A and 143 )
involving electron donating methoxy groups in place of meth-
anesulfanyl groups of 13a is the reason for the absence of
intramolecular folding in 14 (ESI, Fig. S20).† Further work with
other substituents (electron donating/withdrawing) will be done
to understand reasons for this dramatic result. For comparison
Fig. 8 ORTEP diagram showing molecular structure of 14 (at 30%
probability level) with atomic numbering.
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Table 2 Important geometrical data obtained from X-ray crystallographic studies
Distance between
two N atoms
ꢀ
connecting linker/A
Intramolecular p–p
Intermolecular p–p
, ,
Angle between the
least-squares planes/ꢀ
stacking distancea b c d/A
stackinga b c distance/A
,
,
,
ꢀ
ꢀ
Compound no.
1a
7a
9a
13a
3.27
3.29
3.30
3.08
3.71a, 3.94c
3.67a, 3.59b, 3.54c
3.56b, 3.68b,3.60c, 3.64c
3.54b, 3.53c
13.17
13.83
13.53
13.79
3.69a, 3.94c
3.66a, 3.92c
3.53a, 3.78d, 3.93e, 3.87f
Not observed
a
b
Distance between centroids of six membered rings. Distance between centroids of five and six membered rings of two pyrazolo[3,4-d]pyrimidines.
c
d
Distance between centroids of nine membered rings of two pyrazolo[3,4-d]pyrimidines. Distance between centroids of nine membered ring of
e
pyrazolo[3,4-d]pyrimidine and thirteen membered ring of carbazole. Distance between centroids of five membered ring of pyrazolo[3,4-
f
d]pyrimidine and six membered ring of carbazole. Distance between centroids of six membered ring of pyrazolo[3,4-d]pyrimidine and five
membered ring of carbazole.
13 C. A. Hunter and J. K. M. Sanders, J. Am. Chem. Soc., 1990, 112,
5525.
Acknowledgements
14 (a) S. A. Arnstein and C. D. Sherrill, Phys. Chem. Chem. Phys., 2008,
10, 2646; (b) E. C. Lee, B. H. Hong, J. Y. Lee, J. C. Kim, D. Kim,
Y. Kim, P. Tarakeshwar and K. S. Kim, J. Am. Chem. Soc., 2005,
We are very grateful to one referee for bringing our attention to
problems in X-ray data collection/processing of three
compounds. Amantullah Ansari is thankful to CSIR, New Delhi,
India for a fellowship (SRF). We are thankful to SAIF, CDRI,
Lucknow for providing spectral data. This paper has CDRI
communication no. 7907.
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