A modular approach towards functionalized highly stable self-complementary quadruple hydrogen bonded systems

Article abstract of DOI:10.1039/c7ob02358h

Self-complementary quadruple hydrogen bonded systems have shown potential as key building blocks for developing various supramolecular polymers. Opportunities for the introduction of multiple functionalities would further augment, in principle, their application potential. Herein, we report a novel modular approach to simultaneously introduce two closely aligned side chains into AADD-type self-complementary quadruple hydrogen-bonding systems. Dithiane-tethered ureidopyrimidinone has been used as a reactive intermediate to efficiently attach closely aligned side chains by simply reacting with amines to form highly stable molecular duplexes. These duplexes featuring AADD-type arrays of hydrogen bonding codes are highly stable in non-polar solvents (K_dim > 1.9 × 10⁷ M^-1 in CDCl₃) as well as in polar solvents (K_dim > 10⁵ in 10% DMSO-d₆/CDCl₃). Another notable feature of these self-assembling systems is their insensitivity to prototropy-related issues owing to their prototropic degeneracy, which will enhance their application potential in supramolecular chemistry.

Full text of DOI:10.1039/c7ob02358h

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DOI: 10.1039/C7OB02358H
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A Modular Approach Towards Functionalized Highly Stable Self-
complementary Quadruple Hydrogen Bonded Systems†
Suresh Rayavarapu,a Sanjeev Kheria,a Dinesh R. Shinde,b Rajesh G. Gonnade,c and
Gangadhar J. Sanjayan*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Self-complementary quadruple hydrogen bonded systems have shown potential as key building blocks for developing
various supramolecular polymers. Opportunities for introduction of multiple functionalities would further augment, in
principle, their application potential. Herein, we report a novel modular approach to simultaneously introduce two closely
aligned side chains into AADD-type self-complementary quadruple hydrogen-bonding systems. Dithiane-tethered
ureidopyrimidinone has been used as a reactive intermediate to efficiently attach closely aligned side chains by simply
reacting with amines to form highly stable molecular duplexes. These duplexes featuring AADD-type array of hydrogen
bonding codes are highly stable in non-polar solvent (Kdim > 1.9 x 107 M-1 in CDCl3) as well as in polar solvent (Kdim > 105 in
10% DMSO-d6/CDCl3). Another notable feature of these self-assembling systems is their insensitivity to prototropy-related
issues owing to prototropic degeneracy, which will enhance their application potential in supramolecular chemistry.
www.rsc.org/
known to form strong AADD-type hydrogen bonded duplexes.
However, it is noteworthy that these aforementioned
heterocyclic-based systems are often associated with the
Introduction
Multiple hydrogen bonded arrays, particularly, AADD-type self
complementary systems, have received an increasing attention
from the last two decades owing to their specificity, strength,
directionality and easy synthetic accessibility.1 These systems
have been used to develop different non-covalent
supramolecular architectures that have potential applications
in supramolecular polymers,2 molecular recognition3 and
prototropy-related demerits, thereby limiting the applications
of these systems in supramolecular chemistry.7c Further
research in this area by various groups led to the development
of new AADD-type self-assembling modules devoid of
prototropy with promise for diverse applications.9
Despite the considerable progress achieved in the last two
decades in this field, the synthesis of various supramolecular
assemblies has been mainly based on ureidopyrimidinone
(UPy) systems which are often associated with
tautomerization.7c In view of the range of properties required
from supramolecular materials, there is a need for developing
new quadruple hydrogen bonding systems with attractive
features, such as high dimerization constant, easy synthetic
accessibility, tailorability and prototropy-free assembly.
supramolecular
electronics.4
Construction
of
these
supramolecular assemblies is of fundamental importance for
mimicking bimolecular structures and thereby understanding
the functions of natural systems.5 Due to their significance in
supramolecular chemistry, different types of quadruple
hydrogen bonded systems have been developed and studied
extensively.6
Amidst the myriad quadruple hydrogen bonding systems
developed till date, ureidopyrimidinone-based (UPy) self-
assembling systems developed by Meijer group,7 have been
extensively utilized in various applications, due to their high
stability and easy synthetic accessibility. Analogous to UPy,
deazapterin-based self-assembling systems (DeAP)8 are also
Herein we report a new class of UPy-based motif
unique feature of tethered dithiane unit which can serve as
toolbox for the preparation of self-assembled systems
1 with a
2
featuring inbuilt AADD-type self-complementary array (Fig. 1).
As proof-of-principle, the dithiane intermediates were reacted
with various amines to form highly stable and prototropy-free
molecular duplexes - stable in non-polar solvent such as CDCl3
and relatively stable in polar solvents (10% DMSO-d6/CDCl3).
a.Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL), Dr
Homi Bhabha Road, Pune-411008, India. E-mail: gj.sanjayan@ncl.res.in; Fax:
+91-20-25902629; Tel: +91-20-25902082.
b.Central NMR Facility, CSIR-National Chemical Laboratory (CSIR-NCL), Dr Homi
Bhabha Road, Pune-411008, India.
c. Centre for Materials Characterization, CSIR-National Chemical Laboratory (CSIR-
NCL), Dr. Homi Bhabha Road, Pune-411008, India
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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The synthesis of 10a,b was accomplished by reacting 9a,b in
R
H
DMSO with an excess of carbon disulphide and triethylamine
at room temperature, followed by the treatment of reaction
mixture with 1,3-dibromopropane in DMSO.11 Further 10a
,b
S
O
N
O
O
N
H
R
H
S
R
N
N
O
N
H
N
N
O
R
S
R
O
H
N
N
H
N
N
H
N
H
N
H
N
H
R-NH2
were reacted with corresponding amines in DMSO, to get
AADD-type self-assembling systems 3a-h in excellent yields.
Formation of the AADD-type self-complementary molecular
duplex by 3d and 3e was studied in detail by 1H NMR
experiments. 1H and 13C NMR spectra of 3e in CDCl3 clearly
showed a single set of well-resolved signals, which suggested
the formation of strong molecular duplex (Fig. 2).The
formation of strong duplex of 3e was quickly evident from the
downfield shift of urea NHs at 11.52 and 9.78 ppm; suggesting
that the urea NH protons are involved in strong intermolecular
hydrogen bonding. Additionally, the signals at 13.66, 12.79 and
12.60 ppm are due to intramolecular S(6)-type hydrogen
bonding that facilitates self-assembly by the pre-organization
of AADD-type H-bonding codes.
H
N
H
N
N
O
N
O
R
H
N
O
O
H
H
R
O
S
O
N
H
R
1
2
Fig. 1 Dithiane-functionalized reactive AADD-type self-assembling motif (left) and
amine-coupled highly stable self-assembled duplex (right), reported in this work. Note:
The side chains can be arranged in a parallel fashion on the self-assembling motif, as
depicted by the arrows.
Results and discussion
The urea intermediate
three-step process (Scheme 1). The 2-amino-4,6-
dichloropyrimidine was obtained by reacting 2-amino-4,6-
dihydroxypyrimidine with POCl3 and Et3N in acetonitrile
under reflux conditions. Subsequently, was converted to its
isocyanate10, by treatment with oxalyl chloride, in refluxing
benzene. The highly reactive and unstable isocyanate was
treated with amines at room temperature to afford urea
intermediate . Conversion of 7a to 9a via direct hydrolysis
7 could be efficiently synthesized via a
NH5 NH1
NH2
NH3
NH4
5
4
5
15.0
14.5
14.0
13.5
13.0
12.5
12.0
11.5
11.0
10.5
10.0
9.5
Chemical Shift (ppm)
6
NH5
7
,
b
,b
NH1
of chloro substituent proved difficult and resulted in mono
hydroxy compound. Therefore, an alternative two-step
NH4
strategy was adopted in which 7a
followed by demethylation under HBr/acetic acid condition,
resulting in good yields of 9a
,b were methoxylated
NH2 NH3
,b.
Cl
OH
Cl
ii
i
N
iib
N
N
180
160
140
120
100
80
60
40
20
Cl
N
NH2
HO
N
4
NH2
Chemical Shift (ppm)
Cl
iv
N
6
NCO
5 (85%)
OMe
Fig. 2 1H excerpts [top (500 MHz)] and 13C [bottom (125 MHz)] spectra of 3e in CDCl3
OH
Cl
showing single set of well-resolved signals.
N
O
N
O
N
O
iii
)
R1
R1
R1
Cl
N
N
N
H
HO
N
N
H
N
H
MeO
N
N
H
N
The dimerization property of compounds 3d and 3e were
examined by 1H NMR dilution experiments. Upon dilution of
the CDCl3 solution of 3d from 100 mM to 10 µM, no changes
were observed in the chemical shift values of urea protons.
Similarly, the dilution of CDCl3 solution of 3e didn’t afford any
change in chemical shift of urea protons (ESI,† Fig. S15 and S20
for 3d and 3e, respectively). The dilution experiments showed
that both 3d and 3e remain as dimer with high dimerization
constant even at a very low concentration in CDCl3. Assuming a
conservative estimate of more than 95% dimer formation at
the lowest concentration studied (10 µM), the Kdim value of 3d
and 3e was estimated to be at a lower limit of 1.9 × 107 M-1 in
CDCl3.
H
H
9a R1= 2-ethylhexyl (75%)
9b
7a
7b
R1= 2-ethylhexyl (65%
R1= dodecyl (63%)
8a R1= 2-ethylhexyl (95%)
8b
R1= dodecyl (79%)
R1= dodecyl (94%)
R2
H
O
S
O
N
N
O
v
R2
vi
H
H
S
N
O
N
N
O
R1
H
R1
N
O
N
H
N
N
N
H
H
H
3a
R1= dodecyl, R2= cyclohexyl, 77%
3b R1= dodecyl, R2= isobutyl, 90%
3c R1= dodecyl, R2= aniline, 87%
3d R1= 2-ethylhexyl, R2= 2-ethylhexyl, 85%
3e R1= 2-ethylhexyl, R2= 3,4,5(dodecyloxy)benzene, 60%
R1= 2-ethyhexyl, R2= 6-hexanol. 80%
R1= 2ethylhexyl, R2= hexyl-4-(pyren-1-yl)butanoate, 60%
R1= 2ethylhexyl, R2 = dodecyl, 93%
10a R1= 2-ethylhexyl (88%)
10b
)
R1= dodecyl (85%
3f
3g
3h
vii
To further support the strong duplex formation of these
Scheme 1 Synthesis of compounds 3a-h. Reagents and conditions: (i) POCl3, Et3N,
CH3CN, reflux, 1 h; (ii) a) (COCl)2, C6H6, reflux, 2 h, b) R1-amine, C6H6, RT, 18 h; (iii) K2CO3,
MeOH, reflux, 6 h; (iv) HBr in AcOH, reflux, 1 h; (v) Et3N, CS2, 1,3-dibromopropane,
DMSO, 0 oC-RT, 6 h; (vi) R2-amine, DMSO, 0 oC-80 oC, 4 h; (vii) 1-pyrenebutyric acid,
EDC.HCl, DMAP, DCM, 0 oC-RT, 6 h
compounds, we studied the dimerization of 3d
·3d and 3e
·3e in
various DMSO-d6/CDCl3 mixtures. The Kdim values of 3d
·3d and
3e·3e were determined quantitatively in the range from 5% to
30% DMSO-d6/CDCl3 (v/v) mixtures by 1H NMR dilution
experiments (table 1).
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Table 1 Dimerization constants (Kdim) of the duplex 3d·3d and 3e·3e in various DMSO-
d6/CDCl3 mixtures at 298 K.
3e in CDCl3 provided the most diagnostic nOes and these
strong nOes suggest the formation of homodimer structures in
solution. The characteristic nOe between NH2 and NH3
protons of 3e suggested their linear arrangement while the
cross-strand nOes between NH3 and NH4, and NH3 and
DMSO-d6/CDCl3
Kdim (M-1)of 3d·3d
Kdim (M-1) of 3e·3e
5%
>105
>105
>105
10%
20%
30%
>105
>105
(2.09 ± 0.195) × 102
aromatic
proton
confirmed
the AADD-type self-
(2.25 ± 0.12) × 10
-
complementary dimer formation in solution (ESI,† Figures S12
Nonlinear regression analysis12 of the chemical shift of 3d gave and S13). In the HRMS-ESI spectrum of 3d, in addition to
a dimerization constant Kdim value of (2.25 ± 0.12) x 10 in 30% protonated molecular ion peak (M+H)+, signals corresponding
DMSO-d6/CDCl3 and (2.09 ± 0.195) x 102 for 3e in 20% DMSO- to the dimer (2M+H)+ was also found, further supporting the
d6/CDCl3 (ESI,† Fig. S20 and S25 for 3d and 3e, respectively). In duplex formation (ESI,† page S24).
case of 3d, we observed negligible chemical shift changes of
urea protons in 5%, 10% and 20% DMSO-d6/CDCl3 mixtures
(ESI,† Figures S16, S17 and S18, respectively). For 3e in 5% and
10% DMSO-d6/CDCl3 mixtures (ESI,† Fig. S22, S23), we
observed negligible chemical shift changes of urea protons. For
3d and 3e, Kdim values were estimated to be at a lower limit of
105 M-1 under these conditions. These findings suggest that the
self-assembled duplexes are highly stable even in DMSO-
d6/CDCl3 mixtures without any prototropy issues, although
DMSO is considered to be a highly competitive hydrogen bond
breaker.
1
Variable temperature H NMR studies carried out in the range
243-323 K provided further evidence for the strong stability of
molecular duplexes. Urea protons of these compounds NH2 (-
1.85 ppb K-1 for 3a, -1.30 ppb K-1 for 3c and -1.62 ppb K-1 for
3d) and NH3 (-1.20 ppb K-1 for 3a, 2.50 ppb K-1 for 3c and 1.80
ppb K-1 for 3d
) showed small temperature coefficients
indicative of strong intermolecular hydrogen bonding. These
values indicate very high stability of the molecular duplexes
(ESI,† Figures S1, S3 and S5 for 3a, 3c and 3d, respectively).
In addition to NMR methods, the stability of these duplexes
was also investigated by fluorescence spectroscopy using
pyrene-appended self-assembling system 3g. Pyrene is well
known to form an excimer species in solution, featuring
emission band that is well separated from its monomer
emission band.13 The dimerization constant of the pyrene
labeled 3g was determined by a method, that was previously
reported by the Meijer group.7b Concentration-dependent
changes in the emission intensities of pyrene eximer band at
490 nm appeared in the range of 10-9 to 10-7 in chloroform.
Non-linear regression analysis of the fluorescence data of
compound 3g gave a dimerization constant Kdim value of (3.44
± 3.11) x 108 M-1 in chloroform (ESI,† Fig. S27 and S28).12a
Compounds 3a, 3c and 3f, indeed form AADD-type duplex
formation in the solid-state, as clearly evident from their single
X-ray crystal analysis (Fig. 3).14 Comparison of X-ray crystal
structures of these compounds reveals that all three
compounds form dimers through four C(4)-type intermolecular
hydrogen bonds. The urea functionality is in trans-trans
geometry, and three intermolecular S(6)-type hydrogen bonds
preorganize the AADD array of duplexes.15 In all cases, the
AADD array of duplexes slightly deviates from linearity and
outer N-H···O hydrogen bonds being somewhat shorter than
inner N-H···N hydrogen bonds.
Fig. 3 Single-crystal X-ray structure of dimer 3a (a), dimer 3c (b) and dimer 3f (c).
Hydrogen bonding highlighted in dashes (salmon colored), above which hydrogen bond
lengths (N-H···O and N-H···N) are displayed in Å. All hydrogens, other than those at the
hydrogen-bonding sites, have been removed for clarity.14
Dimer formation by 3d and 3e was further investigated by 2D
NMR and HRMS-ESI studies. 2D NOESY NMR studies of 3d and
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Ureidopyrimidone-based self-assembling systems (UPy) are
known to form heterodimer with 2,7-diamido-1,8-
naphthyridine (Napy).7a It had been shown that formation of
heterodimers with Napy may have significant applications,
owing to the possibility for the construction of supramolecular
co-polymers. In this context, we investigated the potential of
heterodimerization between 3h and 11 (Fig. 4).
Conclusions
In conclusion, we have successfully developed a new class of
dithiane-tethered AADD-type quadruple hydrogen bonding
systems, which were further reacted with different amines to
form highly stable self–complementary motifs devoid of
prototropy. These systems are highly stable in non-polar
solvents and relatively stable in polar solvents as well. The
dimerization constants of duplexes were determined
quantitatively by 1H NMR dilution studies and also by
fluorescence spectroscopy. These highly reactive systems
having in-built AADD-array may have potential application in
the preparation of non-covalent supramolecular assemblies.
Furthermore, the formation of heterodimers with Napy may
have practical applications in constructing supramolecular
copolymers. Currently, we are exploring the utility of these
systems in constructing different non-covalent assemblies and
will report the results in due course.
Experimental
General information
Unless otherwise stated, all the chemicals and reagents were
Fig. 4 Formation of heterodimer 3h·11
obtained commercially. Compound 5 17 compound 7a18 and
,
compound 116a were synthesized as per the reported
procedures. Dry solvents were prepared by the standard
procedures. Analytical Thin Layer Chromatography was done
on precoated silica gel plates (Kieselgel 60F254, Merck). Column
chromatographic purifications were done with 100-200 mesh
silica gel. NMR spectra were recorded in CDCl3 on AV 400 MHz,
AV 500 MHz and AV 700 MHz Bruker NMR spectrometers. All
Addition of 1 equiv. of 2,7-diamido-1,8-naphthyridine 11 to a
solution of homodimer 3h
homodimer to dissociate to form a heterodimer 3h
evident from the 1H NMR spectrum. 1H NMR clearly showed
one set of new signals for heterodimer 3h 11 and another set
of signals for homodimer 3h 3h (ESI,† Figure S7) and the yield
of heterodimer 3h 11 was determined to be ~ 75%, at ambient
·
3h in CDCl3 caused most of the
·
11, as
·
·
·
chemical shifts are reported in
δ ppm downfield to TMS and
temperature (298 K), based on the relative integrating
intensity of methylene protons (attached to NH4 and NH5)
signals of both dimers. Dilution of the CDCl3 solution of 1:1
mixture of 3h and 11 resulted in the up-field shift of NH6 signal
peak multiplicities are referred to as singlet (s), doublet (d),
quartet (q), broad singlet (bs), and multiplet (m). The titration
studies were done in CDCl3. Elemental analyses were
performed on an Elmentar-Vario-EL (Heraeus Company Ltd.,
Germany). IR spectra were recorded in CHCl3 using Shimadzu
FTIR-8400 spectrophotometer. Melting points were
determined on a Buchi Melting Point B-540. HRMS (ESI) data
were recorded on a Thermo Scientific Q-Exactive, Accela 1250
pump. MALDI-TOF/TOF mass spectra were obtained from
ABSCIEX TOF/TOFTM 5800 mass spectrometer. Yields
mentioned are isolated yields.
of heterodimer 3h·11. The chemical shift data of NH6 fit well
into an 1:1 binding isotherm giving an association constant Ka
value of 2.38 x 102 M-1 in 10% DMSO-d6/CDCl3 for heterodimer
3h
The formation of heterodimer 3h
2D NMR studies in CDCl3. 2D ROESY NMR studies of 3h
·
11 (ESI,† S26).16
·
11 was further confirmed by
11 gave
·
the most diagnostic ROE for the formation of heterodimer in
solution. The characteristic intermolecular ROE between NH1
and NH6 confirmed the heterodimer formation in the solution
Synthetic procedures
1
state (ESI,† Figure S14). Variable temperature H NMR studies
Compound 7b. Following the same procedure for synthesis of
compound 7a18 and using dodecylamine (2.54 mL, 11.00
mmol, 1 equiv.), 7b was synthesized. Purification by column
chromatography (eluent: 10% AcOEt/pet. ether, Rf: 0.4)
yielded 7b (2.5 g, 63%) as a white fluffy solid. IR (CHCl3) ν (cm-
1): 3416, 3319, 3121, 3018, 2926, 2854, 1696, 1577, 1549,
1498, 1243, 1216, 1102, 771, 667; 1H NMR (500 MHz, CDCl3) δ:
8.42 (s, 1H), 7.59 (s, 1H), 6.97 (s, 1H), 3.40-3.36 (m, 2H), 1.65-
1.59 (m, 2H), 1.41-1.26 (m, 18H), 0.90-0.87 (t, J = 6.3 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ: 161.9, 157.3, 152.7, 113.5, 40.2,
31.8, 29.6, 29.5, 29.4, 29.3, 29.2, 26.9, 22.6, 14.0; HRMS (ESI)
calculated [M+H]+ for C17H29ON4Cl2: 375.1722, found 375.1713.
(ranging from 243-323 K, ESI,† Figure S8) of 3h·11 provided
evidence for high stability of heterodimer. Increasing the
solution temperature to 323 K resulted in the sharpening of
the NH signals. On the contrary, decreasing the temperature
facilitated the formation of heterodimer 3h
·11, as anticipated.
The yield of heterodimer 3h·11 was determined to be ~ 92%,
at 243 K, based on the relative integrating intensity of the
methylene protons (attached to NH4 and NH5) signals of both
dimmers.
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Compound 8a. A solution containing 7a (2 g, 6.287 mmol, 1 Compound 10a. To a solution of 9a (1 g, 3.543 mmol, 1 equiv.)
equiv.) and K2CO3 (2.61 g, 18.861 mmol, 3 equiv.) in 30 ml in 15 ml of dry DMSO at 0 oC, Et3N (1.038 mL, 7.441 mmol, 2.1
MeOH was refluxed for 6 h. After completion of reaction, the equiv) and CS2 (0.703 mL, 11.690 mmol, 3.3 eqiv.) were added
mixture was concentrated under reduced pressure. The dropwise and the reaction mixture was stirred for 2 h at room
residue was partitioned between DCM and water. The organic temperature. A solution of 1, 3-dibromopropane (0.359 mL,
layer was separated, washed with water, brine solution, dried 3.541 mmol, 1 eqiv.) in DMSO (15 mL) was added drop wise to
o
over Na2SO4, filtered and concentrated in vacuo. Purification the above reaction mixture at 0 C. The reaction mixture was
by column chromatography (eluent: 3% MeOH/DCM, Rf : 0.4) stirred for 4 h at room temperature and then poured in to 200
afforded 8a (1.89 g, 95%) as a fluffy white solid. IR (CHCl3) ν mL cold water. The resulting solid was filtered and rinsed with
(cm-1): 3431, 3291, 3009,2960, 2930, 2873, 1688, 1598, 1548, cold water and dried under vacuum giving 10a (1.25 g, 88%) as
1453, 1416, 1375, 1357, 1266, 1216, 1195, 1165, 811, 766, a yellow solid. mp: compound decomposes above 260 oC; IR
666; 1H NMR (400 MHz, CDCl3) δ: 8.75 (s, 1H), 7.32 (s, 1H), 5.66 (Nujol) ν (cm-1): 3209, 1697, 1653, 1607, 1526, 1462, 1395,
1
(s, 1H), 3.87 (s, 6H), 3.34-3.29 (m, 2H), 1.50-1.49 (m, 1H), 1.40- 1378, 1305, 1278, 1251, 1178, 1152, 796, 774; H NMR (400
1.30 (m, 8H), 0.92-0.88 (m, 6H); 13C NMR (100 MHz, CDCl3) δ: MHz, CDCl3) δ: 12.59 (s, 1H), 11.57 (s, 1H), 9.56 (s, 1H), 3.23-
171.5, 156.9, 154.1, 83.1, 54.0, 42.9, 39.6, 31.0, 28.8, 24.1, 3.20 (m, 2H), 3.00-2.95 (m, 4H), 2.42-2.35 (p, 2H), 1.44-1.31
23.0, 14.0, 10.7; HRMS (ESI) calculated [M+H]+ for C15H27O3N4: (m, 9H), 0.93-0.89 (m, 6H); 13C NMR (100 MHz, CDCl3) δ: 195.9,
311.2072, found 311.2078.
170.8, 160.0, 155.5, 155.3, 115.3, 43.3, 39.0, 32.1, 32.0, 30.8,
Compound 8b. Compound 8b was synthesized following the 28.8, 24.3, 24.0, 23.0, 14.1, 10.8; HRMS (ESI) calculated [M+H]+
same procedure for the synthesis of 8a. Purification was for C17H27O3N4S2: 399.1520, found 399.1519, 797.2965
effected by column chromatography (eluent: 3% MeOH/DCM, [2M+H]+.
Rf : 0.4) to yield 8b (1.85, 94%) as a white fluffy solid. IR (CHCl3) Compound 10b. Compound 10b was synthesized following the
ν (cm-1):3430, 3290, 3016, 2927, 2855, 1688, 1600, 1550, 1478, same procedure for the synthesis of 10a. The resulting solid
1
1454, 1416, 1266, 1216, 1196, 1166, 1058, 812, 760, 667; H was filtered and rinsed with cold water and dried under
NMR (400 MHz, CDCl3) δ: 8.80 (s, 1H), 7.27 (s, 1H), 5.67 (s, 1H), vacuum giving 10b (1.15 g, 85%) as a yellow solid. mp:
3.88 (s, 6H), 3.38-3.33 (m, 2H), 1.59-1.56 (m, 2H), 1.37-1.25 (m, compound decomposes above 210 oC; IR (Nujol) ν (cm-1): 3208,
18H) 0.891-0.86 (t, J = 5.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) 2923, 2854, 1701, 1654, 1607, 1577, 1533, 1462, 1377, 1302,
δ: 171.4, 156.8, 154.0, 83.1, 54.0, 40.0, 31.8, 29.8, 29.5, 29.5, 1254, 1154, 974, 920, 870, 773,722; 1H NMR (500 MHz, CDCl3)
29.3, 27.0, 22.6, 14.0; HRMS (ESI) calculated [M+H]+ for δ: 12.56 (s, 1H), 11.53 (s, 1H), 9.63 (s, 1H), 3.29-3.26 (m, 2H),
C19H35O3N4: 367.2699, found 367.2704, 755.5154 [2M+Na]+.
3.01-2.96 (m, 4H), 2.40-2.38 (m, 2H), 1.66-1.61 (m, 2H), 1.58-
Compound 9a. A solution of 8a (1.5 g, 4.835 mmol, 1 equiv.) in 1.52 (m, 16H), 0.91-0.86 (t, 3H); 13C NMR (125 MHz, CDCl3) δ:
15 ml of HBr in AcOH was refluxed for 1 h. The mixture was 196.0, 170.8, 160.0, 155.4, 155.2, 115.3, 40.3, 32.2, 32.0, 31.9,
cooled to RT and poured into ice water. The resulting solid was 29.7, 29.6, 29.6, 29.4, 29.3,28.9, 27.0, 24.4, 22.6, 14.1; HRMS
filtered and rinsed with cold water and dried under vacuum (ESI) calculated [M+H]+ for C21H35O3N4S2: 455.2145, found
giving 9a (1.02 g, 75%) as an off-white solid. The crude product 455.2144, 909.4224 [2M+H]+.
obtained was used for the next step without further Compound 3a. To a solution of 10b (0.1 g, 0.220 mmol, 1
purification. mp: >295 oC; IR (Nujol) ν (cm-1): 3341, 1697, 1641, equiv.) in DMSO, cyclohexylamine (0.0758 ml, 0.660 mmol, 3
1583, 1463, 1435, 1412, 1378, 1321, 1278, 1258, 1237, 1199, equiv.) was added and stirred at room temperature for 6 h.
975, 817, 795, 774, 712; 1H NMR (400 MHz, DMSO-d6) δ: 11.18 After completion of the reaction, the reaction mixture was
(s, 2H), 9.46 (s, 1H), 7.36 (s, 1H), 4.96 (s, 1H), 3.12-3.04 (m, 2H), diluted with DCM and was sequentially washed with KHSO4,
1.42-1.39 (m, 1H), 1.28-1.23 (m, 8H), 0.88-0.83 (m, 6H); 13C water and brine solution. The organic layer was dried over
NMR (100 MHz, DMSO-d6) δ: 154.5, 151.5, 83.2, 41.7, 30.3, Na2SO4 and evaporated in vacuo. The residue obtained was
28.3, 23.6, 22.4, 13.9, 10.71; HRMS (ESI) calculated [M+H]+ for purified by column chromatography (eluent: 2% MeOH/DCM,
C13H23O3N4: 283.1762, found 283.1765, 565.3457 [2M+H]+.
Rf : 0.5) to afford 3a (0.092 g, 77%) as a white solid. mp: 139-
Compound 9b. Compound 9b was synthesized following the 140 °C; IR (CHCl3) ν (cm-1): 3201, 3014, 2930, 2855, 1699, 1645,
same procedure for synthesis of compound 9a. The mixture 1584, 1469, 1450, 1424, 1402, 1375, 1291, 1217, 1069, 844,
was cooled to RT and poured into ice water. The resulting solid 762; 1H NMR (400 MHz, CDCl3) δ: 12.23 (s, 1H), 11.70 (bs, 1H),
was filtered and rinsed with cold water and dried under 11.48 (s, 1H), 11.11 (bs, 1H), 9.73 (s, 1H), 3.50-3.41 (m, 2H),
vacuum giving 9b (1.09 g, 79%) as an off-white solid. The crude 3.24-3.19 (m, 2H), 1.98-1.95 (m, 4H), 1.84-1.80 (m, 4H), 1.62-
product obtained was used for the next step without further 1.56 (m, 4H), 1.49-1.44 (m, 4H), 1.37-1.25 (m, 24H), 0.89-0.86
purification. mp: > 295; IR (Nujol) ν (cm-1): 3340, 1692, 1643, (t, J = 6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 174.8, 164.5,
1617, 1583, 1463, 1414, 1377, 1326, 1279, 1257, 1237, 1200, 160.2, 155.8, 152.4, 85.5, 52.9, 40.0, 33.5, 31.8, 29.6, 29.6,
1
973, 776, 754, 718; H NMR (400 MHz, DMSO-d6) δ: 11.15 (s, 29.5, 29.4, 29.3, 27.2, 25.3, 24.2, 22.6, 14.0: HRMS (ESI)
1H), 9.44 (s, 1H), 7.48 (s, 1H), 4.95 (s, 1H), 3.17-3.06 (m, 2H), calculated [M+H]+ for C30H53O3N6: 545.4181, found 545.4174,
1.44-1.42 (m, 2H), 1.34-1.14 (m, 18H), 0.90-0.78 (t, 3H); HRMS 1089.8275 [2M+H]+.
(ESI) calculated [M+H]+ for C17H31O3N4: 339.2386, found
339.2391, 677.4709 [2M+Na]+.#Note: Owing to poor solubility,
13C and DEPT-135 NMR could not be taken in DMSO-d6.
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Compound 3b. Following the same procedure for synthesis of Compound 3e. To a solution of 10a (0.1 g, 0.251 mmol, 1
compound 3a and using isobutylamine (0.065 ml, 0.660 mmol, equiv.) in DMSO, 3,4,5-(dodecyloxy) aniline (0.486 g, 0.753
o
3 equiv.), 3b was synthesized. After completion of the mmol, 3 equiv.) was added and stirred at 80 C for 6 h. After
reaction, the reaction mixture was diluted with DCM and was completion of the reaction, the reaction mixture was diluted
sequentially washed with KHSO4, water and brine solution. The with DCM and was sequentially washed with KHSO4, water and
organic layer was dried over Na2SO4 and evaporated in vacuo. brine solution. The organic layer was dried over Na2SO4 and
The residue obtained was purified by column chromatography evaporated in vacuo. The residue obtained was purified by
(eluent: 2% MeOH/DCM, Rf : 0.5) to afford 3b (0.098 g, 90%) as column chromatography (eluent: 1% MeOH/DCM, Rf : 0.5) to
a fluffy white solid. IR (CHCl3) ν (cm-1): 3212, 3020, 2962, 2856, afford 3e (0.240 g, 60%) as a brown colored solid. mp: 35-37
1
1701, 1644, 1586, 1468, 1395, 1289, 1139,772, 669; H NMR °C; IR (CHCl3) ν (cm-1): 3207, 3018, 2925, 2854, 1700, 1645,
1
(400 MHz, CDCl3) δ: 12.29 (s, 1H), 11.56 (bs, 1H), 11.46 (s, 1H), 1592, 1466, 1435, 1348, 1289, 1119, 759; H NMR (400 MHz,
10.96 (bs, 1H), 9.78 (s, 1H), 3.29-3.26 (m, 2H), 3.22-3.17 (m, CDCl3) δ: 13.64 (s, 1H), 12.81 (s, 1H), 12.59 (s, 1H), 11.54 (s,
2H), 1.95-1.89 (m, 2H), 1.30-1.36(m, 18H), 1.04-1.04 (d, J = 6.1 1H), 9.75 (s, 1H), 6.09 (s, 4H), 3.76-3.65 (m, 12H), 3.18-3.13 (m,
Hz, 12H), 0.90-0.86 (t, J = 6.7 Hz, 3H); 13C NMR (100 MHz, 2H), 1.71-1.66 (m, 13H), 1.42-1.28 (m, 110H), 1.17-1.11 (m,
CDCl3) δ: 174.8, 164.5, 163.7, 155.8, 152.7, 85.3, 53.1, 39.9, 6H), 0.92-0.87 (m, 18H), 0.80-0.69 (m, 6H); 13C NMR (100 MHz,
31.9, 29.7, 29.6, 29.4, 29.3, 27.1, 22.6, 20.0, 14.1; HRMS (ESI) CDCl3) δ: 174.8, 164.7, 157.3, 155.9, 153.1, 152.6, 152.5, 135.8,
calculated [M+H]+ for C26H49O3N6: 493.3861, found 493.3861, 135.8, 131.7, 131.5, 102.5, 85.5, 73.4, 73.3, 69.0, 68.9, 43.1,
985.7649 [2M+H]+.
39.2, 31.9, 30.7, 30.3, 30.3, 29.8, 29.7, 29.6, 29.5, 29.4, 28.6,
Compound 3c. To a solution of 10b (0.1 g, 0.220 mmol, 1 26.2, 24.0, 22.8, 22.6, 14.0, 13.9, 10.5; MALDI-TOF/TOF
equiv.) in DMSO, aniline (0.060 ml, 0.660 mmol, 3 equiv.) was calculated [M+H]+ for C98H177N6O9: 1582.36, found 1582.2714.
added and stirred at 80 oC for 6 h. After completion of the Compound 3f. To a solution of 10a (0.1 g, 0.251 mmol, 1
reaction, the reaction mixture was diluted with DCM and was equiv.) in DMSO, 6-amino-1-hexanol (0.88 g, 0.753 mmol, 3
sequentially washed with KHSO4, water and brine solution. The equiv.) was added and stirred at room temperature for 6 h.
organic layer was dried over Na2SO4 and evaporated in vacuo. After completion of the reaction, the reaction mixture was
The residue obtained was purified by column chromatography diluted with DCM and was sequentially washed with KHSO4,
(eluent: 1% MeOH/ DCM, Rf: 0.5) to afford 3c (0.102 g, 87%) as water and brine solution. The organic layer was dried over
a fluffy white solid. IR (CHCl3) ν (cm-1): 3214. 3020, 2928, 1701, Na2SO4 and evaporated in vacuo. The residue obtained was
1641, 1590, 1416, 1245, 929, 772, 669, 608; 1H NMR (400 MHz, purified by column chromatography (eluent: 8% MeOH/ DCM,
CDCl3) δ: 13.78 (s, 1H), 12.90 (s, 1H), 12.57 (s, 1H), 11.51 (s, Rf: 0.4) to afford 3f (0.105 g, 80%) as a white solid. mp: 122-
1H), 9.75 (s, 1H), 6.99-6.97 (m, 4H), 6.92-6.88 (m, 2H), 6.86- 123 °C; IR (CHCl3) ν (cm-1): 3623, 3426, 3215, 3019, 2935, 1700,
6.84 (m, 4H), 3.26-3.22 (m, 2H), 1.60-1.52 (m, 2H), 1.28-1.15 1643, 1585, 1531,1246, 1216, 766, 669; 1H NMR (400 MHz,
(m, 18H), 0.90-0.87 (t, J = 6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 12.27 (s, 1H), 11.50 (bs, 2H), 10.91 (bs, 1H), 9.60 (s,
CDCl3) δ: 175.1, 164.8, 158.2, 155.7, 153.3, 136.2, 128.4, 125.5, 1H), 3.66-3.63 (m, 4H), 3.48-3.43 (m, 4H), 3.13-3.08 (m, 2H),
123.5, 123.5, 85.9, 40.2, 31.9, 29.6, 29.5, 29.5, 29.3, 29.3, 28.9, 1.85 (bs, 2H), 1.71-1.68 (m, 4H), 1.60-1.57 (m, 4H), 1.49-1.41
27.1, 22.7, 14.1; HRMS (ESI) calculated [M+H]+ for C30H41O3N6: (m, 8H), 1.35-1.27 (m, 9H), 0.90-0.86 (t, J = 6.7 Hz, 6H); 13C
533.3243, found 533.3235, 1065.6397 [2M+H]+.
NMR (100 MHz, CDCl3) δ: 174.6, 164.5, 163.2, 156.0, 152.6,
Compound 3d. To a solution of 10a (0.2 g, 0.502 mmol, 1 85.2, 62.4, 45.0, 43.2, 39.2, 32.3, 30.8, 30.1, 28.8, 26.3, 25.2,
equiv.) in DMSO, 2-ethylhexylamine (0.246 ml, 1.506 mmol, 3 24.0, 23.0, 14.0, 10.7; HRMS (ESI) calculated [M+H]+ for
equiv.) was added and stirred at room temperature for 6 h. C26H49O5N6: 525.3766, found 525.3759, 1049.7445 [2M+H]+.
After completion of the reaction, the reaction mixture was Compound 3g. To a solution of 3f (0.075 g, 0.143 mmol, 1
diluted with DCM and was sequentially washed with KHSO4, equiv.) in dry DCM (4 mL), 1-pyrenebutyric acid (0.090 g, 0.314
water and brine solution. The organic layer was dried over mmol, 2.2 equiv.), EDC.HCl (0.082 g, 0.429 mmol, 3 equiv.) and
Na2SO4 and evaporated in vacuo. The residue obtained was DMAP (0.01747 g, 0.143 mmol, 1 equiv.) were added and
purified by column chromatography (eluent: 2% MeOH/DCM, stirred at room temperature for 6 h. After completion of the
Rf: 0.4) to afford 3d (0.233 g, 85%) as a colorless liquid. IR reaction, the reaction mixture was diluted with DCM and was
(CHCl3) ν (cm-1): 3214, 3019, 2962, 2931, 1710, 1643, 1586, sequentially washed with KHSO4, water and brine solution. The
1531, 1245, 1216, 758, 669; 1H NMR (400 MHz, CDCl3) δ: 12.30 organic layer was dried over Na2SO4 and evaporated in vacuo.
(s, 1H), 11.58 (bs, 1H), 11.40 (bs, 1H), 10.91 (bs, 1H), 9.65 (s, The residue obtained was purified by column chromatography
1H), 3.41-3.35 (m, 4H), 3.11-3.08 (m, 2H), 1.66-1.53 (m, 3H), (eluent: 5% MeOH/ DCM, Rf: 0.3) to afford 3g (0.090 g, 60%) as
1.48-1.28 (m, 24H), 0.90-0.88 (m, 18H); 13C NMR (100 MHz, a pale-yellow solid. mp: 98-100 °C; IR (CHCl3) ν (cm-1 ): 3210,
CDCl3) δ: 174.7, 164.5, 164.4, 156.0, 152.7, 85.3, 48.2, 43.4, 3019, 2936, 1725, 1702, 1643, 1586, 1531, 1245, 1216, 846,
40.1, 39.3, 30.8, 30.7, 28.8, 24.0, 23.9, 23.1, 22.8, 14.0, 14.0, 753, 668; 1H NMR (400 MHz, CDCl3) δ: 12.28 (s, 1H), 11.41 (bs,
10.7; HRMS (ESI) calculated [M+H]+ for C30H57O3N6: 549.4489, 2H), 10.88 (bs, 1H), 9.60 (s, 1H), 8.30-8.28 (m, 2H), 8.16-8.13
found 549.4487, 1097.8901 [2M+H]+.
(m, 4H), 8.11-8.09 (m, 4H), 8.03-7.96 (m, 6H), 7.86-7.84 (m,
2H), 4.10-4.07 (t, J = 6.7 Hz, 4H), 3.40-3.37 (m, 4H), 3.35-3.30
(m, 4H), 3.16-3.07 (m, 2H), 2.48-2.45 (t, J = 6.7 Hz, 4H), 2.22-
2.18 (quint, J = 7.3 Hz, 4H), 1.65-1.55 (m, 8H), 1.55-1.50 (m,
6 | J. Name., 2012, 00, 1-3
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838; (d) A. P. H. J. Schenning, P. Jonkheijm, E. Peeters, E. W.
Meijer, J. Am. Chem. Soc., 2001, 123, 409.
(a) M. Zhang, D.Sigwalt, L. Isaacs, Chem. Commu., 2015, 51,
14620; (b) T. Aida, E. W. Meijer, S. I. Stupp, Science, 2012,
335, 813.
(a) S. Kheria, S. Rayavarapu, A. S. Kotmale, R. G. Gonnade, G.
J. Sanjayan, Chem. Eur. J., 2017, 23, 783; (b) B. A. Blight, C. A.
Hunter, D. A. Leigh, H. McNab, P. I. T. Thomson, Nat. Chem.,
1H), 1.41-1.33 (m, 8H), 1.32-1.27 (m, 8H), 0.90-0.86 (m, 6H);
13C NMR (100 MHz, CDCl3) δ: 174.5, 173.4, 164.4, 163.2, 155.9,
152.5, 135.6, 131.3, 130.8, 129.9, 128.6, 127.4, 127.3, 127.2,
126.6, 125.7, 125.0, 124.9, 124.8, 124.7, 124.7, 123.2, 85.1,
64.1, 45.0, 43.2, 39.2, 33.8, 32.7, 30.8, 30.0, 28.8, 28.4, 26.7,
26.3, 25.5, 24.0, 23.0, 14.1, 10.7; MALDI-TOF/TOF calculated
[M+H]+ for C66H77N6O7: 1065.58, found 1065.7872, 1087.7468
[M+Na]+.
5
6
2011, 3, 244; (c) X. Li, Y. Fang, P. Deng, J. Hu, T. Li, W. Feng, L.
Yuan, Org. Lett., 2011, 13, 4628; (d) N. Shirai, S. I. Ikeda, K.
Odashima, Y. Hisamatsu, Org. Lett., 2009, 11, 4342; (e) L. Cui,
S. Gadde, A. D. Shukla, H. Sun, J. T. Mague, A. E. Kaifer,
Chem. Commun., 2008, 1446; (f) W. Wienand, C. Schmuck, J.
Am. Chem. Soc., 2003, 125, 452; (g) Y. Yan, H. Zeng, E. S-.
Jankunn, Y. W. Kim, J. Zhu, H. Ickes, B. Gong, J. Am. Chem.
Soc., 1999, 121, 5607.
(a) G. B. W. L. Ligthart, H. Ohkawa, R. P. Sijbesma, E. W.
Meijer, J. Am. Chem. Soc., 2005, 127, 810; (b) S. H. M.
Sontjens, R. P. Genderen, E. W. Meijer, R. P. Sijbesma, J. Am.
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H. Kooijman, A. L. Spek, E. W. Meijer, J. Am. Chem. Soc.,
1998, 120, 6761.
Compound 3h. To a solution of 10a (0.2 g, 0.502 mmol, 1
equiv.) in DMSO, dodecylamine (0.279 g, 0.150 mmol, 3 equiv.)
was added and stirred at room temperature for 6 h. After
completion of the reaction, the reaction mixture was diluted
with DCM and was sequentially washed with KHSO4, water and
brine solution. The organic layer was dried over Na2SO4 and
evaporated in vacuo. The residue obtained was purified by
column chromatography (eluent: 2% MeOH/ DCM, Rf : 0.6) to
afford 3h (0.310 g, 93%) as a white solid. mp: 55-57 °C; IR
(CHCl3) ν (cm-1): 3209, 3016, 2927, 2856, 1701, 1645, 1587,
1531, 1290, 1245, 1216, 839, 759, 668; 1H NMR (400 MHz,
CDCl3) δ: 12.27 (s, 1H), 11.55 (bs, 1H), 11.50 (bs, 1H), 10.91 (s,
1H), 9.64 (s, 1H), 3.46-3.41 (m, 4H), 3.17-3.09 (m, 2H), 1.71-
1.64 (m, 4H), 1.58-1.52 (m, 1H), 1.42-1.26 (m, 44H), 0.91-0.86
(m, 6H); 13C NMR (100 MHz, CDCl3) δ: 174.7, 164.4, 163.2,
156.0, 152.6, 85.2, 45.2, 43.2, 39.2, 31.8, 30.8, 30.2, 29.6, 29.5,
29.4, 29.3, 29.1, 28.8, 26.7, 24.0, 23.1, 22.6, 14.0, 10.7; MALDI-
TOF/TOF calculated [M+H]+ for C38H73N6O3: 661.57, found
661.1044, 683.0699 [M+Na]+, 699.0304 [M+K]+.
7
8
9
P. S. Corbin, S. C. Zimmerman, J. Am. Chem. Soc., 1998, 120,
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
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Chemistry and Photochemistry, ed. H.-J. Schneider, Eds. H.
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GJS thanks CSIR-SSB and DST, New Delhi, for financial support.
Notes and references
13 T. Forster, Angew. Chem. Int. Ed. Engl., 1969,
14 CCDC-1545866 (3a), CCDC-1545867 (3c) and CCDC-1545868
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paper: www.ccdc.cam.ac.uk/data_request/cif.
15 M. C. Etter, Acc. Chem. Res., 1990, 23, 120.
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Organic & Biomolecular Chemistry
Page 8 of 8
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DOI: 10.1039/C7OB02358H
This article reports a new class of highly reactive dithiane-tethered quadruple hydrogen-bonded systems having in-built
AADD-type self-complementary array. These systems further reacted with different amines to form highly stable
molecular duplexes in non-polar (Kdim > 1.9 x 107 M-1 in CDCl3) as well as in polar solvents (Kdim > 105 in 10% DMSO-
d6/CDCl3) without having prototropy-related issues.