Molecular recognition of xanthine alkaloids: First synthetic receptors for theobromine and a series of new receptors for caffeine

Article abstract of DOI:10.1039/b009319j

Synthetic receptors and a series of new receptors were designed and synthesized for theobromine, a xanthine alkaloid used as a diuretic. The binding results of the theobromine and caffeine were also studied using NMR and UV methods. It was observed that the synthesis of the receptor H6 is achieved by Co(PPh₃)₃Cl-mediated homocoupling of 3-(ethoxycarbonyl)benzyl bromide 12 under mild conditions.

Full text of DOI:10.1039/b009319j

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Molecular recognition of xanthine alkaloids: First synthetic
receptors for theobromine and a series of new receptors for
caffeine
1
Shyamaprosad Goswami,* Ajit Kumar Mahapatra and Reshmi Mukherjee
Department of Chemistry, Bengal Engineering College (Deemed University), Howrah-711103,
India
Received (in Cambridge, UK) 20th November 2000, Accepted 10th August 2001
First published as an Advance Article on the web 4th October 2001
Synthetic receptors (H3, H4, H5 and H6) are designed and synthesised for the first time for theobromine, a xanthine
alkaloid used as a diuretic. The synthesis of the receptor H6 is achieved by Co(PPh3)3Cl-mediated homocoupling of
3-(ethoxycarbonyl)benzyl bromide 12 under mild conditions. New caffeine receptors (H7, H8 and H9) are designed
and synthesised. The binding results of theobromine and caffeine (both by NMR and UV studies) are reported.
The design and synthesis of abiotic (i.e., non-natural) receptors
which undergo molecular recognition using weak non-covalent
interactions is an emerging field1,2 with many potential appli-
cations,3,4 such as sensors,5 carriers, and other molecular
devices.5 Such receptors can serve as models for the under-
standing of fundamental molecular recognition processes in
biological systems.
Xanthine derivatives (G1, G2, G3) have several pharmaco-
logical actions, such as antibronchospastic, CNS-stimulation,
and tachycardia activity,6 etc. We report here for the first time
the design and synthesis of receptors H3, H4, H5 and H6 (the
numbering of receptors starts from H3) to recognise theo-
bromine (G1, a difficult recognition substrate because of its
very poor solubility in both chloroform and methanol) and
their binding efficacy to solubilise it in a less polar solvent like
chloroform. It is one of our goals in molecular recognition
research to make the insoluble bio-substrate (e.g., urea7) soluble
in chloroform (a common NMR solvent for binding studies)
by hydrogen-bond complexation with the designed receptors
quenching the individual self-polarity.
are good proton acceptors and that one imide N–H proton
is a good proton donor like thymine11 in the six-membered
pyrimidine ring of xanthines and so it is an ADA (A, D =
hydrogen-bond acceptor and donor, respectively)-type
hydrogen-bonding system along with an AA system of the
imidazole ring. We have designed different host molecules H3,
H4, H5 and H6 for consideration of binding (structures of
receptors and their complexes are shown in Fig. 1) on the basis
of hydrogen-bond donor and acceptor properties of the guest
theobromine and the corresponding receptors. The fact is that
a binuclear guest such as theobromine needs more spacious
receptors compared with H4 and H5, therefore we designed the
bigger receptor H6.
Synthesis of host molecules (H3, H4, H5 and H6)
The synthesis of the receptors H3, H4, H5 and H6 for
theobromine is shown in Scheme 1. The synthesis of H4 is
achieved by the synthesis of carbamate 10 from m-amino-
benzoic acid followed by formation of the amide bond by
the mixed anhydride method. The synthesis of H6, having a
bigger spacer, is made by the important CoI coupling reaction12
of 12 where the ester functionality survives. Compound 12
was prepared by the reaction between 11 and N-bromo-
succinimide in the presence of benzoyl peroxide in carbon
tetrachloride.
Result and discussion
The other xanthine derivative, caffeine (G2) (a trimethyl-
xanthine), which is present in tea and coffee seeds, has long
been known to be responsible for the stimulating effect of tea,
and plays important roles in determining the liquor characters,8
i.e. tea creaming (strength and briskness), for the desirable
attributes of the beverage. So it has interested chemists for its
complexation studies.9
Previously, complexation studies of caffeine in aqueous solu-
tion have been performed with a number of known poly-
phenols10 and cyclodextrins.10 We report here the recognition
of caffeine in chloroform with our new synthetic amidic and
non-amidic receptors H7, H8 and H9.
Energy-minimised structures of theobromine complexes A, B,
C and D with H3, H4, H5 and H6, respectively, are shown in
Fig. 2 using MMX (Serena Software 1993) calculations.
Molecular modelling was done using standard constants, and
the relative permittivity was maintained at 1.5. Alternative
complex structures (Complexes AЈ, BЈ, CЈ and DЈ respectively)
were obtained by flipping over the structure of theobromine,
and the comparative energy values are shown in Table 1.
We therefore examined the simple pyridine diamide H3 as the
first candidate as a receptor for theobromine based on the triple
hydrogen-bonding complementarity (DAD-ADA) between 2,6-
diaminopyridines, but the six-membered ring containing the
imide group of theobromine (Complex A) leaves the imidazole
ring uncomplexed although H3 makes G1 soluble in chloro-
form. The comparative binding13 results of the other designed
receptors (H4, H5 and H6) and the protons undergoing shifts
Recognition of theobromine
Our designs are based on the structural features of theo-
bromine which suggest that the two lactam carbonyl groups
DOI: 10.1039/b009319j
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This journal is © The Royal Society of Chemistry 2001
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Fig. 1 Assignment of hydrogen-bond donors and acceptors in H3, H4, H5 and H6 and their probable hydrogen-bonding patterns in complexes A,
B, C and D with G1.
Table 1 Energy-minimised values of different complexes in different
on complexation with theobromine are shown in Table 2.
The assignments of amide and carbamate protons of H4 are
suggested from the ROESY experiment (500 MHz, Fig. 3). The
assignment of protons of H5 is connoted from a comparison
of the downfield shifts of the corresponding protons due to
acetylation of the pyridine amino group of H4. The different
syn and anti forms of carbamates14 H4 and H5 are shown in
Fig. 4. With the incorporation of a carbamate moiety in the
receptors H4 and H5, the respective binding constant with
G1 is increased to some extent compared with that of H3.
H4 shows a small downfield chemical-shift change for the
carbamate proton (∆δ 0.13 ppm) on complexation with
theobromine (G1). Being frustrated with the isophthaloyl
spacer for this type of binuclear guest, we then designed the
bigger receptor H6 (DADDD) having more space between
the binding groups compared with the isophthaloyl spacer to
accommodate freely the bicyclic theobromine to complex both
the N-methylimidazole moiety as well as the pyrimidine ring.
The receptor H6 more efficiently solubilises G1 by making
one additional hydrogen bond with the most basic nitrogen
[imidazole nitrogen (N-9) of purine ring] forming a total
of four hydrogen bonds and leaving one amide NH in the
host uncomplexed (NHa in Complex D). Interestingly these
receptors do not bind theophylline, i.e. 1,3-dimethylxanthine
G3, possibly due to the presence of the bulky N1–CH3 group
for which the adjacent two imide carbonyls cannot participate
in hydrogen-bond formation with the amide protons of the
receptors.
mode of binding
Complex
Energya/kcal molϪ1
Complex
Energya/kcal molϪ1
A
B
C
D
Ϫ20.620
Ϫ7.056
Ϫ9.749
Ϫ7.601
AЈ
BЈ
CЈ
DЈ
Ϫ20.709
Ϫ6.340
Ϫ10.522
Ϫ8.413
a 1 cal = 4.184 J.
Table 2 NH chemical shifts and association constants Ka for G1 with
different hosts (H3, H4, H5 and H6)
Different amide
and amine
proton shifts of
host (∆δ/ppm)
Imide proton
shift of guest
(∆δ/ppm)
Host
Guest
Ka/MϪ1
H3
H4
G1
G1
NHb
0.37
NHa
NHa
0.61
0.78
Complex A
1.94 × 102
Complex B
9.43 × 102
NHb
NHc
NHd
NHb
NHc
NHd
NHb
NHc
0.13
0.52
0.15
0.18
0.34
0.39
0.28
0.36
H5
H6
G1
G1
NHa
NHa
0.68
1.79
Complex C
9.97 × 102
Complex D
2.41 × 103
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Scheme 1 Synthesis of the hosts H3, H4, H5 and H6.
Recognition of caffeine
In the complexes with caffeine, the phenolic protons of H8
and H9 underwent upfield shifts (maximum ∆δ of OH in H8 =
0.015 ppm and that in H9 = 0.84 ppm, respectively) as expected.
Both H8 and H9 in organic solution may be intramolecularly
hydrogen bonded, giving rise to two possible conformations
in equilibrium as shown in Fig. 5. The intramolecularly
hydrogen-bonded conformations have significant influence on
the chemical shift of the imino C–H and also the complexation
with caffeine.
Previous receptors for caffeine’s interaction with polyphenols15
show the formation of 1 : 1 complexes between caffeine and
known polyphenols in aqueous solution. In aqueous medium,
caffeine forms a number of complexes of variable stoichiometry
with polyphenols and aromatic hydroxy acids such as methyl
gallate,16 3-nitrobenzoic acid,16 5-chlorosalicylic acid,17 pyro-
gallol,9 potassium chlorogenate18 and cyclodextrins,19 etc. For
caffeine recognition, we designed first the tetraamide macro-
cyclic receptor H7 containing the smaller isophthaloyl spacer
which unfortunately failed to bind caffeine. We then designed
polyphenolic receptors (H8 and H9) which form 1 : 1 complexes
with caffeine in chloroform.
In H9, the imine hydrogen appears at δ 8.67 (intramolecular
hydrogen bonds of OH with the imino nitrogen may cause
imino C–H to appear at such
a downfield position).
Interestingly the two different phenolic OH protons of both
H8 and H9 appear at different chemical shifts. The phenolic
OH group which makes a stronger intramolecular hydrogen
bond [probably the OH group ortho to the imino group is more
acidic than the other OH group due to electron-withdrawing
resonance of the imino nitrogen and the formation of a six-
membered intramolecular hydrogen bond (Fig. 5)] appears
more downfield. Surprisingly the most downfield OH proton of
Synthesis of caffeine receptors
The synthesis of the macrocyle H7 is achieved by high-dilution
coupling of 17 with the bis(acid chloride) of 16 (Scheme 2).
The syntheses of other compounds are straightforward and the
procedures are mentioned in the Experimental section.
J. Chem. Soc., Perkin Trans. 1, 2001, 2717–2726
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Fig. 2 Energy-minimised structures in different modes of complexes A, B, C and D.
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Fig. 3 300 MHz NMR spectra of 1 : 1 complex of H4 and G1 (0.02 mmol mLϪ1) by gradual addition of CDCl3 at 25 ЊC and the ROESY (500 MHz)
spectrum of H4.
Fig. 4 anti and syn forms of H5.
H8, unlike H9, does not undergo any chemical-shift change on
complexation with caffeine. The electron-withdrawing influence
of a sulfonyl moiety, as well as it giving a wider spacing in H9
compared with the bridging methylene group in H8, is more
effective in increasing the binding affinity of H9 with caffeine
compared with H8. The values of association constants (Ka) for
the formation of 1 : 1 complexes between caffeine and poly-
phenolic receptors have been calculated using the up field
chemical-shift changes observed for phenolic OH during
addition of increasing amounts of guest. The chemical-shift
changes (∆δ) of the protons of the polyphenol were monitored
as a function of guest (caffeine) concentration. It is clear
that the phenolic hydroxy group is a good proton donor but
poor acceptor in hydrogen bonding, but the amide carbonyl
[CO(NMe)] groups in caffeine may be good proton acceptors.
Thus complexation reactions of caffeine with polyphenols, with
hydrogen bonding between the polyphenol (proton donor)
and caffeine (proton acceptor), may ultimately make specific
J. Chem. Soc., Perkin Trans. 1, 2001, 2717–2726
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Scheme 2 Synthesis of the hosts H7, H8 and H9.
contributions to the stability of the complexes E (1 : 1 complex
of H8 and G2, Ka = 0.56 × 102 MϪ1 at 25 ЊC) and F (1 : 1
complex of H9 and G2, Ka = 1.36 × 102 MϪ1 at 25 ЊC) (Fig. 6).
and the substrate P, ∆0AP = chemical-shift difference between the
caffeine resonance in the unbound state and the state in which
it is totally in the form of a 1 : 1 complex.
Binding studies of H4, H5 and H6 with theobromine and H8 and
H9 with caffeine
(1)
NMR method. The 1H NMR binding studies were carried out
in CDCl3 and in a mixture of DMSO-d6 (10%) in CDCl3. The
NMR spectrum of the host (H8 or H9) at known concentration
was recorded to obtain chemical shifts of unbound host and
then small aliquots of the guest stock solution in CDCl3 were
added to the NMR tube via a microsyringe. The chemical shifts
of selected protons of the host were monitored as a function of
guest concentration. Addition of guest was continued until no
further shift of the selected protons was observed. The binding
constants were measured by using equation (1)18 where ∆ =
chemical-shift change induced by substrate P at concentration
[P0], [P0] = formal substrate concentration, K = equilibrium
constant for the formation of 1 : 1 complex between caffeine
In the case of theobromine, the titration with guests H3, H4,
H5 and H6 was done by gradual dilution of the 1 : 1 complex of
corresponding host and guest, and monitoring of the amide
protons as a function of concentration. The binding constants
were measured by using equation (2)13a where α = (δ Ϫ δ0)/
(δmax Ϫ δ0), δ0 is the initial chemical shift (host only), δ is the
chemical shift at each titration point, δmax is the chemical shift
when the receptor is entirely bound, and [c] = concentration of
the host and guest.
(2)
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Table 3 Comparative binding study results for hosts H4, H5, H6, H8, H9 by UV method
Host
Guest
Concentration of host
Concentration of guest
λmax/nm monitored
Ka/MϪ1
H4
H5
H6
H8
H9
G1
G1
G1
G2
G2
2.66 × 10Ϫ5 mol dmϪ3
2.92 × 10Ϫ5 mol dmϪ3
2.70 × 10Ϫ5 mol dmϪ3
1.2 × 10Ϫ5 mol dmϪ3
3.28 × 10Ϫ5 mol dmϪ3
2.77 × 10Ϫ4 mol dmϪ3
2.77 × 10Ϫ4 mol dmϪ3
2.77 × 10Ϫ4 mol dmϪ3
8.4 × 10Ϫ3 mol dmϪ3
3.61 × 10Ϫ4 mol dmϪ3
334
338
329
324
274
5.51 × 103
4.40 × 103
3.72 × 104
5.78 × 102
7.96 × 103
Fig. 5 Intramolecular hydrogen-bonded conformations of the imines
H8 and H9.
Fig. 7 (I) Benesi–Hildebrand plot of (a) H6 with G1, (b) H4 with G1,
(c) H5 with G1. (II) Benesi–Hildebrand plot of (a) H9 with G2, (b) H8
with G2.
recognition strategy of substrate-induced organisation of the
binding site (induced fit) and we report the first receptors for
theobromine which effectively solubilise it in nonpolar solvents
such as chloroform. Systematic binding studies of caffeine with
a series of newly designed diverse receptors show the impor-
tance of optimum space requirements especially in a macro-
cyclic receptor such as H7 that fails to bind caffeine due to its
smaller-than-optimum cavity. This follows the creation of a
bigger synthetic cavity in the functionalised receptors for
theobromine and caffeine. The synthesis of functionalised and
more highly-spaced receptor H6 for theobromine has been
achieved by an important Col coupling reaction.12
Fig. 6 Hypothetical complexation mode of caffeine with receptors H8
and H9.
UV method. Stock solutions of different hosts were made in
the order of 10Ϫ5 mol dmϪ3. Aliquots of a solution of respective
guest in the order of 10Ϫ4 mol dmϪ3 were added and the UV
spectra were recorded for each addition for each host.
The concentrations of different hosts and the guest were cal-
culated for Benesi–Hildebrand analyses.13d,13e The comparative
binding results are shown in Table 3. The linear nature of the
plot (Fig. 7) suggests a 1 : 1 stoichiometry for the different
complexes.13e
Experimental
General
The following solvents were freshly distilled prior to use: tetra-
hydrofuran (THF) from sodium and benzophenone, ethanol
from calcium oxide, magnesium turnings and I2, methylene
dichloride and triethylamine from calcium hydride. All other
solvents and reagents were of reagent-grade quality and were
used without further purification. Reactions were run under
nitrogen unless otherwise noted. 1H and 13C NMR spectra were
recorded on Bruker-AM-200 and AM-300 spectrometers.
Conclusions
In summary, we have developed a new class of biomimetic
semirigid receptors for xanthine alkaloids that employs the
ROESY experiments were done on
a
Bruker-AM-500
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spectrometer giving 300 ms mixing time. Chemical shifts are
reported in δ ppm, and coupling constants J are in Hz. IR
spectra were recorded on a Perkin-Elmer MODEL No-883
spectrometer; absorptions are reported in cmϪ1. Melting points
were recorded (uncorrected) in open capillaries with a hot-stage
apparatus (Toshniwal). Elemental analyses were performed at
IACS, Calcutta. NMR titrations were carried out in CDCl3
except in the case of titration of H9 with caffeine where d6-
DMSO was added (5%) to solubilise H9 at 25 ЊC. Error limits
of binding constants are within 10%. The water content in the
NMR solutions was checked by integration of the water peak
at δ ca. 1.6 and was found to be 2–4 mM; in some cases where
d6-DMSO was used along with CDCl3, water content was more
likely to be 4–6 mM. Petroleum ether refers to the fraction with
distillation range 60–80 ЊC.
60.47, 14.52; MS (EI) m/z (relative intensity) 300.1 (Mϩ,
56%), 254.1, 192.1, 145.6, 91.1 (Calc. for C15H16N4O3: C, 59.99;
H, 5.37; N, 18.66. Found: C, 60.01; H, 5.20; N, 18.56%).
(3-{[6-(Acetylamino)pyridin-2-yl]carbamoyl}phenyl)carbamic
acid ethyl ester H5
A mixture of H4 (200 mg, 0.66 mmol) and distilled acetic
anhydride (2 mL) was heated to 120 ЊC for 2 h. The reaction
mixture was evaporated to dryness and the solid residue was
dissolved in ethyl acetate. The organic layer was washed
successively several times with 5% aq. sodium bicarbonate and
water. The organic layer was separated, dried over Na2SO4, and
evaporated to afford H5 (0.21 g, 94%) as a grayish white solid,
mp 220–223 ЊC (dec.); IR νmax (KBr) 3265, 1729, 1620, 1445,
1312, 1250 cmϪ1; 1H NMR (200 MHz; CDCl3) δ 8.34 (1H, br s,
carbamate NH), 8.11 (1H, br s, pyr. aromatic amide), 8.04–8.01
(2H, m), 7.92 (1H, d, J 8), 7.75 (1H, d, J 8), 7.56 (2H, t, J 8),
7.42 (1H, d, J 6), 7.00 (1H, br s, pyr. NHCOCH3), 4.25 (2H, q,
J 5), 2.23 (3H, s), 1.32 (3H, t, J 6); 13C NMR (50 MHz; CDCl3)
δC 166.21, 160.34, 158.42, 154.45, 150.78, 139.32, 139.19,
135.98, 129.61, 121.36, 121.19, 117.62, 104.98, 103.07, 60.47,
28.56, 14.39; MS (EI) m/z 342.3 (Mϩ) (Calc. for C17H18N4O4: C,
59.65; H, 5.26; N, 16.37. Found: C, 59.42; H, 5.19; N, 16.13%).
N-[6-(Butyrylamino)pyridin-2-yl]butyramide H3
To an ice-cooled solution of 2,6-diaminopyridine (1 g, 9.17
mmol) and triethylamine (1.85 g, 18.34 mmol) in dry CH2Cl2
(40 mL) was added dropwise a solution of butyryl chloride
(1.95 g, 18.34 mmol) in dry CH2Cl2 (20 mL). The mixture was
stirred for 5 h at 0–10 ЊC and quenched with water (50 mL). The
organic layer was separated, washed with 5% aq. sodium
bicarbonate (20 mL), dried over sodium sulfate, and evaporated
under reduced pressure. The crude solid was recrystallised from
chloroform–hexane to afford H3 (2.14 g, 94%) as a white solid,
mp 101–102 ЊC; IR νmax (KBr) 3320, 2950, 1669, 1531, 1455,
1304 cmϪ1; 1H NMR (200 MHz; CDCl3) δ 8.52 (2H, br s), 7.92
(2H, d, J 8), 7.63 (1H, t, J 8), 2.40 (4H, t, J 7.6), 1.83–1.65 (4H,
m), 1.00 (6H, t, J 6) (Calc. for C13H19N3O2: C, 62.63; H, 7.68; N,
16.85. Found: C, 62.54; H, 7.59; N, 16.82%).
1,2-Bis(3-carboxyphenyl)ethane 14
3-(Ethoxycarbonyl)benzyl bromide 12 (1.0 g, 4.1 mmol) was
treated with Co(PPh3)3Cl (4.34 g, 4.9 mmol) in degassed
dry benzene (70 mL) at 5–10 ЊC for 20 min under argon
atmosphere. The reaction mixture was filtered and the filtrate
was washed with water and concentrated to dryness. The crude
residue 13 was hydrolysed by addition 3 M NaOH (60 mL) and
boiling for 3–4 h. The reaction mixture was cooled to room
temperature and neutralised with dil. H2SO4. The precipitate
was filtered off and the solid was washed several times with
petroleum ether. Finally it was purified by chromatography on
a silica gel column (3 : 1 ethyl acetate–methanol) to afford 14
3-(Ethoxycarbonylamino)benzoic acid 10
Ethyl chloroformate (1.98 g, 17.5 mmol) was added dropwise to
a solution of 3-aminobenzoic acid (2 g, 14.6 mmol) and 1 M
NaOH (50 mL) solution over a period of 30 min at room
temperature. After stirring for an additional 3 h at room
temperature, the mixture was neutralised by dil. phosphoric
acid. The precipitate was filtered off, washed with cold water,
and dried to afford 10 (2.6 g, 82%) as a white solid, mp 234–
1
(0.69 g, 78%) as a white solid, mp 225–228 ЊC; H NMR (200
MHz; CDCl3) δ 8.19 (2H, s), 7.92 (2H, dd, J 2, J 8), 7.69 (2H, d,
J 8), 7.43 (2H, t, J 8), 2.97 (4H, s) (Calc. for C16H14O4: C, 71.10;
H, 5.22. Found: C, 71.21; H, 5.19%).
1
236 ЊC; IR νmax (KBr) 3338, 2922, 1635, 1558,1238 cmϪ1; H
NMR (200 MHz; CDCl3) δ 8.87 (1H, br s), 8.02 (1H, s),
7.66–7.54 (2H, m), 7.20 (1H, d, J 8), 4.09 (2H, q, J 6), 1.22
(3H, t, J 6) (Calc. for C10H11NO4: C, 57.74; H, 5.29; N, 6.69.
Found: C, 57.65; H, 5.24; N, 6.61%).
1,2-Bis{3-[(6-amino-2-pyridyl)carbamoyl]phenyl}ethane 15
A slurry of 14 (0.2 g, 0.74 mmol) in dry CH2Cl2 (2 mL), oxalyl
dichloride (0.8 mL) and a drop of DMF was stirred under an
inert atmosphere for 3 h, resulting in a clear orange solution.
The reaction mixture was evaporated to dryness under vacuum
and the resulting light orange solid was re-dissolved in dry
CH2Cl2 (50 mL). The dissolved acid chloride solution was
added slowly via cannula to a vigorously stirred solution of 2,6-
diaminopyridine (0.49 g, 4.44 mmol) in triethylamine (0.3 mL)
and dry CH2Cl2 (50 mL) at 0 ЊC. The reaction mixture was
allowed to attain room temperature and was then stirred for
24 h. The reaction mixture was concentrated, and washed
with water to remove excess of 2,6-diaminopyridine and tri-
ethylamine hydrochloride. The crude product was purified by
crystallisation from THF–hexane to afford 15 (0.24 g, 72%) as a
{[3-(6-Aminopyridin-2-yl)carbamoyl]phenyl}carbamic acid ethyl
ester H4
A mixture of 10 (0.5 g 2.39 mmol), ethyl chloroformate (0.26 g,
2.39 mmol), dry THF (50 mL), and triethylamine (0.4 mL) was
stirred under argon at room temperature for 3 h. 2,6-Diamino-
pyridine (0.26 g, 2.39 mmol) was added to the mixture, which
was then refluxed for an additional 3 h before being cooled to
room temperature and the solvent was removed under reduced
pressure. The residue was chromatographed (5% petroleum
ether in chloroform) to afford H4 (0.49 g, 64%) as grey solid,
mp 199–200 ЊC (dec.); IR νmax (KBr) 3401, 3279, 1732, 1617,
1454, 1309, 1234 cmϪ1; 1H NMR (200 MHz; 10% d6-DMSO in
CDCl3) δ 8.75 (1H, br s, carbamate NH), 8.35 (1H, br s, pyr.
amide), 7.78 (1H, s), 7.47 (1H, d, J 8), 7.30 (2H, t, J 8), 7.22–
7.07 (2H, m), 6.02 (1H, d, J 8), 4.62 (2H, s), 3.97 (2H, q, J 6),
1.09 (3H, t, J 6); 1H NMR (500 MHz; 10% d6-DMSO in CDCl3)
δ 8.85 (1H, br s, carbamate NH), 8.58 (1H, br s, pyr. amide),
7.76 (1H, s), 7.35 (1H, d, J 7.75), 7.19 (1H, d, J 8), 7.16 (1H,
d, J 8), 7.06 (1H, t, J 8), 7.00 (1H, t, J 8), 5.94 (1H, d, J 8), 4.74
(2H, br s), 3.85 (2H, q, J 7), 0.97 (3H, t, J 7); 13C NMR
(50 MHz; d6-DMSO) δC 165.42, 158.25, 153.90, 149.99, 139.48,
139.19, 135.07, 128.82, 121.72, 121.35, 117.58, 104.32, 102.04,
light yellow powder; IR νmax (KBr) 3398, 3282, 1617 cmϪ1; H
1
NMR (200 MHz; CDCl3) δ 8.58 (2H, br s), 8.20 (2H, s), 7.92
(2H, d, J 8), 7.69–7.65 (4H, m), 7.50 (2H, t, J 8), 7.43 (2H, t,
J 8), 6.29 (2H, d, J 8), 4.40 (4H, br s), 2.97 (4H, s) (Calc. for
C26H24N6O2: C, 69.01; H, 5.35; N, 18.57. Found: C, 69.11; H,
5.28; N, 18.42%).
1,2-Bis(3-{[6-(butyrylamino)-2-pyridyl]carbamoyl}phenyl)ethane
H6
To a solution of 15 (0.2 g, 0.44 mmol) and triethylamine
(0.13 mL, 0.88 mmol) in anhydrous THF (50 mL) was added
2724
J. Chem. Soc., Perkin Trans. 1, 2001, 2717–2726

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butyryl chloride (0.094 g, 0.88 mmol). After stirring at room
temperature overnight, the reaction mixture was concentrated
to give a sticky light yellow solid. Chromatography on silica
gel using ethyl acetate–chloroform (1 : 3) as eluant yielded H6
Trisphenyl macrocycle H7
A solution of diamine 17 (0.1 g, 0.195 mmol) in THF (50 mL)
and triethylamine (54 µL) was added simultaneously with a
solution of 5-octyloxyisophthaloyl dichloride (0.065 g,
0.195 mmol) in THF (30 mL) to stirred THF (30 mL) at room
temperature over a period of 3 h. The reaction mixture was
evaporated to dryness and the residue was purified by column
chromatography on silica gel (6% MeOH in CHCl3 eluant).
Crystallisation from CHCl3–MeOH (1 : 1) afforded the product
macrocycle H7 (0.042 g, 28%); mp 310–311 ЊC (dec.); IR νmax
(KBr) 3309, 3055, 1978, 1820, 1721, 1649 cmϪ1; 1H NMR (200
MHz; CDCl3) δ 9.42 (1H, br s), 9.10 (1H, br s), 8.00 (2H, br s),
7.87 (3H, m), 7.68 (2H, d, J 8), 7.55 (2H, s), 7.46 (2H, d, J 8),
7.13 (2H, t, J 8), 6.95 (2H, d, J 8), 6.80 (2H, d, J 8), 4.07 (4H,
m), 3.81 (2H, t, J 6), 2.09–2.02 (4H, m), 1.61–1.63 (4H, m),
1.28–1.11 (12H, m), 0.78–0.73 (5H, m); 13C NMR (50 MHz;
CDCl3) δC 179.71, 170.92, 164.72, 159.26, 156.86, 138.78,
138.41, 135.68, 135.29, 128.44, 124.54, 123.83, 117.22, 116.89,
116.12, 114.94, 111.88, 105.40, 71.04, 66.24, 38.23, 32.12, 29.01,
28.41, 24.21, 23.23, 22.39, 22.02, 13.51; HRMS (FAB) 771
(MHϩ, 100%), 705, 453, 435, 307 (Calc. for C46H50N4O7: C,
71.66; H, 6.54; N, 7.27. Found: C, 71.53; H, 6.78; N, 7.32%).
1
(0.16 g, 62%), mp 60–62 ЊC; H NMR (200 MHz; CDCl3)
δ 8.20 (2H, br s), 7.99 (2H, br s), 7.98–7.87 (4H, m), 7.83–7.64
(4H, m), 7.48–7.28 (6H, m), 3.03 (4H, s), 2.46 (4H, t, J 6), 1.53–
151 (4H, m), 1.07 (6H, t, J 6); 13C NMR (50 MHz; CDCl3)
δC 171.53, 165.72, 149.58, 140.85, 138.73, 134.07, 133.00,
128.64, 127.84, 124.08, 109.63, 109.56, 39.57, 21.27, 18.72,
13.63; MS (EI) m/z 592 (Mϩ, 15%), 549, 521, 479, 370, 344
(Calc. for C34H36N6O4: C, 68.90; H, 6.12; N, 14.18. Found:
C, 68.47; H, 6.34; N, 13.99%).
Bis{4-[(2,3-dihydroxyphenyl)methylideneamino]phenyl}methane
H8
Bis(4-aminophenyl)methane (0.2 g, 1.01 mmol) was added
gradually to a methanolic (60 mL) solution of 2,3-dihydroxy-
benzaldehyde (0.28 g, 2.02 mmol) and the solution was stirred
for 1 h at 50 ЊC. The orange solid precipitate was collected by
filtration; mp 183 ЊC; IR νmax (KBr) 3420, 1624, 1461, 1369,
1275, 1228 cmϪ1; 1H NMR (300 MHz; CDCl3) δ 8.59 (2H, br s),
7.24–7.21 (6H, m), 7.03 (4H, d, J 7.5), 6.94 (4H, d, J 8), 6.82
(2H, t, J 8), 4.08 (2H, s); 1H NMR (500 MHz; CDCl3) δ 13.87
(2H, br s) (at 300 MHz it had broadened), 8.60 (2H, s), 7.28–
7.24 (8H, m), 7.03 (2H, d, J 7.5), 6.94 (2H, d, J 8), 6.82 (2H, t,
J 8), 5.79 (2H, br s), 4.05 (2H, s); MS (EI) m/z 438.3 (Mϩ,
81%) (Calc. for C27H22N2O4: C, 73.96; H, 5.06; N, 6.38. Found:
C, 73.89; H, 5.26; N, 6.23%).
Complex of H3–G1
1H NMR (200 MHz; CDCl3) δ 11.37 (1HG1, br s), 8.95 (2H, br
s), 7.96 (2H, d, J 8), 7.69 (1H, t, J 8), 7.59 (1HG1, s), 4.00 (3HG1
s, NCH3), 3.59 (3HG1, s, NCH3), 2.43 (4H, t, J 7.6), 1.84–1.66
(4H, m), 1.00 (6H, t, J 6).
,
Complex of H4–G1
1H NMR (300 MHz; 2% d6-DMSO in CDCl3) δ 9.85 (1HG1, br
s), 8.61 (1H, br s), 8.39 (1H, br s), 7.99 (1H, s), 7.72 (1H, d, J 8),
7.63 (1H, d, J 7.5), 7.55 (1HG1, s), 7.50–7.41 (2H, m), 7.37 (1H,
d, J 7.4), 6.34 (1H, d, J 7.8), 4.70 (2H, br s), 4.23 (2H, q, J 6.6),
3.96 (3HG1, s, NCH3), 3.52 (3HG1, s, NCH3), 0.86 (3H, t, J 6).
Bis{[(2,3-dihydroxyphenyl)methylideneamino]phenyl} sulfone
H9
Bis(4-aminophenyl) sulfone (0.2 g, 0.81 mmol) was added
gradually to a methanolic (60 mL) solution of 2,3-dihydroxy-
benzaldehyde (0.22 g, 1.61 mmol), the solution was stirred for
1 h at 50 ЊC and the orange solid precipitate was collected by
filtration; mp 250 ЊC (dec.); IR νmax (KBr) 3432, 1622, 1577,
1466, 1368, 1316, 1279, 1206; 1H NMR (300 MHz; d6-DMSO)
δ 8.67 (4H, br s), 8.01 (4H, d, J 8), 7.64 (2H, s), 7.43 (4H, d,
J 8), 7.05–6.98 (4H, m), 6.81 (2H, t, J 7.5); MS (EI) m/z 487.9
(Mϩ, 18%) (Calc. for C26H20N2O6S: C, 63.93; H, 4.13; N, 5.73.
Found: C, 63.86; H, 4.25; N, 5.52%).
Complex of H5–G1
1H NMR (200 MHz, CDCl3) δ 9.84 (1HG1, br s), 9.29 (1H, br s),
9.24 (1H, br s), 8.55 (1H, br s), 7.93 (1H, br s, peri), 7.90 (1H,
d, J 8.6), 7.76 (1H, d, J 8), 7.62 (1H, d, J 8), 7.56–7.49 (2H,
m), 7.45 (1HG1, s), 7.29 (1H, t, J 7.9), 4.11 (2H, q, J 7.2), 3.84
(3HG1, s), 3.39 (3HG1, s), 2.16 (3H, s), 1.22 (3H, t, J 7.2).
Complex of H6–G1
2,7-Bis{3-[(3-aminophenyl)carbamoyl]propoxy}naphthalene 17
1H NMR (200 MHz; CDCl3) δ 10.58 (1HG1, br s), 8.38 (3H, br
s), 8.24 (1H, br s), 7.99–7.86 (4H, m), 7.82–7.67 (4H, m), 7.52
(1HG1, s), 7.49–7.23 (6H, m), 3.9 (3HG1, s), 3.50 (3HG1, s), 3.02
(s, 4H), 2.44 (4H, t, J 7.2), 1.87–1.69 (4H, m), 1.02 (6H, t, J 6).
2,7-Bis(3-carboxypropoxy)naphthalene 16 (0.36 g, 1 mmol) was
suspended in dry CH2Cl2 and oxalyl dichloride (0.5 mL) and
DMF (1 drop) were added; the reaction mixture was stirred at
room temperature for 2 h. After some time all the starting
material had dissolved. The solvent was removed on a rotary
evaporator and the residue was kept under high vacuum for 3 h.
The diiacid dichloride was used without purification.
Complex of H8–G2
1H NMR (300 MHz; CDCl3) δ 8.59 (4H, br s), 7.50 (1HG2
,
To a solution of 1,3-diaminobenzene (0.702 g, 6.50 mmol)
and triethylamine (0.25 mL) in dry THF (50 mL) was added
dropwise a solution of the above diacid dichloride (0.300 g,
0.81 mmol) in dry THF (10 mL). After 3 h the reaction mixture
was evaporated to dryness and the solid residue was washed
several times with water. Purification by column chromato-
graphy (THF–CH2Cl2 eluant 20 : 80) gave diamine 17 (0.29 g,
52%) which was directly used for further reaction, mp 165 ЊC;
IR νmax (KBr) 3440, 3281, 1654, 1618, 1532 cmϪ1; 1H NMR (200
MHz; d6-DMSO) δ 9.00 (2H, br s), 7.36 (2H, d, J 10), 7.04
(2H, s), 6.90–6.67 (8H, m), 6.26 (2H, d, J 8), 3.88 (4H, t, J 6),
3.12 (4H, br s), 2.33 (4H, t, J 6), 1.99–1.91 (4H, m); 13C NMR
(50 MHz; d6-DMSO) δC 171.01, 157.19, 144.38, 139.72, 135.67,
129.18, 128.75, 123.91, 116.01, 115.30, 111.04, 107.69, 106.04,
66.96, 33.40, 24.92 (Calc. for C30H32N4O4: C, 70.29; H, 6.29;
N, 10.93. Found: C, 70.21; H, 6.18; N, 10.79%).
s), 7.25 (6H, br s), 7.03 (4H, d, J 7.8), 6.95 (4H, d, J 7.2), 6.82
(2H, t, J 7.8), 4.04 (2H, s), 3.99 (3HG2, s), 3.58 (3HG2, s), 3.41
(3HG2, s).
Complex of H9–G2
1H NMR (300 MHz; 10% d6-DMSO in CDCl3) δ 8.66 (4H, br
s), 8.0 (4H, d, J 8.4), 7.69 (1HG2, s), 7.61 (2H, br s), 7.43 (4H,
d, J 8.4), 7.05–6.98 (4H, m), 6.82 (2H, t, J 7.8), 3.99 (3HG2, s),
3.56 (3HG2, s), 3.31 (3HG2, s).
Acknowledgements
We thank DST and CSIR, Government of India for financial
support. We appreciate the help of IACS, Calcutta for elemen-
tal analysis and we thank Dr S. Roy and Mr B. Majumder,
J. Chem. Soc., Perkin Trans. 1, 2001, 2717–2726
2725

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6 O. Agostini, G. Bonacchi, P. Dapporto, P. Paoli, L. Pogliani and
E. Toja, J. Chem. Soc., Perkin Trans. 2, 1994, 1061 and references
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7 S. Goswami and R. Mukherjee, Tetrahedron Lett., 1997, 38, 1619
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8 (a) E. A. H. Roberts and R. F. Smith, J. Sci. Food. Agric., 1963, 14,
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9 A. Arnone and R. H. Marchessault, Molecular Association in
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publication No. 84, 1968, p. 235.
Biophysics Department, Bose Institute, Calcutta for the 500
MHz ROESY spectrum. We thank IIT, Kharagpur and IICB,
Calcutta for the NMR spectra. We are grateful to Professor
A. D. Hamilton, Yale University and Dr R. S. Pilato, University
of Maryland, College Park, USA for the mass spectra. We wish
to thank IUPAC for AutoNom software. We also thank the
referees for their valuable suggestions.
10 Y. Cai, S. H. Gaffiney, T. H. Lilley, D. Magnolato, R. Martin,
C. M. Spencer and E. Haslam, J. Chem. Soc., Perkin Trans. 2, 1990,
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