Synthesis of macrocyclic compounds with steric barriers in macroheterocycle proceeding from (Z)-1,2,3,6-tetrahydrophthalic and phthalic acids

Article abstract of DOI:10.1134/S1070428009110232

Using 1,2-dibromoethane, (E)-1,4-dibromo-2-butene, (Z)-1,2,3,6-tetrahydrophthalic and phthalic acids we obtained along [1+1] scheme uncommon macrocyclic compounds containing ester groups, multiple bonds, and amide moieties in the macroheterocycle. The neu

Full text of DOI:10.1134/S1070428009110232

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 11, pp. 1714−1717. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.L. Shabanov, U.A. Gasanova, Z.O. Gakhramanova, M.M. Gasanova, 2009, published in Zhurnal Organicheskoi Khimii,
2009, Vol. 45, No. 11, pp. 1720−1723.
Synthesis of Macrocyclic Compounds with Steric Barriers
in Macroheterocycle Proceeding
from (Z)-1,2,3,6-Tetrahydrophthalic and Phthalic Acids
A. L. Shabanova, U.A. Gasanovab, Z. O. Gakhramanovaa, and M. M. Gasanovaa
aResearch Institute of Geotechnologic Problems of Oil, Gas, and Chemistry,
Azerbaijan State Petroleum Academy, Az 1010, Baku, Azerbaijan
e-mail: a.shabanov_36@mail.ru
b Azerbaijan Medical University, Baku, Azerbaijan
Received March 13, 2009
Abstract—Using 1,2-dibromoethane, (Ε)-1,4-dibromo-2-butene, (Z)-1,2,3,6-tetrahydrophthalic and phthalic acids
we obtained along [1+1] scheme uncommon macrocyclic compounds containing ester groups, multiple bonds,
and amide moieties in the macroheterocycle. The neutralization of bis-acids with ethylenediamine gave the
corresponding macrocyclic diammonium salts that on heating to the melting point were converted into the
corresponding macrocyclic diamides. The structure of compounds obtained was established from the elemental
analyses, IR and NMR spectra.
DOI: 10.1134/S1070428009110232
We showed formerly that the introduction of alkyl
radicals and functional groups into the macrocycle of
crown ethers strongly affected the conformation of the
cavity of the polyether ring [1]. The introduction of alkyl
substituente as a rule leads to the narrowing of the
macrocyclic ring, two butyl groups in the positions C6
and C15 of dibenzo-18-crown-6 so strongly change the
cavity of the polyether ring that it acquires the twist (T)
conformation [2].
extractive reagent of lithium ion and practically did not
bind potassium ion in spite of the presence of the 18-
membered polyether ring. On trhe contrary, the intro-
duction of a hydroxy group into the polyether ring results
in the extension of the ring due to the formation of
intermolecular hydrogen bond between the hydroxy
groups [1].
Hydroxy-substituted crown ether IIb forms a stable
complex with K+ ion whereas crown ether IIa
notwithstanding the identical size of the cavity is inert
toward K+ (Scheme 1).
Owing to this fact the dibutyl derivative I in contrast
to dibenzo-18-crown-6 became an efficient and selective
Scheme 1.
II, X = H (a), OH (b).
1714

SYNTHESIS OF MACROCYCLIC COMPOUNDS WITH STERIC BARRIERS IN MACROHETEROCYCLE
1715
Scheme 2.
H
H
O
Br
O
H
H
H
H
H
H
H
H
Br
O C
COOH
COOH
COOK
COOH
C O
KOH, 1-butanol
H
H
H O C
O
C O H
O
III
H2N
NH2, ethanol
KOH, 1-butanol
H
H
O
H
O
O
O
H
H
H
H
H
O C
O C
C O
C O
H
H
_
_
+
+
K O C
O
C O K
O
C ONH3 H3NO C
H
H
H
O
O
IV
VI
_2H2O
Br
Br
H
H
O
O
H
H
O C
H
O
C O
O
H
H
H
H
O C
H
C O
C
O
NH
HN
C
O
H
H
H
H
O C
O
C O
O
VII
H
V
The improvement of analytical, catalytic, sensor, and
other properties of crown compounds at their func-
tionalization opens wide prospects for their application
[3]. It is of primary importance to synthesize macrocylic
compounds containing in the polyether ring multiple bonds
and peptide fragments that might promote the appearance
of steric and conformational barriers improving the
selectivity of these reagents in complex formation [1, 3],
in extraction of metal ions, in ion transport through the
liquid membranes etc. The accessible and cheap initial
compounds for the synthesis are 1,2,3,6-tetrahydro-
phthalic, phthalic acids, (Ε)-1,4-dibromo-2-butene, etc. The
closure of (Z)-1,2,3,6-tetrahydrophthalic acid into crown
compound V was carried out along the [1+1] rule
(Scheme 2).
that in further reaction with (Ε)-1,4-dibromo-2-butene
(molar ratio 2:1) afforded bis-acid III. The latter in its
turn easily enters into a closure of macrocyclic compound
V by reaction of its dipotassium salt with (Ε)-1,4-dibromo-
2-butene in 1-butanol. The structure of the obtained
macrocyclic compound V was established from the data
of IR and NMR spectroscopy.
In the IR spectrum of compound V strong absorption
bands were found at 1731 and 1776 cm–1 characteristic
of ester fragments located equatorially and axially respec-
tively [4, 5]. The bands at 1654 and 1627 cm–1 correspond
to the multiple bonds in the cyclohexene ring and the
macrocycle. In the 1H NMR spectrum the eight-proton
multiplet signal belonging to the methylene hydrogen atoms
of the cyclohexene ring appears at δ 1.4 ppm. The four-
proton quintet at 4.08 ppm originates from the olefin
hydrogen atoms of the cyclohexene rings, and the eight-
As seen from the scheme, the tetrahydrophthalic acid
in 1-butanol was converted into a monopotassium salt
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 11 2009

SHABANOV et al.
1716
Scheme 3.
O
O
O
O
COOK
COOH
C O
O C
C O
O C
_
_
+
HOOC
+ O C
COOH
C ONH3 H3N
O
O
IX
X
VIII
O
O
C O
O C
C
O
C
O
NH
HN
XI
protom complex multiplet centered at 3.22 ppm, from
groups CH2O in the macrocyclic. The four protons located
in the α-position to the carbonyl groups give rise to two
distorted triplets at 2.31 and 2.55 ppm that are char-
acteristic, as should be expected, of the presence of two
equatorial and two axial C–H bonds respectively. The
four-proton triplet at 5.8 ppm corresponds to the olefin
hydrogen atoms of the macrocycle.
Analogously to the above procedures we prepared
from o-phthalic acid monopotassium salt VIII and 1,2-
dibromoethane in 1-butanol bis-acid IX that readily closed
into a macrocyclic salt X at the neutralization of its dilute
solution in 1-butanol (5 × 10–2 mol l−1) with ethylene-
diamine (Scheme 3).
EXPERIMENTAL
On hydrolysis of macrocyclic compound V in alkaline
medium the (Z)-4-cyclohexene-1,2-dicarboxylic acid was
isolated identical to the sample obtained by boiling with
water the anhydride of this acid.
IR spectra were recorded on a spectrophotometer UR-
20 from mulls in mineral oil and in pellets with KBr. 1H
NMR spectra of compounds V and VII were register-
ed on a spectrometer Bruker-300 at operating frequency
300 ΜHz in deuterated solvents (D2O, DMSO), internal
reference TMS. The reaction progress was monitored
and the purity of compounds was checked by TLC on
Silufol plates. Monopotassium salts of (Z)-1,2,3,6-
tetrahydro-1,2-phthalic and o-phthalic acids were obtained
by potentiometric titration in 1-butanol using glass and
silver chloride electrodes and measuring pH on an
instrument pH-340.
The neutralization of the dilute ethanol solution of bis-
acid III (5 × 10–2 mol l−1) with ethylenediamine provided
macrocyclic ammonium salt VI that at heating to the
melting point in a nitrogen atmosphere converted into
macrocylic compound VII containing two amide
fragments in the macroheterocycle. The alkaline
hydrolysis of diamide VII provided the (Z)-4-cyclohexene-
1,2-dicarboxylic acid, ethylenediamine, and (Ε)-2-butene-
1,4-diol.
(Ε)-1,4-Dibromo-2-butene was synthesized according
to technique presented in [6], mp 54°C (from octane).
The structure of macrocylic compound VII was
confirmed by the data of IR and NMR spectra. In the IR
spectrum of this compound strong absorption bands are
present at 1762 and 1698 cm–1 characteristic of amide
and ester carbonyl groups. The broad band at 3440 cm–1
belongs to the N–H bonds in the macrocycle.
(1R,6S,1'S,6'R)-6,6'-[(Ε)-2-Butene-1,4-diylbis-
(oxycarbonyl)]bis(cyclohex-3-ene-1-carboxylic acid)
(III). In 150 ml of 1-butanol was dissolved 8.5 g
(0.05 mol) of (Z)-4-cyclohexene-1,2-dicarboxylic acid.
The solution obtained was neutralized at stirring with
a solution of KOH in 20 ml of 1-butanol. Water formed
at neutralization was removed by azeotropic distillation.
Then to the reaction mixture obtained was added by small
portions 5.35 g (0.025 mol) of (Ε)-1,4-dibromo-2-butene
in 20 ml of 1-butanol within 1.5 h at stirring while boiling.
Inasmuch as the stretching vibrations of both cyclo-
hexene multiple bonds in the IR spectrum of compound
VII are identical (νC=C 1631 cm–1) it is presumable that
occurs the cis,syn,cis-junction of the cyclohexene and
polyester rings.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 11 2009

SYNTHESIS OF MACROCYCLIC COMPOUNDS WITH STERIC BARRIERS IN MACROHETEROCYCLE
1717
The mixture was heated at reflux for 16 h. The comple-
tion of the reaction was monitored by TLC. On
completion of the reaction 1-butanol was removed in
a vacuum (25 mm Hg.), the reaction product was extract-
ed from the residue with ethyl ether (5×40 ml). Yield
7.02 g (36%). Colorless crystals, mp 48–50°C. Found,
%: C 60.95; H 6.14 C20H24O8. Calculated, %: C 61.22;
H 6.16. Titration results show that compound III is diacid.
was added dropwise 9.4 g (0.05 mol) of dibromoethane.
The reaction mixture was stirred for 20 h at 70°C, then it
was cooled to room temperature. The precipitated reaction
product was recrystallized from octane. Yield 22 g (60%),
colorless crystals, mp 120–122°C. Found, %: C 60.11;
H 3.98. C18H14O8. Calculated, %: C 60.34; H 3.94.
Ethylenediammonium 2,2'-[ethane-1,2-diylbis-
(oxycarbonyl)]dibenzoate (X). Into a solution of 7.16 g
(0.02 mol) of dicarboxylic acid IX in 50 ml of ethanol
was added at stirring excess of ethylenediamine; therewith
the temperature of the obtained suspension rose by 10°C.
The reaction mixture was stirred for 4 h at room tempera-
ture, then 1 h at 70°C. On cooling the separated precipitate
was filtered off and washed with ethanol. Yield 2.1 g
(25%). Colorless crystals like cotton wool, mp 205–
207°C. Found, %: C 57.12; H 5.56; N 6.47. C20H22O8N2.
Calculated, %: C 57.41; H 5.30; N 6.69.
(2S,3R,12S,13R)-Di(1,2,3,6-tetrahydrobenzo)-
[b,e]-5,10,15,20-tetraoxacyclo-7,17-eicosadiene-
1,4,11,14-tetraone (V). In 150 ml of 1-butanol was dis-
solved 3.92 g (0.01 mol) of bis-acid III. The solution
obtained was neutralized at stirring with a solution of
1.12 g (0.02 mol) of KOH in 20 ml of 1-butanol. Water
formed at neutralization was removed by azeotropic
distillation. Then to the reaction mixture obtained was
added by small portions 2.14 g (0.01 mol) of (Ε)-1,4-
dibromo-2-butene in 15 ml of 1-butanol within 1.5 h at
stirring while boiling. The completion of the reaction was
monitored by TLC. On completion of the reaction 1-butanol
was removed in a vacuum (25 mm Hg.), the reaction
product was extracted from the residue with octane (5 ×
50 ml). Yield 1.02 g (23%). Colorless crystals, mp 119–
120°C. Found, %: C 64.59; H 6.61. C24H28O8. Calculated,
%: C 64.86; H 6.30.
Dibenzo[b,j]-5,8-dioxa-13,16-diazacyclohexa-
decane-1,4,9,12-tetraone (XI). In a porcelain evapor-
ating dish was heated for 30 min under nitrogen
atmosphere 1 g (0.03 mol) of macrocyclic ammonium
salt X to its melting point (205°C). The obtained diamide
crystals were recrystallized from ethanol. Yield 0.65 g
(77%).Yellow crystals, mp 235–236°C. Found, %: C 62.93;
H 4.42; N 7.49. C20H18O6N2. Calculated, %: C 62.82;
H 4.74; N 7.33.
(2S,3R,12S,13R)-Di(1,2,3,6-tetrahydrobenzo)-
[b,l]-5,10-dioxa-15,18-diazacyclooctadec-7-ene-
1,4,11,14-tetraone (VII). To a solution of 3.92 g
(0.01 mol) of dicarboxylic acid III in 50 ml of ethanol
was added at stirring 0.6 g (0.01 mol) of ethylenediamine,
and the mixture was stirred for 6 h. After neutralization
ethanol was removed in a vacuum (20 mm Hg), the
residue was transferred into a porcelain evaporating dish
and heated at its melting point for 30 min. The reaction
product was extracted from the residue with octane (5 ×
40 ml), the solvent was removed in a vacuum, the residue
was recrystallized from octane. Yield 1.76 g (42%).
Colorless crystals, mp 143°C. Found, %: C 63.72; H 6.49;
N 6.52. C22H28O6N2. Calculated, %: C 63.45; H 6.78;
N 6.73.
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2,2'-[Ethane-1,2-diylbis(oxycarbonyl)]dibenzoic
acid (IX). To a solution of 16.6 g (0.1 mol) of phthalic
acid in 100 ml of 1-butanol was added at stirring 4.0 g
(0.1 mol) of sodium hydroxide.After dissolution of alkali
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 11 2009