The first immobilisation of glycoluril-based molecular clips on silica gel and alumina

Article abstract of DOI:10.3184/030823407X245606

The first example of immobilisation of some glycoluril-based molecular clips, which are good receptors for dihydroxybenzenes, on silica gel and alumina is described. 4,4'-Bis(methoxyphenyl)glycoluril was used as the base scaffold for the synthesis of mole

Full text of DOI:10.3184/030823407X245606

JOURNAL OF CHEMICAL RESEARCH 2007
SEPTEMBER, 525–527
RESEARCH PAPER 525
The first immobilisation of glycoluril-based molecular clips on silica gel
and alumina
Mohammad Rahimizadeha, Esmaeel Rezaei Sereshtb, Mehdi Bakavolia* and Neda Golaria
aDepartment of Chemistry, School of Sciences, Ferdowsi University, Mashhad 91375-1436, Iran
bDepartment of Chemistry, School of Sciences, Tarbiat Moallem University, Sabzevar, Iran
The first example of immobilisation of some glycoluril-based molecular clips, which are good receptors for
dihydroxybenzenes, on silica gel and alumina is described. 4,4'-Bis(methoxyphenyl)glycoluril was used as the base
scaffold for the synthesis of molecular clips. After demethylation of the methoxy groups, the clip compounds were
attached to silica gel and alumina using the linker (3-chloropropyl)trimethoxysilane. The resulting clip-functionalised
silica gel and alumina could be applied as a stationary phase in an affinity chromatography technique for the
separation and purification of dihydroxybenzenes and the more important biologically active catecholamines.
Keywords: glycoluril, immobilisation, molecular clips, silica gel, alumina
In the late 1980s, a new class of synthetic receptors based on
diphenylglycoluril (1) was reported in the literature.1 These
receptors, ‘molecular clips' as they became known could
bind aromatic guests particularly dihydroxybenzenes by
sandwiching them between two aromatic surfaces.2 The origin
of the term ‘molecular clip' for these molecules is clearly
visible from the X-ray structure of compound 2.3 The o-xylene
walls define a tapered cavity and the two fused five-membered
rings of the glycoluril form a shallow floor which is electron-
rich with two hydrogen-bond receptor sites. 1H NMR studies
revealed that clip molecules with their preorganised clefts are
excellent receptors for neutral aromatic guests, particularly
phenols and dihydroxybenzenes.4,5 The binding strength of
these types of guests within the host can span a wide range of
values (ka = 0–105 M-1), which vary with simple modifications
in either the host or the guests molecule. The binding is the
result of three cooperative effects; hydrogen bonding, π–π
stacking and a ‘cavity effect’.3 Affinity chromatography is a
widely applied separation technique for isolating molecules
of biological interest. The technique is based on molecular
recognition where one recognition partner is immobilised on
a base matrix and soluble target molecules can be retained
from a crude mixture. For example, affinity columns with a
nucleotide-bonded solid support are used for the separation
of various nucleic acids and proteins.6 Chiral columns with
selector-bound solid phase are also used for the separation
of enantiomers.7 Here, we report the first immobilisation of
glycoluril-based molecular clips 3a–c on the surface of silica
gel and alumina. The immobilisation led to a new class of
materials consisting of rigidly immobilised molecular clips on
an inorganic oxide surface, which is expected to find use in the
separation and purification of dihydroxybenzenes including
catechol, resorcinol and biologically active catecholamines
such as dopamine, L-DOPA and adrenaline.
O
HN
HN
NH
NH
Ph
Ph
O
1
OMe
MeO
OMe
O
O
MeO
OMe
OMe
OMe
OMe
O
O
N
N
N
N
N
N
Ph
Ph
N
N
2
Results and discussion
We have used 4,4'-bis(methoxyphenyl)glycoluril (4) as the
base skeleton for the clips' subunit. This compound is readily
accessible and its methoxy groups can be demethylated to
give the more reactive hydroxyl groups for the purpose of
immobilising or linking the glycoluril scaffold to a solid phase.
So compound 4 was prepared from 4,4'-dimethoxybenzil (5)
O
O
R3
O
R3
O
R2
R2
HN
HN
NH
NH
TFA, Toluene
Dean-Stark Apparatus
81%
R4
R4
MeO
OMe
2 NH2CONH2
+
R1
R1
O
MeO
12.. 6a-c, 120oC, 2-4h
KOH, DMSO
OMe
O
57-65%
4
5
N
N
N
N
R1
R2
R3
X
X
R4
OMe
6
MeO
3
6a R1 , R2 , R3 , R4 = H; X = Br
6b R1 , R4 = H; R2 , R3 = Me; X = Cl
6c R1 , R2 , R3 , R4 = Me; X= Cl
3a R1 , R2 , R3 , R4 = H
3b R1 , R4 = H; R2 , R3 = Me
3c R1 , R2 , R3 , R4 = Me
Scheme 1
* Correspondent. E-mail: mbakavoli@yahoo.com
PAPER: 07/4718

526 JOURNAL OF CHEMICAL RESEARCH 2007
R3
R3
R3
R3
commercially available (3-chloropropyl)trimethoxysilane (8)
was used as a linker.
R2
R2
R2
R2
The reaction of activated silica gel10 with 8 in toluene
according to a literature procedure afforded (3-chloro-
propyl)silyl-functionalised silica gel (9).11 Subsequent reaction
of 9 with compounds 7a–c in the presence of potassium iodide
and K2CO3 in DMSO resulted in immobilisation of 7a–c on
silica gel (10a-c) (Scheme 3). The degree of functionalisation
of the silica gel was determined by elemental analysis;
for example 0.42 mequiv of 7a was immobilised on 1 g of
10a. Similarly, the reaction of alumina with 8 as described
for 9 afforded (3-chloropropyl)silyl-functionalised alumina
(11). Subsequent reaction of 11 with compounds 7a–c led
to immobilisation of 7a–c on alumina (12a–c) (Scheme 3).
The degree of funtionalisation of the alumina was determined
by elemental analysis; for example 0.19 mequiv. of 7a was
immobilised on 1 g of 12a.
R4
R4
O
R4
R4
R1
R1
O
R1
R1
O
O
N
N
N
N
N
N
Pyridine.HCl
190-200o C, 4h
65-70%
N
N
OMe
OH
MeO
HO
3
7
7a R1 , R2 , R3 , R4 = H
7b R1 , R4 = H; R2 , R3 = Me
7c R1 , R2 , R3 , R4 = Me
Scheme 2
Experimental
and urea in TFA and toluene in 81% yield.8 It was treated with
1,2-bis(halomethyl) compounds 6a–c and KOH in DMSO to
afford the molecular clips 3a–c in 57–65% yields (Scheme 1).
Caution: The bis(halomethyl) compounds 6a–c, especially 6a, are
irritants.
Toluene was distilled from sodium benzophenone ketyl. 4,4'-
Dimethoxybenzil (5) and 1,2-bis(bromomethyl)benzene (6a) were
purchased from the Merck company. 1,2,3,4-tetramethylbenzene
was purchased from the Aldrich company. 1,2-Bis(chloromethyl)-
4,5-dimethylbenzene (6b),9 pyridine hydrochloride12 and activated
silica gel10 were prepared according to the literature procedures.
Melting points were recorded on an electrothermal type 9100 melting
point apparatus and are uncorrected. The IR spectra were obtained on
a 4300 Shimadzu spectrometer and only noteworthy absorptions are
1
The H NMR spectrum of 3b in CDCl3 displays one pair
of well-defined doublets for the CH2 protons at δ 4.10 and
δ 4.71 ppm (J = 16 Hz), two sharp singlets for the methyl
and the methoxy groups protons at δ 2.12 and δ 3.70 ppm
respectively, and finally the aromatic ring protons as a singlet
at δ 7.04 and an AA'XX' system at δ 6.65 and δ 6.98 ppm
(J = 8 Hz). It is rational that the binding strength of host and
guest molecules is affected by the extent of steric hindrance
around the receptor site. Therefore, compounds of type 6a–c
were selected as alkylating agents for the clips in order to
exert a variation of steric hindrance around the clip cavity.
Compound 6a is commercially available, but compound
6b was prepared by chloromethylation of o-xylene using
paraformaldehyde and concentrated hydrochloric acid
according to a literature procedure.9 Compound 6c was
prepared in 60% yield from 1,2,3,4,-tetramethylbenzene
by the same procedure as described for 6b. In the next step,
compounds 6a–c were treated with 4 and KOH in DMSO
to yield the clip molecules 3a–c respectively. The hydroxy-
containing molecular clips 7a–c were prepared in 65-70%
yields upon reaction of compounds 3a–c with an excess of
fused pyridine hydrochloride at 200°C (Scheme 2). For linking
compounds 7a–c to solid supports (silica gel or alumina),
1
listed. The H NMR (100 MHz) spectra were recorded on a Bruker
AC 100 spectrometer. Chemical shifts are reported in ppm downfield
from TMS as internal standard; coupling constants J are given in Hz.
For AA'XX' systems J* = J23 + J25. The mass spectra were scanned
on a Varian Mat. CH-7 at 70 eV. Elemental analysis was performed
on a Thermo Finnigan Flash EA microanalyser.
1,2-Bis(chloromethyl)-3,4,5,6-tetramethylbenzene (6c): Prepared
in a similar way to 6b with slight modification as follows: a mixture
of 1,2,3,4-tetramethylbenzene (26.8 g, 0.2 mol), paraformaldehyde
(18 g, 0.6 mol) and conc. HCl (125 ml) was refluxed with stirring
for 10 h. The reaction mixture was cooled and the precipitated solid
filtered and washed with water (2 × 50 ml) and cooled hexane (30 ml)
and dried in vacuo. Yield: 27.7 g (60%); white needles; m.p. = 140–
1
142°C. IR (KBr): 2913, 1439, 1270, 685 cm-1. H NMR (CDCl3):
δ = 2.25 (s, 6 H, 2 × CH3), 2.36 (s, 6 H, 2 × CH3), 4.80 (s, 4 H,
2 × CH2).MS (EI): m/z (%) = 231 (M+) Anal. Calc. for C12H16Cl2: C,
89.94; H, 10.06. Found: C, 89.8; H, 10.3.
13b,13c-Di(4-methoxyphenyl)-,7,12,13b,13c,14-hexahydro-
5a,6a,12a,13a-tetraazabenzo[5,6]azuleno[2,1,8-ija]benzo
R1
R2
R3
O
O
O
OH
OH
OH
O
O
O
Si(CH2)3Cl
Si(CH2)3Cl
O
O
Si(CH2)3
Si(CH2)3
N
R4
R1
a
O
b
SiO2
SiO2
N
SiO2
N
O
O
O
O
OH
OH
OH
O
O
O
N
R2
R3
R4
9
10a–c
Reaction Condition:(a) 8, toluene, reflux; (b) 7a–c, KI, K2CO3, DMSO, 120oC, 5day
R1
R4
R1
R2
R3
O
O
O
O
O
O
OH
OH
OH
O
O
Si(CH2)3
Si(CH3)3
Si(CH2)3Cl
Si(CH2)3Cl
N
O
b
a
N
Alumina
Alumina
Alumina
N
O
O
O
O
O
O
O
N
R2
R3
OH
OH
OH
R4
11
12a–c
Reaction Condition:(a) 8, toluene, reflux; (b) 7a–c, KI, K2CO3, DMSO, 120oC, 5day
Scheme 3
PAPER: 07/4718

JOURNAL OF CHEMICAL RESEARCH 2007 527
[f]azulene-6,13-dione (3a): This compound was synthesised
according to a literature procedure using 3.96 g (15 mmol) of
compound 6a and 2.48 g (7 mmol) of compound 4.8 M.p. >300°C
1H NMR (CDCl3): δ = 3.70 (s, 6 H, 2 × OCH3), 4.15 (d, J = 16 Hz,
4 H, 4 × CHH), 4.76 (d, J = 16 Hz, 4 H, 4 × CHH), 6.67 (m, J* = 8 Hz,
4 H, Ar–H), 6.97-7.30 (m, 12 H, Ar–H).
13b,13c-Di(4-hydroxyphenyl)-1,2,3,4,8,9,10,11-octamethyl-
5,7,12,13b,13c,14-hexahydro-5a,6a,12a,13a-tetraazabenzo[5,6]
azuleno[2,1,8-ija]benzo[f]azulene-6,13-dione (7c): Prepared according
to the general procedure using 1.67 g (2.5 mmol) of compound 3c
and 11.5 g (0.1 mol) of pyridine hydrochloride. Yield: 1.04 g (65%);
m.p. >300°C. IR (KBr): 3381 (br), 1685, 1614, 1515, 1470, 1278 cm-1.
1H NMR (DMSO-d6): δ = 2.07 (s, 12 H, 4 × CH3), 2.34 (s, 12 H,
4 × CH3), 3.73 (d, J = 16 Hz, 4 H, 4 × CHH), 4.94 (d, J = 16 Hz,
4 H, 4 × CHH), 6.55 (m, J* = 8 Hz, 4 H, Ar–H), 6.90 (m, J* = 8 Hz,
4 H, Ar–H), 9.42 (s, 2 H, 2 × OH). MS (EI): m/z = 642 (M+) Anal.
Calc. for C40H42N4O4: C, 74.74; H, 6.59; N, 8.72. Found: C, 74.5; H,
6.8; N, 8.55.
(3-Chloropropyl)silyl-functionalised silica gel (9): The procedure
previously described for 911 was followed: 10 g of activated silica
gel (Fluka No. 60741) and 3.0 g of 8 in 50 ml anhydrous toluene
yielded 10.5 g chloropropyl silica. By elemental analysis for chlorine
(3.38%) the loading was found to be 0.95 mequiv g-1.
13b,13c-Di(4-methoxyphenyl)-2,3,9,10-tetramethyl-
5,7,12,13b,13c,14-hexahydro-5a,6a,12a,13a-tetrazaabenzo[5,6]
azuleno[2,1,8-ija]benzo[f]azulene-6,13-dione(3b):4,4′-Bis(methoxy-
phenyl)glycoluril (4) (2.48 g, 7 mmol) and freshly ground potassium
hydroxide (4.0 g, 70 mmol) in DMSO (50 ml) were heated to 120°C
with vigorous stirring for 30 min. Then 1,2-bis(chloromethyl)-4,5-
dimethylbenzene (6b) (3.04 g, 15.0 mmol) was added in one portion
and stirring was continued at this temperature for 4 h. On cooling,
the reaction mixture was added to water (500 ml) and stirred for 30
min. The resulting light brown precipitate was collected by filtration,
washed with water (3 × 400 ml) and acetone (3 × 100 ml), and dried
in vacuo.Yield: 2.66 g (62%); m.p. >300°C.IR (KBr): 2963, 1709,
1
1611, 1512, 1458, 1253 cm-1. H NMR (CDCl3): δ = 2.12 (s, 12 H,
Preparation molecular clips immobilised on silica gel (10a–c);
general procedure
4 × CH3), 3.70 (s, 6 H, 2 × OCH3), 4.10 (d, J = 16 Hz, 4 H, 4 × CHH),
4.71 (d, J = 16 Hz, 4 H, 4 × CHH), 6.65 (m, J* = 8 Hz, 4 H, Ar–
H), 6.98 (m, J* = 8 Hz, 4 H, Ar–H), 7.04 (s, 4 H, Ar–H).MS (EI):
m/z = 614 (M+) Anal. Calc. for C38H38N4O4: C, 74.25; H, 6.23; N,
9.11. Found: C, 74.3; H, 6.5; N, 9.0.
13b,13c-Di(4-methoxyphenyl)-1,2,3,4,8,9,10,11-octa-methyl-,
7,12,13b,13c,14-hexahydro-5a,6a,12a,13a-tetraazabenzo[5,6]azuleno
[2,1,8-ija]benzo[f]azulene-6,13-dione (3c): Prepared as described for
3b using 3.46 g (15 mmol) of compound 6c and 2.48 g (7 mmol) of
compound 4. Yield: 2.67 g (57%); mp >300°C. IR (KBr): 2912, 1703,
1610, 1512, 1460, 1253 cm-1. 1H NMR (CDCl3): δ = 2.15 (s, 12 H, 4
× CH3), 2.43 (s, 12 H, 4 × CH3), 3.67 (s, 6 H, 2 × OCH3), 3.85 (d, J =
16 Hz, 4 H, 4 × CHH), 5.12 (d, J = 16 Hz, 4 H, 4 × CHH), 6.62 (m,
J* = 8 Hz, 4 H, Ar–H), 7.02 (m, J* = 8 Hz, 4 H, Ar–H). MS (EI): m/z
= 670 (M+) Anal. Calc. for C42H46N4O4: C, 75.20; H, 6.91; N, 8.35.
Found: C, 75.0; H, 6.9; N, 8.1.
A mixture of 9 (1 g), K2CO3 (0.26 g), potassium iodide (0.32 g) and
7 (0.47 mmol) in 10 ml DMSO was stirred and heated in a bath at
120°C for 5 days. The functionalised silica 10 was filtered and washed
successively with DMSO (2 × 5 ml), H2O (2 × 5 ml) and finally
MeOH (2 × 5 ml) and then dried in vacuo at 70°C for 24 h. Elemental
analysis of nitrogen for 10a–c indicated a loading of 0.42 mequiv,
0.45 mequiv and 0.40 mequiv 7a–c g-1 of 10a–c respectively.
(3-Chloropropyl)silyl-functionalised alumina (11): Prepared
according to the literature procedure from dry (dried at 100°C at
2 mmHg; 5 h) alumina (Merck No. 101067) (10 g) and 8 (1.95 ml,
10 mmol) in refluxing toluene.13 Elemental analysis showed that
0.45 mmol of 8 was immobilised on 1 g of 11.
Preparation molecular clips immobilised on alumina (12a–c);
general procedure
Prepared in a manner similar to that described for the preparation of
10a–c. Elemental analysis for nitrogen of 12a–c showed a loading
of 0.19 mequiv, 0.20 mequiv and 0.17 mequiv 7a–c g-1 of 12a–c
respectively.
Synthesis of hydroxy-functionalised Clips 7a-c: general procedure
Compound 3 (2.5 mmol) was added to a flask containing pyridine
hydrochloride (11.5 g, 0.1 mol) and the mixture was heated at 190–
200°C for 4 h. The hot brown syrup was poured into aqueous HCl
(5%, 50 ml) and the precipitated solid was filtered and washed with
water (3 × 50 ml) and CHCl3 (2 × 25 ml) and dried (in vacuo at 80°C)
to give compound 7.
Received 27 June 2007; accepted 11 September 2007
Paper 07/4718
doi: 10.3184/030823407X245606
13b,13c-Di(4-hydroxyphenyl)-5,7,12,13b,13c,14-hexahydro-
5a,6a,12a,13a-tetraazabenzo [5,6]azuleno[2,1,8-ija]benzo[f]azulene-
6,13-dione (7a): Prepared according to the general procedure using
1.40 g (2.5 mmol) of compound 3a and 11.5 g (0.1 mol) of pyridine
hydrochloride. Yield: 0.93 g (70%); m.p. >300°C. IR (KBr): 3356
(br), 1682, 1614, 1516, 1464, 1277 cm-1. 1H NMR (DMSO-d6):
δ = 4.08 (d, J = 16 Hz, 4 H, 4 × CHH), 4.60 (m, J* = 16 Hz, 4 H,
4 × CHH), 6.58 (m, J* = 8 Hz, 4 H, Ar–H), 6.83 (d, J = 8 Hz, 4 H,
Ar–H), 6.97–7.30 (m, 8 H, Ar–H), 9.49 (s, 2 H, 2 × OH). MS (EI):
m/z = 530 (M+) Anal. Calc. for C32H26N4O4: C, 72.44; H, 4.94; N,
10.56. Found: C, 72.6; H, 5.1; N, 10.4.
13b,13c-Di(4-hydroxyphenyl)-2,3,9,10-tetramethyl-
5,7,12,13b,13c,14-hexahydro-5a,6a,12a,13a-tetra-azabenzo[5,6]
azuleno[2,1,8-ija]benzo[f]azulene-6,13-dione(7b):Preparedaccording
to the general procedure using 1.53 g (2.5 mmol) of compound 3b and
11.5 g (0.1 mol) of pyridine hydrochloride. Yield: 0.98 g (67%); m.p.
>300°C. IR (KBr): 3374 (br), 1691, 1615, 1515, 1464, 1279 cm-1.
1H NMR (DMSO- d6): δ = 2.09 (s, 12 H, 4 × CH3), 3.99 (d, J = 16
Hz, 4 H, 4 × CHH), 4.52 (d, J = 16 Hz, 4 H, 4 × CHH), 6.56 (m,
J* = 8 Hz, 4 H, Ar–H), 6.81 (m, J* = 8 Hz, 4 H, Ar–H), 6.94 (s, 4 H,
Ar–H), 9.47 (s, 2 H, 2 × OH). MS (EI): m/z = 586 (M+) Anal. Calc.
for C36H34N4O4: C, 73.70; H, 5.84; N, 9.55. Found: C, 73.95; H, 6.0;
N, 9.7.
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