A new diaza heteroaromatic crown of 3,5-disubstituted 1H-pyrazole which forms solid dinuclear complexes with lipophilic phenethylamines

Article abstract of DOI:10.1139/v98-117

The cyclic stannoxane obtained from N-methyldiethanolamine and dibutyltin oxide reacts with 1H-pyrazole-3,5-dicarbonyl dichloride to afford the new 26-membered diaza tetraester crown 3. In neutral medium, the above crown forms 1:2 solid dinuclear complexes with phenethylamine (3a) and homoveratrylamine (3b), which, after crystallization from acetonitrile, were isolated in high yield (90% and 85%, respectively). The 3, 3a, and 3b structures were identified from their analytical and spectroscopic (¹H, ¹³C NMR, and MS (FAB)) data. The spectroscopic properties of 3a and 3b are demonstrating that, in each complexation centre, simultaneously to the strong participation of the four pyrazole nitrogens, an additional weaker interaction between the aliphatic nitrogen of the side chain and the amine is involved. Comparison of the total interaction energies calculated (GenMol software) for phenethylamine-derived complex (3a) and homoveratrylamine- derived one (3b) suggests that the o-dimethoxy substitution of the guest aromatic ring could be improving the stability of 3b in relation to 3a.

Full text of DOI:10.1139/v98-117

1174
A new diaza heteroaromatic crown of 3,5-
disubstituted 1H-pyrazole which forms solid
dinuclear complexes with lipophilic
phenethylamines
Ana M. Sanz, Pilar Navarro, Fernando Gomez-Contreras, Mercedes Pardo,
Gèrard Pèpe, and André Samat
Abstract: The cyclic stannoxane obtained from N-methyldiethanolamine and dibutyltin oxide reacts with 1H-pyrazole-
3,5-dicarbonyl dichloride to afford the new 26-membered diaza tetraester crown 3. In neutral medium, the above crown
forms 1:2 solid dinuclear complexes with phenethylamine (3a) and homoveratrylamine (3b), which, after crystallization
from acetonitrile, were isolated in high yield (90% and 85%, respectively). The 3, 3a, and 3b structures were identified
from their analytical and spectroscopic (1H, 13C NMR, and MS (FAB)) data. The spectroscopic properties of 3a and 3b
are demonstrating that, in each complexation centre, simultaneously to the strong participation of the four pyrazole
nitrogens, an additional weaker interaction between the aliphatic nitrogen of the side chain and the amine is involved.
Comparison of the total interaction energies calculated (GenMol software) for phenethylamine-derived complex (3a)
and homoveratrylamine-derived one (3b) suggests that the o-dimethoxy substitution of the guest aromatic ring could be
improving the stability of 3b in relation to 3a.
Key words: diazacrown, 1H-pyrazole, dinuclear, complexes, phenethylamines.
Résumé : Le stannoxane cyclique obtenu à partir du N-méthyldiéthanolamine et de l’oxyde de dibutylétain réagit avec
le dichlorure de 1H-pyrazole-3,5-dicarbonyle pour conduire à un nouvel éther diazacouronne tétraester à 26 chaînons
(3). En milieu neutre, cette couronne forme des complexes dinucléaires solide 1:2 avec la phénéthylamine (3a) et
l’homovératrylamine (3b) qui ont été isolés avec d’excellents rendements (90 et 85% respectivement) après
cristallisation dans l’acétonitrile. On a identifié les structures 3, 3a et 3b à partir de leurs données analytiques et
1
spectroscopiques (RMN du H et du 13C et SM (FAB)). Les propriétés spectroscopiques des composés 3a et 3b
démontrent que, pour chaque centre de complexation, en plus de la forte participation des quatre azotes des pyrazoles,
il existe une faible interaction entre l’azote aliphatique de la chaîne latérale et celui de l’amine. Une comparaison des
énergies totales d’interaction (calculées à l’aide du programme GenMol) des complexes dérivés de la phénéthylamine
(3a) et de l’homovératrylamine (3b) suggère que le substituant o-diméthoxy du noyau aromatique de l’invité améliore
la stabilité du composé 3b par rapport à 3a.
Mots clés : diazacouronne, 1H-pyrazole, dinucléaire, complexes, phénéthylamines.
[Traduit par la Rédaction] Sanz et al. 1179
disorders of thinking such as paranoia) are hallucinogen
phenethylamines methoxy and (or) methylenedioxy substi-
tuted at the aromatic ring (1).
One of the two main categories of psychedelic drugs that
produce perceptual distortions (hallucinations, illusions, and
The selective complexation of such hallucinogen sub-
strates by adequately arranged synthetic receptors, in rela-
tion to neurotransmitter catecholamines, is an important but
difficult target due to the similarity of their structures. Thus,
dopamine and norepinephrine, involved in the normal emo-
tional and autonomic control of humans, have in common a
hydrophilic 3,4-dihydroxyphenethylamine nucleus, while its
3,4-dimethoxy substituted analogue (homoveratrylamine) of
higher lipophilic character shows hallucinogen effects (2).
Received January 28, 1998.
A.M. Sanz and P. Navarro.1 Instituto de Química Médica,
Centro Nacional de Química Orgánica, Manuel Lora Tamayo,
C.S.I.C., c/ Juan de la Cierva 3, 28006 Madrid, Spain.
F. Gomez-Contreras and M. Pardo. Departamento de
Química Orgánica I, Facultad de Química, Universidad
Complutense, 28040 Madrid, Spain.
G. Pèpe and A. Samat. UERS CNRS 158, Faculté des
Sciences de Luminy, Université de la Méditerranée, Case 901,
Cedex 9, 13288 Marseille, France.
It is well known that synthetic oxaaza and polyaza
macrocycles containing a trigonal symmetrical arrangement
of NH binding sites are able to selectively complex ammo-
nium and catecholammonium ions (3). In this way, we have
previously synthesized and studied the transport properties
of different series of synthetic heteroaromatic receptors
1Author to whom correspondence may be addressed.
Telephone: 34 91 5622900. Fax: 34 91 5644853. E-mail:
iqmnt38@fresno.csic.es
Can. J. Chem. 76: 1174–1179 (1998)
© 1998 NRC Canada

Sanz et al.
1175
Fig. 1.
Scheme 1.
containing one to three 1,3,5- or 3,5-substituted pyrazole
units (4). As the result of the above studies, we discovered a
dinuclear receptor of 1H- pyrazole of similar size to that of
valinomycin (36-membered) 1 [L1H2] (X = H2; n = 3)
(Fig. 1), which behaves as an effective and selective carrier
Considering the strong insoluble character of the above
dioxa substituted coronand 2, and taking into account that
N···HN hydrogen bonds are more effective than O···HN
ones, in this paper we have synthesized a more convenient
diazatetraester crown of 1H-pyrazole 3, [L3H2], which is sol-
uble in common lipophilic organic solvents. This new
diazacoronand is containing a double trigonal symmetrical
arrangement of NH binding sites in which the two basic ni-
trogens incorporated to the side chains are improving the
complexing properties of 3 toward phenethylamine and
homoveratrylamine.
+
of NH4 (5). Furthermore, it has been recently discovered
that such crown is able to form dinuclear complexes with
+
lipophilic phenethylamine R-NH3 ions of higher stability
than those formed with those of hydrophilic
phenethylamines.2
On the other side, we have also synthesized an analogous
dinuclear receptor of 1H- pyrazole 2 [L2H2] of smaller size
(26-membered), which strongly interacts with neutral
lipophilic R-NH2 phenethylamines, affording dinuclear com-
plexes 2a R = H; phenethylamine) and 2b R = OMe;
homoveratrylamine), which were isolated in the solid state
(6). Besides, the theoretical calculations (GenMol software)
The synthesis of the 3 has been achieved as depicted in
Scheme 1.
N-Methyldiethanolamine was heated to reflux in benzene
with dibutyltin oxide to give the corresponding cyclic
stannoxane (8), which was reacted with 1H-pyrazole-3,5-
dicarbonyl dichloride to afford crown 3 (mp 190–192°C;
C20H26N6O8·2H2O; MH+ 479) in a 10% overall yield.
In the FAB mass spectrum of the diaza tetraester crown 3,
the expected molecular ion MH+ corresponds to the base
peak (m/z 479, 100%). From MH+, the fragmentation is
mainly governed by usual ruptures of amine and ester bonds,
1
together with a careful H and 13C NMR study has recently
demonstrated that in both complexes, the two sp2 pyrazole
nitrogens and the two NH pyrazole protons are involved in
the complexation of the two guest amine molecules, afford-
ing a molecular association mainly stabilized by symmetri-
cal hydrogen bonds (7), while other hydrogen bonds with
ether oxygens belonging to the receptor side chains were
discarded.
2
M.I. Rodriguez-Franco, B. Gonzalez, A. Sanz, P. Navarro, C. Ochoa, A. Doménech, and E. García-España. 1998. Unpublished results.
© 1998 NRC Canada

1176
Can. J. Chem. Vol. 76, 1998
Table 1. The 13C NMR spectral data (75 MHz, Cl3CD, δ) of
complexes 3a and 3b compared with those of the free guests
(phenethylamine(Ph), homoveratrylamine (Ho)) and host (3).
As could be expected in the formation of strong NH···N
hydrogen bonds (9), in the H NMR spectra of 3a and 3b
registered in Cl3CD, the complexation strongly affects the
amine RNH···Nϭ signals, which are deshielded by 3.55 and
3.07 ppm in relation to the free phenethylamine and
homoveratrylamine respectively.
Comparison of the 13C NMR spectral data of these com-
plexes with those corresponding to the free guests and host
(Table 1) affords some relevant structural information. The
two methylene carbons closer to the complexation centre, as
well as the ipso aromatic carbons of the guest amines experi-
ence considerable upfield shifts, which are larger for the β
than for the α and C1-Ar carbons (Table 1a). This behaviour
agree with a reduction of electronic density at the sp3 nitro-
gen, which takes place when the complex is formed (10).
Furthermore, it may be noted that shieldings measured are
much higher for homoveratrylamine (∆δ 3b-Ho) than for
phenethylamine (∆δ 3a-Ph).
1
Compd. Ph
3a
42.95 –0.40
39.38 –0.55
139.62 139.40 –0.22
∆δ3a-Ph Ho
3b
∆δ3b-Ho
Cα
Cβ
43.35
39.93
43.33
39.20
42.73 –0.60
38.06 –1.14
132.07 131,48 –0.59
C1-Ar
Compd.
3
3a
∆δ3a-3
3
3b
∆δ3b-3
C(3,5)
C(4)
CO
139.36 139.56 +0.20
111.70 111.52 –0.18
159.60 159.57 –0.03
139.36 139.93 +0.57
111.70 111.59 –0.11
159.60 160.07 +0.47
CH2O
CH2N
NMe
59.74
55.91
40.01
59.41 –0.33
55.79 –0.12
39.74 –0.27
59.74
55.91
40.01
59.37 –0.37
56.07 +0.16
39.82 –0.19
On the other hand, the comparison of the 13C NMR data
of 3a and 3b and those of the free host 3 (Table 1b) shows
that the signals belonging to the pyrazole ring undergo in
both complexes chemical shifts to downfield carbons C(3,5)
and highfield carbons C(4), which are much more smaller
but of identical sign to those previously observed in the for-
mation of dipyrazolate anions by deprotonation of 26-
membered dinuclear 1H-pyrazole macrocycles (6b). Further-
more, the pyrazole carbons C(3,5), which in 3 appear as a
broad signal due to the pyrazole prototropic equilibrium,
collapse after complexation to a sharp singlet. As it was pre-
viously observed from dioxa tetraester crown-derived com-
plexes(7), the above behaviour confirms that in complexes
3a and 3b, the NH pyrazole protons are not ambigously lo-
cated but fastened to the guest amines. The above situation
agrees with a molecular association mainly stabilized by
symmetric RN·HN(Pz) and RNH···Nϭ(Pz) hydrogen bonds.
On the other hand, taking as reference the basic nitrogens lo-
cated in middle of the host flexible side chains, it can be ob-
served that after complexation, the β methylene carbons
(CH2O) as well as the a methyl ones (MeN) experience in
both complexes upfield shifts, which suggest an additional
interaction between the sp3 nitrogens and the guest amines.
responsible for sequential losses of a = C3H7N (57) and b =
C5H9N (83) fragments belonging to the host flexible chain,
as well as c = C5H2N2O2 (122) and d = C5H2N2O3 (138)
fragments corresponding to the losses of one of the two
diceto pyrazolo moieties. Furthermore, as usually occurs
with tetraester and polyether crowns of dimmer structure (5),
from M+ other important decompositions give rise to the
characteristic (M/2 + H)+ species (m/z 240, 7%).
The complexing ability of crown 3 [L3H2] was tested by
stirring
for
15
min
with
phenethylamine
or
homoveratrylamine in a 1:2 molar ratio using chloroform as
solvent. In both cases, after concentration, the diaza substi-
tuted complexes were isolated as white solids and crystal-
lized from acetonitrile. Their analytical and spectroscopic
data were consistent with neutral dinuclear complexes 3a
(mp 140–142°C; C36H48N8O8·3H2O; MH+ – C3H7N 664)
and 3b (mp 170–172°C; C40H56N8O12·H2O; MH+ – C3H7N
684), which were obtained in 90% and 85% yield, respec-
tively (Fig. 1).
The FAB mass spectra of both dinuclear complexes are
clearly demonstrating the strong interaction of the two
amino groups with both pyrazole rings. The phenethylamine
complex 3a shows a pattern in which two a = C3H7N (57), b
= C4H9N (71), or c = C5H11N (85) fragments belonging to
the host flexible side chain, as well as two d = C6H5 (77) ar-
omatic fragments belonging to the amine guest, are simulta-
neously lost giving up a series of peaks of m/z: 606 (M+ –
2(C3H7N)) (0.1); 578 (M+ – 2(C4H9N)) (1.9); 567 (MH+ –
2(C6H5)) (0.6); 551 (MH+ – 2(C5H11N)) (11.0); 550 (M+ –
2(C5H11N)) (26.3). In a similar way, the homoveratrylamine
complex 3b show a pattern in which one or two host flexible
side chain fragments (a = C3H7N (57); b = C4H9N (71); c =
C5H10N (84); and d = C5H11NO2 (117)) and one or two
homoveratrylamine fragments (e = C8H9O2 (137) and f =
C8H9O2 (138)) are successively or simultaneously lost from
the MH+(H2O), M+(H2O), MH+, and M+ molecular ions, af-
fording different series of peaks of m/z: 801 (M+(H2O) –
C3H7N) (0.2); 744 (M+(H2O) – 2(C3H7N)) (0.2); 788
(MH+(H2O) – C4H9N) (0.2); 716 (MH+(H2O) – 2(C4H9N))
(0.1); 703 (M+ – C8H9O2) (0.5); 566 (M+ – 2(C8H9O2)) (0.5);
606 (M+ – 2(C5H11NO2)) (0.1); 565 (M+ – (C8H9O2) –
(C8H10O2)) (0.46); 373 (MH+ – 2 (C5H10N) – 2(C9H10O2))
(11.0).
Theoretical approach of the stability of diaza tetraester
crown-derived complexes 3a and 3b
The stability of the complexes has been evaluated using
molecular modelling GenMol software (11). This program
based on molecular mechanics calculations is designed to
build molecules and to find their preferred conformations
(12). It also allows to model molecular interactions and to
find the minimum energy of complex molecular systems
(13).
We have previously shown that, for dinuclear complexes
obtained from the dioxa tetraester crown 2 [L2H2] with
phenethylamine (2a) and homoveratrylamine (2b), syn- con-
formations (both amines on the same face of the crown)
were more stable than the anti-conformations (amines on the
opposite faces of the crown) (7).
Now, starting from the syn-conformation of the diaza
tetraester crown 3 [L3H2], we have calculated the interaction
energy between the host (crown) and the guest (both
© 1998 NRC Canada

Sanz et al.
1177
Table 2. Relative stability of dinuclear cyclic complexes 3a and
3b modelled from diaza substituted coronand 3. (EI, EH, Evdw, EC
are, respectively, the interaction, hydrogen bond, van der Waals,
and coulombic energies (kcal mol–1).)
Fig. 2.
Compound
EI
EH
Evdw
EC
3a (Ph)
3b (Ho)
–18.4
–22.1
–5.3
–5.8
–13.2
–16.2
–0.01
–0.12
molecules of amine), which is directly connected to the as-
sociation constants.
In Table 2 are reported the interaction energies (EI, kcal
mol–1) and the hydrogen bond energies (EH, kcal mol–1) cor-
responding to the new dinuclear complexes obtained from
the diaza substituted receptor 3 [L3H2] with phenethylamine
(3a) and homoveratrylamine (3b).
The value EI is the sum of classic nonbond interactions
occurring between the crown and the amines:
complexes (3a) and homoveratrylamine-derived ones (3b) is
suggesting that the o-dimethoxy substitution of the guest ar-
omatic ring could be improving the stability of 3b in relation
to 3a. Now, work is in progress in order to evaluate the ex-
perimental stability constants of phenethylamine and homo-
veratrylamine dinuclear complexes 2a, 2b and 3a, 3b, as
well as those formed from mescaline, amphetamine, and
neurotransmitter catecholamines (dopamine and norepine-
phrine).
EI = Evdw + EC + EH
in which Evdw, Ec, and EH are, respectively, van der Waals,
coulombic, and hydrogen bond energies. The more EI is neg-
ative, the more the complex is stable.
Regarding the geometries of the most stable complexes
obtained for 3a and 3b it seems that hydrogen bonds exist
really between the guest amine nitrogen atoms and the host
pyrazole nitrogen ones (the distance is close to 2.9 Å), while
the distances with nitrogen atoms of the NMe groups (3.2 Å)
may correspond to weaker hydrogen bonds.
Comparison of the total interaction energies suggest that
the theoretical stability of the homoveratrylamine complex
3b is higher than that of the phenethylamine 3a. Detail of
the interaction energies (Table 2) shows that this increase is
due at once to hydrogen bonding and van der Waals type in-
teractions.
The IR spectra were recorded in KBr, and the NMR spec-
tra in CDCl3 solution, taking Me4Si as internal reference.
Analytical TLC and flash column chromatography were per-
formed using silica gel 60 PF254 (Merck) and silica gel
(Merck), 200–400 mesh, respectively. All reagents were of
commercial quality from freshly opened containers. Thionyl
chloride (Scharlau) was freshly purified prior to use as fol-
lows: distilled from quinoline (to remove acid impurities)
followed by distillation from boiled linseed oil under argon.
Pyrazole-3,5-dicarboxylic acid monohydrate (Aldrich), N-
methyldiethanolamine (Aldrich), dibutyltin oxide (Merck),
homoveratrylamine (Aldrich), phenethylamine (Aldrich),
and reagent quality solvents were used without further puri-
fication.
The more stable conformations of the diaza tetraester
crown-derived homoveratrylamine complex 3b is shown in
Fig. 2.
1H-Pyrazole-3,5-dicarbonyl dichloride
(i) The synthesis of a new proton ionizable ester crown 3
(mp 190–92°C) has been performed in 10% yield by direct
cyclization of 1H-pyrazole-3,5 dicarbonyl dichloride and
2,2-dibutyl-6-methyl-6-aza-1,3-dioxa-2-stannocyclooctane.
(ii) Using chloroform as solvent, the reaction of crown 3
with phenethylamine and homoveratrylamine (molar ratio
1:2) affords solid dinuclear complexes, which after being
crystallized from acetonitrile were obtained in high yield
(3a, mp 140–142°C, 90%; 3b, mp 170–72°C, 85%). (iii) The
structure of the new compounds 3, 3a, and 3b have been
identified from their analytical and spectroscopic (FAB MS,
IR, 1H, and 13C NMR) data. (iv) The 13C NMR study is dem-
onstrating that, in the new diaza substituted complexes 3a
and 3b, simultaneously to a strong molecular association
through NH···Nϭ(Pz) and N·HN(Pz) hydrogen bonds, an ad-
ditional weaker interaction between the host sp3 nitrogens
and the guest amines is contributing to the formation of
these new solid complexes. (v) Comparison of the total in-
teraction energies calculated for phenethylamine-derived
Thionyl chloride freshly purified (350 mL) was slowly
added to 1H-pyrazole-3,5-dicarboxylic acid monohydrate
(2 g, 11.49 mmol) by stirring and heating until all the acid
was completely dissolved. Then, the temperature was al-
lowed to 140°C over 2 h. The hot reaction mixture was fil-
tered, and the resulting solution evaporated to dryness to
give the title compound (2 g, 10.3 mmol) as a white solid
(mp 72–74°C) in 93% yield.
2,2-Dibutyl-6-methyl-6-aza-1,3-dioxa-2-
stannocyclooctane (8)
To a solution of N-methyl diethanolamine (1.36 g,
11.46 mmol) in benzene (200 mL), solid dibutyltin oxide
(2.85 g, 11.49 mmol) was slowly added. The reaction mix-
ture was refluxed for 2 h, and the water formed in the
cyclocondensation was removed by azeotropic distillation.
The resulting suspension was diluted into dry toluene
(260 mL) and collected to be used in the following step.
© 1998 NRC Canada

1178
Can. J. Chem. Vol. 76, 1998
6.78 (brs, 6H, NH), 3.04 (t, 4H, CH2-NH2), 2.80 (t, 4H,
CH2-C6H3(OMe)2), 6.76 (m, 6H, C6H3(OMe)2), 3.87 (s, 6H,
MeO), 3.85 (s, 6H, MeO). MS (FAB): 801 (M+(H2O) –
C3H7N)) (0.2); 788 (MH+(H2O) – (C4H9N)) (0.2), 684 (MH+
– (C3H7N)) (0.1), 744 (M+(H2O) – 2(C3H7N)) (0.2), 716
(M+(H2O) – 2(C4H9N)) (0.1), 703 (M+ – (C8H9O2)) (0.5),
702 (M+ – (C8H10O2)) (1.0), 660 (MH+ – (C10H15NO2))
(0.3), 606 (M+ – 2(C5H11NO2)) (0.1), 566 (M+ – 2(C8H9O2))
(0.5); 565 (M+ – (C8H9O2) – (C8H10O2)) (0.5), 551 (M+ –
(C8H10 O2) – (C9H11O2)) (8.0), 550 (M+ – (C8H10O2) –
(C9H11O2)) (18.0), 479 (MH+ – 2(C10H15NO2)) (39.0), 373
(MH+ – 2(C9H10O2) – 2(C5H10N)) (11.0), 181 (C10H15NO2)+
(9.0), 165 (C10H13O2)+ (66.0), 164 (C10H12O2)+ (31.0), 150
(C9H10O2)+ (11.0), 151 (C9H11O2)+ (21.0), 138 (C8H10O2)+
(17.0), 137 (C8H9O2)+ (31.0), 117 (C5H11NO2)+ (9.0), 73
(C4H11N)+ (100%), 71 (C4H9N)+ (36.0), 57 (C3H7N)+ (70.0).
Anal. calcd. for C40H56N8O12·H2O: C 55.94, H 6.75, N
13.05; found: C 56.33, H 6.49, N 12.94.
6,18-Dimethyl-25(26),27(28)-H,H-3,9,15,21-tetraoxa-
6,18,25,26,27,28-hexaazatricycle[21.2.1.211,13]-octacosa-
1(26),13(28),11,23-tetraen-2,10,14,22-tetraone 3
The suspension obtained above was heated to 60°C under
nitrogen, and a solution of pyrazole-3,5-dicarbonyl chloride
(21 g, 11.46 mmol) in dry dimethoxyethane (80 mL) was
added dropwise. The reaction mixture was kept at 60°C un-
der nitrogen for 24 h. After that, the solvent was removed in
vacuo to give a syrup that was purified by flash column
chromatography, eluting with an ethyl acetate – ethanol –
ammonium hydroxide (5:1:0.15 v/v) mixture. From the frac-
tion of Rf = 0.36, compound 3 was isolated as a pure solid
compound (mp 190–92°C) in 10% yield. IR (KBr, cm–1):
1
3360, 2950, 1725, 1750, 1600, 1250, 1000, 760. H NMR
(300 MHz, Cl3CD (after treated with D2O)), δ (ppm): 7.36
(s, 2H, Pz-H), 4.48 (t, 8H, COOCH2), 2.79 (t, 8H, CH2-
NMe), 2.42 (s, 6H, MeN). MS (FAB): 479 (MH+) (100), 435
(MH+ – C2H4O) (1.0), 422 (MH+ – C3H7N) (3.0), 396 (MH+
– C5H9N) (5.2), 359 (MH+ – C5H2N2O2) (2.0), 341(MH+ –
C5H2N2O3) (8.0), 240 (M+/2 + 1) (7.0), 139 (C5H3N2O3)+
(5.4), 122 (C5H3N2O2)+ (5.4). Anal. calcd. for
C20H26N6O8·2H2O: C 46.69, H 5.83, N 16.34; found: C
46.36, H 5.42, N 16.69.
1
Free homoveratrylamine; H NMR (300 MHz, Cl3CD), δ
(ppm): 1.38 (brs, 2H, NH), 2.92 (t, 2H, CH2NH2), 2.66 (t,
2H, CH2C6H3(OMe)2), 6.75 (m, 3H, C6H3(OMe)2), 3.85 (s,
3H, OMe), 3.83, (s, 3H, OMe).
Molecular modelling
GenMol (11) is a molecular mechanics software including
some specificities, able to treat atomic and molecular sys-
tems till 105 atoms of 96 types: (i) The program uses local
stretching and bending parameters, which depend not only
on the chemical neighbourhood (nature of the bonded atoms,
which is the case in all molecular mechanic programs), but
also of the geometrical neighbourhood. This concept allows
to win an order of magnitude in the geometry accuracy if
compared to X-ray data. (ii) An original algorithm deform-
ing the molecule by rotation around the bonds, and based on
empirical rules deduced from X-ray observations, allow to
very quickly find the most probable conformation of a mole-
cule. (iii) The π systems are taken into account. The pro-
gram calculates the atomic charges.
For the design of the complex, different packing of mole-
cules were tested, and the most stable corresponding to the
minimum of the nonbonded energy (van der Waals,
coulombic, and hydrogen bond) was considered. Then in a
first step, a calculation imposing all the possible hydrogen
bonds was performed, and in a second step these constraints
were removed in order to find the true hydrogen bonds and
the more stable assemblage of the molecules.
Cyclic dinuclear complex 3a
Crown 3 (18 mg, 0.037 mmol) was dissolved at rt in chlo-
roform (5 mL), and a solution of phenethylamine (9.11 mg,
0.075 mmol) in chloroform (2 mL) was added dropwise un-
der stirring. After that, the solvent was removed in vacuo to
give a residue, which was crystallized from acetonitrile, af-
fording the pure dinuclear complex 3a as a white solid (mp
140–142°C) in 90% yield. IR (KBr, cm–1): 3400–3100,
1720, 1630, 1265, 1220, 1035, 795, 760. 1H NMR
(300 MHz, Cl3CD), δ (ppm): 7.31 (s, 2H, Pz-H), 4.40 (m,
8H, COOCH2), 2.70 (m, 8H, CH2-NMe), 2.31 (s, 6H, MeN),
4.70 (brs, 6H, NH), 3.00 (t, 4H, CH2-NH2), 2.80 (t, 4H,
CH2-C6H5), 7.18 (m, 10H, C6H5). MS (FAB): 664 (MH+ –
C3H7N) (0.1), 663 (M+ – C3H7N) (0.2), 606 (M+
2(C3H7N)) (0.1), 600 (MH+ – C8H11N) (0.8), 578 (M+
–
–
2(C4H9N)) (1.9), 567 (MH+ – 2(C6H5)) (0.6), 551 (MH+ –
2(C5H11N)) (11.0), 550 (M+ – 2(C5H11N)) (26.3), 479 (MH+
– 2(C8H11N)) (63.0), 122 (C5H2N2O2)+ (100), 121 (C8H11N)+
(14.0), 77 (C6H5)+ (31.0), 85 (C5H11N)+ (8.0), 71 (C4H9N)+
(14.0), 57 (C3H7N)+ (31.0). Anal. calcd. for
C36H48N8O8·3H2O: C 55.81, H 7.02, N 14.47; found: C
56.12, H 6.62, N 14.32.
Free phenethylamine; 1H NMR (300 MHz, Cl3CD), δ
(ppm): 1.13 (brs, 2H, NH), 2.94 (t, 2H, CH2NH2), 2.72 (t,
2H, CH2C6H5), 7.15 (m, 5H, C6H5).
Financial support of this work by the Spanish Comision
Interministerial de Ciencia y Tecnología (CICYT, Co-
ordinated Project SAF-96–0242-CO2) is gratefully acknowl-
edged.
Cyclic dinuclear complex 3b
Crown 3 (18 mg, 0.037 mmol) was dissolved at rt in chlo-
roform (5 mL), and a solution of homoveratrylamine
(13.63 mg, 0.075 mmol) in chloroform (2 mL) was added
dropwise under stirring. After that, the solvent was removed
in vacuo to give a residue, which was crystallized from
acetonitrile, affording the pure complex 3b in 85% yield as a
white solid (mp 170–172°C). IR (KBr, cm–1): 3480–3200,
2920, 1720, 1635, 1260, 1235, 1035, 785, 760. H NMR
(300 MHz, Cl3CD), δ (ppm): 7.37 (s, 2H, Pz-H), 4.47 (m,
8H, COOCH2), 2.78 (m, 8H, CH2-NMe), 2.38 (s, 6H, MeN),
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