A proton-ionizable ester crown of 3,5-disubstituted 1H-pyrazole able to form stable dinuclear complexes with lipophilic phenethylamines

Article abstract of DOI:10.1021/jo9623651

A convenient synthesis of the proton-ionizable crown 3 is reported that uses dibutyltin oxide. In acetonitrile, the reaction of 3 (LH₂) with phenethylamine and homoveratrylamine (molar ratio 1:2) affords solid dinuclear complexes [LH₂]2RNH₂ (4a,b), which spectroscopic (FAB-MS, IR, ¹H and ¹³C NMR) data point toward a strong participation of the pyrazole nitrogens in the amine complexation. In DMSO-d₆ solution, a ¹³C NMR study demonstrates the formation in situ of analogous neutral 4a-d[LH₂]2RNH₂ or charged 5a-d[L^2-]2RNH₃⁺ dinuclear complexes by reaction of 3 [LH₂] or 3'[L^2-]2Na⁺ with RNH₂ (phenethylamine, homoveratrylamine, dopamine, and norepinephrine) or their RNH₃⁺Cl^- salts, respectively. Differences between the structure of complexes 4 and 5 have been evaluated by taking the homoveratrylamine derivatives 4b and 5b as models. An ¹H and ¹³C NMR study (by raising the temperature) and measurements of intermolecular NOE effects (from NOESY and ROESY spectra) demonstrate that both complexes behave as prototropic isomers showing different conformations. By increasing the ionic strength, the 4b isomer structure becomes similar to that of 5b. The molecular modeling (GenMol software) of 4a-d and 5a-d shows that the assemblage in which both amine molecules are on the same side of the crown is the more stable. Lipophilic amines afford more stable complexes than hydrophilic ones and charged species are much more stable than the neutral ones.

Full text of DOI:10.1021/jo9623651

2684
J . Org. Chem. 1997, 62, 2684-2693
Articles
A P r oton -Ion iza ble Ester Cr ow n of 3,5-Disu bstitu ted 1H-P yr a zole
Able To F or m Sta ble Din u clea r Com p lexes w ith Lip op h ilic
P h en eth yla m in es
Lucrecia Campayo,† J ose´ M. Bueno,† Pilar Navarro,*,† Carmen Ochoa,†
J esu´s J imenez-Barbero,‡ Ge`rard Pe`pe,§ and Andre´ Samat§
Instituto de Quı´mica Me´dica and Instituto de Quı´mica Orga´nica General, Centro Nacional de Qu´ımica
Orga´nica Manuel Lora-Tamayo, Consejo Superior de Investigaciones Cientı´ficas (CSIC), c/ J uan de la
Cierva 3, 28006 Madrid, Spain, and Laboratoire de Chimie et Mate´riaux Organiques-Mode´lisation ERS
158 CNRS, Faculte´ des Sciences Luminy, 163 Av de Luminy, 13288 Marseille Ce´dex 09, France
Received December 17, 1996X
A convenient synthesis of the proton-ionizable crown 3 is reported that uses dibutyltin oxide. In
acetonitrile, the reaction of 3 (LH2) with phenethylamine and homoveratrylamine (molar ratio 1:2)
1
affords solid dinuclear complexes [LH2]2RNH2 (4a ,b), which spectroscopic (FAB-MS, IR, H and
13C NMR) data point toward a strong participation of the pyrazole nitrogens in the amine
complexation. In DMSO-d6 solution, a 13C NMR study demonstrates the formation in situ of
analogous neutral 4a -d [LH2]2RNH2 or charged 5a -d [L2-]2RNH3+ dinuclear complexes by reaction
of 3 [LH2] or 3′[L2-]2Na+ with RNH2 (phenethylamine, homoveratrylamine, dopamine, and
norepinephrine) or their RNH3+Cl- salts, respectively. Differences between the structure of
complexes 4 and 5 have been evaluated by taking the homoveratrylamine derivatives 4b and 5b
as models. An 1H and 13C NMR study (by raising the temperature) and measurements of
intermolecular NOE effects (from NOESY and ROESY spectra) demonstrate that both complexes
behave as prototropic isomers showing different conformations. By increasing the ionic strength,
the 4b isomer structure becomes similar to that of 5b. The molecular modeling (GenMol software)
of 4a -d and 5a -d shows that the assemblage in which both amine molecules are on the same
side of the crown is the more stable. Lipophilic amines afford more stable complexes than
hydrophilic ones and charged species are much more stable than the neutral ones.
In tr od u ction
ions of catecholamines.3-5 Furthermore, it has been
demonstrated that polyether crowns 1 (R ) CH3, H) form
ammonium dinuclear complexes in which two sp2 pyra-
zole nitrogens and four oxygen atoms belonging to the
poly(ethyleneglycol) chains are involved in two [NO2]-
The structure of neurotransmitter catecholamines
(dopamine and norepinephrine) involved in the normal
emotional and autonomic control of humans, is charac-
terized by a common hydrophilic 3,4-dihydroxypheneth-
ylamine nucleus. In contrast, 3,4-dimethoxyphenethy-
lamine (homoveratrylamine) and other lipophilic amines
of related structure such as mescaline (3,4,5-trimetoxy-
phenethylamine) are psychedelic drugs showing hal-
lucinogen effects.1
NH4 centers.6
+
In this way, we have previously obtained a smaller 26-
membered proton-ionizable ester crown of 1H-pyrazole
3[LH2], which was isolated and identified as free ligand
and as disodium dipyrazolate salt 3′[L2-]2Na+.7 This
receptor, in neutral or in basic medium, is able to form
mono- and dinuclear complexes with transition metals
of the general structure M2+[LH2]2X- and 2M2+[L2- ]2X-,
respectively.
Polyoxa and polyaza macrocycles containing a trigonal
symmetrical arrangement of HN binding sites are able
to complex catecholamines by interaction with their
primary ammonium ions.2 In this way, we previously
reported dinuclear ether and ester crowns of 3,5-disub-
stituted pyrazoles 1 and 2 (Scheme 1) of similar size to
that of valinomycin (36-membered ring), which are able
Now, taking into account that crown 3 contains four
nitrogens and two oxygens in an optimal double trigonal
symmetrical arrangement of NH binding sites, we have
studied the behavior of both the free ligand 3 and its
dipyrazolate salt 3′ as complexing agents of phenethyl-
amine derivatives.
+
+
to facilitate the passive transport of NH4 and RNH3
* To whom correspondence Tel: 34 1-5622900. Fax: 34 1-5644853.
† Instituto de Qu´ımica Me´dica.
(3) Navarro, P.; Rodr´ıguez-Franco, M. I. J . Chem. Soc., Chem.
Commun. 1988, 1365-1367.
(4) Navarro, P.; Rodr´ıguez-Franco, M. I.; Foces-Foces, C.; Cano, F.
H.; Samat, A. J . Org. Chem. 1989, 54, 1391-1398.
(5) Gonza´lez, B.; J imeno, M. L.; Navarro, P.; Ochoa, C.; Rodr´ıguez-
Franco, M. I.; Sanz, A.; Trevin˜o, M. A. An. Acad. Cienc. Exact., Fis.
Nat. Madrid 1993, 87, 105-110.
(6) Navarro, P.; Rodr´ıguez-Franco, M. I. Trends Org. Chem. 1993,
4, 69-100.
(7) Acerete, C.; Bueno, J . M.; Campayo, L.; Navarro, P.; Rodriguez-
Franco, M. I.; Samat, A. Tetrahedron 1994, 50, 4765-4774.
‡ Instituto de Qu´ımica Orga´nica General.
§ Faculte´ des Sciences Luminy.
X Abstract published in Advance ACS Abstracts, April 15, 1997.
(1) (a) Pearson, J . in An Introduction to Neurotransmission in Health
and Disease; Riederer, P., Kopp, N., Pearson, J ., Eds.; Oxford Univer-
sity Press: Oxford, 1990; Chapters 21 and 26. (b) Metzler, D. E.
Biochemistry; Academic Press: New York, 1977; Chapter 16, p 1017.
(2) (a) Lehn, J . M. Angew. Chem., Int. Ed. Engl. 1988, 27, 89-112.
(b) Shutherland, I. O. Chem. Soc. Rev. 1986, 15, 63-91.
S0022-3263(96)02365-1 CCC: $14.00 © 1997 American Chemical Society

Ester Crown of 3,5-Disubstituted 1H-Pyrazole
J . Org. Chem., Vol. 62, No. 9, 1997 2685
Sch em e 1
Structural differences between complexes of general
structure 4 and 5 have been studied, taking as models
the homoveratrylamine derivatives 4b and 5b by means
of different NMR experiments (e.g., by raising the tem-
perature, evaluation of intermolecular NOE effects, influ-
ence of increased ionic strength).
On the other hand, using molecular modeling based
on molecular mechanics calculations (GenMol software),
a theoretical approach of the stability of both uncharged
4a -d [LH2]2RNH2 and charged 5a -d [L2-]2RNH3 di-
+
nuclear complexes has been performed.
Finally, regarding the great interest of this versatile
ligand 3, we have carried out an additional effort in order
to improve its synthesis, which had previously been
reported by us following more complicated procedures.
Resu lts a n d Discu ssion
Im p r oved Syn th esis of Cr ow n 3[LH2]. In general,
the synthesis of proton-ionizable tetraester-polyether
crowns derived from 1H-pyrazole by direct cyclization of
1H-pyrazole-3,5-dicarbonyl dichloride and poly(ethylene
glycol)s is very difficult and occurs in low yield, which
dramatically diminishes as the length of the polyethylene
chain is shortened. On the other hand, the obtention of
the precursor 1H-pyrazole-3,5-dicarbonyl dichloride by
heating pyrazole-3,5-dicarboxylic acid with thionyl chlo-
ride occurred in very low yield due to the simultaneous
formation of undesirable amounts of diketopiperazine
derivatives as reaction byproducts. In fact, the first
synthesis of crown 3 was performed in 2% overall yield
following a troublesome procedure that involved the
previous cyclization of 1-benzylpyrazole-3,5-dicarbonyl
dichloride with diethylene glycol (DEG) followed by Lewis
acid-catalyzed debenzylation of the corresponding [2 +
2] cyclization adduct.9
On the other hand, we later obtained optimal reaction
conditions leading to 1H-pyrazole-3,5-dicarbonyl dichlo-
ride as a pure solid in 92% yield, and on the basis of the
above result, we carried out an alternative and selective
synthesis of 3 in 5% overall yield that included the
following reaction steps: (a) obtention of the acyclic diol
5′-hydroxy-3′-oxapentyl-1H-pyrazole-3,5-dicarboxylate by
deprotection of its 6′-(2′′-tetrahydropyranyl)-3′,6′-dioxa-
hexylpyrazole-3,5-dicarboxylate precursor and (b) cycliza-
tion reaction of the acyclic diol mentioned above with 1H-
pyrazole-3,5-dicarbonyl dichloride.7
In fact, this is the full paper corresponding to a
previous short communication8 in which we announced
the excellent complexing properties of crown 3 toward
homoveratrylamine. Firstly, we report that when aceto-
nitrile is used as solvent, crown 3 strongly interacts with
lipophilic phenethylamines leading to neutral dinuclear
complexes of structure 4a ,b (see Scheme 1), which were
isolated as stable solid compounds. Both structures have
been clearly established on the basis of their analytical
and spectroscopic FAB MS, IR, and 1H and 13C NMR
data. In addition, by means of a 13C NMR study carried
out in DMSO-d6 as solvent, we have confirmed the
formation in situ of neutral dinuclear complexes of
structure 4a -d [LH2] 2RNH2 by treatment of crown
3[LH2] with not only phenethylamine and homoveratryl-
amine but also with dopamine and norepinephrine.
Taking into account the great interest of getting synthetic
ligands able to selectively complex psychedelic drugs as
ammonium salts, we have also carried out a similar 13C
NMR study on the formation in situ of charged 5a -d [L2-]-
Now, when dibutyltin oxide and 1H-pyrazole-3,5-
dicarbonyl dichloride were used as the starting materials
the synthesis of crown 3 was directly achieved in 15%
yield as depicted in Scheme 2.
Diethylene glycol was heated to reflux in toluene with
dibutyltin oxide to give the corresponding cyclic stan-
noxane,10 which was treated with 1H-pyrazole-3,5-dicar-
bonyl dichloride to afford crown 3 [mp 258-260 °C; FAB
453 (100% abundance) MH+ ] in a one-step reaction.
Syn th esis a n d Str u ctu r e of Solid Din u clea r Com -
p lexes 4a ,b. The complexing ability of crown 3 [LH2]
was tested by stirring for 15 min with phenethylamine
or homoveratrylamine in a 1:2 molar ratio using aceto-
nitrile as the solvent. In both cases, white pure solids
were isolated, which after crystallization from EtOAc
+
2RNH3 dinuclear complexes by treatment of the diso-
dium dipyrazolate salt 3′ with the ammonium salts of
the four phenethylamine derivatives mentioned above.
(9) Bueno, J . M.; Navarro, P.; Rodr´ıguez-Franco, M. I.; Samat, A.
J . Chem. Res. Synop. 1991, 126-127; J . Chem. Res., Miniprint 1991,
1101-1116.
(10) Shanzer, H.; Libman, J .; Gottlieb, H. E. J . Org. Chem. 1983,
48, 4612-4617.
(8) Campayo, L.; Bueno, J . M.; Ochoa, C.; Navarro, P.; Samat, A.
Tetrahedron Lett. 1993, 34, 7299-7300.

2686 J . Org. Chem., Vol. 62, No. 9, 1997
Campayo et al.
Sch em e 2a
Sch em e 3
a
Key: (i) toluene, N2, reflux 2 h; (ii) high dilution; N2; toluene-
DME (5:1 v/v); 60 °C, 24 h.
showed analytical and spectroscopic data consistent with
neutral dinuclear complexes 4a [mp 262-264 °C, FAB
695 (M + 1)+] and 4b [mp 156-157 °C, FAB 815 (M +
1)+] obtained in 74% and 95% yield, respectively (Scheme
1).
behavior agrees with a reduction of electronic density at
the sp3 nitrogen that takes place when the complex is
formed.12
It is interesting to point that the IR(KBr) spectra of
4a and 4b show weak ammonium ion bands between
2750 and 2000 cm-1 of similar type to those observed in
the IR spectra of hydrochlorides of phenethylamine and
homoveratrylamine. This fact could be indicative of a
strong interaction of the basic amino group of pheneth-
ylamine derivatives with the pyrazole nitrogens. Besides,
as could be expected in the formation of two different N‚‚
HN hydrogen bonds,11 in the 1H NMR spectra of both
complexes, the complexation strongly affects the NH
signals of the primary amines (deshielded 4-5 ppm in
relation to the free phenethylamine derivatives) and
those belonging to the pyrazole ring (shielded -8 ppm
in relation to the free crown 3).
In agreement with the above IR, 1H NMR, and 13C
NMR data, the FAB mass spectrum of the phenethyl-
amine dinuclear complex (4a ) shows a pattern in which
characteristic C2H7O, C4H8O, C4H8O2, and C5H8O3 frag-
ments belonging to the host flexible side chain, as well
as C7H7 and C8H9 aromatic fragments belonging to the
amine guest, are successively or simultaneously lost,
giving up a series of peaks of m/ z 647 (M+ - C2H7O) (1.0);
607 [(M + 1)+ - C4H8O2] (9.9); 603 (M+ - C7H7) (2.0);
579 [(M + 1)+ - C5H8O3 ] (4.6); 550 [M+ - 2(C4H8O)] (2.0);
460 {(M + 1)+ - [C7H7 + 2(C4H8O)]} (2.2); and 340 [M+
- [2(C4H8O) + 2(C8H9)] (1.7). All of them are clearly
demonstrating the strong interaction of the two amino
groups with both pyrazole rings.
In the complexed host moiety of 4a and 4b, the signals
corresponding to PzH(4) and those of the COOCH2
methylene groups show intermediate values between
those observed in the free ligand (3) and those of its
dipyrazolate salt (3′). In relation to the guest moiety,
the R-CH2 and â-CH2 methylenes that are nearer to both
complexation centers experiment chemical shifts to lower
field (0.2 ppm) very close to those observed when the
same methylenes of free phenethylamine and homovera-
trylamine are compared with those of their corresponding
hydrochlorides.
The 13C NMR spectral data also afford relevant struc-
tural information. First, the pyrazole carbons C(3,5),
which in 3 appeared as a very broad signal due to the
pyrazole prototropic equilibrium, collapse after complex-
ation to a sharp singlet, confirming that in 4a and 4b
the above-mentioned equilibrium has disappeared. Fur-
thermore, the above carbons C(3,5) undergo in both
complexes chemical shifts to downfield that are smaller
but of identical sign to those observed when crown 3 is
fully deprotonated leading to its dipyrazolate salt (3′).7
In a similar way, the FAB mass spectrum of the
homoveratrylamine dinuclear complex (4b) shows a
pattern in which a host side-chain fragment (C4H8O) as
well as a complete series of aromatic fragments belonging
to the amine guest (C8H9O2, C9H11O2, C10H13O2, and
C10H15O2 ) are also successively or simultaneously lost,
affording characteristic peaks: 677 (M+ - C8H9O2) (1.0);
663 (M+ - C9H11O2) (1.3); 649 (M+ - C10H13O2 ) (1.1);
647 (M+ - C10H15O2 ) (1.8); 607 [ (M + 2)+ - (C8H9O2 +
C4H8O)] (9.6); 606 [(M + 1)+ - (C8H9O2 + C4H8O)] (2.3);
579 [(M + 1)+ - (C10H11O2 + C4H8O)] (4.9); 577 [(M +
1)+ - (C10H13O2 + C4H8O)] (1.8); 485 [(M + 1)+
-
2(C10H13O2)] (1.0); 369 {(M + 1)+ - [2(C9H11O2) + 2
(C4H8O)]} (2.0); and 341 {(M + 1)+ - [2(C10H13O2) +
2(C4H8O)]} (29). Furthermore, in the 4a mass spectrum,
the C8H9 phenethylamine fragment is giving up a intense
peak of m/ z 105 (32.4) while, in that of 4b, the homo-
veratrylamine aromatic fragments C8H9O2, C9H11O2, and
C10H13O2 are directly responsible of three peaks of m/ z
137 (77), 151 (7.5), and 165 (19.5), respectively.
On the other hand, after complexation, the two meth-
ylene carbons belonging to the guest amines as well as
the ipso aromatic carbon experience considerable upfield
shifts that are larger for the Câ (4a , -3.65 ppm; 4b, -2.73
ppm) than for the CR (4a , -2.3 ppm; 4b, -1.72 ppm) and
C1Ar (4a , -1.62 ppm; 4b, -1.36 ppm) carbons. This
All of this points again toward a strong participation
of both pyrazole nitrogens in the amine complexation, so
that two pairs of NH‚‚‚Nd and N‚‚‚HN hydrogen bonds
could be polarizing the nitrogens involved in both com-
plexation centers in such a way that a partial positive
charge at the guest amine and a negative one at the
(11) Hibbert, F. in Advances in Physical Organic Chemistry; Gold,
V., Bethell, D., Eds.; Academic Press: London, 1986; Vol. 22, p 138.
(12) Hamilton, A. D. Tetrahedron Lett. 1990, 31, 2401-2404.

Ester Crown of 3,5-Disubstituted 1H-Pyrazole
J . Org. Chem., Vol. 62, No. 9, 1997 2687
Ta ble 1. 13C NMR Sp ectr a l Da ta (50 MHz, DMSO-d 6, δ)
of Neu tr a l (4a -d ) a n d Ch a r ged (5a -d ) Com p lexes
Com p a r ed w ith Th ose of th e F r ee Host (3), Its Disod iu m
Dip yr a zola te Sa lt (3′), th e F r ee Gu ests P h en eth yla m in e
(P h ), Hom over a tr yla m in e (Ho), Dop a m in e (Do),
Nor ep in ep h r in e (No), a n d Th eir Cor r esp on d in g
Am m on iu m Ch lor id es (P h H+), (HoH+), (DoH+),
a n d (NoH+)
of uncharged complexes 4a -d are compared with those
of the macrocyclic cavity of the free crown 3 and carbons
belonging to the host moiety of charged complexes 5a -d
with those of the macrocyclic cavity of the dipyrazolate
salt 3′. On the other hand, the chemical shifts of carbons
belonging to the guest moiety of 4a -d are compared with
those of the corresponding free phenethylamine deriva-
tive and carbons belonging to the guest moiety of 5a -d
with those corresponding to the hydrochlorides of phen-
ethylamine, homoveratrylamine, dopamine, and norepi-
nephrine.
compd
3
4a
5a
3′
C(3,5)
C(4)
CO
COCO
CO
138.40a
110.60
159.60
63.30
140.33b
110.83
160.81
62.75
141.20c
110.71
160.20
63.17
143.20b
110.10
161.60
62.20
As we have previously observed for isolated complexes
4a ,b, when the uncharged 4a -d complexes are formed
in situ, the C(3,5) pyrazole carbons appear as sharp
singlets that are shifted to lower field in relation to the
free ligand 3. Besides, the CR, Câ and C1-Ar pheneth-
ylamine carbons experience in the four complexes sig-
nificant chemical shifts to higher field which in 4(a , b)
are of similar absolute values to those previously ob-
served. In constrast with the above behavior, the C(3,5)
pyrazole carbons, which in the dipyrazolate salt 3′ appear
as a singlet, in the four charged complexes 5a -d experi-
ence a clear broadening indicating that the protons
belonging to the RNH3+ ions may be in fast equilibrium
among the ammonium and the pyrazole nitrogens. On
the other hand, taking the dipyrazolate salt 3′ as refer-
ence, the chemical shifts induced by the formation in situ
of charged complexes 5a -d show opposite sign to those
observed in the formation of 4a -d by complexation of 3
with free amines as can be clearly observed in Table 1.
The above behavior suggests that electrostatic interac-
tions with permanent charges may be mainly involved
in complexes 5, while a molecular association through
hydrogen bonds may play an important role in the
structure of complexes 4. Since compounds that have
identical molecular formulas but differ in the nature of
bonding of their atoms or in the arrangement of their
atoms in space are termed isomers,13 it could be consid-
ered that complexes of general structure 4 are prototropic
isomers of charged complexes of type 5.
67.80
68.30
67.97
68.00
compd
P h
4a
5a
PhH+
CR
Câ
C1-Ar
43.77
40.02
140.39
41.64
36.77
138.94
40.53
34.22
137.99
39.91
32.83
137.51
compd
3
4b
5b
3′
C(3,5)
C(4)
CO
COCO
CO
138.40a
110.60
159.60
63.30
140.40b
110.79
160.86
62.68
142.00c
110.10
161.10
62.46
143.20b
110.10
161.60
62.20
67.80
68.31
67.78
68.00
compd
Ho
4b
5b
HoH+
CR
Câ
C1-Ar
43.77
39.50
132.96
41.69
36.27
131.36
40.69
33.84
130.44
40.06
32.51
129.80
compd
3
4c
5c
3′
C(3,5)
C(4)
CO
COCO
CO
138.40a
110.60
159.60
63.30
142.17b
110.99
161.86
62.99
141.17c
110.35
160.91
62.59
143.20b
110.10
161.60
62.20
67.80
68.37
67.94
68.00
compd
Do
4c
5c
DoH+
CR
Câ
C1-Ar
43.50
38.50
130.79
41.25
34.02
129.12
41.10
33.65
128.53
40.38
32.37
128.04
compd
3
4d
5d
3′
C(3,5)
C(4)
CO
COCO
CO
138.40a
110.60
159.60
63.30
139.29b
110.81
160.07
63.35
141.03c
110.35
160.96
62.62
143.20b
110.10
161.60
62.20
1H a n d 13C NMR Sp ectr oscop ic Beh a vior of Ho-
m over a tr yla m in e Isom er s 4b a n d 5b by In cr ea sin g
th e Tem p er a tu r e. In order to obtain more clear infor-
mation about the structural differences between both
types of complexes, taking as models those corresponding
to homoveratrylamine (4b and 5b), we have carried out
67.80
67.98
67.93
68.00
compd
No
4d
5d
NoH+
CR
Câ
C1-Ar
47.77
71.60
134.27
46.52
69.81
133.31
46.93
70.21
133.34
46.01
68.87
132.79
1
additional H and 13C NMR experiments by gradually
raising the temperature.
a
b
Very broad signal. Sharp singlet. c Broad signal.
The 13C NMR chemical shift changes experimented by
4b at 30, 50, 70, and 90 °C suggest that as the temper-
ature is gradually increased the guest amine CR, Câ, and
C1-Ar carbons are shifted to higher field in such a manner
that at 90 °C their values are very close to those of free
homoveratrylamine. In a similar way, the host C(3,5)
pyrazole carbons neighboring both complexation centers
are shifted to lower field. As a result, at 90 °C their
values are very close to those of the free host 3. On the
other hand, we have verified that the 13C NMR spectrum
of 4b initially registered at 30 °C is identical to that of a
sample previously heated at 90 °C and then cooled again
to 30 °C. The above behavior clearly indicates that 4b
is a very stable complex. However, after being heated
at 90 °C, their host-guest interactions are strongly
weakened.
pyrazole ring could be responsible of many of the above
1
FAB+, IR, and H and 13C NMR spectroscopic data.
13C NMR stu d y on th e F or m a tion of Un ch a r ged
a n d Ch a r ged Din u clea r Com p lexes in Or ga n ic
Solu tion . The formation in situ of uncharged dinuclear
complexes of structure 4a -d has been performed by
comparison of the 13C NMR spectrum of 3 (LH2) in
DMSO-d6 solution with those obtained after addition of
the free amines (phenethylamine, homoveratrylamine,
dopamine, or norepinephrine) in a molar ratio of 1:2 (see
Scheme 3). In a similar way, the formation of charged
dinuclear complexes of general structure 5a -d was
studied by comparison of the DMSO-d6 spectrum of
3′[L2-]2Na+ with those obtained after addition of the
corresponding ammonium chlorides (molar ratio 1:2) and
filtration of the NaCl formed in the reaction mixture.
In Table 1, the carbons belonging to the host moiety
(13) Rigaudy, J .; Klesney, S. P. Stereochemistry. In Nomenclature
of Organic Chemistry; Pergamon Press: Oxford, 1979; pp 473-490.

2688 J . Org. Chem., Vol. 62, No. 9, 1997
Campayo et al.
F igu r e 1.
In relation to 5b, the 13C NMR chemical shift changes
experienced as the temperature is similarly increased
demostrate that after heating to 90 °C, the chemical
shifts of the guest homoveratrylammonium CR, Câ, and
C1-Ar carbons are close to those exhibited by the com-
plexed homoveratrylamine of 4b at 30 °C. In a similar
way, the host C(3,5) pyrazole carbons as well as the CO
carbonyl ones experience strong chemical shifts to lower
field in such a manner that at 90 °C the corresponding
values are very close to those found for 4b at 70 °C.
Consequently, it can be concluded that when 5b is heated
to 90 °C its structure is very close to that of 4b.
sharp singlets. This behavior confirms that after com-
plexation with free homoveratrylamine the prototropic
equilibrium of 3 has disappeared, and the NH pyrazole
protons are not ambiguously located but fastened to the
guest amine. The above situation agrees with a molec-
ular association in which polarized hydrogen bonds may
be involved.
1
We have also studied the differences between the H
NMR signals of the methylene groups belonging to the
host flexible side chains in the free ligand 3 and its
dipyrazolate sodium salt (3′) as well as in their corre-
sponding dinuclear complexes 4b and 5b when their
spectra are registered at 30 and 90 °C. From the above
data, the following have been clearly demonstrated: (1)
Either at 30 or at 90 °C, the conformation of the
macrocyclic cavity belonging to the free host (3) is
different from that of its disodium dipyrazolate salt (3′).
(2) At 30 °C, there are small differences between the host
methylenes COOCH2 and CH2O of 4b and 5b that
indicate that the conformation of both macrocyclic cavi-
ties are different. (3) After the temperature increases
to 90 °C, the macrocyclic cavity conformations of both 4b
and 5b complexes are similar to that of the free host 3
at the same temperature.
Figure 1 graphically shows the clear differences be-
tween both the C(3,5) pyrazole carbons and the neighbor
CO carbonyl carbons of 4b and 5b at 30 °C (a) and 70 °C
(b).
In the spectrum of 5b registered at 30 °C the C(3,5)
pyrazole carbons display a very broad signal at 147.01
ppm and the CO carbonyl ones a broad singlet at 160.96
ppm. By increasing the temperature to 70 °C, the broad
signal corresponding to the C(3,5) pyrazole carbons is not
significantly modified. Only at 90 °C does it appear as a
singlet. The above behavior confirms that in the am-
monium dipyrazolate complex 5b the NH pyrazole pro-
tons are “smeared” among the guest and the host
nitrogens. Then, it seems reasonable to think that
electrostatic (coulombic) interactions with permanent
charges may be mainly involved in complexes of 5 type.
In contrast with the above behavior, at 30 and 70 °C
the C(3,5) pyrazole carbons and the neighbor CO carbonyl
carbons belonging to the neutral complex 4b appear as
Stu d y of In ter m olecu la r NOE Effects fr om Both
th e NOESY a n d ROESY Sp ectr a of 4b a n d 5b. In
order to obtain more clear information about the different
geometries involved in both complexes, we have per-
formed a series of NOE measurements. In Table 2 are
gathered the interproton NOEs found for both molecular

Ester Crown of 3,5-Disubstituted 1H-Pyrazole
J . Org. Chem., Vol. 62, No. 9, 1997 2689
Ta ble 2. In ter p r oton NOEs in th e NOESY a n d ROESY Sp ectr a of th e Com p lexes 4b a n d 5b by In ver sion of th e
Host P r oton s
inverted proton
Pz-H(4)
obsd NOE 4b
obsd ROE 4b
inverted proton
Pz-H(4)
obsd NOE 5b
obsd ROE 5b
CH2-(R) (inter)
0.2%
CH2-â (inter)
0.7%
CH2-(â) (inter)
0.2%
OMe (inter)
2.0%
OMe (inter)
1.6%
OMe (inter)
2.0%
OMe (inter)
3.0%
Ar-H (inter)
(H6 > H2 > H5))
0.4%
Ar-H(inter)
(H6 > H5)
0.5%
COOCH2 (intra)
0.1%
COOCH2 (intra)
0.8%
COOCH2 (intra)
0.2%
COOCH2 (intra)
0.5%
OCH2(intra)
0.1%
OCH2(intra)
0.1%
COO-CH2
COO-CH2
CH2-(â) (inter)
3.0%
Ar-H (inter)
(H2 > H5 > H6)
0.1%
Ar-H (inter)
(H2, H5 > H6)
0.4%
Ar-H (inter)
(H2 > H5 . H6)
1.0%
OMe (inter)
2%
OMe (inter)
0.6%
OMe (inter)
2%
OCH2 (intra)
5.0%
OCH2 (intra)
23.0%
OCH2 (intra)
1.5%
OCH2 (intra)
10.0%
Pz-H(4) (intra)
0.1%
Pz-H(4) (intra)
3.0%
Pz-H(4) (intra)
0.5%
Pz-H(4) (intra)
5.0%
OCH2
OCH2
CH2(R) (inter)
2.2%
Ar-H (inter)
(H2 . H5)
0.4%
Ar-H (inter)
(H2 . H5)
0.8%
Ar-H (inter)
(H2 . H5, H6)
1.0%
Ar-H (inter)
(H2 > H5 . H6)
2.0%
COOCH2 (intra)
4%
COOCH2 (intra)
9.0%
COOCH2 (intra)
5.0%
COOCH2 (intra)
12%
Pz-H(4) (intra)
0.3%
Pz-H(4) (intra)
1.4%
Pz-H(4) (intra)
0.2%
Pz-H(4) (intra)
2.0%
complexes (4b and 5b) in their NOESY and ROESY
spectra by inversion of the host protons.
of at least three interaction mechanisms [electrostatic
(coulombic), dispersive, and charge transfer], the pre-
dominant role of the coulombic forces has become in-
creasingly apparent trough quantum-chemical calcula-
tions utilizing larger basis sets. Besides, it is supported
by experimental evidence of a stability dependence for
appropriate complexation systems on the acidity of the
donor XH and the basicity of the acceptor. For this
reason, structure and energies of such complexes are
most often calculated on the basis of Coulomb poten-
tials.14
In particular, pyrazole/aromatic interactions are evi-
dent in both systems from which a different orientation
of the guest aromatic rings in relation to the host pyrazole
rings can be deduced from the NOESY spectra of 4b and
5b. Thus, in 4b the Pz-H(4) interact with the Ar-H(2, 5,
6) aromatic guest protons in the following order Ar-H (6)
> Ar-H (2) > Ar-H (5). However, in 5b the Pz-H(4) only
interact with the Ar-H(5, 6) protons in the following
order: Ar-H (6) > Ar-H (5).
On the hypothesis that electrostatic (coulombic) forces
could be a common factor in both type of complexes, the
main differences between both isomers should arise from
the major or minor participation of such electrostatic
forces in 5b and 4b, respectively.
In this way, it is important to point out that in the in
situ obtention of 5b 2 equiv of NaCl are simultaneously
formed. However, the formation in situ of 4b occurs in
the absence of NaCl.
Taking into account that in molecular associations
involving electrostatic interactions salt effectssby way
of the ionic strengthsare able to induce ∆GHG changes,15
we have studied the effect of an excess of NaCl on the
last mentioned complex (4b). Comparison of the 1H NMR
signals corresponding to the guest amine in 4b, 5b, and
(4b + NaCl) has demonstrated that at 30 °C marked
differences exist between the complexed homoveratryl-
amine in 4b and the complexed homoveratrylammonium
in 5b. However, in (4b + NaCl) all the guest signals are
much more similar to those of 5b than those of 4b.
Different intermolecular cross peaks are also observed
between the OMe groups and the Ar-H (2, 5, 6) protons
of the guest aromatic moiety and the methylene protons
of the host in both complexes.
Finally, major differences between 4b and 5b are found
in contacts involving the CH2-(R) and CH2-(â) groups of
the guest. Thus, the NOESY and ROESY spectra of 5b
show CH2-(â) intermolecular contacts with both the Pz-
H(4) and the COO-CH2 host protons. However, the CH2-
(R) guest protons mainly interact with the CH2O host
protons. In contrast with the above behavior, in the
NOESY and ROESY spectra of 4b any of the above-
mentioned contacts are observed.
In conclusion, all the host/guest intermolecular inter-
actions observed in the NOESY and ROESY spectra of
4b and 5b indicate that the guest amine in 4b adopts a
different orientation in relation to the host macrocycle
than that found for the guest amine in 5b.
On the basis of the spectroscopical data previously
commented it can be deduced that the conformation of
4b is different from that of 5b.
(14) Schneider, H.-J . Angew. Chem., Int. Ed. Engl. 1991, 30, 1417-
1436.
(15) Schneider, H.-J .; Kramer, R.; Simova, S.; Schneider, V. J . Am.
Chem. Soc. 1988, 110, 6442 and references cited therein.
In flu en ce of Sa lt Effects on Solu tion s Con ta in in g
th e 4b Isom er . It has been reported that, in spite of
hydrogen-bonded association involving the participation

2690 J . Org. Chem., Vol. 62, No. 9, 1997
Campayo et al.
Consequently, the above spectroscopical data seem to
confirm that, starting from 4b, when the ionic strength
is strongly increased the structural differences between
both complexes 4b and 5b disappear.
On the other hand, considering that the filtered solu-
tion of 5b could contain traces of NaCl (most of the
1
formed NaCl is filtered off), we have registered the H
and 13C NMR spectra of a 1:1 mixture of both isomers.
The resulting (4b + 5b) 13C NMR spectrum registered
at 30 °C clearly demostrates the following: (1) There are
only a series of carbon signals that show intermediate
values between those previously registered for 4b and
5b. (2) The chemical shift differences ∆δ1 [(4b + 5b) -
4b] and ∆δ2 [(4b + 5b) - 5b] corresponding to the guest
amine [CR, Câ, and C1-Ar carbons] show similar absolute
values of opposite sign. Therefore, in the 1:1 mixture
solution of 4b and 5b both isomers may be in equilibrium.
(3) The C(3,5) pyrazole signals of the 1:1 mixture of 4b
and 5b registered at 30 °C are much more similar to
those of 5b than to those of 4b. This last result confirms
that in the presence of NaCl traces the NH-pyrazole
protons belonging to 4b are not fastened to the guest
amine but “smeared” between the host and the guest
nitrogens as occurs in 5b.
F igu r e 2. Conformation of 3 allowing the building of syn
complexes (C1) or anti complexes (C2).
On the basis of both experiments, it is obvious that the
presence of NaCl traces in 5b solution may increase the
stability of the isomer 5b but never favor the formation
of the isomer of 4b. Besides, the behavior previously
demonstrated for both homoveratrylamine-derived iso-
mers could be extended to the rest of complexes of general
structures 4 and 5 shown in Scheme 1.
Finally, the small structural differences found between
both type of complexes demostrate that, in agreement
with the previous report of Schneider,14 one of the main
advantages of synthetic host-guest chemistry is that it
permits targeted construction of supramolecular com-
plexes with infinitely variable noncovalent interactions
arranged in conformationally defined ways.
Th eor etica l Ap p r oa ch of th e Sta bility of Di-
n u clea r Com p lexes 4a -d a n d 5a -d . In order to
better understand the formation of dinuclear complex
structure, we calculated their relative stability in a
theoretical approach. The main question to answer is
as follows: are the two guest molecules on the same or
on different faces of the macrocycle?
The stability of the complexes was evaluated using
molecular modeling through GenMol sofware.16 This
program based on molecular mechanics calculations is
designed to build molecules and to find their preferred
conformations.17 It also allows us to model molecular
interactions and to find the minimum energy of complex
molecular systems.18-20
The strategy used is summarized below. In the first
step, among the set of possible conformations for the host
molecule (bipyrazole crown), we selected two conforma-
tions able to lead to both desired complexes, i.e., with
amines on the same side or on the opposite sides of the
mean plane of the crown. These conformations (C1 and
C2, respectively) are reported in Figure 2. The first one,
F igu r e 3. Syn and anti structures of uncharged (4a ) and
charged (5a ) dinuclear complexes of bipyrazole crown (3) and
phenethylamine.
with the aza parts of the two pyrazole nuclei in the syn
position, is more stable (total constrain energy, ETC ) 83
kcal) than the second one with the aza parts in the anti
position (ETC ) 91.4 kcal).
The corresponding dinuclear uncharged (4a ) and
charged (5a ) complexes with the phenethyalamine were
modeled starting from C1 and C2 (Figure 3).
The building was realized automatically according to
the docking technique. Each molecule of amine is ap-
proached along a perpendicular axis to the mean plane
of the ester crown. The relative position of the molecules
(the geometry of which is fixed) in the complex is found
by minimizing the intermolecular energy (sum of van der
Waals, coulombic, and eventually hydrogen bond ener-
gies). Then, the geometry of the complex is optimized
by complete force field calculation and the corresponding
energy ETC calculated, with or without some structural
constrains. Three cases were simulated with different
fixed distances between nonbonded atoms (amino and
pyrazolic nitrogens, ether oxygens).
(16) Pe`pe, G.; Siri, D. Stud. Phys. Theor. Chem. 1990, 71, 93-101.
(17) Cavelier-Frontin, F.; Pe`pe, G.; Verducci, J .; Siri, D.; J acquier,
R. J . Am. Chem. Soc. 1992, 114, 8885-8890.
(18) Pe`pe, G.; Siri, D.; Samat, A.; Pottier, E.; Guglielmetti, R. Mol.
Cryst. Liq. Cryst. 1994, 246, 247-250.
The results of the refinement of the complexes 4a and
5a are reported in Table 3.
Entries 1 and 4 of Table 3 concern the model of complex
in which we strained the distance between the phen-
(19) Vila, F.; Tordo, P.; Siri, D.; Pe`pe, G. Free Rad. Res. Commun.
1993, 19, 517-522.
(20) Cavelier-Frontin, F.; Sadijah, A.; Pe`pe, G.; Verducci, J .; J ac-
quier, R. THEOCHEM 1993, 286, 125-130.

Ester Crown of 3,5-Disubstituted 1H-Pyrazole
J . Org. Chem., Vol. 62, No. 9, 1997 2691
Ta ble 3. Rela tive Sta bility of th e Differ en t Mod eled
Din u clea r Com p lexes of Bip yr a zole fr om Cr ow n 3 a n d
P h en eth yla m in ea
syn
anti
entry
compd
ETC
EH
ETC
EH
1
2
3
4
5
6
4a b
4a c
4a d
5a b
5a c
5a d
77.1
89.3
78.2
-14.3
-8.6
-9.8
-3.8
-6.1
-1.5
-5.3
-8.3
-4.5
91.5
130.0
94.1
10.0
29.1
22.7
-2.0
-4.9
-1.1
-3.4
-9.3
-2.2
a
ETC (kcal) is the constrain energy (from GenMol). ETC is the
sum of nonbonded energies (van der Waals, coulombic, hydrogen)
and the bonded energies (stretching, bending, torsion). EH (kcal)
b
F igu r e 4.
is the value of hydrogen bond energy. Constraints on distances:
for the syn complexes, N1-N3, N1-N5, N2-N4, N2-N6 ) 2.7 Å;
for the anti complexes, N1-N3, N1-N4, N2-N5, N2-N6 ) 2.7 Å.
c Constraints on N-N distances as described in footnote b and N1-
Ta ble 4. Rela tive Sta bility of th e Differ en t Mod eled
Din u clea r Com p lexes of Bip yr a zole Cr ow n 3 a n d
P h en eth yla m in e (a ), Hom over a tr yla m in e (b), Dop a m in e
(c), a n d Nor ep in ep h r in e (d )a
d
Oâ1, N2-Oâ2 ) 2.7 Å. Without constrain.
syn
anti
ethyl-N and the pyrazolic-N to 2.7 Å (distance for which
there is a possibility of a strong hydrogen bond, H+ being
shared between both nitrogen atoms).
In the case of the syn complexes the concerned atoms
are N1-N3, N1-N5, N2-N4, and N2-N6 (Figure 3). For
the anti complexes, they are N1-N3, N1-N4, N2-N5, and
N2-N6, respectively.
Entries 2 and 5 of Table 3 are related to complexes for
which, the distances between the phenethyl-N and the
ether-O are also strained to a value of 2.7 Å, in additional
to the previous set.
Entries 3 and 6 of Table 3 correspond to a conformation
obtained from the last structure, optimized without any
constrain.
compd
ETC
EH
ETC
EH
4a
4b
4c
4d
5a
5b
5c
5d
77.1
89.3
-3.8
-4.1
-4.0
-4.6
-5.3
-6.2
-5.4
-6.3
91.5
106.0
134.0
120.0
10.0
23.8
47.7
26.7
-2.0
-2.7
-2.2
-3.3
-3.4
-4.0
-3.4
-4.7
109.0
102.0
-14.3
-4.8
17.5
-3.2
a
ETC and EH are, respectively, the constrain energy and the
hydrogen bond energy (kcal). Calculations have been performed
from the structure with forced distances between N-(amine) and
N-(pyrazole) to 2.7 Å (see text).
dinuclear complex is obtained when the distance between
the amine-N and the pyrazole-N allows hydrogen bond-
ing.
This kind of constraints were chosen to calculate
complexes obtained with homoveratrylamine, dopamine
and norepinephrine (Table 4).
From a general point of view, the substitution of the
aromatic ring seems to increase the total energy of
uncharged and charged complexes, and much more when
it bears hydroxy group (dopamine and norepinephrine)
instead of methoxy groups (homoveratrylamine).
The main observation is that whatever the nature of
the complexes charged or uncharged and whatever the
strains about distances between nonbonded heteroatoms
the syn complex is always the most stable.
Thus, considering the uncharged complex 4a , the
structures corresponding to the forced hydrogen bonds
between the amine-N and the ether-O are the less
stable: the gain of energy by the hydrogen bond is lost
by the increase of the nonbonded interactions. The
models optimized without structural constrain and those
in which N-N distances are forced to 2.7 Å have very
similar total strain energies of 78.2 and 77.1 kcal,
respectively. In fact, in the structure corresponding to
the former models, the distance between the amine-
nitrogen and the pyrazole-nitrogen lightly increases,
which explains the weaker energy of H-bonding.
It is interesting to note that the preferred complex
obtained when the refinement is performed with forced
N-N distances is more stable than the free macrocycle.
In the most stable conformation, the aromatic ring
would be bent toward the macrocycle mean plane, in a
quite parallel direction, leading to attractive interactions
with the oxygen atoms (Figure 4).
Con clu sion s
An improved synthesis of the proton-ionizable ester
crown 3 has been performed in 15% yield by direct
cyclization of 1H-pyrazole-3,5-dicarbonyl dichloride and
2,2-dibutyl-6-oxa-1,3-dioxa-2-stannocyclooctane.
Using acetonitrile as solvent, the reaction of crown 3
with phenethylamine and homoveratrylamine [molar
ratio 1:2] affords solid dinuclear complexes 4a and 4b,
respectively, whose structures have been identified by
analytical and spectroscopic data (FAB MS, IR, 1H NMR,
and 13C NMR).
Finally, calculations performed on charged complexes
521 indicate that the latest would be always more stable
than the parent one, with negative values for the
constrain energies, due to high dipole-dipole interac-
tions. In such calculations, the coulombic energy is
probably overestimated. Thus, the best stability of the
Following a similar procedure and using 3 and 3′ as
starting ligands, a 13C NMR study in DMSO-d6 has been
carried out by in situ formation of uncharged 4a -d and
charged 5a -d dinuclear complexes of phenethylamine,
homoveratrylamine, dopamine, and norepinephrine.
The 13C NMR spectra of complexes 4a -d demonstrate
that the NH pyrazole protons are not ambiguously
located but fastened to the guest amine. However, in
5a -d the NH pyrazole protons are “smeared” among the
guest and the host nitrogens.
(21) The geometries of the charged complexes have been obtained
from the corresponding uncharged complexes by adding the charges
(proton transfer from the pyrazole-N to the amine) and by optimizing
the energy.

2692 J . Org. Chem., Vol. 62, No. 9, 1997
Campayo et al.
method of Perrin and co-workers.22 Homoveratrylamine hy-
drochloride was prepared from an anhydrous solution of
homoveratrylamine (Aldrich) in ether followed by treatment
with HCl (gas).
1H-P yr a zole-3,5-d ica r bon yl Dich lor id e. A suspension
of 1H-pyrazole-3,5-dicarboxylic acid (2.0 g, 12.81 mmol) in
freshly distilled thionyl chloride (350 mL) was heated at 140
°C over 2 h. The hot reaction mixture was filtered and the
resulting solution evaporated to dryness to give the title
compound (2.27 g, 11.78 mmol) as a white solid (mp 72-74
°C) in 92% yield.
2,2-Dibu tyl-1,3,6-tr ioxa -2-sta n n ocycloocta n e. To a so-
lution of diethylene glycol (1.21 g, 11.40 mmol) in toluene (200
mL) was slowly added solid dibutyltin oxide (2.84 g, 11.40
mmol). The reaction mixture was refluxed for 2 h, and the
water formed in the cyclocondensation was removed by azeo-
tropic distillation. The resulting suspension was diluted with
dry toluene (260 mL) and collected to be used in the following
step.
P r ep a r a tion of Tetr a ester Cr ow n 3. The suspension
obtained above was stirred and heated to 60 °C under nitrogen.
Then, a solution of 1H-pyrazole-3,5-dicarbonyl chloride (2.20
g, 11.40 mmol) in dry dimethoxyethane (80 mL) was added
dropwise over a period of 2.5 h. When the addition was
complete, the reaction mixture was allowed to proceed for 24
h at the same temperature (60 °C) and then cooled to rt. The
residual tin salts were filtered off and the filtrate evaporated
to dryness to give an oil that when treated with dry acetone
afforded a white solid (236 mg) that was identified as crown
3. Then, the filtrate was evaporated in vacuo and the residue
purified by flash column chromatography, eluting with an
acetone/chloroform (4:1 v/v) mixture. From the fraction of Rf
) 0.50, an additional amount of pure crown 3 (150 mg) was
obtained: mp 258-259 oC (acetonitrile); overall yield 15%; MS
(FAB) 453 (MH+, 100). Anal. Calcd for C18H20N4O10: C, 47.78;
H, 4.42; N, 12.38. Found: C, 47.76; H, 4.53; N, 12.38.
Disod iu m Dip yr a zola te Sa lt 3′. A vigorously stirred
suspension of 3 (0.1 g, 0.22 mmol) in anhydrous acetonitrile
(60 mL) was heated at 75 °C until a clear solution was
obtained. The resulting mixture was slowly cooled to room
temperature, and a solution of sodium hydroxide (0.018 g, 0.45
mmol) dissolved in anhydrous ethanol (10 mL) was slowly
added. When the addition was complete, a fine solid was
formed, which was isolated by filtration and dried in vacuo to
give compound 3′ as a white crystalline solid: mp 338 °C dec
(0.108 g, 99% yield); IR (KBr, cm-1) 1710; MS (FAB) 497 (MH+,
2), 475 [MH+ - (Na+ + 1), 4], 453 [MH+ - (2Na+ + 2), 17],
451 [MH+ - 2Na+, 2]. Anal. Calcd for C18H18N4O10Na2: C,
43.55; H, 3.62; N, 11.29. Found: C, 43.61; H, 3.80; N, 11.28.
Syn th esis of Solid Din u clea r Com p lexes 4a,b. Gen er a l
P r oced u r e. A suspension of crown 3 (0.025 g, 0.055 mmol)
in anhydrous acetonitrile (5 mL) was heated at 75 °C until a
clear solution was obtained. The resulting mixture was slowly
cooled to room temperature. Then, a solution of the corre-
sponding phenethylamine derivative (0.11 mmol) in acetoni-
trile (1 mL) was added dropwise under stirring. After con-
centration of the solvent, a white solid was formed, filtered
off and dried in vacuo.
The above behavior suggests that electrostatic interac-
tions with permanent charges may be mainly involved
in complexes of general structure 5 while in complexes
of general structure 4 a molecular association through
hydrogen bonds may play an important role.
In order to demonstrate if complexes of general struc-
ture 4 and 5 behave as prototropic isomers, taking as
models the homoveratrylamine derivatives 4b and 5b,
additional 1H and 13C NMR studies by raising the
temperature have been performed. Furthermore, the
intermolecular NOE effects have been measured from
both their NOESY and ROESY spectra. From them the
following can be deduced:
(a) In agreement with our earlier hypothesis, the 13C
NMR spectra of 4b and 5b confirm that at 30 °C the NH-
pyrazole protons of 5b are cleary “smeared” among the
guest and the host nitrogens while those of 4b are
fastened to the guest amine. The above differences
gradually diminish as the temperature increases to 50,
70, and 90 °C.
(b) The 4b isomer is a very stable complex in which
host-guest interactions are strongly weakened at 90 °C.
(c) By raising the temperature to 90 °C, the structure
of 5b became similar to that of 4b.
1
(d) The H NMR spectra of both the free host 3 and its
dipirazolate sodium salt 3′ show conformational differ-
ences that are more clearly demostrated by raising the
temperature to 90 °C.
(e) The 1H NMR signals corresponding to both the
guest amine and the host macrocyclic cavity of 4b and
5b also show marked conformational differences at 30
°C that disappear by raising the temperature to 90 °C.
(f) Intermolecular NOE effects from the NOESY and
ROESY spectra of 4b and 5b confirm that the conforma-
tion of 4b is different to that of 5b.
(g) By increasing the ionic strength, the 4b isomer
structure becomes similar to that of 5b.
(h) In a 1:1 mixture solution, both 4b and 5b isomers
are in equilibrium.
The molecular modeling approach shows that the
assemblage in which both amine molecules are on the
same side of the crown is more stable than the structure
in which the amines are on opposite sides.
Hydrogen bonds between the amine and the pyrazole
nitrogens are stabilizing the complexes. These complexes
are more stable with the charged species.
The theoretical calculations show that the hypothesis
of other hydrogen bonds with the ethers-O is not probable
because of the too high values of the bending energies in
the complex. Furthermore, from a general point of view,
the o-dihydroxy substitution of the phenethylamine
aromatic ring increases the total energy of uncharged and
charged complexes in relation to o-dimethoxy derivatives.
Complex 4a . Following the above procedure, 4a was
obtained in 74% yield: mp 262-64 °C dec. Anal. Calcd for
C34H42N6O10‚0.5H2O: C, 58.03; H, 6.11; N, 11.94. Found: C,
58.04; H, 6.07; N, 11.91.
Complex 4b. Following the general procedure, 4b was
obtained in 95% yield: mp 156-157 °C (EtOAc); Anal. Calcd
for C38H50N6O14‚H2O: C, 54.80; H, 6.29; N, 10.09. Found: C,
54.80; H, 6.58; N, 10.00.
F or m a tion in Situ of Un ch a r ged Din u clea r Com p lexes
4a -d fr om Cr ow n 3. Com p lexes 4a ,b. To a solution of the
free host 3 (0.02 g, 0.044 mmol) in DMSO-d6 (300 µL) was
added a solution of phenethylamine or homoveratrylamine
(0.088 mmol) in DMSO-d6 (200 µL) and the resulting solution
shaken under sonication at rt. After 2 h, the 50-MHz 13C NMR
spectra showed that the very broad signal corresponding to
Exp er im en ta l Section
Analytical TLC and flash column chromatography were
performed 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 distilled
prior use. Pyrazole-3,5-dicarboxylic acid (Aldrich), diethylene
glycol (Aldrich), dibutyltin oxide (Merck), phenethylamine
(Aldrich), homoveratrylamine (Aldrich), phenethylamine hy-
drochloride (Aldrich), dopamine hydrochloride (Aldrich), nore-
pinephrine hydrochloride (Aldrich), and reagent quality sol-
vents were used without further purification. Anhydrous
acetonitrile free of acetic acid was prepared following the
(22) Perrin, D. D.; Armarego, W. L. F.; Perrin D. R. In Purification
of Laboratory Chemicals; Pergamon Press: Oxford, 1980; p 79.

Ester Crown of 3,5-Disubstituted 1H-Pyrazole
J . Org. Chem., Vol. 62, No. 9, 1997 2693
both pyrazole C(3,5) carbons had changed to a sharp singlet,
indicating that the corresponding dinuclear complexes had
been completely formed.
and the spin locking field was 2.5 KHz. The experiments were
carried out at 303 K. Estimated errors are better than 10%.
Com p lexes 4c,d . Dopamine hydrochloride (or norepineph-
rine hydrochloride) (0.088 mmol) dissolved in DMSO-d6 (150
µL) under argon was treated with NaOH (3.45 mg, 0.088
mmol) dissolved in D2O (50 µL). The NaCl formed was filtered
off and the clear solution containing the free amine added to
the host 3 (0.044 mmol) previously dissolved in DMSO-d6 (300
µL) under argon. After the solution was shaken for 2 h under
sonication at rt, the 50-MHz 13C NMR spectra indicated the
complete formation of the corresponding dinuclear complexes.
F or m a tion in Situ of Ch a r ged Din u clea r Com p lexes
5a -d fr om 3′. Gen er a l p r oced u r e. The hydrochloride (0.08
mmol) of the corresponding amine (phenethylamine, homo-
veratrylamine, dopamine, and norepinephrine) previously
dissolved in DMSO-d6 (150 µL) under argon was added to a
solution of disodium dipyrazolate salt 3′ (0.02 g, 0.04 mmol)
in DMSO-d6 (350 µL), and the NaCl formed was filtered off.
The filtrate was shaken under sonication as indicated before.
After 2 h, the corresponding 50-MHz 13C NMR spectra showed
that the sharp singlet corresponding to the pyrazole carbons
C(3,5) had changed to a characteristic broad signal indicating
the formation of charged dinuclear complexes.
Ack n ow led gm en t. The authors are grateful to Prof.
J . Elguero for helpful suggestions on this work. Finan-
cial support by the Spanish “Comisio´n Interministerial
de Ciencia y Tecnolog´ıa” (CICYT, Co-ordinated Project
SAF-93-0745 is also gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: IR and 1H and 13C
NMR data of the free host 3, its dipyrazolate salt 3′, the solid
complexes 4a and 4b, the free amines [phenethylamine (P h )
and homoveratrylamine (Ho], and their corresponding hydro-
chlorides (P h H+ and HoH+). 13C NMR data of charged and
neutral complexes 5b and 4b registered at 30, 50, 70, and 90
°C compared with those of 3, 3′, Ho, and HoH+. 13C NMR
data registered at 30 °C of a 1:1 mixture of 4b + 5b compared
with those of 4b and 5b. Graphical differences between both
the C(3,5) pyrazole carbons and the CO carbonyl carbons of
4b and 5b at 30, 50, 70, and 90 °C. Graphical differences
between the 1H NMR signals of the methylene groups of the
host flexible side chains in 3, 3′, 4b, and 5b when their spectra
are registered at 30 and 90 °C. Comparison of 1H NMR
graphical data (at 30 °C) corresponding to homoveratrylamine
in 4b, 5b, and (4b + NaCl). Comparison of 13C NMR graphical
data (at 30 °C) corresponding to a 1:1 mixture of 4b and 5b (9
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
NMR Exp er im en ts. NMR spectra were recorded on a
Varian Unity 500 spectrometer, using millimolar solutions in
DMSO-d6. Selective inversion 1D experiments were performed
by using a DANTE-Z module23 during 80 ms. In particular,
1D-NOESY and 1D-ROESY experiments were carried out.
NOESY experiments were recorded using mixing times of 600
ms. The rf carrier frequency for ROESY was set at δ 6.0 ppm,
(23) Boudot, D.; Canet, D.; Brondeau, J .; Bouber, J . C. J . Magn.
Reson. 1989, 83, 428.
J O9623651