Synthesis and Protonation Behavior of 26-Membered Oxaaza and Polyaza Macrocycles Containing Two Heteroaromatic Units of 3,5-Disubstituted Pyrazole or 1-Benzylpyrazole. A Potentiometric and 1H and 13C NMR Study

Article abstract of DOI:10.1021/jo981699i

The synthesis and acid-base behavior of two series of 26-membered dioxatetraamine and hexaamine heterocyclophanes containing two nuclei of either pyrazole (4a and 6a) or 1-benzylpyrazole (4b and 6b), respectively, are reported. Dipodal (2 + 2) condensations of 3,5-pyrazoledicarbaldehyde 2a or its 1-benzyl derivative 2b with 1,5-diamino-3-oxapentane afford in both cases the stable Schiff bases 3a,b in 90% yield, which after reduction with NaBH₄ gave 4a,b in 75% and 84% yield, respectively. Condensation of 2a with diethylenetriamine leads to a complex mixture containing imidazolidine isomers, which was reduced in situ to afford 6a in 30% yield. Condensation of 2b with the same amine gave the stable diimidazolidine derivative 5b, which after crystallization was isolated as a pure compound in 80% yield and fully identified from analytical and ¹H and ¹³C NMR data as a constitutional isomer with both imidazolidine rings located at the side of the pyrazole closer to the benzylic substituents. Reduction of 5b with NaBH₄ afforded the polyamine 6b in 86% yield. Protonation constants of 4a,b and 6a,b have been determined by potentiometric methods in the pH 2-11 range, and their protonation sequences were established by a ¹H and ¹³C NMR study in D₂O at variable pH. For each compound, the number of protonation constants equals the number of nitrogens in the side chains. In the pH range studied, the pyrazole rings are not involved in protonation or deprotonation processes.

Full text of DOI:10.1021/jo981699i

J . Org. Chem. 1999, 64, 6135-6146
6135
Syn th esis a n d P r oton a tion Beh a vior of 26-Mem ber ed Oxa a za a n d
P olya za Ma cr ocycles Con ta in in g Tw o Heter oa r om a tic Un its of
3,5-Disu bstitu ted P yr a zole or 1-Ben zylp yr a zole. A P oten tiom etr ic
1
a n d H a n d 13C NMR Stu d y
Vicente J . Ara´n,† Manoj Kumar,† J ose´ Molina,† Laurent Lamarque,† Pilar Navarro,*,†
Enrique Garc´ıa-Espan˜a,*,‡ J ose´ A. Ram´ırez,‡ Santiago V. Luis,§ and Beatriz Escuder§
Instituto de Quı´mica Me´dica, Centro de Qu´ımica Orga´nica “Manuel Lora Tamayo”, CSIC.
c/ J uan de la Cierva 3, 28006 Madrid, Spain, Departamento de Qu´ımica Inorga´nica, Facultad de
Quı´mica, Universidad de Valencia. c/ Dr Moliner 50, 46100 Burjassot, Valencia, Spain, and
Laboratorio de Quı´mica Orga´nica, Departamento de Ciencias Experimentales, Universidad J aime I,
12080 Castello´n, Spain
Received August 20, 1998
The synthesis and acid-base behavior of two series of 26-membered dioxatetraamine and hexaamine
heterocyclophanes containing two nuclei of either pyrazole (4a and 6a ) or 1-benzylpyrazole (4b
and 6b), respectively, are reported. Dipodal (2 + 2) condensations of 3,5-pyrazoledicarbaldehyde
2a or its 1-benzyl derivative 2b with 1,5-diamino-3-oxapentane afford in both cases the stable Schiff
bases 3a ,b in 90% yield, which after reduction with NaBH4 gave 4a ,b in 75% and 84% yield,
respectively. Condensation of 2a with diethylenetriamine leads to a complex mixture containing
imidazolidine isomers, which was reduced in situ to afford 6a in 30% yield. Condensation of 2b
with the same amine gave the stable diimidazolidine derivative 5b, which after crystallization
1
was isolated as a pure compound in 80% yield and fully identified from analytical and H and 13C
NMR data as a constitutional isomer with both imidazolidine rings located at the side of the pyrazole
closer to the benzylic substituents. Reduction of 5b with NaBH4 afforded the polyamine 6b in 86%
yield. Protonation constants of 4a ,b and 6a ,b have been determined by potentiometric methods in
1
the pH 2-11 range, and their protonation sequences were established by a H and 13C NMR study
in D2O at variable pH. For each compound, the number of protonation constants equals the number
of nitrogens in the side chains. In the pH range studied, the pyrazole rings are not involved in
protonation or deprotonation processes.
In tr od u ction
tance such as polycarboxylate anions, carbonate, and
phosphates,5 are selectively recognized by macrocyclic
polyamines as polyprotonated species in neutral pH
solutions. In such receptors the ammonium groups are
separated from each other by hydrocarbon chains and
aromatic or heteroaromatic rings.6 Indeed, these com-
pounds may act as ambivalent receptors; in their fully
or partly protonated forms, they may interact with the
catechol group or with anionic species, whereas when
disposing of free lone pairs they can act as Lewis bases
toward metal ions. Hence, their ability to interact with
catechol groups, anions, or metal cations can be simply
switched by changing the pH of the medium.
Dopamine and norepinephrine are neurotransmitter
catecholamines involved in the normal emotional and
autonomic control of humans, the physiological levels of
which are altered in neurodegenerative and mental
illnesses,1 as well as in toxic syndromes induced by
cocaine and psychotropic drugs of hallucinogen effects.2
Consequently, the development of synthetic receptors
able to diminish or increase the level of some of these
neurotransmitters by selective complexation and/or trans-
port mechanisms is of great interest.
It is well-known that neutral polyoxa, oxaaza, and
polyaza macrocycles containing a trigonal arrangement
of binding sites are able to selectively bind the primary
ammonium cation of dopamine and norepinephrine.3
Also, the catechol groups of dopamine and its deriva-
tives,4 as well as anionic substrates of biological impor-
Previously, we have reported on a series of hetero-
aromatic crowns containing two or more units of 3,5- or
(4) (a) Kimura, E.; Watanabe, A.; Kodama, M. J . Am. Chem. Soc.
1983, 105, 2063-2066. (b) Kimura, E. Top. Curr. Chem. 1985, 128,
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Commun. 1986, 1158-1159.
(5) (a) Kimura, E.; Kuramoto, Y.; Koike, T.; Fijioka, H.; Kodama,
M. J . Org. Chem. 1990, 55, 42-46 and references contained therein.
(b) Llobet, A.; Reibenspies, J .; Martell, A. E. Inorg. Chem. 1994, 33,
5946-5951. (c) Aguilar, J . A.; Garc´ıa-Espan˜a, E.; Guerrero, J . A.; Luis,
S. V.; Llinares, J . M.; Miravet, J . F.; Ramirez, J . A.; Soriano, C. J .
Chem. Soc., Chem. Commun. 1995, 2237-2239.
(6) (a) Supramolecular Chemistry of Anions; Bianchi, A., Bowman-
J ames, K., Garc´ıa-Espan˜a, E., Eds.; J ohn Wiley & Sons: New York,
1997; Chapters 5 and 9. (b) Martell, A. E. In Crown Compounds:
Toward Future Applications; Copper, S. R., Ed.; VHS: New York, 1992.
(c) Mertes, K. B.; Lehn, J . M. In Comprehensive Coordination Chem-
istry; Wilkinson, G., Ed.; Pergamon Press: New York, 1987.
* Address correspondence to Pilar Navarro. Tel: 34 1-5622900.
Fax: 34 1-5644853.
† Instituto de Qu´ımica Me´dica de Madrid.
‡ Universidad de Valencia.
§ Universidad J aime I de Castello´n.
(1) Hoffman, B. B.; Lefkowitz, R. J . In Goodman & Gilman′s The
Pharmacological Basis of Therapeutics; Hardman, J . G., Limbird, L.
E., Eds.; McGraw-Hill: New York, 1996; Chapter 10.
(2) (a) Nestler, E. J . J . Neurosci. 1992, 12, 2439-2450. (b) Giros,
B.; J aber, M.; J ones, R. S.; Wightman, R. M.; Caron, M. G. Nature
1996, 379, 606-612.
(3) (a) Lehn, J . M. Angew. Chem., Int. Ed. Engl. 1988, 27, 89-112.
(b) Shutherland, I. O. Chem. Soc. Rev. 1986, 15, 63-91.
10.1021/jo981699i CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/27/1999

6136 J . Org. Chem., Vol. 64, No. 17, 1999
Ara´n et al.
Sch em e 1
1,3,5-substituted pyrazole linked to the side chains by
ester or ether bonds, which are able to either irreversibly
complex or transport NH4 ions7 and/or RNH3 ions of
dopamine and norepinephrine.8 We have also reported a
different series of polyaza macrocycles and macrobicycles
containing two or three 3,5-disubstituted pyrazole units
linked to the polyamine side chains by imine or amine
bonds.9,10 In basic medium, these ligands formed di- or
tripyrazolate sodium salts from which di- and/or tetra-
nuclear Zn(II) and Cu(II) complexes were formed.10,11
Now, we are interested in the study of the basicity of the
last mentioned polyamine macrocycles of pyrazole to
subsequently evaluate their potential ability as complex-
ing receptors of dopamine and norepinephrine by selec-
tive interaction with their catechol groups.
+
+
The influence of different aromatic and heteroaromatic
rings on the basicity of dinuclear polyamine cyclophanes12
and heterocyclophanes13 in relation to [18]aneN6 (1,4,7,-
10,13,16-hexaazacyclooctadecane) has been previously
reported. In this paper we have studied the influence of
both the 3,5-disubstituted pyrazole and the 1-benzylpyra-
zole rings on the basicity of two different series of 26-
membered dioxatetraamine and hexaamine heterocyclo-
phanes of general structures I and II, respectively
(Scheme 1).
1
Herewith, we present the H and 13C NMR spectra in
In this paper we also report on the preparation of the
pure imidazolidine derivative IV (R ) Bn) and its
D2O at different pH values of polyaza macrocycles of 3,5-
disubstituted pyrazole of general structure I (R ) H) and
II (R ) H) previously mentioned in a short communica-
tion,9 as well as the synthesis and spectroscopic proper-
ties of a new series of 1-benzyl analogue receptors of
structures I (R ) Bn) and II (R ) Bn). All of them were
obtained by reduction of tetraimine or diimine derivatives
of general structures III (X ) O, NH; R ) H, Bn) or IV
(R ) H, Bn), respectively.
Although several groups have detected the formation
of imidazolidine derivatives related to IV in equilibrium
with Schiff bases similar to III (X ) NH), as far as we
know there are few examples including X-ray struc-
tures14,15 and a detailed NMR characterization of such
compounds has not previously been reported.
1
characterization by H and 13C NMR spectroscopy.
Resu lts a n d Discu ssion
Syn th esis. Heteroaromatic polyazamacrocycles con-
taining pyridine, pyrrole, furan, and thiophene rings have
been obtained following a two-step synthetic method that
includes a first dipodal (2 + 2) condensation of R,ω-
diamines with the corresponding dialdehydes, followed
by hydrogenation of the Schiff base imine bonds.14,16,17
However, several authors have pointed out that when
such R,ω-diamines have additional NH or OH groups in
the middle of the chain, the first condensation step
affords a mixture of two isomers. Thus, Fenton and co-
workers reported that, in the absence of metal ions, the
condensation of 2,5-thiophenedicarbaldehyde with di-
1
ethylenetriamine affords a solid product whose H NMR
(7) Elguero, J . Pyrazoles. In Comprehensive Heterocyclic Chemistry
II, A Review of the Literature 1982-1995; Katritzky, A. R., Rees C. V.,
Scriven, E. F. V., Eds.; Pergamon: New York, 1997; Vol. 3, pp 68-70
and references contained therein.
spectrum corresponds to a mixture of the desired tet-
raimine Schiff base together with an imidazolidine isomer
formed by nucleophilic addition of the two secondary
amine groups of the tetraimine macrocycle across the
adjacent imine bonds.14
Similar processes have also been reported in the
synthesis of tetraimine Schiff base macrocycles in which
Ba(II)18 and Pb(II)19 were used as metal templating
agents. In fact, tetraimine dicopper(II) complexes have
been prepared from ring-contracted oxazolidine lead
complexes by transmetalation with concomitant expan-
sion of the macrocycle.20 Furthermore, as mentioned
above, Martell et al. have characterized by X-ray diffrac-
(8) (a) Gonza´lez, B.; J imeno, M. L.; Navarro, P.; Ochoa, C.; Rod-
r´ıguez-Franco, M. I.; Sanz, A.; Trevin˜o, M. A. An. R. Acad. Cienc. Exact.
Fı´s. Nat. Madrid 1993, 87, 105-110. (b) Fierros, M.; Conde, S.;
Martinez, A.; Navarro, P.; Rodriguez-Franco, M. I. Tetrahedron 1995,
51, 2417-2426. (c) Rodriguez-Franco, M. I.; Fierros, M.; Martinez, A.;
Navarro, P.; Conde. S. Bioorg. Med. Chem. 1997, 5, 363-367. (d)
Bueno, J . M.; Campayo, L.; Navarro, P.; Ochoa, C.; J imenez-Barbero,
J .; Samat, A.; Pe`pe. G. J . Org. Chem. 1997, 62, 2684-2693. (e) Sanz,
A. M.; Navarro, P.; Gomez-Contreras, F.; Pardo, M.; Pe`pe, G.; Samat,
A. Can. J . Chem. 1998, 76, 1-6.
(9) Kumar, M.; Ara´n, V. J .; Navarro, P. Tetrahedron Lett. 1993, 34,
3159-3162.
(10) Kumar, M.; Ara´n, V. J .; Navarro, P. Tetrahedron Lett. 1995,
36, 2161-2164.
(11) Kumar, M.; Ara´n, V. J .; Navarro, P.; Ramos-Gallardo, A.; Vega,
A. Tetrahedron Lett. 1994, 35, 5723-5726.
(12) Nation, D. A.; Reinbenspies, J .; Martell, A. E. Inorg. Chem.
1996, 35, 4597-4603.
(16) Chen, D.; Martell, A. E. Tetrahedron 1991, 47, 6895-6902.
(17) Dhont, K. I.; Lippens, W.; Herman, G.; Goeminne A. M. Bull.
Soc. Chim. Belg. 1992, 101, 1061-1064.
(18) Drew, M. G. B.; Nelson, J .; Nelson, S. M. J . Chem. Soc., Dalton
Trans. 1981, 1678-1684.
(19) Bailey, N. A.; Fenton, D. E.; J ackson, I. T.; Moody, R.; de
Barbarin, C. R. J . Chem. Soc., Chem. Commun. 1983, 1463-1465.
(20) Bailey, N. A.; Fenton, D. E.; Moody, R.; Rodriguez de Barbarin,
C. O.; Sciambarella, I. N.; Latour, J . M.; Limosin, D.; McKee, V. J .
Chem. Soc., Dalton Trans. 1987, 2519-2529.
(13) Lu, Q.; Motekaitis, R. J .; Reibenspies, J . J .; Martell, A. E. Inorg.
Chem. 1995, 34, 4958-4964.
(14) Bailey, N. A.; Eddy, M. M.; Fenton, D. E.; Moss, S.; Mukho-
padhyay, A.; J ones, G. J . Chem. Soc., Dalton Trans. 1984, 2281-2288.
(15) (a) Menif, R.; Martell, A. E.; Squattrito, P. J .; Clearfield, A.
Inorg. Chem. 1990, 29, 4723-4729. (b) Adams, H.; Bailey, N. A.;
Fenton, D. E.; Hempstead, P. D.; Westwood, G. P. J . Inclusion Phenom.
Mol. Recognit. Chem. 1991, 11, 63-69.

Protonation Behavior of Oxaaza and Polyaza Macrocycles
Sch em e 2
J . Org. Chem., Vol. 64, No. 17, 1999 6137
tion the structure of a crystalline imidazolidine isomer
obtained by (2 + 2) Schiff base condensation of diethyl-
enetriamine and m-phthalaldehyde.15
methanol at room temperature there was not precipita-
1
tion of the expected Schiff base. The H and 13C NMR
spectra of the solution indicated the presence of more
than one species, which could correspond to a mixture of
tetraimine and imidazolidine isomers of structures III
(X ) NH, R ) H) and IV (R ) H) (Scheme 1). Conse-
quently, the mixture was directly reduced in situ with
NaBH4 to obtain the hexaamine macrocycle 6a , which
after being carefully purified by chromatography and
later crystallized from toluene was obtained as a pure
compound in moderate yield (Scheme 2).
Starting from 1-benzyl-3,5-bis(hydroxymethyl)pyrazole
1b22 and following similar procedures, we have now
obtained the 1-benzyl-3,5-pyrazoledicarbaldehyde 2b in
high yield. With acetonitrile as solvent, the (2 + 2)
dipodal condensation of 2b with 1,5-diamino-3-oxapen-
In a previous communication9 we have reported briefly
the synthesis of 3,5-pyrazoledicarbaldehyde 2a from 3,5-
bis(hydroxymethyl)pyrazole 1a 21 by oxidation with MnO2
in 1,2-dimethoxyethane (DME) (Scheme 2). The dioxa-
tetraimine 3a was obtained as a crystalline solid, which
precipitated in almost quantitative yield from the solu-
tion by dipodal (2 + 2) condensation of 2a with 1,5-
diamino-3-oxapentane. Further reduction of 3a with
NaBH4 in absolute ethanol gave the expected dioxatet-
raazamacrocycle 4a , which after crystallization from
toluene was also isolated as a pure compound.
In contrast with the above behavior, in the (2 + 2)
dipodal condensation of 2a with diethylenetriamine in
(21) Schenck, T. G.; Downes, J . M.; Milne, C. R. C.; Mackenzie, P.
B.; Boucher, H.; Whelan, J .; Bosnich, B. Inor. Chem. 1985, 24, 2334-
2337.
(22) Iturrino, L.; Navarro, P.; Rodriguez-Franco, M. I.; Contreras,
M.; Escario, J . A.; Martinez, A.; Pardo, M. R. Eur. J . Med. Chem. 1987,
22, 445-451.

6138 J . Org. Chem., Vol. 64, No. 17, 1999
Ara´n et al.
Ta ble 1. 13C NMR (δ, p p m ) Sp ectr a of 2a [(CD3)2So],
2a ′ [(CD3)2SO], a n d 2b (CDCl3)
Ta ble 2. 13C NMR (δ, p p m ) Sp ectr a of 3a [(CD3)2SO],
3b (CDCl3), a n d 5b (CDCl3)
compound
compound
2a a
n.o.
2a ′
151.47
2b
3a
3b
5b
C3
C5
C4
OC2
OC6
N-HCOH-C5
C7
Cgem
Co
Cm
Cp
150.50
135.17
114.55
185.46
179.50
C3
C5
C4
145.32b
145.32b
104.63
153.57
153.57
149.00
150.18 (149.99)
144.70 (145.76)
105.66 (105.22)
155.62 (155.37)
n.o.
140.06 (139.78)c
104.54 (104.22)c
186.68
139.00
109.00
157.00
152.00
110.97
184.85b
184.85b
NdC2
NdC6
C6<(Im)a
CR-3
Câ-3
CR-5
Câ-5
CR-5(Im)a
Câ-5(Im)a
C7
75.48 (74.97)c
74.78 (74.69)
59.24 (59.52)
54.04 (54.34)
56.14
139.98
127.97
128.74
128.40
59.45
67.94
59.45
67.94
60.53
68.52
60.67
68.79
45.18 (45.62)
52.35 (52.80)
53.44 (53.42)
137.10 (136.94)
126.73; 126.61
128.68; 128.60
127.61; 127.49
a
Registered from a diluted solution (<0.04 M solution). In such
conditions the signals of both C3 and C5 carbons could not be
54.84
137.50
127.46; 127.32
128.43; 128.33
127.87; 127.56
Cgem
Cm
Co
observed. Broad signal. c These signals correspond to a diaster-
b
eomeric mixture as 2a ′ contains two asymmetric carbons.
Cp
Sch em e 3
a
b
(Im) ) Imidazolidine ring. Broad signal.
and CR-5, and Câ-3 and Câ-5 the carbons are magnetically
equivalent.
However, for the derivative 3b (Scheme 2), the 1-benzyl
substituents break the magnetic equivalence of the
pyrazole environment. In the 13C NMR spectrum, differ-
ent signals can be observed for the quaternary carbon
atoms labeled as C3 and C5 [the pyrazole N ) C3 appears
at lower field than C4 ) C5], as well as for those of the
imine carbons [the C2 more deshielded than C6] (see
Table 2).
tane or diethylenetriamine at room temperature gave in
both cases stable solids, which separated from the
solution and after crystallization from ethanol were
identified as the Schiff base 3b and the imidazolidine
isomer 5b, respectively (90% and 80% yield) (Scheme 2).
Further treatment of 3b and 5b with NaBH4 in ethanol
afforded in both cases the desired saturated polyamines
4b and 6b, which crystallized from toluene and benzene,
respectively, and were obtained in yield close to 85%.
Str u ctu r es Ch a r a cter iza tion . It is known that the
solubility of the 3(5)-pyrazolecarbaldehyde in common
solvents is low as a result of its existence in equilibrium
with dimers formed by intermolecular addition of the NH
protons to the carbonyl groups.23 For 3,5-pyrazoledi-
carbaldehyde a similar situation is found. Indeed, we
have verified that the 3,5-pyrazoledicarbaldehyde 2a is
To fully characterize compound 5b, a comparison with
the tetraimines 3a and 3b is very illustrative, because
in these compounds the formation of imidazolidine rings
is precluded by the presence of the oxygen atoms. The
13C NMR spectrum of 5b was rather complex, showing
28 different signals (Table 2). The signals are arranged
in two sets of 14 of close relative intensities. All of these
spectral features suggest that the species formed could
be either a unique one with all its carbon nuclei magneti-
cally nonequivalent or a mixture of at least two different
species with 2-fold symmetry in almost the same propor-
tion. To decide which one of these two possibilities was
the correct one, it was necessary to analyze the HMQC
(Figure 1a) and multiple-bond HMBC (Figure 1b) 2D-
NMR heteronuclear correlation spectra.
1
not soluble in chloroform and that its H NMR spectrum
recorded in (CD3)2SO shows two sets of signals corre-
sponding to a mixture of the monomer 2a and the
diastereomers of the dimeric 2a ′ species (Scheme 3).
We have also observed that in a 0.2 M solution the ratio
2a :2a ′ increases with the temperature, being 73:27, 93:
7, and 98:2 at 30, 60, and 80 °C, respectively. The
mentioned ratio also increases with dilution, being 92:8
at 30 °C in a 0.04 M solution. Moreover the signals of
2a ′ disappear in highly dilute solutions. A parallel
phenomenon has been detected in the 13C NMR spectrum
(Table 1). In contrast with the above behavior, the
1-benzyl-3,5-pyrazoledicarbaldehyde 2b is soluble in
In addition to the expected one bond correlations shown
in Figure 1a, the long-range heteronuclear correlations
presented in Figure 1b are very important for a correct
assignment. In particular, the correlation of protons H4
and H4′, which present well-separated chemical shifts in
1
the H NMR spectrum [7.72 and 7.23 ppm, see Figure
1a] is a key point. In Figure 1b, it can be seen that one
of these signals (H4′) only presents cross-peaks with the
carbon resonance of C5′ and C3′, whereas the other one
(H4) correlates with C5 and C3. Similarly, it can be
observed that C4 correlates with H2 and H6, and C4′
correlates with H2′ and H6′. Additionally, H7 and H7′ only
present cross-peaks with C5 and C5′ respectively.
1
chloroform and other common solvents and presents H
and 13C NMR spectra corresponding to a single species.
1
The H NMR of 3a shows a very simple spectrum with
only three signals at 6.34 (H4), 8.08 [N ) HC2,6] and 3.64
(H2CR-3,5 and H2Câ-3,5) ppm due to the prototropic equi-
librium of the pyrazole ring. By the same reason, in the
13C NMR spectrum (Table 2), the C3 and C5 carbons
appear as a broad signal and in the pairs C2 and C6, CR-3
All these spectral features indicate that both pyrazole
rings present the same arrangement with respect to the
imidazolidine rings and confirm that these rings are
located at the side of the pyrazole ring closer to the benzyl
substituents. Taking into account that in the HMBC
NMR spectra there are not cross-peaks between proton
(23) McNab, H. J . Chem. Soc., Perkin Trans. 1 1987, 653-656.

Protonation Behavior of Oxaaza and Polyaza Macrocycles
J . Org. Chem., Vol. 64, No. 17, 1999 6139
Ta ble 3. 1H NMR (δ, p p m , D2O) of 4a (p H 9.0), 4b
(p H 12.0), 6a (p H 11.0), a n d 6b (p H 12)
compound
4a
4b
6a
6b
H4
6.22 (s)
3.82 s)
3.82 s)
2.87 (t)
2.87 (t)
3.54 (t)
3.54 (t)
6.12 (s)
3.54 (s)
3.54 (s)
2.56 (t)
2.49 (t)
3.37 (t)
3.27 (t)
5.13 (s)
6.96 (m)
7.15 (m)
6.13 (s)
3.60 (s)
3.60 (s)
2.45 (t)
2.45 (t)
2.45 (t)
2.45 (t)
6.17 (s)
3.57 (s)
3.57 (s)
2.41 (s)
2.41 (s)
2.32 (t)
2.23 (t)
5.17 (s)
6.97 (m)
7.15 (m)
H2C2
H2C6
H2CR-3
H2CR-5
H2Câ-3
H2Câ-5
H2C7
Ho
H
m, Hp
Ta ble 4. 13C NMR (δ, p p m , D2O) of 4a (p H 9.0), 4b
(p H 12.0), 6a (p H 11.0), a n d 6b (p H 12)
compound
4a
4b
6a
6b
C3
C5
C4
C2
148.33a
148.33a
104.68
45.43
151.20
143.69
105.86
46.15
148.53b
148.53b
104.72
45.01
150.75
143.70
106.34
45.90
C6
45.43
43.73
45.01
43.42
CR-3
CR-5
Câ-3
Câ-5
C7
48.60
48.60
70.64
70.64
47.80
48.22
70.33
69.99
47.59
47.59
48.58
48.58
47.14
47.14
48.15
46.73
53.24
53.20
Cgem
Cm
Co
137.94
127.73
130.03
129.05
138.03
127.64
130.02
129.05
Cp
a
b
Low singlet. Singlet.
crystallization in both cases. Consequently, the saturated
polyamines 4b and 6b, which were obtained by reduction
of crystalline compounds 3b and 5b, respectively, may
also correspond to the isomers with the same disposition
depicted in Scheme 2 (with the benzyl groups in opposing
positions).
F igu r e 1. HMQC (a) and HMBC (b) spectra for compound
5b in CDCl3. Most significant correlations have been marked.
and carbon resonances of the atoms labeled as prime and
nonprime, it has to be concluded that the 28 carbon
resonances should be attributed to two different diaste-
reoisomers with C2 symmetry each displaying 14 signals.
The only possible structural type fulfilling all these
requirements is the one presented as 5b in Scheme 2.
The 1H and 13C NMR spectra of pyrazole-derived
polyamines 4a ,b and 6a ,b registered in D2O at basic pH
(were the nonprotonated species predominates) are re-
ported by the first time in Tables 3 and 4, respectively.
As usually occurs for 3,5-disubstituted 1H-pyrazole de-
1
In the expansions of the aliphatic regions of the H-
1
1H and H-13C NMR spectra of 5b it can be seen that
1
rivatives, 4a and 6a show very simple H and 13C NMR
each one of the signals of the methylene carbons cor-
relates with its two different protons as a consequence
of the rigidity afforded by the five-membered imidazoli-
dine rings of the molecule (Supporting Information,
Figure 1). This rigidity is particularly evident from the
nonequivalence of the benzyl protons that, in contrast
to 3b, display an AB spin-system and also from the fact
that the ethylene chains of the imidazolidine fragments,
R(3)-â(3), R(5)-â(5) in one diastereoisomer and R(3′)-
â(3′) and R(5′)-â(5′) in the other one, present ABCD spin-
systems.
spectra in which signals indicate that, because of the
prototropic equilibrium of the pyrazole ring, both com-
pounds present average 4-fold symmetry on the NMR
time scale. The quaternary C3 and C5 carbons appear
together as a more or less broad signal, and the pairs of
methylene carbons C2 and C6, CR-3 and CR-5, and Câ-3
and Câ-5 are magnetically equivalent. However, in 4b
and 6b , the 1-benzyl substituents break the magnetic
equivalence of the pyrazole environment, and as a
consequence both compounds show a reduction from 4-
to 2-fold symmetry with respect to 4a and 6a . The 13C
NMR spectra of 4b and 6b show that in general, the
carbon atoms C5, C6, and Câ-5, which are closer to the
pyrazole 1-benzyl substituent, appear at higher field than
C3, C2, and Câ-3 which are closer to the pyrazole sp2
nitrogen (see Table 4).
On the basis of the above results, and taking into
account both the structure of the imidazolidine derivative
5b and the fact that the NMR spectra of the Schiff base
3b suggest the existence of only one constitutional
isomer, it is reasonable to suppose that although the
condensation of 2b with either 1,5-diamino-3-oxapentane
or diethylenetriamine could afford a mixture of the two
possible constitutional isomers, the most abundant should
be the one with the 1-benzylpyrazole substituents in
opposing position and displaying C2 symmetry. This
isomer has to be just the one that we have isolated by
P r oton a tion Con sta n ts. In Table 5 are shown the
logarithms of the stepwise stability constants of receptors
4a , 4b, 6a , and 6b determined at 298.1 K in 0.15 mol
dm-3 NaCl. For comparison, the values reported in the
literature12,13,24,25 for the related azamacrocycles 7-10

6140 J . Org. Chem., Vol. 64, No. 17, 1999
Ta ble 5. Loga r ith m s of Step w ise P r oton a tion Con sta n ts of Recep tor s 4a , 4b, 6a , a n d 6ba
Ara´n et al.
reaction
4a
4b
6a
6b
7d
8e
9f
10g
H + L ) HLb
H + HL ) H2L
H + H2L ) H3L
H + H3L ) H4L
H + H4L ) H5L
H + H2L ) H6L
log âh
8.49(3)c
7.92(2)
6.97(3)
6.31(4)
8.74(1)
7.74(1)
6.40(2)
5.42(3)
9.74(2)
8.86(2)
7.96(2)
6.83(2)
4.57(3)
3.19(3)
41.15
8.90(3)
8.27(2)
6.62(3)
5.85(4)
3.37(4)
2.27(6)
36.28
9.51
8.77
7.97
7.09
3.79
3.27
40.40
9.62
8.89
8.29
7.62
3.82
3.30
41.54
9.44
8.68
7.63
6.46
3.84
3.16
39.21
8.93
8.22
7.35
6.44
1.5
29.69
28.30
32.44
a
Determined in 0.15 mol dm-3 NaCl at 298.1 K. Constants of related compounds 7, 8, 9, and 10 taken from the literature are also
included. Charges have been omitted for clarity. c Figures in parentheses are standard deviations in the last significant figure. Taken
b
d
from ref 12, I ) 0.1 mol dm-3 KCl, 298.1 K. e Taken from ref 24, I ) 0.1 mol dm-3 KCl, 298.1 K. f Taken from ref 13, I ) 0.1 mol dm-3
KCl, 298.1 K. f Taken from ref 25, I ) 0.15 mol dm-3 NaCl, 298.1 K. Taken from ref 25, I ) 0.15 mol dm-3 NaCl, 298.1 K. log â )
g
h
Σ log KH L
.
i
Sch em e 4
(Scheme 4) are also included in Table 5. In Figure 2 are
presented the distribution diagrams of receptors 4b and
6b.
A first analysis of the protonation constants of these
compounds allows one to derive several general features.
Dioxatetraamines 4a and 4b show relatively high con-
stants in all of their four protonation steps, whereas 6a
and 6b display high basicity in their first four protonation
steps and greatly reduced basicity constants for the fifth
and sixth protonation steps. For instance, for 6a log
KH - log KH ) 1.13, log KH - log KH ) 2.26, and
F igu r e 2. Distribution diagram for the systems (a) 4b[L4]-
H+ and (b) 6b[L8]-H+.
atoms in the middle of the side chains, which are adjacent
to two ammonium groups, yielding then a drop in
basicity.
Another point to be considered is that the 1-ben-
zylpyrazole derivatives display lower overall basicities
than the nonbenzylated ones. As a matter of fact, whereas
6a has basicity constants similar to those of 7 and 8, 6b
presents lower values of basicity than these receptors.
The two first basicity constants of 6b compare well with
the corresponding ones of 10 with all tertiary nitrogens,25
and it is well-known that the basicity of such tertiary
nitrogens in aqueous solution is lower than that of
secondary ones as a result of solvation effects. The
remaining constants for these two receptors (6b and 10)
differ markedly probably because of the particular hy-
drogen bond network that has been evidenced for the last
receptor.25 Therefore, benzylation of the pyrazole moiety
produces a marked drop in basicity.
3L
4L
4L
5L
for 6b, log KH - log KH ) 0.77, log KH - log KH
)
3L
4L
4L
5L
2.48. This grouping of constants has also been observed
in related [2.2]-macrocycles containing m-xylylene 7,
oxydimethyl 8, or 2,5-furandimethyl 9 linkages connect-
ing two diethylenetriamine side chains and can be
explained considering minimum electrostatic repulsion
criteria.12,13,24 Indeed, these macrocycles may bind four
protons at the terminal nitrogens of both diethylenetri-
amine side chains without introducing severe electro-
static repulsions between ammonium groups. Fifth and
sixth protonation steps necessarily involve the nitrogen
(24) Motekaitis, R. J .; Martell, A. E. Inorg. Chem. 1992, 31, 5534-
5542.
(25) Bazzicaluppi, C.; Bencini, A.; Bianchi, A.; Fusi, V.; Giorgi, C.;
Paoletti, P.; Stefani, A.; Valtancoli, B. J . Chem. Soc., Perkin Trans. 2
1995, 275-280.
A last point that deserves comment is the protonation
of the pyrazole fragments in 4a ,b and 6a ,b. First of all,

Protonation Behavior of Oxaaza and Polyaza Macrocycles
J . Org. Chem., Vol. 64, No. 17, 1999 6141
for all these receptors the number of protonation steps
detected in the pH range of study, pH 2-12, equals the
number of nitrogen atoms in the side chains. Moreover,
the magnitude of the protonation constants for 4a and
6a correlates well with those of [2.2]-macrocycles with
diethylenetriamine side chains, such as 7-9. These
results would suggest that there is not net involvement
of the pyrazole moieties in protonation or deprotonation
processes in aqueous solution, as can be expected accord-
ing to the pKa values found in the literature for pyrazole
derivatives.26 Thus, with regard to protonation of 4a and
6a , despite alkyl substituents in position 3 and/or 5 of
pyrazole, increase in the basicity of the ring (pyrazole,
log K ) 2.48; 3(5)-methylpyrazole, log K ) 3.27; 3,5-
dimethylpyrazole, log K ) 4.06), a 3(5)-(2-aminoethyl)
moiety (log K ) 1.97) has a strong opposite effect.
However, considering the protonation of 1-benzylpyrazole
derivatives 4b and 6b, the available data show that
alkylation or arylation of the pyrazole nitrogen yields a
significant drop in basicity (1-methylpyrazole, log K )
2.06; 1-ethylpyrazole, log K ) 1.94; 1-phenylpyrazole, log
K ) 0.43). Nevertheless, this aspect will be further
discussed in the following NMR section.
NMR Stu d ies a t Differ en t p H Va lu es. To identify
the protonation sequences and to verify whether the
pyrazole moieties are involved in the protonation steps
1
of the receptors we have recorded the H and 13C NMR
spectra of 4a , 4b, 6a , and 6b at different pH values, and
the signals have been analyzed on the basis of their
HMQC and multiple-bond HMBC 2D-NMR heteronu-
clear correlation spectra (Supporting Information, Tables
1-4).
In general, the variation with the pH of the NMR
resonances of the â-carbon atoms and the R-hydrogens
with respect to the nitrogen atoms bearing the protona-
tion processes are of great help in establishing protona-
tion schemes of polyamine molecules.27
F igu r e 3. Variation with pH of the line width of signals C3,5
and C2.6 of 4a .
shifts upon protonation.28,29 For instance, in the case of
the 2,5,8,11-tetraaza[12]paracyclophane 11 (Scheme 4),
the C3-â aromatic carbon atoms experience an upfield
shift of 7.3 ppm upon full protonation, and the C4-γ atoms
experience a downfield shift of 2.8 ppm. Also, the lower
pKa value of 4a is 6.31, and as commented before, the
expected pKa values for protonation of aminoalkyl-
substituted pyrazole rings should be much lower.
However, it is interesting to observe that upon pro-
tonation the signal corresponding to the pyrazole carbon
atoms C3,5 of 4a experience a progressive line-broadening
that disappears within the baseline of the spectrum at
pH 5.9 where the macrocycle is almost fully protonated
(see Figure 3). In a similar way, the neighboring meth-
ylene carbon atoms C2,6 also experience a significant
broadening, whereas both signals become sharp singlets
at stronger acid medium.
For compound 4a , the carbon resonance of the pyrazole
quaternary carbon atoms C3,5 is of particular interest
because are only placed in â-position with respect to the
aliphatic nitrogen atoms and might serve as a probe for
their protonation. This signal experiences a great upfield
variation (7.76 ppm) in the pH 9-6 range where pro-
tonation of 4a occurs. Analogously, the signal of carbon
atoms Câ-3,5, also placed in â-position with respect to
aliphatic nitrogens, strongly shifts upfield (3.9 ppm) in
this pH range in agreement with the protonation of these
nitrogens. The downfield variation of the proton reso-
nance of the methylene groups H2C2,6 (0.57 ppm) and
H2CR-3,5 (0.62 ppm) in this pH range further confirms
this fact.
It is important to point out that the pyrazole carbons
C3,5 and C4 are respectively located in â- and γ-position
in relation to the closer aliphatic nitrogens. The upfield
(7.76 ppm for C3,5) and downfield (3.96 ppm for C4)
variations that such carbons experience upon protonation
do not reflect any particular implication of the pyrazole
subunits in the protonation mechanism, because it is
well-known that similar â and γ aromatic carbons
belonging to [1:1] and [2:2] polyamine cyclophanes con-
taining benzene units also experience similar chemical
It is known that such 13C NMR spectroscopic changes
are usually produced by alterations in the dynamic
exchange rate of the pyrazole prototropic equilibrium.30
(28) (a) Andre´s, A.; Burguete, M. I.; Garc´ıa-Espan˜a, E.; Luis, S. V.;
Miravet, J . F.; Soriano, C. J . Chem. Soc., Perkin Trans. 2 1993, 749-
755. (b) Bianchi, A.; Escuder, B.; Garc´ıa-Espan˜a, E.; Luis, S. V.;
Marcelino, V.; Miravet, J . F.; Ramı´rez, J . A. J . Chem. Soc., Perkin
Trans. 2 1994, 1253-1259. (c) Andre´s, A.; Bazzicaluppi, C.; Bianchi,
A.; Garc´ıa-Espan˜a, E.; Luis, S. V.; Miravet, J . F.; Ram´ırez, J . A. J .
Chem. Soc., Dalton Trans. 1994, 2995-3004.
(29) Aguilar, J . A.; Garc´ıa-Espan˜a, E.; Guerrero, J . A.; Llinares, J .
M.; Ram´ırez, J . A.; Soriano, C.; Luis, S. V.; Bianchi, A.; Ferrini, L.;
Fusi, V. J . Chem. Soc., Dalton Trans. 1996, 239-246.
(30) Elguero, J .; Marzin, Z.; Katrytzky, A. R.; Linda, P. The
Tautomerism of Heterocycles; Academic Press: New York, 1976.
(26) Catalan, J .; Abboud, J . L. M.; Elguero, J . Adv. Heterocycl. Chem.
1987, 41, 187-274.
(27) Sarnesky, J . E.; Surprenant, H. L.; Molen, F. K.; Reilley, C. N.
Anal. Chem. 1975, 47, 2116-2124.

6142 J . Org. Chem., Vol. 64, No. 17, 1999
Ara´n et al.
Sch em e 5
F igu r e 4. (a) Variation with pH of 13C chemical shifts of
carbon atoms C3 and C5 of 4b. (b) Variation with pH of 13C
chemical shifts of carbon atoms Câ-3 and Câ-5 of 4b.
nium sites. Therefore, for this receptor a protonation
model in which the two first protons preferentially bind
the amino groups closer to the nonbenzylated position of
the pyrazole heterocycle may be assumed (see Scheme
5b).
For the hexaamine 6a , the two first protonations occur
in the pH 11-8 range. In this case, the signal shifted
most upfield is that of carbon atoms CR-3,5, whereas the
signal of carbons Câ-3,5 and those of the quaternary
carbon atoms C3,5 do not experience significant shifts in
this pH region (see Figure 5).
Depending on the nature of the pyrazole C-substituents,
the N-H proton exchange rate can be slowed to the point
where separate signals can be observed for the C3 and
C5 pyrazole carbons.31 Taking this into account, MM2
calculations seem to support that consecutive conforma-
tional changes induced by the progressive protonation of
4a (see Scheme 5a) may lead to N‚‚‚NH interactions
between the sp2 pyrazole nitrogens and the closer pro-
tonated aliphatic nitrogens.
With respect to the protonation of the 1-benzyl sub-
stituted dioxatetraamine 4b, in Figure 4 are presented
plots of the variation of the 13C chemical shifts of carbon
atoms C3, C5, Câ-3, and Câ-5 that allow some interesting
conclusions. From this figure it is evident that the signals
of carbon atoms C3 and Câ-3 start moving upfield at pH
values higher than those for C5 and Câ-5, which are closer
to the benzyl substituent. The latter signals do not move
significantly upfield until pH 8.0, when the third proton
starts binding 4b (see Figure 4a). The variations in the
1H chemical shifts also support this point. In the pH 12-
7.5 range protons on CR-3 and C2 move downfield 0.42
and 0.51 ppm, respectively, while those closer to the
benzyl substituents CR-5 and C6 experience downfield
shifts of only 0.18 and 0.10 ppm. Therefore, the sp2
pyrazolic nitrogens somehow address the protonation to
this side, which probably may be explained in terms of
differences in hydrophobicity between both sites or the
formation of intramolecular hydrogen bonds between the
sp2 pyrazole nitrogen and positively charged polyammo-
This observation implies that 6a protonates first on
the middle nitrogens of the diethylenetriamine side
chains. In Figure 5b it can be seen that below pH 7 the
signals of carbon atoms CR-3,5 start moving downfield,
while those of Câ-3,5 move upfield. This can be explained
by assuming that third and fourth protonations promote
the migration of the protons in the middle nitrogens of
the side chains to those at the end to achieve a minimum
energy situation (see Scheme 6a).
Fifth and sixth protonations (pH < 5) yield again
upfield shifts of the signal of CH2-R carbons, denoting
the reprotonation of nitrogen atoms located in the middle
of the chains at these stages. In this receptor, for
intermediate pH values, a line broadening of the C3,5
signals is also observed, which can probably be attributed
to reasons similar to those already discussed for 4a
(Supporting Information, Figure 4).
In relation to 6b, when the pH is decreased from 12 to
8 the 13C signal of carbon C3 in â-position in respect to
C3-H2C2-HN aliphatic nitrogens shifts upfield consider-
ably more (2.69 ppm) than that of C5 (1.00 ppm),
suggesting that as in 4b the first two protonations are
(31) Claramunt, R. M.; Elguero, J .; Marzin, C.; Seita, J . An. Chim.
1979, 75, 701.

Protonation Behavior of Oxaaza and Polyaza Macrocycles
J . Org. Chem., Vol. 64, No. 17, 1999 6143
pH range, carbons CR-3 and CR-5 do not bear significant
shielding effects, indicating that central nitrogens are not
the preferential targets in these early protonation steps.
These last signals, however, bear strong upfield shifts
(CR-3, 3.51 ppm; CR-5, 4.01 ppm) below pH 5 where the
last two protonations of the macrocycle occur. Therefore,
these data support the preferential protonation order
shown in Scheme 6b.
Con clu sion s
(i) Dipodal (2 + 2) condensation of 3,5-pyrazoledi-
carbaldehyde 2a or its 1-benzyl derivative 2b with 1,5-
diamino-3-oxapentane gave the tetraimine Schiff bases
3a or 3b (in 90% yield), which after reduction with
NaBH4 afforded the corresponding dioxatetraamines 4a
and 4b (75% and 84% yield, respectively). Similar
condensation of 2a with diethylenetriamine leads to the
formation of a mixture of imine and imidazolidine
isomers, which after being reduced in situ gave the
hexamine 6a in only 30% yield. In contrast with the
above behavior, the condensation of 2b with the same
amine gave a stable diimine-diimidazolidine isomer (5b)
(80% yield), which when reduced with NaBH4 afforded
the dibenzyl-substituted hexaamine 6b in high yield
(86%).
F igu r e 5. (a) Variation with pH of 13C chemical shifts of
carbon atoms C3,5 of 6a . (b) Variation with pH of 13C chem-
ical shifts of carbon atoms CR-3,5 and Câ-3,5 of 6a .
(ii) The analytical and spectroscopical 1H and 13C NMR
data of 3b and 5b indicate the following conclusions: (a)
Although condensation of 2b with either 1,5-diamino-3-
oxapentane or diethylenetriamine could afford a mixture
of two possible constitutional isomers, the most abundant
mainly affecting terminal nitrogens closer to the non-
benzylated side of pyrazole. At difference with 6a in this
Sch em e 6

6144 J . Org. Chem., Vol. 64, No. 17, 1999
Ara´n et al.
GHMQC, and GHMBC). Confirmation of the assignments has
been performed by combined 2D NMR GHSQC-TOCSY ex-
periments. Bibliographic studies for similar compounds have
also been taken into account for the assignment and interpre-
tation of the NMR data. In the NMR study of the protonation
sequences of ligands, the pH was calculated from the measured
pD values using the correlation pH ) pD - 0.4.32 The mass
spectra (MS) were registered by electronic impact (EI) at 70
eV ionizing potential or by fast atomic bombardment (FAB)
technique using a m-nitrobenzyl alcohol matrix.
should be the one with the 1-benzylpyrazole substituents
in positions opposite each other and displaying C2 sym-
metry. (b) The structure of 5b corresponds to a diaster-
eomeric mixture of a unique constitutional isomer with
both imidazolidine rings located at the side of the
pyrazole closer to the 1-benzyl substituted nitrogens.
(iii) The analysis of the protonation constants of
dioxatetraamine and hexaamine receptors 4a ,b and 6a ,b
allows one to derive the following conclusions: (a) In the
studied pH range (2-11) the number of protonation steps
detected equals the number of nitrogen atoms in the side
chains. Consequently, in such pH range there is not net
involvement of the pyrazole moieties in protonation or
deprotonation processes. (b) In general, the benzyl-
substituted derivatives 4b and 6b display lower overall
basicities than the nonbenzylated 4a and 6a . (c) The
dioxatetraamines 4a ,b show relatively high constants in
all of their protonation steps. (d) The hexaamines 6a ,b
display high basicity in their first four protonation steps
and basicity constants much more reduced for the fifth
and sixth ones, which involve the nitrogen atoms located
in the middle of the side chains.
Electr om otive F or ce (em f) Mea su r em en ts. The poten-
tiometric titrations were carried out in 0.15 M NaCl at
298.1 ( 0.1 K by using the experimental procedure (buret,
potentiometer, cell, stirrer, microcomputer, etc.) that has been
fully described elsewhere.33 The acquisition of the emf data
was performed with the computer program PASAT.34 The
reference electrode was a Ag/AgCl electrode in saturated KCl
solution. The glass electrode was calibrated as a hydrogen ion
concentration probe by titration of well-known amounts of HCl
with CO2-free NaOH solutions35 and determination of the
equivalent point by Gran’s method,36 which gives the standard
potential, E°′, and the ionic product of water (pKw ) 13.73-
(1)). The computer program HYPERQUAD37 was used to
calculate the protonation and stability constants, and the
DISPO38 program was used to obtain the distribution dia-
grams. The titration curves for each system (ca. 200 experi-
mental points corresponding to at least three measurements,
pH 2-11, concentration of ligands 1 × 10-3 to 5 × 10-3 M)
were treated either as a single set or as separated curves
without significant variations in the values of the stability
constants. Finally, the sets of data were merged together and
treated simultaneously to give the final stability constants.
(iv) For either dioxatetraamines (4a ,b) or hexaamines
(6a ,b), the variation with the pH of the NMR resonances
of the â-carbon atoms and the R-hydrogen atoms with
respect to the nitrogen atoms bearing the protonation
procesess have allowed for the conclusions on the pro-
tonation sequences graphically indicated in Schemes 5
and 6, respectively.
P r ep a r a tion of P yr a zole P r ecu r sor s. Dieth yl 3,5-P yr a -
zoled ica r boxyla te. This compound was prepared following
a procedure similar to that previously reported by Bosnich and
co-workers21 for the dimethyl ester. To a stirred solution of
3,5-dimethylpyrazole (7.20 g, 75 mmol) in 300 mL of H2O
heated at 60 °C was added solid KMnO4 (65 g, 0.41 mol)
portionwise. When the addition was complete, the temperature
was carefully raised to 80 °C until the foam stopped and then
refluxed for 5 h. The reaction mixture was cooled to room
temperature and filtered on a Celite pad. The solvent was then
removed under reduced pressure, the resulting solid was
dissolved in 150 mL of EtOH, and the solution was saturated
with HCl(g) and stirred for 24 h at room temperature. Removal
of the solvent afforded a white solid, which was treated with
H2O (100 mL) and extracted with CHCl3 (3 × 40 mL). This
extract was dried (MgSO4) and evaporated to give an oily
residue, which after being purified by flash column chroma-
tography (hexane/Et2O, 2:3) afforded the title compound as a
white solid (8.51 g, 53%); mp 52-54 °C, lit.22 mp 53-54 °C.
(v) In 4a ,b and 6a ,b the upfield and downfield shifts
experienced upon protonation by the carbon atoms C3,5
and C4 of the pyrazole rings, respectively, are parallel to
those found for aromatic rings of [1:1] and [2:2] cyclo-
phanes and do not reflect a direct implication of the
pyrazole subunits in the protonation mechanism.
(vi) The most significant change for the pyrazole rings
in the different protonation steps comes from the re-
markable line-broadening observed for carbon atoms C3,5
of 4a and 6a , which could be attributed to an alteration
in the dynamic exchange rate of the pyrazole prototropic
equilibria due to consecutive conformational changes
induced by the gradual protonation process.
Now, work is in progress to evaluate the complexing
ability of polyamine receptors 4a ,b and 6a ,b toward
dopamine in aqueous solution at variable pH using
potentiometric and NMR methods.
3,5-Bis(h yd r oxym eth yl)p yr a zole (1a ). To a solution of
diethyl 3,5-pyrazoledicarboxylate (10.60 g, 50 mmol) in 100
mL of dry toluene cooled at -78 °C was slowly added 170 mL
of a 1.5 M solution of DIBALH in toluene under argon. After
addition, the reaction was allowed to reach room temperature
overnight, cooled to 0 °C, and treated with 150 mL of MeOH.
The precipitated solid was collected by filtration, air-dried, and
extracted in a Soxhlet apparatus with MeOH for 4 d. Evapora-
tion of MeOH afforded an oil, which after trituration with
Exp er im en ta l Section
Gen er a l. All starting materials were purchased from com-
mercial sources and used without further purification. The
solvents were dried using standard techniques. All reactions
were monitored by thin-layer chromatography (TLC) on pre-
coated aluminum sheets of silica gel; compounds were detected
with UV light (254 nm) and/or iodine chamber. Flash column
chromatography was performed in the indicated solvent
system on silica gel (particle size 0.040-0.063 mm). Melting
points were determined in a hot-stage microscope and are
uncorrected. The 1H NMR spectra were recorded at 300 or 400
MHz, and the 13C NMR spectra were recorded at 75 or 100
MHz at room temperature, employing D2O, (CD3)2SO, or CDCl3
as solvent. The chemical shifts are reported in ppm from TMS
(δ scale) but were measured against the solvent signals;
dioxane (δ 67.4 ppm) was used as reference for 13C NMR
spectra in D2O. All assignments have been performed by
means of different standard 1H-1H homonuclear correlation
experiments (COSY, GCOSY) and 1H-13C heteronuclear
multiple quantum coherence experiments (HMQC, HMBC,
(32) Covington, A. K.; Paabo, M.; Robinson, R. A.; Bates, R. G. Anal.
Chem. 1968, 40, 700-706.
(33) Garc´ıa-Espan˜a, E.; Ballester, M. J .; Lloret, F.; Moratal, J .-M.;
Faus, J .; Bianchi, A. J . Chem. Soc., Dalton Trans. 1988, 101-104.
(34) Fontanelli, M.; Micheloni, M. Proc. 1st Spanish-Italian Congr.
Thermodynamics of Metal Complexes; Pen˜´ıscola, Castello´n (Spain),
3-6 J une, 1990.
(35) Micheloni, M.; Sabatini, A.; Vacca, A. Inorg. Chim. Acta 1977,
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(36) (a) Gran, G. Analyst (London) 1952, 77, 661. (b) Rossoti, F. J .
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(38) Vacca, A. FORTRAN program for the determination of species
distribution in multicomponent systems.

Protonation Behavior of Oxaaza and Polyaza Macrocycles
J . Org. Chem., Vol. 64, No. 17, 1999 6145
EtOAc gave compound 1a as a white solid, which was crystal-
lized from EtOAc (5.38 g, 84%); mp 95-96 °C, lit.39 mp 91-92
°C.
24-h exa en e (5b). This compound was prepared as described
for 3b, using diethylenetriamine (206 mg, 2.0 mmol) instead
of 1,5-diamino-3-oxapentane. The desired compound separated
as a thick oil, which solidified after scratching to give a white
solid that was crystallized from EtOH (450 mg, 80%); mp 160-
1-Ben zyl-3,5-bis(h yd r oxym eth yl)p yr a zole (1b). A solu-
tion of diethyl 1-benzyl-3,5-pyrazoledicarboxylate22 (4.83 g, 16
mmol) in 100 mL of dry THF was slowly added under argon
to an ice-cooled solution of 3.04 g (80 mmol) of LiAlH4 in 100
mL of the same solvent. After addition, the reaction was
allowed to reach room temperature overnight, cooled to 0 °C,
and hydrolyzed by slow and consecutive addition of 15 mL of
MeOH and 100 mL of saturated aqueous NH4Cl. After separa-
tion of the solid in suspension by filtration and evaporation of
organic solvents, the aqueous phase was extracted with 5 ×
50 mL of CHCl3. This solution was dried (MgSO4) and
evaporated to afford the title compound as a white solid, which
was crystallized from EtOAc (2.48 g, 71%); mp 92-94 °C, lit.22
mp 92-93 °C.
1
162 °C. H NMR (CDCl3) δ 8.35 (s, H2), 8.31 (s, H2′), 7.72 (s,
H4), 7.23 (s, H4′), 5.55 (d, H7A), 5.41 (d, H7B), 5.47 (d, H7′A), 5.40
(d, H7′B), 4.17 (s, H6), 4.32 (s, H6′), 3.78 (m, HR-3A), 3.54 (m,
HR-3B), 3.67 (m, HR-3′A), 3.49 (m, HR-3′B), 3.05 (m, Hâ-3A), 2.51
(m, Hâ-3B), 3.01, (m, Hâ-3′A), 2.57 (m, Hâ-3′B), 3.22 (m, HR-5A),
3.17 (m, HR-5B), 3.18 (m, HR-5′A), 3.12 (m, HR-5′B), 3.47 (m,
Hâ-5A), 2.34 (m, Hâ-5B), 3.33 (m, Hâ-5′A), 2.37 (m, Hâ-5′B); MS
(FAB) m/z 563 (MH+, 54). Anal. Calcd for C32H38N10: C, 68.30;
H, 6.81; N, 24.89. Found: C, 68.60; H, 7.05; N, 24.68.
6,19-Dioxa -3,9,12,13,16,22,25,26-octa a za tr icyclo-[22.2.-
1.111,14]-oct a cosa -1(27),11,14(28),24-t et r a en e (4a ). To a
stirred suspension of Schiff base 3a (154 mg, 0.4 mmol) in 10
mL of EtOH was added solid NaBH4 (151 mg, 4.0 mmol)
portionwise. After 2 h at room temperature the solvent was
evaporated, and after addition of 10 mL of H2O the pH was
adjusted to 9 by addition of 5% aqueous HCl. Water was then
evaporated, and the dry residue was extracted with toluene
in a Soxhlet apparatus. Evaporation of toluene gave a solid,
which was crystallized from benzene, affording pure compound
4a as white crystals (118 mg, 75%); mp 144-146 °C. MS (FAB)
m/z 393 (MH+, 100). Anal. Calcd for C18H32N8O2: C, 55.08; H,
8.22; N, 28.55. Found: C, 55.30; H, 8.17; N, 28.30.
13,26-Diben zyl-6,19-d ioxa -3,9,12,13,16,22,25,26-octa a za -
t r icyclo-[22.2.1.111,14]-oct a cosa -1(27),11,14(28),24-t et r a -
en e (4b). This compound was prepared as described for 4a
from Schiff base 3b (226 mg, 0.4 mmol) and NaBH4 (151 mg,
4.0 mmol), but in this case the reduction was carried out at
70 °C for 2 h. The solvent was then evaporated, and after
addition of 10 mL of water the pH was adjusted to 9 as before.
The solution was extracted with 3 × 25 mL of CHCl3, and the
organic layer was dried (Na2SO4) and evaporated to yield 4b
as a white solid, which was crystallized from benzene (192 mg,
84%); mp 131-133 °C. MS (FAB) m/z 573 (MH+, 100). Anal.
Calcd for C32H44N8O2: C, 67.11; H, 7.74; N, 19.56. Found: C,
66.92; H, 8.04; N, 19.34.
P r ep a r a tion of P yr a zoled ica r ba ld eh yd es 2a a n d 2b .
These compounds were prepared by oxidation of 3,5-bis-
(hydroxymethyl)pyrazoles 1a and 1b as follows. To a refluxing
solution of 10 mmol of the corresponding dialcohol in DME
(250 mL for 1a and 100 mL for 1b) was added solid MnO2 (10
g, 115 mmol) portionwise. The reflux was then continued, and
after 2 h the reaction was usually complete. Insoluble material
was then removed by filtration through a Celite pad and
washed with 3 × 100 mL of hot MeOH. The solution was
decolorized with some charcoal and, after filtration, evaporated
to dryness to give the corresponding dicarbaldehydes (2a and
2b) as chromatographically homogeneous materials. Each of
them was crystallized in solvent as indicated below.
3,5-P yr a zoled ica r ba ld eh yd e (2a ). White microcrystals
(0.93 g, 75%); mp 193-194 °C (PrOH or H2O); IR (KBr) 3125
and 1710 cm-1 1H NMR [(CD3)2SO] δ 9.94 (s, 2H), 7.49 (s,
;
1H) (monomer 2a ), 9.99 (s, 1H), 9.98 (s, 1H), 7.01 (s, 1H), 7.00
(s, 1H), 6.92 (s, 1H), 6.90 (s, 1H) (dimer 2a ′) (2a /2a ′ ratio at
30 °C in 0.2 M solution, 73/27); MS (EI) m/z 124 (M+, 100).
Anal. Calcd for C5H4N2O2: C, 48.39; H, 3.25; N, 22.57. Found:
C, 48.20; H, 3.52; N, 22.60.
1-Ben zyl-3,5-p yr a zoled ica r ba ld eh yd e (2b). White crys-
tals (1.93 g, 90%); mp 96-97 °C (hexane); IR (KBr) 1690 cm-1
;
3,6,9,12,13,16,19,22,25,26-Deca a za tr icyclo-[22.2.1.111,14]-
octa cosa -1(27),11,14(28),24-tetr a en e (6a ). 3,5-Pyrazoledi-
carbaldehyde 2a (400 mg, 3.2 mmol) was dissolved in 250 mL
of hot MeOH. This solution was then cooled to room temper-
ature and added dropwise under an argon atmosphere to a
stirred solution of diethylenetriamine (328 mg, 3.2 mmol) in
60 mL of MeOH. The reaction was monitored by TLC (CHCl3/
MeOH, 10:1), and when it was complete (ca. 3.5 h) NaBH4 (268
mg, 4.1 mmol) was added portionwise. After 2 h the solvent
was evaporated to dryness under reduced pressure; the
residual syrup was purified by flash column chromatography
(MeOH/30% aqueous NH4OH, 49:1 to 43:7 mixtures). The
fractions containing the product of Rf 0.40 (TLC, MeOH/30%
aqueous NH4OH, 5:2) were evaporated to dryness. The residue
was then extracted with boiling toluene and on concentration
and cooling gave 6a as a white solid, which was crystallized
from toluene (188 mg, 30%); mp 167-169 °C. MS (FAB) m/z
391(MH+, 39). Anal. Calcd for C18H34N10: C, 55.36; H, 8.78;
N, 35.87. Found: C, 55.35; H, 8.77; N, 35.57.
13,26-Diben zyl-3,6,9,12,13,16,19,22,25,26-d eca a za tr icy-
clo-[22.2.1.111,14]-octa cosa -1(27),11,14(28),24-tetr a en e (6b).
This compound was prepared from Schiff base imidazolidine
5b (225 mg, 0.4 mmol) and NaBH4 (151 mg, 4.0 mmol) as
described for oxapolyamine 4b, but the reduction was carried
out at room temperature. The title compound was thus isolated
as a white solid, which was crystallized from toluene (196 mg,
86%); mp 136-138 °C. MS (FAB) m/z 571 (MH+, 69). Anal.
Calcd for C32H46N10: C, 67.34; H, 8.12; N, 24.54. Found: C,
67.12; H, 8.36; N, 24.63.
1H NMR (CDCl3) δ 10.01 (s, 1H), 9.85 (s, 1H), 7.40 (s, 1H),
7.30 (s, 5H), 5.78 (s, 2H); MS (EI) m/z 214 (M+, 24). Anal. Calcd
for C12H10N2O2: C, 67.28; H, 4.71; N, 13.08. Found: C, 67.00;
H, 4.50; N, 12.79.
P r ep a r a tion of Ma cr ocyclic Liga n d s. 6,19-Dioxa -3,9,-
12,13,16,22,25,26-octa a za tr icyclo-[22.2.1.111,14]-octa cosa -
1(27),2,9,11,14(28),15,22,24-octa en e (3a ). 3,5-Pyrazoledi-
carbaldehyde 2a (248 mg, 2.0 mmol) was dissolved in 20 mL
of warm PrOH. This solution was then cooled to room tem-
perature and added dropwise to a stirred solution of 1,5-
diamino-3-oxapentane (208 mg, 2.0 mmol) in 10 mL of PrOH.
After the mixture stirred overnight, the title Schiff base
separated as white crystals, which were isolated by filtration,
washed with PrOH and Et2O, dried under vacuum, and
crystallized from EtOH (346 mg, 90%); mp 177-178 °C. MS
(FAB) m/z 385 (MH+, 64). Anal. Calcd for C18H24N8O2: C,
56.24; H, 6.29; N, 29.15. Found: C, 56.50; H, 6.44; N, 28.95.
13,26-Diben zyl-6,19-d ioxa -3,9,12,13,16,22,25,26-octa a za -
t r icyclo-[22.2.1.111,14]-oct a cosa -1(27),2,9,11,14(28),15,22,-
24-octa en e (3b). A solution of 1-benzyl-3,5-pyrazoledicarbal-
dehyde (2b) (428 mg, 2.0 mmol) in 20 mL of MeCN was added
dropwise to a stirring solution of 1,5-diamino-3-oxapentane
(208 mg, 2.0 mmol) in 20 mL of the same solvent. After the
mixture stirred overnight, the desired Schiff base separated
as white crystals, which were isolated by filtration, washed
with MeCN and Et2O, dried under vacuum, and crystallized
from EtOH (508 mg, 90%); mp 173-175 °C. IR (KBr) 1650
cm-1; MS (EI) m/z 564 (M+, 18). Anal. Calcd for C32H36N8O2:
C, 68.06; H, 6.43; N, 19.84. Found: C, 67.96; H, 6.51; N, 19.63.
13,26-Diben zyl-3,6,9,12,13,16,19,22,25,26-d eca a za p en ta -
cyclo-[22.2.1.111,14.02,6.015,19]-octa cosa -1(27),9,11,14(28),22,-
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 “Comision Interministerial
de Ciencia y Tecnolog´ıa” (CICYT, Coordinated Project
SAF-96-0242-CO2-01) is also gratefully acknowledged.
(39) Llamas-Saiz, A. L.; Foces-Foces, C.; Elguero, J .; Meutermans,
W. Acta Crystallogr. C 1992, 48, 714-717.

6146 J . Org. Chem., Vol. 64, No. 17, 1999
Ara´n et al.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
data registered in D2O at different pH values and chemical
shift differences between protonation steps of 4a [L2], 4b[L4],
Câ-3,5 of 4a [L2]. Variation of the line width of signals C3,5 of
6a [L6] with pH. Variation with the pH of 13C chemical shifts
of carbon atoms C3, C5 and CR-3, CR-5, Câ-3, and Câ-5 of 6b[L8].
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
6a [L6], and 6b[L8]. H-1H correlation for the aliphatic region
of the spectrum of 5b[L7] in CDCl3 and expansion of the
aliphatic region of the HMBC spectrum of 5b[L7]. Variation
with the pH of 13C chemical shifts of carbon atoms C3,5 and
J O981699I