Quantitative evaluation of the chloride template effect in the formation of dicationic [14]imidazoliophanes

Article abstract of DOI:10.1021/jo0262311

The formation of macrocycles containing two imidazolium rings such as 1·2X and 2·2X is anion-directed through hydrogen bonding. The template effect exerted by the chloride anion in the ring-closure reaction of the monocationic model intermediate 9⁺ to yield the [1₄]imidazoliophane 2²⁺ has been evaluated. This effect was quantified following the kinetics of the macrocyclization by using a UV-vis technique. The rate of the ring closure of monocation 9⁺ is increased up to 10 times, in the presence of Bu₄NCl 0.04 M. This finding confirms that the template effect is operative in the macrocyclization leading to dicationic [1₄]imidazoliophanes.

Full text of DOI:10.1021/jo0262311

Qu a n tita tive Eva lu a tion of th e Ch lor id e Tem p la te Effect in th e
F or m a tion of Dica tion ic [14]Im id a zoliop h a n es
Susana Ramos,‡ Ermitas Alcalde,‡ Giancarlo Doddi,*,† Paolo Mencarelli,*,† and
Llu¨ısa Pe´rez-Garc´ıa‡
Dipartimento di Chimica e CNR-ICCOM-Sezione di Roma, Universita` di Roma “La Sapienza’’,
P.le Aldo Moro, 2, 00185 Roma, Italy, and Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia,
Universitat de Barcelona, Avda. J oan XXIII s/ n, 08028-Barcelona, Spain
paolo.mencarelli@uniroma1.it
Received J uly 24, 2002
The formation of macrocycles containing two imidazolium rings such as 1‚2X and 2‚2X is anion-
directed through hydrogen bonding. The template effect exerted by the chloride anion in the ring-
closure reaction of the monocationic model intermediate 9+ to yield the [14]imidazoliophane 22+
has been evaluated. This effect was quantified following the kinetics of the macrocyclization by
using a UV-vis technique. The rate of the ring closure of monocation 9+ is increased up to 10
times, in the presence of Bu4NCl 0.04 M. This finding confirms that the template effect is operative
in the macrocyclization leading to dicationic [14]imidazoliophanes.
CHART 1
In tr od u ction
In recent years, the use of template-directed synthesis1
has enormously benefited the obtention of macrocycles.
Countless examples of metal cations and organic neutral
molecules as templates have been reported in the prepa-
ration of macrocycles. However, despite the increasing
use of templates that can be found in the literature,
anions have been employed in only a few cases.2
It should be noted that generally the evidence of the
template effect is based on yield increases,3 and only a
few examples of the evaluation of the operating effect
through kinetic studies have been reported.4
Part of our research has been focused on the prepara-
tion of novel macrocyclic systems built up from hetero-
cyclic betaine subunits, and an ensemble of [1n]het-
erophanes has been reported.5 The “3 + 1” convergent
stepwise synthesis of several examples of dicationic
[14]heterophanes,6 frameworks containing two imidazo-
lium rings, such as 1‚2X, is template-controlled in the
presence of anions.7 Moreover, the molecular recognition
motifs for anion templating involve the interaction of a
multicentered chloride ion with the heteroaromatic and
aromatic rings. In fact, there is structural evidence for
the existence of hydrogen bonds between chloride ions
and the C(2)-H of the imidazolium ring components of
the dicationic [14]heterophanes 1‚2X, as shown by X-ray
crystallography;6 chloride anions selectively increased the
yield in comparison with other anions.7
† Universita` di Roma “La Sapienza”.
‡ Universitat de Barcelona.
(1) For general reviews on template effects see: (a) Anderson, S.;
Anderson, H.; Sanders, J . K. M. Acc. Chem. Rev. 1993, 26, 469-475.
(b) Hoss, R.; Vo¨gtle, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 375-
384. (c) Busch, D. H.; Vance, A. L.; Kolchinski, A. G. Comprehensive
Supramolecular Chemistry; Atwood, J . L., Davies, J . E. D., MacNicol,
D. D., Vo¨gtle, F., Sauvage, J .-P., Hosseini, M. W., Eds.; Pergamon:
Oxford, 1996; Vol. 9, Chapter 1. (d) Gerbeleu, N. V.; Arion, V. B.;
Burgess, J . Template Synthesis of Macrocyclic Compounds; Wiley-
VCH: New York 1999. (e) Templated Organic Synthesis; Diederich,
F.; Stang, P. J ., Eds.; Wiley-VCH: New York, 2000. (f) Hubin, T. J .;
Busch, D. H. Coord. Chem. Rev. 2000, 200-202, 5-52.
The significant increase of the yield in the preparation
of dicationic [14]imidazoliophanes using the chloride
(4) (a) D’Acerno, C.; Doddi, G.; Ercolani, G.; Mencarelli, P. Chem.
Eur. J . 2000, 6, 3540-3546, and references therein. (b) Doddi, G.;
Ercolani, G.; Franconeri, S.; Mencarelli, P. J . Org. Chem. 2001, 66,
4950-4953. (c) Mandolini, L. Pure Appl. Chem. 1986, 58, 1485-1492.
(d) Cacciapaglia, R.; Mandolini, L. Chem. Soc. Rev. 1993, 22, 221-
231.
(5) (a) Alcalde, E.; Dinare`s, I.; Mesquida, M.; Pe´rez-Garc´ıa, L.
Targets in Heterocyclic Systems 2000, 4, 379-403. (b) Alcalde, E.;
Mesquida, N.; Pe´rez-Garc´ıa, L.; Ramos, S.; Alemany, M.; Rodr´ıguez,
M. L. Chem. Eur. J . 2002, 8, 474-484, and references therein.
(6) Alcalde, E.; AÄ lvarez-Ru´a, C.; Garc´ıa-Granda, S.; Garc´ıa-Rod-
r´ıguez, E.; Mesquida, N.; Pe´rez-Garc´ıa, L. Chem. Commun. 1999, 295-
296.
(2) For some examples of anion templates in the synthesis of organic
molecules and supramolecules see: (a) Beer, P. D.; Gale, P. A. Angew.
Chem., Int. Ed. 2001, 40, 486-516. (b) Aoyagi, M.; Biradha, K.; Fujita,
M. J . Am. Chem. Soc. 1999, 121, 7457-7458. (c) Hu¨bner, M.; Gla¨ser,
J .; Seel, C.; Vo¨gtle, F. Angew. Chem., Int. Ed. Engl. 1999, 38, 383-
386. (d) Reuter, C.; Wienand, W.; Hu¨bner, G. M.; Seel, C.; Vo¨gtle, F.
Chem. Eur. J . 1999, 5, 2692-2697. (e) Fyfe, M. C. T.; Glink, P. T.;
Menzer, S.; Stoddart, J . F.; White, A. J . P.; Williams, D. J . Angew.
Chem., Int. Ed. Engl. 1997, 36, 2068-2070. (f) Li, F.; Yang, K.;
Tyhonas, J . S.; MacCrum, K. A.; Lindsey, J . S. Tetrahedron 1997, 53,
12239-12360.
(7) (a) Alcalde, E.; Ramos, S.; Pe´rez-Garc´ıa, L. Org. Lett. 1999, 1,
1035-1038. (b) Ramos, S. Ph.D. Dissertation, University of Barcelona,
Spain, 2002.
(3) Anderson, S.; Anderson, H. L.; Sanders, J . K. M. J . Chem. Soc.,
Perkin Trans. 1 1995, 2255-2267.
10.1021/jo0262311 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/05/2002
J . Org. Chem. 2002, 67, 8463-8468
8463

Ramos et al.
SCHEME 1. “3 + 1” Con ver gen t Syn th esis of
Dica tion ic [14]Heter op h a n e 2‚2Cl
tal conditions used (base, solvent, and temperature), and
interestingly, it was also counterion dependent: the
formation of 2‚2X was always more favored for chloride
5H‚2Cl than for hexafluorophosphate 5H‚2PF6. These
facts were in good agreement with the previous results
obtained in the formation of dicationic macrocycles such
as 2‚2X.7
Due to the difficult isolation of compound 5‚X, its
protonated form 5H‚2X was selected in order to carry out
the deprotonation in situ during the kinetic study, using
an organic base, for instance, triethylamine. Initially, the
kinetics of cyclization of the more soluble hexafluoro-
phosphate 5H ‚2PF6 was examined by 1H NMR in
CD3CN. Unfortunately, fast cyclization of 5H‚2PF6 did
not permit us to record sufficient experimental data to
calculate meaningful kinetic constants. Furthermore, to
avoid the formation of the chloride anions, which could
act as templates during the cyclization, the preparation
of an alternative intermediate, 9H‚2Pic,9,10 was taken
into consideration. In this case, the use of picrate as
leaving group could permit us to follow the kinetics of
the reaction by a UV-vis technique.
The preparation of 9H‚2Pic was performed as shown
in Scheme 3. The ester 7‚Br, previously synthesized, was
converted to the hydrobromide 8H ‚2Br by treatment
with 48% HBr, at 95 °C for 24 h. The reaction of 8H‚2Br
with silver picrate11a,b at 60 °C afforded the compound
9H‚2Pic in 98% yield.
anion as template7 prompted us to carry out a kinetic
study of the reaction to quantitatively evaluate the
template effect. Here we report the quantitative results
obtained for the template-controlled macrocyclization
reaction in the presence of chloride anions, leading to the
dicationic [14]imidazoliophane 22+
.
Resu lts a n d Discu ssion
Sp ectr oscop ic Meth od s. The structures of new com-
pounds 5/6-9H‚2Pic were determined by 1H and 13C
NMR spectroscopy. Assignment of the most characteristic
signals was made by using NMR experiments (HMBC
and HMQC), and the data are shown in Table 1 for
compounds 5H,7-9H‚2Pic.
E lect r osp r a y Ion iza t ion Ma ss Sp ect r om et r y.
ESI-MS was used to examine charged compounds in the
gas phase. ESI-MS was measured as described else-
where,12 samples being dissolved in H2O/CH3CN (1:1),
while the cone voltage was kept at 60 V (Table 2).
Compounds 5H ‚2PF6, 5H ‚2Cl, 8H ‚2Br, and 9H ‚2Pic
(M‚2X), containing two aromatic rings and two imidazo-
lium units, show two common characteristic peaks: the
ion [M]2+ corresponding to the loss of both counterions,
and the ion [M-H]+ also corresponding to the loss of both
counterions and deprotonation. For compounds 5H‚2Cl
and 8H‚2Br, the base peak corresponds to the singly
charged fragment ion [3H]+ at m/z 239, due to the proto-
nated trinuclear 1,3-bis(1-imidazolylmethyl)benzene, thus
The “3 + 1” convergent synthesis leading to the
imidazoliophane 2‚2Cl is based on the coupling of pro-
tophane 36 with the bis-chloromethyl derivative 4 in
acetonitrile under reflux. The reaction occurs in two
steps, as shown in Scheme 1, and only the second one,
i.e., the ring closure reaction of the intermediate 5‚Cl,
should benefit from the template ability of the guest.
However compound 5‚Cl has never been isolated.
To evaluate the template effect of the chloride anion
in the formation of the cyclophane 2‚2Cl, the prepara-
tion of the acyclic intermediate 5‚Cl, the immediate
precursor of macrocycle 2‚2Cl along the reaction path, is
required.
The preparation of 5‚Cl was attempted according to
the route illustrated in Scheme 2. Equimolecular amounts
of compounds 3 and 6 were allowed to react in acetonitrile
at room temperature for 24 h, affording, after column
chromatography, the monocationic ester salt 7‚Br in 20%
yield. The ester 7‚Br was converted to the hydrochloride
5H‚2Cl by treatment with 37% HCl, at 95 °C for 24 h
and was isolated as 5H‚2PF6, after anion exchange with
silver hexafluorophosphate (Scheme 2).
Pure compounds 5H‚2X were isolated and fully char-
acterized both as the chloride and hexafluorophosphate
salts 5H‚2Cl and 5H‚2PF6, and their neutralization to
5‚X was attempted. Different experimental conditions
were tried in order to carry out the neutralization,8 but
compound 5‚X was never isolated pure: its formation was
always accompaniedsmore or lesssby the formation of
the macrocyclic compound 2‚2X. The rate of formation
of 2‚2X was variable, and it depended on the experimen-
(9) Previously, compound 10H‚2OTs (see Experimental Section) was
also considered, which contained in its structure two tosylate counte-
rions and a tosyl as leaving group. The cyclization of compound 10H‚
2OTs was followed by 1H NMR in CD3CN. Similarly to compound 5H‚
2PF6, the cyclization reaction was too fast to record enough experimental
data to obtain significant kinetic constants.
(10) The reactivity of picrate as leaving group was tested, by re-
acting 2,4,6-trinitrophenylbenzyl ether 11 (see Experimental Section)
and 1-methylimidazole. The quaternization reaction was monitored by
UV-vis in CH3CN at 65 °C. The quaternization was complete after 2
days.
(11) (a) Silver picrate was prepared from 2,4,6-trinitrophenol by
treatment with sodium hydroxide and silver nitrate, and after crystal-
lization in water. (b) Kolthoff, I. M.; Lingane, J . J .; Larson, W. D. J .
Am. Chem. Soc. 1938, 60, 2512-2515.
(8) Neutralization was attempted by adding different aqueous
solutions such as NH4OH, NaHCO3, and Na2CO3 to a solution of
compound 5H‚2X in H2O or CH3NO2, and fitting the pH to 7-8. Et3N
was also added to a solution of compound 5H‚2X in CH3CN.
(12) (a) Alcalde, E.; Mesquida, N.; Ferna´ndez, I.; Giralt, E. Rapid
Commun. Mass Spectrom. 2000, 14, 1014-1016. (b) Alcalde, E.;
Mesquida, N.; Vilaseca, M. Rapid Commun. Mass Spectrom. 2000, 14,
1443-1447.
8464 J . Org. Chem., Vol. 67, No. 24, 2002

Kinetic Study on Dicationic [14]Imidazoliophanes
SCHEME 2. P r ep a r a tion of P r ecu r sor 5‚X
SCHEME 3. P r ep a r a tion of th e P r ecu r sor 9H‚2P ic
of chloride anions, up to 10 times at [Bu4NCl] ca. 4 ×
10-2 M.
Such rate enhancements can be related to the template
concentration by eq 1,
kobs 1 + (k1/k0)Ksub[Cl-]
)
(1)
1 + Ksub[Cl-]
k0
which can be obtained from the kinetic Scheme 4 by
assuming that the association equilibrium between 9+
and the chloride ion is fast with respect to the ring closure
reaction. Equation 1 can be transformed into eq 2
kobs 1 + KT#[Cl-]
indicating that fragmentation occurs even under these
soft experimental conditions.
)
(2)
Ksub[Cl-]
k0
Compound 7‚Br (M‚X), which has one imidazolium ring
in its structure, showed the formation of the ion [M]+,
which corresponds to the loss of one counterion, and of
the fragment ion [3H]+ produced with a relative abun-
dance of 91% (Vc ) 60 V).
Kin etic Stu d y. The following kinetic scheme (Scheme
4) can be envisaged for the reaction of the monocation
9+ in the presence of chloride anions.
by considering the distribution Scheme 5, which takes
into account the association of the template with the open
chain precursor 9+ and with the cyclic transition state.4a,b
In eq 2 KT# ()k1Ksub/k0) and Ksub have the meaning as
the association constant of the template with the cyclic
transition state and with the open chain precursor 9+,
respectively (Scheme 5).4c,d
The ring closure reaction of the monocation 9+, benefits
from the template ability of the chloride anion when it
binds the transition state more strongly than the reac-
tant.13 This is mainly due to the preorganization of the
cyclic transition state and, secondarily, to the develop-
ment of a further positive charge on the initially neutral
nitrogen atom (Scheme 5).
The kinetics of cyclization has been studied by
UV-vis spectroscopy in acetonitrile at 25 °C, following
the absorbance variation, at λ 370 nm, which is the λmax
of the picrate anion. To avoid polymerization reactions,
the concentration of the substrate 9‚Pic was kept as low
as possible (ca. 7 × 10-4 M).
The first-order rate constant k0 is the rate constant for
the cyclization reaction of the monocation 9+, in the
absence of chloride anions, to yield the macrocycle 22+
(Scheme 4). However, since by adding variable amounts
of Bu4NCl the ionic strength of the solution is changed,
for each kinetic measurement at a given concentration
of Bu4NCl the k0 value was evaluated at the same ionic
strength, utilizing Et4NCF3CO2 as a buffering salt (see
Experimental Section for details).
Nonlinear least-squares fit14 to eq 1 of the kobs/k0 ratios
provided the following values for the association con-
stants: KT# ) 941 ( 78 M-1 and Ksub) 72 ( 9 M-1
.
The saturation value, which is given by the KT#/Ksub
ratio, is the maximum theoretical rate enhancement that
would be attained when the substrate is completely
bound to the template.4c,d This value indicates that the
complexed form of 9+ with the chloride ion, is ca. 13 times
more reactive than the free one.
First-order rate constants (kobs) have been obtained in
the presence of variable excess amounts of the chloride
anion as Bu4NCl (see Experimental Section), up to its
solubility limit. The ratios kobs/k0, plotted in Figure 1
against the concentration of Bu4NCl, provide a mea-
sure of the rate enhancement produced by the pres-
ence of the template. The data show that the ring closure
of the monocation 9+‚Pic is accelerated by the presence
In conclusion, the chloride anion serves as a template
for the synthesis, leading to the dicationic [14]imidazo-
liophane 22+. The rate enhancement observed, up to 10
(13) Kraut, J . Science 1988, 242, 533-540, and references therein.
(14) The nonlinear least-squares fitting program used was Sigma-
Plot Program, SPSS Inc., 233 S. Wacker Drive, 11th floor, Chicago, IL
60606.
J . Org. Chem, Vol. 67, No. 24, 2002 8465

Ramos et al.
TABLE 1. Selected 1H NMRa Da ta for Com p ou n d s 7‚Br , 5H‚2Cl, 5H‚2P F 6, 8H‚2Br , a n d 9H‚2P ic
compd
H-2
H-4
7.83
H-5
H-2′
H-4′
6.89
H-5′
CH2-LG
LG
2.05 (CH3)
7‚Brb
9.37
9.45
9.40
8.60
9.51
8.75
7.80
7.80
7.80
7.72
9.30
8.90
8.60
9.37
8.64
7.14
7.76
5.07
4.76
4.76
4.69
4.69
5.26
5H‚2Clb
7.84
7.84
7.70
5H‚2PF6b
5H‚2PF6c
8H‚2Brb
9H‚2Picc
7.54/7.61c
7.38/7.44
7.81
7.38/7.44b
7.85/7.86c
7.37/7.46b
7.73
7.37/7.46b
8.91 (Pic-LGd)
8.72 (Pic-anion)
a
b
d
Previous related compounds have been useful for the assignment of the signals. DMSO-d6 (500 MHz). c CD3CN (200 MHz). LG
means picrate as leaving group.
TABLE 2. Su m m a r y of Da ta Obta in ed fr om P ositive Ion
SCHEME 4. Kin etic Sch em e
ESI-MSa of 7‚Br , 5H‚2Cl, 5H‚2P F 6, 8H‚2Br , a n d 9H‚2P ic
ions, m/z ratio
relative abundance (%)
compd (Mw)
[M]2+
[M - H]+
[M + X]+
[3H]+ b
5H‚2Cl (449.8)
189.8
23
189.3
100
211.2
39
377.8
68
377.5
44
421.1
68
570.0
100
c
239.7
100
239.4
61
239.3
100
c
5H‚2PF6 (668.8)
8H‚2Br (582.1)
9H‚2Pic (1027.7)
7‚Br (481.4)
523.5
35
c
285.8
48
c
400.6d
100
239.4
91
a
b
Vc ) 60 V. Protophane (3, Mw 238.3). c No signal observed.
[M]+.
d
times in the presence of 0.04 M Bu4NCl, indicates that
the ring closure reaction is accelerated in the presence
of the template. Thus, the chloride anion stabilizes the
transition state, favoring the macrocyclization through
hydrogen bonding, as appears to be also suggested by the
X-ray structure of the imidazoliophane product 2‚2Cl.6
The quantitative evaluation of the template effect caused
by the chloride anions allows us to justify the improve-
ment of the yields observed for dicationic [14]imidazo-
liophanes, and it will be useful to understand and take
advantage of the anionic template effect in the prepara-
tion of related compounds.
HPLC-grade acetonitrile was used in the kinetic experiments
without further purification.
3-(Br om om eth yl)ben zyl Aceta te (6). A suspension of 1,3-
bis(bromomethyl)benzene (5.3 g, 20.0 mmol) and potassium
acetate (1.96 g, 20.0 mmol) was allowed to react in DMF (50
mL) at 80 °C for 24 h. The solvent was removed in vacuo and
the solid extracted with ethyl ether (4 × 25 mL). The organic
fractions were combined and dried (Na2SO4) and the solvent
was removed in vacuo. Column chromatography (silica gel,
toluene) afforded 7 as a colorless oil (1.5 g, 32%): 1H NMR
(200 MHz, CDCl3) δ 2.12 (s, 3H), 4.49 (s, 2H), 5.10 (s, 2H),
7.26-7.35 (m, 3H), 7.37 (s, 1H); 13C NMR (50.3 MHz, CDCl3)
δ 21.0, 51.8, 65.7, 127.9-128.8, 136.5, 138.1, 170.8; IR (film)
1740, 1223 cm-1; MS (EI) m/z (%) 163 (100) [M - Br]+, 242 (6)
[M - 1]+. Anal. Calcd for C10H11BrO2: C 49.0, H 4.6. Found C
49.1, H 4.6.
Exp er im en ta l Section
Gen er a l a n d In str u m en ta tion . Thin-layer chromatogra-
phy (TLC) were carried out on precoated 60 F254 silica gel
and precoated 60-200 UV254 aluminum gel plates. Column
chromatography was performed on silica gel 60 70-200 mesh
(SDS) and aluminum oxide 90 standardized. 1H NMR spectra
were recorded at 200, 300, and 500 MHz. 13C NMR spectra
were recorded at 50.3 MHz.
Ma ter ia ls. Silver hexafluorophosphate, tetraethylammo-
nium trifluoroacetate (98%), tetrabutylammonium chloride
(g99%), and trifluoroacetic acid (99%) were used without
further purification.Triethylamine was distilled from Na, and
1-(3-Acetoxym eth yl)ben zyl-3-[3-(1-im id a zolilm eth yl)-
ben zyl]im id a zoliu m Br om id e (7‚Br ). A solution containing
6 (0.5 mg, 2.05 mmol) in acetonitrile (10 mL) was added
dropwise (ca. 5h) to a solution of protophane 3 (0.49 g, 2.05
8466 J . Org. Chem., Vol. 67, No. 24, 2002

Kinetic Study on Dicationic [14]Imidazoliophanes
138.7. Anal. Calcd for C22H23N4Cl3: C 58.7, H 5.1, N 12.5.
Found: C 58.3, H 5.2, N 12.8.
3-(3-Ch lor om eth yl)ben zyl-1-[3H-3-(1-im id a zoliom eth -
yl)b en zyl]im id a zoliu m Bish exa flu or op h osp h a t e (5H ‚
2P F 6). Silver hexafluorophosphate (0.29 g, 1.14 mmol) was
added to an absolute methanol solution (6 mL) of 5H‚2Cl
(0.255 g, 0.57 mmol). The gray precipitate formed was filtered
and the solvent was removed in vacuo at 25 °C, affording 5H‚
2PF6 as a colorless oil (0.34 g, 90%): 13C NMR (50.3 MHz,
DMSO-d6) δ 45.8, 51.4, 51.9, 120.7, 122.4, 123.1, 128.0, 128.1,
128.2, 128.3, 128.4, 129.0, 129.2, 129.5, 130.5, 135.3, 135.5,
135.7, 136.0, 136.6, 138.6. Anal. Calcd for C22H23N4ClF12P2:
C 39.5, H 3.5, N 8.4. Found: C 39.9, H 4.0, N 8.5.
3-(3-Ch lor om eth yl)ben zyl-1-[3H-3-(1-im id a zoliom eth -
yl)ben zyl]im id a zoliu m Dibr om id e (8H‚2Br ). The salt 7‚
Br (0.17 g, 0.35 mmol) in 48% HBr (9 mL) was heated at 95
°C for 24 h. After cooling, the suspension obtained was fil-
tered and the solvent was evaporated in vacuo, affording
8H‚2Br as a colorless oil (0.20 g, quant): 13C NMR (50.3 MHz,
DMSO-d6) δ 51.4, 51.8, 52.3, 62.6, 120.4, 122.2, 123.0, 126.4,
126.8, 128.5, 128.7, 128.9, 129.8, 134.7, 135.7, 136.0, 136.5,
143.6.
3-[3-(2,4,6-Tr in itr op h en oxy)m eth yl]ben zyl-1-[3H-3-(1-
im id a zoliom eth yl)ben zyl]im id a zoliu m Bis(2,4,6-tr in itr o-
p h en ola te) (9H‚2P ic). 8H‚2Br (0.1 g, 0.17 mmol) was added
to an acetonitrile solution (6 mL) of silver picrate (0.19 g,
0.58 mmol). The solution was kept at 65 °C for 1.5 h. The
suspension obtained was filtered and the solvent was removed
in vacuo at 25 °C, affording 9H‚2Pic as a colorless oil (0.17 g,
98%). 13C NMR (50.3 MHz, DMSO-d6) δ 51.6, 52.0, 52.2, 71.5,
120.6, 122.2, 123.1, 124.4, 127.6, 128.0, 128.3, 128.6, 129.2,
129.9, 134.9, 135.6, 135.7, 135.9, 136.6, 139.2, 141.9, 160.9.
Anal. Calcd for C40H29N13O21‚2H2O: C 45.1, H 3.1, N 17.1.
Found: C 44.9, H 2.7, N 17.2.
F IGURE 1. Rate enhancement produced by the chloride ion
on the ring closure reaction of the monocation 9+. The points
are experimental and the curve is calculated from eq 2.
SCHEME 5. Distr ibu tion Sch em e
P r ep a r a tion of Com p ou n d 10H‚2OTs a n d 1H NMR
Stu d y of th e Cycliza tion Rea ction . Compound 10H‚2OTs
was prepared from the hydrochloride precursor 5H‚2Cl by
treatment with silver tosylate as follows.
Silver tosylate (0.19 g, 0.69 mmol) was added to an aceto-
nitrile suspension of 5H‚2Cl (0.1 g, 0.22 mmol) (5 mL). The
suspension was kept at 50 °C for 6 h. After this time, the
suspension was filtered and the solvent was removed in vacuo
at 25 °C, affording 10H‚2OTs as a hygroscopic solid (0.08 g,
42%): 1H NMR (300 MHz, CD3CN) δ 2.29 (s, 6H), 2.39 (s, 3H),
5.00 (s, 2H), 5.27/5.30/5.33 (3xs, 6H), 7.1-7.8 (m, 24H), 8.91
and 9.27 (s, 2H); ESI-MS (60V) m/z (%) 513.8 (2) [M - H]+,
239.4 (100) [3 + H]+.
1H NMR Stu d y. The cyclization reaction was started by
adding 1 equiv of triethylamine to a solution of compound 10H‚
2OTs in CD3CN. The reaction progress was monitored by
following the disappearance of the CH2OTs signal and the
appearance of a new signal at δ 9.6 ppm (H2-Im+ of the
macrocycle formed). A clean cyclization reaction was observed,
but it was too fast to allow us to obtain a sufficient number of
experimental data to calculate meaningful kinetic constants.
P r ep a r a tion of 2,4,6-Tr in itr op h en ylben zyl Eth er (11).
Benzyl chloride (43 µL, 0.37 mmol) was added to an acetonitrile
solution of silver picrate (0.13 g, 0.47 mmol) (2 mL). The
solution was kept at 60 °C for 6 h. After this time, the
suspension obtained was filtered and the solvent was removed
in vacuo. The residue was partitioned between CH2Cl2 (15 mL)
and an aqueous saturated solution of K2CO3 (10 mL). The
aqueous phase was washed again with an aqueous K2CO3
solution (2 × 10 mL), and then the organic extracts were dried
(Na2SO4) and concentrated in vacuo. The yellow solid obtained
was crystallized from toluene/hexane, affording 11 (35 mg,
30%). 1H NMR (300 MHz, CD3CN) δ 5.27 (s, 2H), 7.43 (m, 5H),
8.91 (s, 2H).
mmol) in acetonitrile (16 mL). The solution was kept at room
temperature for 24 h. The solvent was removed in vacuo and
the residue was purified by column chromatography (stan-
dardized alumina, CHCl3/CH3OH increased polarity until 3%).
The fractions containing 7‚Br were combined, and the solvent
was removed in vacuo, affording 7‚Br as a colorless oil (0.19
g, 20%): 13C NMR (50.3 MHz, CDCl3) δ 21.0, 49.4, 52.1, 65.3,
119.8, 123.2, 127.0, 127.6, 127.8, 128.0, 128.2, 128.6, 128.9,
129.0, 129.5, 129.7, 135.3, 135.5, 136.6, 138.5, 138.9, 170.5;
IR (film) 1732, 1230 cm-1
.
3-(3-Ch lor om eth yl)ben zyl-1-[3H-3-(1-im id a zoliom eth -
yl)ben zyl]im id a zoliu m Dich lor id e (5H‚2Cl). The salt 7‚
Br (0.25 g, 0.5 mmol) in 37% HCl (7 mL) was heated at 95 °C
for 24 h. After cooling, the suspension obtained was filtered
and the solvent was evaporated in vacuo, affording 5H‚2Cl as
a colorless oil (0.22 g, quant): 13C NMR (50.3 MHz, DMSO-
d6) δ 45.9, 51.5, 51.9, 120.5, 122.3, 123.1, 128.5, 128.7, 128.8,
128.85, 129.0, 129.5, 129.6, 129.9, 135.5, 135.7, 136.1, 136.7,
Kin etic Mea su r em en ts. Kinetic measurements were car-
ried out at 25 °C in acetonitrile, in a 3 mL cuvette (optical
path 1 cm) kept in the thermostated cell compartment of the
spectrophotometer.
J . Org. Chem, Vol. 67, No. 24, 2002 8467

Ramos et al.
TABLE 3. Ra te Con sta n ts in CH3CN a t 25 °C
started by adding 2 µL of triethylamine [pKa triethylamine )
18.5 (CH3CN)18] to the cuvette. The progress of reaction was
followed at λ 370 nm, which is the λmax of the picrate anion. In
all of the cases a first-order behavior was observed.
[Bu4NCl]
(M)
[Et4NCF3CO2]
(M)
kobs (s-1
)
k0 (s-1
)
kobs/k0
0
9.63 × 10-4
0
9.63 × 10-4
1
The concentration of the tetrabutylammonium chloride was
varied from 0 to 4.12 × 10-2 M and a total of eight kinetic
measurements were carried out. To take into account the effect
of the ionic strength which increases on increasing the salt
concentration, for each kinetic experiment carried out at a
given concentration of tetrabutylammonium chloride (kobs), an
independent kinetic was carried out at the same ionic strength
by using tetraethylammonium trifluoroacetate at the same
concentration (k0 value). All the kinetic constants obtained are
reported in Table 3 together with the kobs/k0 ratios.
2.06 × 10-3 2.49 × 10-3
4.12 × 10-3 4.18 × 10-3
8.23 × 10-3 6.00 × 10-3
1.23 × 10-2 7.41 × 10-3
1.65 × 10-2 8.43 × 10-3
2.47 × 10-2 1.01 × 10-2
4.12 × 10-2 1.39 × 10-2
2.06 × 10-3
4.12 × 10-3
8.23 × 10-3
1.23 × 10-2
1.65 × 10-2
2.47 × 10-2
4.12 × 10-2
9.91 × 10-4 2.51
1.05 × 10-3 4.00
1.06 × 10-3 5.65
1.10 × 10-3 6.73
1.15 × 10-3 7.33
1.23 × 10-3 8.21
1.34 × 10-3 10.37
A stock solution (0.0073 M) of picrate 9H‚2Pic was prepared
by dissolving 0.075 g of 9H‚2Pic in 10 mL of acetonitrile
containing trifluoroacetic acid 0.2 M. The trifluoroacetic acid
was necessary to prevent the dissociation of the protonated
imidazole ring of 9H‚2Pic by the picrate ions which are present
as counterions [pKa picric acid ) 11 (CH3CN);15 pKa N-
methylimidazole ) 7.4 (CH3CN);16 pKa trifluoroacetic acid )
7.4 (CH3CN)17].
In a typical run, 5 µL of a 0.0073 M solution of 9H‚2Pic was
added to 3 mL of acetonitrile solution containg tetrabutylam-
monium chloride or tetraethylammonium trifluoroacetate at
the appropriate concentration (see below). The reaction was
Ack n ow led gm en t. This research was financially
supported by the Direccio´n General de Investigacio´n
(MCYT, Spain) through project PB 98-1164. Additional
support came from the Comissionat per a Universitats
i Recerca de la Generalitat de Catalunya through grant
1999SGR-77. S. R. thanks the Universitat de Barcelona
for a fellowship and a grant for a stay at the Universita`’di
Roma ‘La Sapienza’.
Su p p or tin g In for m a tion Ava ila ble: 1H spectra for all
new compounds and intermediates. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Leito, I.; Kaljurand, I.; Koppel, I. A.; Yagupolskii, L. M.; Vlasov,
V. M. J . Org. Chem. 1998, 63, 7868-7874.
(16) Gagliano, R. A.; Knowlton, R. C.; Byers, L. D. J . Org. Chem.
1989, 54, 5247-5250.
(17) Forcier, G. A.; Olver, J . W. Electrochim. Acta 1970, 15, 1609-
1613.
J O0262311
(18) Beltrame, P.; Gelli, G.; Loi, A. Gazz. Chim. Ital. 1980, 110, 491-
494.
8468 J . Org. Chem., Vol. 67, No. 24, 2002