Selective lower rim reactions of 5,17-upper rim-disubstituted calix[4]arenes

Full text of DOI:10.1021/jo952013e

2564
J . Org. Chem. 1996, 61, 2564-2568
alization of the upper rim,4,7-9 and it is this general
scheme that is employed in the present work.
Selective Low er Rim Rea ction s of
5,17-Up p er Rim -Disu bstitu ted
Ca lix[4]a r en es1
Starting with dibenzyl ether 1 obtained by treatment
of calix[4]arene with benzyl bromide and K2CO3 using
previously described procedures,10 nitration yields 5,17-
dinitro-25,27-dibenzyl ether 2 (Scheme 1). The benzyl
groups of 2 can be removed by treatment with AlCl3 to
give 5,17-dinitrocalix[4]arene (3)11 and can be restored
by treatment of 3 with benzyl bromide and Me3SiOK, the
benzylation occurring on the less acidic phenol moieties
which provide the more nucleophilic phenolate anions.
O-Methylation of 2 with NaH proceeds smoothly to give
5 from which the benzyl groups can be selectively
removed to yield 6, isomeric with the compound obtained
by Reinhoudt and co-workers7 in which the methyl ether
groups are on the phenolic rather than the p-nitrophe-
nolic rings. Conformational control can be exerted in the
conversion of 2 to the corresponding tetrabenzyl ether.
When the reaction is carried out with weak bases such
Shiv Kumar Sharma and C. David Gutsche*
Department of Chemistry, Texas Christian University,
Fort Worth, Texas 76129
Received November 14, 1995
p-tert-Butylcalix[4]arene,2 easily accessible via base-
induced condensation of p-tert-butylphenol and formal-
dehyde, provides a convenient starting material for the
preparation of calixarenes carrying a wide variety of
groups on the upper and lower rims.3 The selective
introduction of these groups, however, continues to be a
challenge to the synthetic chemist, and several ap-
proaches to this problem have appeared in the literature.
The work described in this paper employs one that
involves the preparation of calix[4]arenes disubstituted
on the upper rim followed by selective substitution on
the lower rim to yield calix[4]arenes that can be captured
in one of three conformations.
The introduction of nitro groups into the para positions
of calixarenes was first described by Shinkai and co-
workers who treated p-sulfonatocalix[4,6,8]arenes with
nitric acid.4 Direct nitration of calix[4]arene was subse-
quently accomplished by No and Noh,5 and ipso nitration
of the tetrapropyl ether of p-tert-butylcalix[4]arene has
more recently been described by Reinhoudt and co-
workers6. The latter reaction provides a mixture of fully
nitrated and partially nitrated compounds that requires
separation by column chromatography. However, the 5,-
17-dinitro-11,23-di-tert-butyl compound is more cleanly
prepared by ipso nitration of the 25,27-dipropyl ether of
p-tert-butylcalix[4]arene,6 the p-tert-butyl groups para to
the free OH groups being the ones more readily replaced.
The greater reactivity of these positions has been used
to advantage in other procedures for selective function-
12
as K2CO3 or Cs2CO3, the product is fixed in the 1,3-
alternate conformation (8), whereas with a stronger base
such as NaH the cone conformer (7) is produced. The
products of esterification of 2 proved to be dependent on
the esterifying reagent. Whereas acetyl chloride and
butyryl chloride yield tetrasubstituted compounds 4a and
4b, benzoyl chloride yields only trisubstituted compound
9, as previously noted.13
As mentioned above, benzylation of 3 in the presence
of Me3SiOK produces 1,3-dibenzyl ether 2 even when an
excess of benzyl bromide is employed. When the weaker
base K2CO3 is used, only monobenzylation occurs to yield
11 in which the benzyl group resides on a p-nitrophenolic
oxygen (Scheme 2). Here, also, a large excess of benzyl
bromide fails to alter the outcome. The structure of 11
was based on the elemental analysis and the appearance
1
in the H NMR spectrum of resonances at δ 10.04 and
8.72 in a 1:2 ratio for the OH groups and resonances at
δ 7.98 and 7.91 in a 1:1 ratio for the Ar-H protons of the
p-nitrophenyl rings. The conformation was established
as the cone on the basis of four doublets at δ 4.53, 4.22,
1
3.56, and 3.54 in the H NMR spectrum arising from the
(1) Paper 45 in the series Calixarenes. For paper 44, cf. Kanama-
thareddy, S.; Gutsche, C. D. J . Org. Chem. 1996, 61, 2511.
(2) The term “calixarene” is variously employed in different contexts.
In colloquial usage (as employed in the Discussion section), it implies
the presence of hydroxyl groups. In the more precise and complete
specification of a compound (as used in the Experimental Section), it
implies only the basic skeleton to which the substituents, including
the OH groups, are attached at positions designated by appropriate
numbers as shown in the following structure.
ArCH2Ar methylene hydrogens3a and a resonance at δ
31.67 in the 13C NMR spectrum arising from the ArCH2-
Ar methylene carbons.14 Further benzylation of monoben-
zyl ether 11 using Me3SiOK as base yielded tribenzyl
ether 13, once again the result of the weaker phenolic
moieties providing the more nucleophilic oxyanions. Its
structure is based on the elemental analysis and the
(7) van Loon, J .-D.; Arduini, A.; Verboom, W.; Ungaro, R.; van
Hummel, G. J .; Harkema, S.; Reinhoudt, D. N. Tetrahedron Lett. 1989,
30, 2681. van Loon, J .-D.; Arduini, A.; Coppi, L.; Verboom, W.; Pochini,
A.; Ungaro, R.; Harkema, S.; Reinhoudt, D. N. J . Org. Chem. 1990,
55, 5639.
(8) Kelderman, E.; Derhaeg, L.; Heesink, G. J . T.; Verboom, W.;
Engbersen, J . F. J .; van Hulst, N. F.; Persoons, A.; Reinhoudt, D. N.
Angew. Chem., Int. Ed. Engl. 1992, 31, 1075.
(9) Beer, P. D.; Gale, P. A.; Hesek, D. Tetrahedron Lett. 1995, 36,
767.
(10) Dijkstra, P. J .; Brunink, J . A. J .; Bugge, K. E.; Reinhoudt, D.
N.; Harkema, S.; Ungaro, R.; Ugozzoli, F.; Ghidini, E. J . Am. Chem.
Soc. 1989, 111, 7567. Gutsche, C. D.; Reddy, P. A. J . Org. Chem. 1991,
56, 4783.
(11) Attempts to prepare a dinitrocalix[4]arene by nitration of calix-
[4]arene or its ethyl ether led to mixtures of the tetranitro and dinitro
compounds (see Experimental Section).
(3) (a) Gutsche, C. D. Calixarenes in Monographs in Supramolecular
Chemistry; Stoddart, J . F., Ed.; Royal Society of Chemistry: London,
1989. (b) Calixarenes, A Versatile Class of Macrocyclic Compounds,
Vicens, J ., Bo¨hmer, V., Eds.; Kluwer: Dordrecht, 1991. (c) Bo¨hmer, V.
Angew. Chem., Int. Ed. Engl. 1995, 34, 713-745. (d) Gutsche, C. D.
Aldrichimica Acta 1995, 28, 3-9.
(4) Shinkai, S.; Tsubaki, T.; Sone, T.; Manabe, O. Tetrahedron Lett.
1985, 26, 3343. Shinkai, S.; Araki, K.; Tsubaki. T.; Arimura, T.;
Manabe, O. J . Chem. Soc., Perkin Trans. 1 1987, 2297.
(5) No, K.; Noh, Y. Bull. Korean Chem. Soc. 1986, 7, 314.
(6) Verboom, W.; Durie, A.; Egberink, R. J . M.; Asfari, Z.; Reinhoudt,
D. N. J . Org. Chem. 1992, 57, 1313.
(12) When K2CO3 (50 equiv) was employed in very dilute solution,
the product was the 1,3-alternate conformer, but the cone conformer
was the major product when a more concentrated solution was used.
(13) Gutsche, C. D.; Lin, L.-g. Tetrahedron 1986, 42, 1633.
(14) J aime, C.; deMendoza, J .; Prados, P.; Nieto, P. M.; Sanchez, C.
J . Org. Chem. 1991, 56, 3372.
0022-3263/96/1961-2564$12.00/0 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 7, 1996 2565
Sch em e 1
appearance in the 1H NMR spectrum of singlets at δ 8.02
and 7.94 in a 1:1 ratio for the Ar-H protons of the
p-nitrophenyl rings, a singlet at δ 7.84 for the lone proton
on the OH group, a pair of doublets at δ 5.03 and 4.85
from the methylene groups (diastereotopic H) of the two
equivalent benzyl groups on the phenol moieites, and a
singlet at δ 4.78 for the methylene group (equivalent H)
of the benzyl group on the p-nitrophenol moiety. The
conformation was established as a partial cone (“up,
down, up” orientation with respect to the three benzyl-
ated moieties) on the basis of four doublets at δ 3.99, 3.82,
3.68, and 3.30 for the ArCH2Ar methylene protons in the
1H NMR spectrum along with a pair of signals at δ 37.48
and 30.75 for the ArCH2Ar methylene carbons in the 13C
NMR spectrum.
Treatment of 3 with benzoyl chloride and AlCl3 pro-
duces 1,3-diester 12 in a flattened cone conformation (a
pair of doublets at δ 4.01 and 3.68 in the 1H NMR
spectrum and a singlet at δ 34.59 in the 13C NMR
spectrum), while with NaH or 1-methylimidazole tet-
raester 10 in the 1,3-alternate conformation is the major
product (close-lying pair of doublets centered at δ 3.46).
Although Cs2CO3 is generally the required base for
directing alkylations to produce the 1,3-alternate con-
formation,15 acylation and aroylation are known to follow
this pathway under a variety of conditions.13,16 Tet-
raester 10 is also produced when 1,3-diester 12 is treated
with benzoyl chloride. However, an attempt to convert
diester 12 to a mixed benzyloxy-benzoyloxy compound
failed, the only product formed being the tetrabenzyl
ether as a mixture of conformers.
To explore the monobenzylation reaction of 3 in more
detail, 5,17-bis-tert-butylcalix[4]arene (15) was treated
with benzyl bromide under the conditions used to convert
3 to 11. However, the only product isolated was 1,3-
dibenzyl ether 14 in which, in contrast with 11, the
benzyl groups are attached to the unsubstituted phenolic
moieties. This is rationalized by the assumption that the
phenolic moieties are slightly stronger acids than the
p-tert-butylphenolic moieties and, with a weak base, are
preferentially removed in the formation of the mono- or
dianion. The structure of 14 was established on the basis
of the elemental analysis and the constancy of the
position of the 1H NMR resonance of the tert-butyl
hydrogens in starting compound 15 and product 14.17
Benzoylation of 15, on the other hand, introduces the
benzoyl groups on the oxygens of the p-tert-butyl moieties
to give diester 16, as indicated by the shift in the
resonance position of the tert-butyl hydrogens from δ 1.24
in the starting material 15 to δ 1.08 in the product 16.
Con clu sion . The present work shows that nitration
of the 25,27-dibenzyl ether of calix[4]arene (1) yields the
(15) Verboom, W.; Datta, S.; Asfari, Z.; Harkema, S.; Reinhoudt, D.
N. J . Org. Chem. 1992, 57, 5394.
(16) Iqbal, M.; Mangiafico, T.; Gutsche, C. D. Tetrahedron 1987, 21,
4917.
(17) When O-benzylation takes place on the p-tert-butylphenolic
rings the 1H NMR resonance of the tert-butyl groups generally moves
upfield from its position at δ 1.24 in the starting material.

2566 J . Org. Chem., Vol. 61, No. 7, 1996
Notes
Sch em e 2
corresponding 5,17-dinitro compound 2 from which the
benzyl groups can be removed to produce 5,17-dinitrocalix-
[4]arene (3). Alkylation and acylation reactions have
been carried out with 2 and 3 under a variety of
conditions to yield products in which one (11), two (12),
three (9, 13), or all four (4, 5, 7, 8, 10) of the phenolic
oxygens carry substituent groups and in which the
systems are fixed in cone (1-3, 7, 11, 12), partial cone
(13), or 1,3-alternate (8) conformations. Benzylation of
5,17-di-tert-butylcalix[4]arene (15) takes place on the
oxygens at the 25,27 positions (14), while benzoylation
takes place on the oxygens at the 26,28 positions (16).
Exp er im en ta l Section 18
25,27-Diben zylca lix[4]a r en e-26,28-d iol (1) (Con e Con -
for m er ). A 15.3 g (115 mmol) sample of anhydrous K2CO3 and
2.0 g of NaI were suspended in 200 mL of acetone followed by
21.2 g (50 mmol) of calix[4]arene-25,26,27,28-tetrol. To the
stirred reaction mixture was added benzyl bromide (19.7 g, 115
mmol), and the mixture was stirred at rt for 6 h. The solvent
was removed under reduced pressure, ice-cold water was added
with stirring, the contents were neutrallized with 20% HCl, and
a light yellow precipitate formed. It was removed by filtration
and washed thoroughly with water. The resulting material was
stirred with MeOH, insoluble material was removed by filtration,
and the product was purified by column chromatography (CHCl3
eluent) to yield 26.4 g (87%) of 1 as a colorless powder: mp 221-
223 °C (lit.7 mp 220-222 °C).
(18) Unless otherwise noted, starting materials were obtained from
commercial suppliers and used without further purification. HPLC
grade N,N-dimethylformamide (DMF), acetonitrile, and acetone were
used. Tetrahydrofuran (THF) was dried over benzophenone/Na and
distilled immediately before using. Column chromatography was
carried out by using Aldrich 70-230 mesh, 60 Å silica gel. Thin-layer
chromatography (TLC) was performed on 250 µm silica gel plates
containing a fluorescent indicator. Melting points were taken in sealed
and evacuated capillary tubes on a MEL-Temp apparatus (Laboratory
Devices, Cambridge, MA) using a 400 °C thermometer calibrated
against a thermocouple and are uncorrected. The 1H NMR and 13C
NMR spectra were recorded on a Varian XL-300 spectrometer, and
the chemical shifts are reported as δ values in ppm. 1H NMR spectra
are referenced to tetramethylsilane (TMS) at 0.00 ppm as an internal
standard and recorded at room temperature (20 + 1 °C), and 13C NMR
spectra are referenced to either CDCl3 (77.00 ppm), DMSO-d6 (40.0
ppm), or TMS (0.00 ppm) and also recorded at room temperature (20
( 1 °C). Microanalytical samples were dried for at least 48-72 h at
111 °C (toluene) or at 140 °C (xylene) at 1-2 mm, and the analyses
were carried out by Desert Laboratories, Tucson, AZ. Solvent of
crystallization was retained in some of the analytical samples and
affected the elemental analysis. In such cases, best fits between the
analytical values and appropriate increments of the solvents were used.
5,17-Din itr o-25,27-bis(ben zyloxy)ca lix[4]a r en e-26,28-d i-
ol (2) (Con e Con for m er ). To a slurry of 20.15 g (33 mmol) of
1 in 200 mL of glacial AcOH was added 50 mL of 70% HNO3 in
portions at 0 °C. The reaction mixture was stirred for 2 h and
poured into ice-cold water, and the light yellow precipitate was
separated by filtration. This material was washed with cold
water and triturated with MeOH to afford a single compound
pure enough for subsequent reactions. An analytical sample was
obtatined by passing the product through a silica gel column
(CHCl3 eluent), crystallizing from CHCl3-n-hexane (1:3), and
stirring with MeOH to yield 19.6 g (85%) of a colorless solid:
mp 285-286 °C; 1H NMR (CDCl3) δ 8.99 (s, 2H), 8.03 (s, 4H),
7.60-7.57 (m, 4H), 7.44-7.38 (m, 6H), 6.97 (d, 4H, J ) 7.4 Hz),
6.86 (t, 2H, J ) 6.9 and 8.1 Hz), 5.09 (s, 4H), 4.27 (d, 4H, J )
13.38 Hz), 3.47 (d, 4H, J ) 13.44 Hz); 13C NMR (CDCl3) δ 159.46,
151.67, 139.85, 135.83, 131.78, 129.75, 129.00, 128.29, 127.71,

Notes
J . Org. Chem., Vol. 61, No. 7, 1996 2567
126.10, 124.56 (ArC), 78.98, 31.25. Anal. Calcd for C42H34
-
7.16 (d, 4H, J ) 7.5 Hz), 6.77 (t, 2H, J ) 7.5 Hz), 4.34 (d, 4H, J
) 13.2 Hz), 4.07 (s, 6H), 3.52 (d, 4H, J ) 13.2 Hz); 13C NMR
(CDCl3) δ 157.15, 151.74, 143.79, 133.59, 128.23, 127.18, 123.77,
119.19, 63.18, 30.21. Anal. Calcd for C30H26N2O8: C, 66.41; H,
4.83. Found: C, 66.43; H, 4.88.
N2O8‚0.5H2O:19 C, 71.68; H, 5.01. Found: C, 71.95; H, 5.21.
5,17-Din itr ocalix[4]ar en e-25,26,27,28-tetr ol (3) (Con e Con -
for m er ). A 21.4 g (160 mmol) sample of anhydrous AlCl3 and
100 mL of toluene were placed in a 250 mL round-bottomed flask
and stirred for 5 min at rt. A slurry of 13.9 g (20 mmol) of 2 in
20 mL of toluene was added with stirring (dark brown semisolid
material settled to bottom of flask). The reaction mixture was
stirred for 30 min at rt and poured into 200 mL of ice-cold water,
and unreacted AlCl3 was destroyed with 20% HCl. The greyish
precipitate was removed by filtration, toluene was evaporated
from the filtrate, and the remaining aqueous phase was ex-
tracted with CH2Cl2. Evaporation of the CH2Cl2 left a residue
which was combined with the greyish precipitate and triturated
with MeOH (100 mL) to leave 8.03 g (78%) of a light brown
5,17-Din it r o-25,26,27,28-t e t r a k is(b e n zyloxy)ca lix[4]-
a r en e (7) (Con e Con for m er ). A 0.60 g (15 mmol) sample of
NaH (60% in oil dispersion) was placed in a 150 mL round-
bottomed flask followed by dry, freshly distilled THF (40 mL)
and DMF (10 mL). To this was added 0.69 g (1 mmol) of 2, and
the mixture was stirred for 5 min at rt. A solution of benzyl
bromide (1.71 g, 10 mmol) in 10 mL of dry THF was added, and
the reaction contents were stirred 12 h. The solvent was
removed under reduced pressure on a rotary evaporator, and
the concentrated residue was neutralized with ice-cold 20% HCl
to produce a light yellow semisolid which was extracted into CH2-
Cl2. The organic layer was separated, concentrated, and tritu-
rated with n-hexane (50 mL) followed by MeOH (50 mL) to give
a white precipitate which was purified by column chromatog-
raphy (CHCl3 eluent) to yield 0.79 g (91%) of a colorless powder.
An analytical sample was obtained by recrystallization from
CHCl3-n-hexane (1:3): mp 199-201 °C; 1H NMR (CDCl3) δ 7.38
(s, 4H), 7.33-7.20 (m, 20H), 6.68-6.60 (m, 6H), 4.99 (s, 4H),
4.95 (s, 4H), 4.15 (d, 4H, J ) 13.8 Hz), 2.95 (d, 4H, J ) 14.1
Hz); 13C NMR (CDCl3) δ 160.74, 154.6, 142.62, 136.84, 136.19,
134.38, 129.87, 129.57, 128.88, 128.78, 128.60, 128.42, 128.35,
128.24, 123.48, 123.42 (ArC), 77.00, 76.76, 31.37. Anal. Calcd
for C56H46N2O8‚H2O:19 C, 75.32; H, 5.42. Found: C, 75.67; H,
5.16.
1
product: 351 °C dec (turns brown at 325 °C); H NMR (CDCl3)
δ 10.14 (b, 4H), 7.99 (s, 4H), 7.18 (d, 4H, J ) 7.5 Hz), 6.87 (t,
2H, J ) 7.5 and 7.3 Hz), 4.31 (bs, 4H), 3.72 (bs, 4H); 13C NMR
(CDCl3) δ 155.48, 148.35, 141.46, 129.45, 129.07, 127.01, 124.56,
122.69 (ArC), 31.24. Anal. Calcd for C28H22N2O8: C, 65.37; H,
4.31. Found: C, 66.05; H, 4.40.
5,17-Din itr o-26,28-d ia cetyl-25,27-bis(ben zyloxy)ca lix[4]-
a r en e (4a ). A mixture of 0.70 g (1 mmol) of 2, 1.0 mL of
1-methylimidazole, 50 mL of CH3CN, and 2 mL of acetyl chloride
was stirred for 18 h at rt and poured over ice-cold water to give
a white precipitate which was removed by filtration, dried, and
purified by column chromatography (CH2Cl2 eluent) to give 0.68
g (89%) of 4a as a mixture of conformers. However, further
chromatography (CH2Cl2 eluent) followed by crystallization from
CH2Cl2-MeOH (1:2) gave 0.46 g (58%) of the 1,3-alternate
conformer of 4a : mp 257-258 °C; 1H NMR (CDCl3) δ 7.64 (s,
4H), 7.26-7.22 (m, 6H), 7.04-6.96 (m, 6H), 6.77 (d, 4H, J ) 7.2
Hz), 4.75 (s, 4H), 3.75 (d, 4H, J ) 16.2 Hz), 3.59 (d, 4H, J )
15.9 Hz), 1.66 (s, 6H); 13C NMR (CDCl3) δ 167.54, 156.28, 152.90,
144.86, 136.01, 134.89, 133.44, 130.40, 128.65, 128.60, 127.35,
5,17-Din it r o-25,26,27,28-t e t r a k is(b e n zyloxy)ca lix[4]-
a r en e (8) (1,3-Alter n a te Con for m er ). A 10.0 g (30 mmol)
sample of Cs2CO3 was placed in a 150 mL round-bottomed flask
followed by DMF (80 mL). To this was added 0.70 g (1 mmol)
of 2, and the contents were stirred at rt. A solution of benzyl
bromide (1.40 g, 8 mmol) was added, and the reaction mixture
was stirred at rt for 18 h. It was then poured onto ice-cold water
and neutrallized with 20% HCl to produce a light yellow oil
which was extracted into CH2Cl2. The organic layer was
removed, concentrated, and poured over n-hexane to give a light
yellow precipitate which was removed by filtration and tritu-
rated with MeOH (100 mL). The resulting material was purified
by column chromatography (CHCl3 eluent), and 0.74 g (85%) of
an analytical sample was obtained by trituration with MeOH:
mp 275-277 °C; 1H NMR (CDCl3) δ 7.65 (s, 4H), 7.42-7.36 (m,
12H), 7.14-7.11 (m, 4H), 7.05-7.03 (m, 4H), 6.72 (d, 4H, J )
7.5 Hz), 6.52 (t, 2H, J ) 7.8 Hz), 4.85 (s, 8H), 3.64 (d, 4H, J )
15.0 Hz), 3.55 (d, 4H, J ) 14.7 Hz); 13C NMR (CDCl3) δ 161.29,
155.73, 142.48, 136.74, 136.38, 135.25, 132.59, 131.13, 128.56,
128.21, 127.99, 127.83, 127.27, 126.66, 125.71, 122.73 (ArC),
73.02, 36.82. Anal. Calcd for C56H46N2O8‚0.5H2O:19 C, 76.10;
H, 5.36. Found: C, 76.30; H, 5.14.
124.56, 123.73 (ArC), 72.80, 37.79, 20.78. Anal. Calcd for C46
38O10N2: C, 70.94; H, 4.92. Found: C, 70.89; H, 5.02.
5,17-Din itr o-26,28-d ibu tyr yl-25,27-bis(ben zyloxy)ca lix-
-
H
[4]a r en e (4b). A mixture of 0.70 g (1 mmol) of 2, 1.0 mL of
1-methylimidazole, 50 mL of CH3CN, and 2 mL of butyryl
chloride was stirred for 18 h at rt and poured over ice-cold water
to give a white precipitate which was removed by filtration,
dried, and purified by column chromatography (CH2Cl2 eluent)
to give 0.70 g (84%) of 4b as a mixture of conformers in which
1
the 1,3-alternate was the dominant form: mp 259-261 °C; H
NMR (CDCl3) δ 8.01 (s, 1H), 7.57 (m, 4H), 7.33 (s, 1H), 7.23-
7.14 (m, 6H), 6.95-6.84 (m, 4H), 6.72-6.60 (m, 4H), 4.70-4.50
(m, 4H), 3.76-3.10 (m, 8H), 1.72-1.68 (m, 4H), 1.52-1.48 (m,
4H), 0.90-0.85 (m, 6H).
5,17-Din itr o-26,28-d im eth oxy-25,27-bis(ben zyloxy)ca lix-
[4]a r en e (5). A 0.6 g (15 mmol) sample of NaH (60% in oil
dispersion) was placed in a 150 mL round-bottomed flask and
treated with a mixture of dry, freshly distilled THF and DMF
(60 mL, 5:1 ratio) followed by 0.69 g (1 mmol) of 2 and stirred
for 3 min at rt. Methyl iodide was added, and the reaction
mixture was stirred an additional 18 h at rt. It was poured over
ice-cold water and neutralized with 20% HCl to produce a light
yellow semisolid which was extracted into CH2Cl2. The organic
layer was separated, concentrated, and triturated with n-hexane
(50 mL) to give a white precipitate which was purified by column
chromatography (CHCl3 eluent) to yield 0.61 g (85%) of a
5,17-Din itr o-25,27-bis(ben zyloxy)-26-(ben zoyloxy)ca lix-
[4]a r en -28-ol (9) (P a tr ia l Con e Con for m er ). A solution of
0.70 g (1 mmol) of 2 and 1.0 mL of 1-methylimidazole in 50 mL
of CH3CN was stirred for 5 min and treated with 1.40 g (10
mmol) of benzoyl chloride. The reaction mixture was stirred 10
h and poured over ice-cold water to give a white precipitate
which was removed by filtration and stirred with MeOH (20 mL)
to afford 0.76 g which TLC showed to be a mixture of three
products. Compound 9 was isolated by column chromatography
(CH2Cl2 eluent) and purified by stirring with cold acetone to give
0.62 g (78%) of a colorless solid: mp 302-304 °C; 1H NMR
(CDCl3) δ 8.19 (s, 2H), 8.01 (s, 2H), 7.97 (s, 1H), 7.70 (m, 1H),
7.30-7.15 (m, 8H), 6.84 (d, 2H, J ) 7.8 Hz), 6.65-6.56 (m, 6H),
6.37 (d, 2H, J ) 6.9 Hz), 6.07 (t, 2H, J ) 7.5 Hz), 4.28 (dd, 4H),
3.77 (d, 2H, J ) 13.2 Hz), 3.55 (s, 4H), 3.14 (d, 2H, J ) 12.9
Hz); 13C NMR (CDCl3) δ 165.72, 162.53, 154.13, 153.79, 145.39,
145.12, 138.04, 136.16, 135.57, 134.25, 133.33, 132.76, 132.16,
132.03, 130.17, 129.77, 129.38, 128.76, 128.46, 127.71, 127.28,
124.69, 124.17, 123.24 (ArC), 76.81, 38.21, 30.79. Anal. Calcd
for C49H38N2O9: C, 73.67; H, 4.69. Found: C, 74.02; H, 4.69.
1
colorless powder: mp 142-143 °C; H NMR (CDCl3) δ 7.83 (s,
2H), 9.38 (bs, 8H), 7.20-6.80 (m, 10H), 4.89-4.77 (m, 4H), 4.35-
2.90 (m, 14H). O-Debenzylation of 5 (vide infra) yielded 6, for
which elemental analytical data are given.
5,17-Din itr o-26,28-d im eth oxyca lix[4]a r en e-25,27-d iol (6)
(Con e Con for m er ). A mixture of 0.68 g (5 mmol) of anhydrous
AlCl3, 15 mL of toluene, and 0.36 g (0.5 mmol) of 5 was stirred
for 10 min in a 150 mL round-bottomed flask and worked up as
described above for 3 to give a light yellow compound which was
purified by column chromatography (CHCl3 eluent). The product
was triturated with anhydrous MeOH (30 mL) and dried under
reduced pressure to give 0.20 g (77%) of a white powder: mp
336-338 °C dec; 1H NMR (CDCl3) δ 7.82 (s, 4H), 7.54 (s, 2H),
5,17-Din it r o-25,26,27,28-t et r a k is(b en zoyloxy)ca lix[4]-
a r en e (10) (1,3-Alter n a te Con for m er ). A solution of 0.25 g
(0.5 mmol) of 3 and 0.5 mL of 1-methylimidazole in 20 mL of
CH3CN was stirred 5 min and treated with 1.05 g (7.5 mmol) of
benzoyl chloride. The reaction mixture was stirred 6 h and
poured over ice-cold water to give a white precipitate which was
(19) The presence of water was qualitatively supported by the
appearance of a broad signal in the 1H NMR spectrum at δ 1.5 in CDCl3
or 3.4 in DMSO-d6.

2568 J . Org. Chem., Vol. 61, No. 7, 1996
Notes
removed by filtration and triturated with MeOH (20 mL) to
afford 0.41 g (91%) of 10 as a colorless powder: mp > 400 °C;
1H NMR (CDCl3-DMSO-d6) δ 7.66-7.56 (m, 8H), 7.50-7.40 (m,
12H), 7.35-7.30 (m, 4H), 7.24 (s, 2H), 6.57-6.53 (m, 4H), 3.46
(dd, 8H, J ) 12.0 and 12.6 Hz). The insolubility of 10 precluded
124.23 (ArC), 76.03, 72.47, 37.48, 30.75. Anal. Calcd for C49H40
N2O8: C, 74.99; H, 5.14; N, 3.46. Found: C, 74.62; H, 5.01; N,
3.46.
-
5,17-Di-ter t-bu tyl-25,27-bis(ben zyloxy)ca lix[4]a r en e-26,-
28-d iol (14) (Con e Con for m er ). A mixture of 0.70 g (5 mmol)
of anhydrous K2CO3, 0.2 g of NaI, and 0.26 g (0.5 mmol) of 15
in 50 mL of acetone was stirred 5 min and treated with 0.8 g (4
mmol) of benzyl bromide in 5 mL of acetone. The mixture was
stirred at rt for 18 h and worked up to give a crude product from
which an analytical sample was obtained by column chroma-
tography (CHCl3 eluent) and crystallization from CHCl3-n-
hexane (1:3) as 0.29 g (83%) of a colorless powder: mp 256-258
°C; 1H NMR (CDCl3) δ 7.80 (s, 2H), 7.65 (d, 4H, J ) 7.5 Hz),
7.34-7.36 (m, 6H), 7.02 (s, 4H), 6.93 (d, 4H, J ) 7.5 Hz), 6.79
(t, 2H, J ) 7.5 Hz), 5.05 (s, 4H), 4.30 (d, 4H, J ) 12.9 Hz), 3.31
(d, 4H, J ) 12.9 Hz), 1.26 (s, 18H); 13C NMR (CDCl3) δ 151.99,
150.94, 141.47, 136.84, 133.55, 129.01, 128.71, 127.97, 127.61,
127.15, 125.46, 125.27 (ArC), 78.44, 33.85, 31.91, 31.70. Anal.
Calcd for C50H52O4‚2/5CHCl3: C, 79.16; H, 6.91. Found: C, 79.25;
H, 6.91.
obtention of a 13C NMR spectrum. Anal. Calcd for C56H38
-
N2O12‚1.5 H2O:19 C, 70.21; H, 4.31. Found: C, 70.20; H, 4.39.
Compound 10 was also obtained in 84% yield by the reaction of
0.25 g (0.5 mmol) of 3, 0.5 g of NaH (60% in oil dispersion), and
1.05 g (7.5 mmol) of benzoyl chloride in 60 mL of THF-DMF (5:
1) refluxed 5 h.
5,17-Din it r o-26-(b en zyloxy)ca lix[4]a r en e-25,27,28-t r iol
(11) (Con e Con for m er ). A mixture of 1.40 g (10 mmol) of
anhydrous K2CO3, 0.3 g of NaI, and 1.03 g (2 mmol) of 3 was
suspended in 100 mL of acetone and stirred for 5 min. Benzyl
bromide (0.85 g, 5 mmol) was added. The mixture was stirred
at rt for 6 h (or refluxed 4 h). Excess solvent was removed under
reduced pressure, and the reaction was worked up according to
the procedure described above for 8. The product was purified
by column chromatography (CHCl3 eluent), and an analytical
sample was obtained by stirring with MeOH to yield 0.98 g (82%)
5,17-Di-ter t-b u t yl-26,28-b is(b en zoyloxy)ca lix[4]a r en e-
25,27-d iol (16) (Con e Con for m er ). A mixture of 1.0 g (0.75
mmol) of anhydrous AlCl3 and 24 mL of CH2Cl2 in a 150 mL
round-bottomed flask was treated with 6 mL of DMF and stirred
for 2 min. To this was added 0.26 g (0.5 mmol) of 15, the reaction
mixture was stirred for 5 min, 1.05 g (15 mmol) of benzoyl
chloride was added, and stirring was continued for 18 h at rt.
The crude product was purified by triturating with MeOH to
give 0.30 g (79%) of a white solid: mp 348-351 °C; 1H NMR
(CDCl3) δ 8.21 (d, 4H, J ) 7.2 Hz), 7.73 (d, 2H, J ) 6.9 Hz), 7.54
(t, 4H, J ) 7.8 Hz), 6.99 (s, 4H), 6.93 (d, 4H, J ) 6.9 Hz), 6.59
(t, 2H, J ) 7.5 Hz), 5.09 (s, 2H), 3.87 (d, 4H, J ) 14.4 Hz), 3.57
(d, 4H, J ) 14.4 Hz), 1.08 (s, 18H); 13C NMR (CDCl3) δ 165.12,
153.25, 149.39, 144.39, 134.10, 132.29, 131.05, 129.62, 129.37,
129.03, 128.40, 126.65, 119.97 (ArC), 34.51, 34.20, 31.55. Anal.
Calcd for C50H48O6: C, 80.62; H, 6.49. Found: C, 80.63 H, 6.72.
5,11,17,23-Tet r a n it r o-25,26,27,28-t et r a et h oxyca lix[4]-
a r en e. To a 1.08 (2 mmol) sample of tetraethyl ether of calix-
[4]arene in a 150 mL round-bottomed flask were added 15 mL
of glacial acetic acid, 40 mL of CH2Cl2, and 5 mL of 70% HNO3.
The reaction mixture was stirred at rt for 4 h, turning light
yellow and then dark brown. It was poured into ice-cold water
to give a light yellow precipitate which was removed by filtration
and washed throughly with cold water and triturated with
MeOH to give 0.81 g of a light yellow material which TLC
showed to be a mixture of the tetranitro and dinitro compounds.
The tetranitro compound was separated by column chromatog-
raphy (3:1 CH2Cl2-n-hexane eluent). Trituration with MeOH
produced 0.61 g (42%) of an analytical sample as a white
1
of a colorless solid: mp 166-168 °C; H NMR (CDCl3) δ 10.04
(s, 1H), 8.72 (s, 2H), 7.98 (s, 2H), 7.91 (s, 2H), 7.68-7.64 (m,
2H), 7.55-7.53 (m, 3H), 7.16-7.10 (m, 4H), 6.78 (t, 2H, J ) 7.5
Hz), 5.29 (s, 2H), 4.53 (d, 2H, J ) 13.2 Hz), 4.22 (d, 2H, J )
14.1 Hz), 3.56 (d, 2H, J ) 14.1 Hz), 3.54 (d, 2H, J ) 13.2 Hz);
13C NMR (CDCl3) δ 156.33, 155.07, 150.47, 145.19, 142.04,
136.08, 129.79, 129.55, 129.51, 129.31, 129.26, 129.14, 126.98,
126.82, 124.97, 124.72, 121.88 (ArC), 80.14, 31.67. Anal. Calcd
for C35H28N2O8: C, 69.53; H, 4.67; N, 4.63. Found: C, 69.78;
H, 4.68; N, 4.42.
5,17-Din it r o-25,27-b is(b en zoyloxy)ca lix[4]a r en e-26,28-
d iol (12) (Con e Con for m er ). A mixture of 1.33 g (10 mmol)
of anhydrous AlCl3 and 24 mL of CH2Cl2 in a 250 mL round-
bottomed flask was treated with 6 mL of DMF, stirred for 2 min,
and 0.26 g (0.5 mmol) of 3 then added. The reaction mixture
was stirred for 5 min, 1.05 g (7.5 mmol) of benzoyl chloride was
added, and stirring was continued 6 h at rt. The CH2Cl2 was
removed under reduced pressure, ice-cold water was added, and
the mixture was neutralized with 20% HCl to give a white
precipitate which was removed by filtration and triturated with
MeOH (20 mL) to give 0.30 g (84%) of a white powder: mp 355-
1
357 °C; H NMR (DMSO-d6) δ 8.67 (s, 2H), 7.83 (t, 2H, J ) 7.5
Hz), 7.75 (d, 4H, J ) 7.5 Hz), 7.52 (t, 4H , J ) 7.5 Hz), 7.46 (s,
4H), 7.30 (d, 4H, J ) 7.5 Hz), 7.03 (t, 2H, J ) 8.4 Hz), 3.87 (d,
4H, J ) 14.4 Hz), 3.53 (d, 4H, J ) 14.4 Hz); 1H NMR (CDCl3) δ
8.24 (d, 4H, J ) 8.4 Hz), 7.99 (s, 4H), 7.75 (t, 2H, J ) 7.5 Hz),
7.55 (t, 4H, J ) 7.5 and 8.1 Hz), 7.06-7.00 (m, 6H), 6.34 (bs,
2H), 4.01 (d, 4H, J ) 14.7 Hz), 3.68 (d, 4H, J ) 14.7 Hz); 13C
NMR (DMSO-d6) δ 163.70, 160.02, 147.56, 138.00, 133.94,
131.47, 130.86, 129.75, 128.88, 128.65, 127.87, 125.12, 124.40
(ArC), 34.59. Anal. Calcd for C42H30N2O10‚H2O:19 C, 68.10; H,
4.35. Found: C, 67.99; H, 4.10.
1
powder: mp 310-312 °C; H NMR (CDCl3) δ 7.62 (s, 8H), 4.55
(d, 4H, J ) 13.8 Hz), 4.14 (q, 8H, J ) 7.2 Hz), 3.42 (d, 4H, J )
14.1 Hz), 1.50 (t, 12H, J ) 6.9 and 6.9 Hz); 13C NMR (DMSO-
d6) δ 161.50, 142.02, 135.98, 123.56 (ArC), 71.06, 29.77, 15.17.
5,17-Din it r o-25,26,27-t r is(b en zyloxy)ca lix[4]a r en e-28-
ol (13) (P a r tia l Con e Con for m er ). A 3.35 g (10 mmol) sample
of Me3SiOK was placed in a 150 mL round-bottomed flask
followed by dry, freshly distilled THF (90 mL). To this was
added 0.61 g (1 mmol) of 11, and the reaction mixture was stirred
at rt for 2 min. A solution of benzyl bromide (1.70 g, 10 mmol)
in 10 mL of dry THF was then added, the reaction mixture was
stirred at rt for 18 h, and it was worked up as described above
for 7 to give a crude product which was recrystallized from
CHCl3-n-hexane (1:3) to yield 0.63 g (81%) of 13 as a white
Anal. Calcd for C36H36N4O12
60.32; H, 5.31.
: C, 60.33; H, 5.06. Found: C,
5,17-Din itr o-25,26,27,28-tetr aeth oxycalix[4]ar en e was iso-
lated from the above mixture (9:1 CHCl3-n-hexane eluent) and
purified by crystallization from CH2Cl2-n-hexane (1:3) followed
by trituration with MeOH which yielded 0.15 g (12%) of a pale
yellow powder: mp 225-226 °C; 1H NMR (CDCl3) δ 7.47 (s, 4H),
6.80-6.70 (m, 6H), 4.49 (d, 4H, J ) 13.4 Hz), 4.10-4.01 (m, 8H),
3.26 (d, 4H, J ) 13.4 Hz), 1.52-1.43 (m, 12H); 13C NMR (CDCl3)
δ 161.53, 155.96, 142.57, 136.55, 134.41, 128.89, 123.35, 123.12
(ArC), 70.97, 70.37, 31.10, 15.61, 15.57 Anal. Calcd for
1
powder: mp 220-221 °C; H NMR (CDCl3) δ 8.02 (s, 2H), 7.94
(s, 2H), 7.84 (s, 1H), 7.40-7.34 (m, 6H), 7.29-7.18 (m, 7H), 6.84-
6.76 (m, 4H), 6.66-6.56 (m, 4H), 5.03 (d, 2H, J ) 12.0 Hz), 4.85
(d, 2H, J ) 12.0 Hz), 4.78 (s, 2H), 3.99 (d, 2H, J ) 13.5 Hz),
3.82 (d, 2H, J ) 15.0 Hz), 3.68 (d, 2H, J ) 15.0 Hz), 3.30 (d, 2H,
13.5 Hz); 13C NMR (CDCl3) δ 159.35, 153.89, 142.73, 139.66,
136.28, 136.05, 135.35, 131.96, 131.60, 130.44, 129.79, 128.72,
128.51, 128.30, 128.07, 127.67, 127.30, 126.72, 126.18, 124.29,
C
36H38N2O8: C, 68.99; H, 6.11. Found: C, 68.67; H, 6.06.
Ack n ow led gm en t. We are indebted to the National
Science Foundation and the Robert A. Welch Founda-
tion for generous support of this work.
J O952013E