Synthesis of amine, halide, and pyridinium terminated 2-alkyl-p-tert-butylcalix[4]arenes

Article abstract of DOI:10.1016/j.tet.2009.08.033

The synthesis of calix[4]arenes with functional groups tethered to a single methylene bridge has been explored. Mono-lithiated calix[4]arenes react with 1,ω-bromochloroalkanes to give 2-(ω-chloroalkyl)-calix[4]arenes, which function as key intermediates i

Full text of DOI:10.1016/j.tet.2009.08.033

Tetrahedron 65 (2009) 8657–8667
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of amine, halide, and pyridinium terminated 2-alkyl-p-tert-
butylcalix[4]arenes
,
Matthew P. Hertel a, Andrew C. Behrle a, Samantha A. Williams b, Joseph A.R. Schmidt a
,
*
,
Jordan L. Fantini b
*
a Department of Chemistry, The University of Toledo, 2801 W. Bancroft St., MS 602, Toledo, OH 43606-3390, USA
b Department of Chemistry and Biochemistry, Ebaugh Laboratories, Denison University, Granville, OH 43023, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2009
Received in revised form 11 August 2009
Accepted 12 August 2009
Available online 18 August 2009
The synthesis of calix[4]arenes with functional groups tethered to a single methylene bridge has been
explored. Mono-lithiated calix[4]arenes react with 1, -bromochloroalkanes to give 2-( -chloroalkyl)-
calix[4]arenes, which function as key intermediates in the synthesis of a variety of tether-functionalized
calix[4]arenes. Subsequent reactivity of these chloroalkyl species has allowed for successful synthesis of
u
u
2-(u-iodoalkyl)-calix[4]arenes, 2-(u-pyridiniumalkyl)-calix[4]arenes, and 2-(u-aminoalkyl)-calix[4]
arenes. This latter group of amine-terminated calix[4]arenes are especially significant as they may serve
as useful entries to a wide range of subsequent chemistry, including metal coordination or attachment to
a solid support. Both alkyl and aryl amines have been incorporated at the end of the tether, and a 2,6-
diisopropylaniline derivative has been analyzed by X-ray diffraction.
Keywords:
Amino compounds
Calixarenes
Halogen compounds
Macrocyclic compounds
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
groups attached to the phenolic oxygen atoms, the different con-
formations rapidly equilibrate at ambient temperature due to the
Calixarenes are a class of macrocyclic compounds in which
a series of phenolic groups are linked to one another through
methylene units at their 2- and 6-positions. Calixarenes provide an
attractive scaffold for the construction of sophisticated, functional
molecular assemblies because this class of molecules exhibits
rigidity and well-defined conformations along with ample sites for
modification and elaboration.1–3 The cyclic nature of these com-
pounds provides a natural cavity that can be exploited directly or
used in tandem with further functional groups appended to the core
structure in such applications as molecular recognition.4 Further, the
phenolic oxygen moieties can be utilized as ligands for the seques-
tration of metal centers within or directly below these cyclic cavi-
ties.5,6 Through careful design, many calixarene systems have been
successfully used in a wide range of applications, including use in
sensors, catalysis, and separations; several reviews and books serve
to summarize the work in this field.7–13 Calix[4]arenes exhibit four
idealized structural conformations (cone, partial cone, 1,2-alternate,
and 1,3-alternate; Fig. 1) and in many cases the calix[4]arene can be
forced to adopt a selected conformation through proper choice of
substituents.1 For calix[4]arenes with methyl or sterically smaller
ability of the aryl rings to flip via passage of the phenolic group
through the center of the macrocycle.14 Calix[4]arenes with ethyl
substituents attached to the phenolic oxygen atoms favor the partial
cone conformation upon synthesis at room temperature, but exhibit
fluxional behavior at temperatures as low as 50 ꢀC.14–16 Sterically
larger substituent groups exist in a locked conformation, preventing
interconversion in solution.14–16 The equilibrium interconversion of
conformers results in fluxional NMR spectra that are often very
challenging to interpret. It has been shown that calix[4]arenes have
a high affinity for the sodium cation, with preferential formation of
1:1 calix[4]arene/Naþ complexes.17 Thus, by collecting the NMR
spectra of these species in solvent with a high concentration of NaI,
the calix[4]arene is forced to adopt the cone conformation through
coordination to sodium, producing simple and readily interpretable
NMR spectra that are quite useful in characterizing reaction
products.18
Considering the cone conformation of a typical calix[4]arene, the
wide rim (further from the methylene bridges) has been designated
the upper rim, while the narrow rim (nearer to the methylene
bridges) is designated the lower rim (Fig. 2). In the cone conforma-
tion, the two protons of each methylene bridge are spatially arranged
in axial and equatorial positions similar to that of a cyclohexane ring
(Fig. 2).19 Many methods are known for the modification of the cal-
ixarene at its upper and lower rims.20–22 In contrast, there are very
few reports of functionalization at the methylene bridge region (the
* Corresponding authors. Fax: þ1 419 530 4033 (J.A.R.S.).
E-mail addresses: joseph.schmidt@utoledo.edu (J.A.R. Schmidt), fantinij@
denison.edu (J.L. Fantini).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.033

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M.P. Hertel et al. / Tetrahedron 65 (2009) 8657–8667
OR'
OR'
R'O
OR'
OR'
R'O
OR'
OR'
OR'
OR'
OR'
OR'
R'O
OR'
OR'
OR'
partial cone
1,3-alternate
1,2-alternate
cone
Figure 1. Calix[4]arenes have four primary conformations, related to each other by flipping of the aryl units.
secondary amines at the end of an alkyl tether at the methylene
upper rim
bridge position. The incorporation of tethered amines would yield
compounds retaining properties associated with calix[4]arenes,
while the tethered amines allow for subsequent coordination to
a metal center or covalent attachment to a solid support. Attach-
ment to a surface or bead could be achieved in one step by amide
bond formation upon reaction with a functionalized solid support.42
Additionally, dehydrogenation of the secondary amine would pro-
vide a route to the related imine,43 which could be further elabo-
rated using the wide range of reaction chemistry associated with
imines.44–50 Herein, we report the attachment of halide (chloro and
iodo), amine, and pyridinium moieties at the end of a single alkyl
tether of three to six carbons in length attached to the methylene
bridge position of tetramethoxy-p-tert-butylcalix[4]arene 1.
equatorial
H
R'O
OR'
R'O
OR'
axial
H
lower rim
Figure 2. The wide rim of the calix[4]arene is designated the upper rim, while the
narrow rim formed by the phenolic oxygens is called the lower rim. In the cone
conformation, the methylene bridge protons reside in axial and equatorial positions.
2-, 8-,14-, and 20-positions) of the calix[4]arene. Reports in the mid-
1990s of methylene bridge functionalized calixarenes were of those
created by fragment condensation, either condensation of two 2-ring
units, or bridging of a 3-ring unit by a fourth ring.19,23–27 In later
studies, substituents were added by direct reaction of the fully
formed calixarene, employing methods such as anionic ortho Fries
reaction28 or oxidation of the calixarene to a spirodienone in-
termediate.29–33 Calixarenes with substituents at all four methylene
bridges have been achieved by radical bromination, followed by
substitution reactions,34–36 or nucleophilic attack on a ketocalix[4]-
arene.37 Recently, early metal complexes of calix[4]arenes have been
shown to oxidatively add to the C–H bond of the methylene bridge
intramolecularly, producing 2-metalated calixarene complexes and
subsequent reaction products.38,39 Modifications at the methylene
bridge present a significant opportunity to expand the range of
structural motifs available in calixarene chemistry. While sub-
stituents on the upper and lower rims of calixarenes in the cone
conformation are generally oriented parallel to its central axis, sub-
stituents attached to the methylene bridge are likely to favor the
equatorial position and thus extend nearly perpendicular to the axis
passing through the calixarene cavity (Fig. 2).19,40
2. Results and discussion
Utilizing the previously reported synthesis, treatment of tetra-
methoxy-p-tert-butylcalix[4]arene (1) with n-butyllithium gave the
mono-lithiated product (2), in which a single methylene group was
deprotonated (Scheme 1).18 Due to quenching of the lithiated spe-
cies in the presence of amines, installation of an alkyl-tethered
amine at the 2-position required a two-step synthesisdaddition of
a linker unit followed by amination. Reaction of 2 with 6-bromo-
hexanenitrile as a means to produce a tethered nitrile was un-
successful due to proton abstraction from this reagent and
concomitant quenching to give the unsubstituted calix[4]arene 1.
An alternate strategy for the formation of an amino tether involved
the use of an
a,u-dihaloalkane, such as 1,4-dibromobutane. Un-
fortunately, the use of symmetrically substituted alkanes of this sort
led to complicated mixtures of products under a wide range of
conditions. After quenching with water, the resulting mixture
contained unreacted calix[4]arene (1), the desired 2-(u-bro-
moalkyl)-calix[4]arene, and a bis-calix[4]arene species spanned by
the alkyl group, which had been substituted on both ends. Separa-
tion of these three products was generally challenging and isolated
product yields were unacceptably low for further applications.
Previous work in the Fantini41 group described a new method for
the production of calix[4]arenes functionalized at a single methy-
lene bridge position.18 This was achieved by mono-lithiation of
tetramethoxy-p-tert-butylcalix[4]arene (1), followed by reaction of
this lithiated species with an electrophile. The initial report de-
scribed the attachment of a methyl, ethyl, benzyl, or carboxy group
to a single methylene bridge of the calix[4]arene.18 The aim of the
current work is to develop a synthesis for the installation of
Successful synthesis of 2-(
ieved by reaction of the lithiated species 2 with 1 equiv of
a 1-bromo- -chloroalkane of 3–6 methylene units in length. The
lithiated calix[4]arene reacted preferentially at the brominated end
u-haloalkyl)-calix[4]arenes was ach-
u
of the alkyl tether to produce the 2-(
u
-chloroalkyl)-calix[4]arenes
n-BuLi
Br(CH2)nCl
- LiBr
n = 3-6
- n-BuH
H
Li
(CH2)nCl
R'O
R'O
R'O
OR'
OR'
OR'
R'O
R'O
R'O
OR'
OR'
OR'
3-Cl - 6-Cl (65-85%)
-chloroalkyl)-calix[4]arenes n-Cl (n¼3–6, where the number indicates
H
H
H
1
2
Scheme 1. Lithiation of the calix[4]arene 1, followed by reaction with a 1-bromo-
u-chloroalkane gives 2-(u
the length of the alkyl tether; R0¼Me).

M.P. Hertel et al. / Tetrahedron 65 (2009) 8657–8667
8659
with nearly quantitative conversion (3-Cl to 6-Cl, where 3–6 refers
to number of methylene units in the alkyl tether; Scheme 1). The
products were then isolated by recrystallization from pentane at
ꢁ25 ꢀC (Table 1). Alternatively, a traditional organic workup utiliz-
ing extraction into methylene chloride, washing with brine, and
crystallization from methanol also yielded pure product as a slightly
sticky microcrystalline material. As noted above, calix[4]arenes
with methoxy groups at the lower rim have been shown to be quite
fluxional in solution, with four different conformations accessible
(Fig. 1).14 Likewise, solutions of compounds 3-Cl to 6-Cl exhibited
significant fluxionality by 1H NMR spectroscopy. To eliminate this
fluxionality, the NMR spectra were collected in solvent that had
been presaturated with NaI.18 The interaction of the calix[4]arene
with the sodium cation in solution forced these species to adopt the
full cone conformation,18 and the NMR spectra of 3-Cl to 6-Cl were
successfully obtained in CD3CN saturated with NaI.
positions on the methylene bridges of the calix[4]arene can be
considered as axial and equatorial, with the axial position pointed
toward the lower rim and the equatorial position extending into the
solvent. The two protons have beenwell characterized with the low-
field resonances indicative of the axial position and the higher field
resonances diagnostic of the equatorial position.19 Examination of
the spectra for 3-Cl to 6-Cl reveals that the tertiary proton at the
functionalized methylene group is located exclusively in the axial
position for each compound, indicating that the tether is extending
away from the calix[4]arene in the equatorial position, as expected
based on energetic considerations.19 Additionally, the NMR spectra
show approximate mirror symmetry in solution, although for the
longer tethers the methoxy groups are inequivalent in the 13C NMR
spectra. This is most likely due to slight deviations from a true
mirror plane at the sodium coordination center. The remaining
resonances are all found at typical chemical shifts. When each bulk
synthetic product (3-Cl to 6-Cl) was recrystallized from pentane,
elemental analysis (C,H,N) percentages consistent with cocrystal-
lized lithium bromide (the reaction byproduct) were observed. In
almost every case, 4/3 equiv of LiBr was calculated to be present in
the microcrystalline material. Given that the preferred coordination
number for lithium is four and each calix[4]arene has four accessible
oxygen donor atoms, we hypothesize that each lithium is co-
ordinated by one bromide anion and three calix[4]arene oxygen
atoms, requiring 4/3 equiv of salt to utilize all donor atoms. Thus far,
we have been unable to successfully isolate X-ray quality single
crystals to confirm this assertion.
Table 1
Summary of new compounds
(CH2)nR
R'O
OR'
R'O
OR'
H
(R' = Me)
Compound
Tether length (n)
R
Isolated yield (%)
The 2-(u-chloroalkyl)-calix[4]arenes were converted to 2-(u-
iodoalkyl)-calix[4]arenes by utilization of the Finkelstein reaction.51
This reaction was accomplished by treating 3-Cl to 5-Cl with NaI in
refluxing 2-butanone. After approximately 6 days, the reaction was
3-Cl
4-Cl
5-Cl
6-Cl
3-I
4-I
5-I
3
4
5
6
3
4
5
3
4
5
3
5
5
3
4
4
4
4
5
5
5
5
6
6
6
3
4
5
Cl
Cl
Cl
Cl
I
I
I
68
79
85
83
67
37
50
97
98
97
44
49
31
82
82
68
89
86
60
86
74
90
89
82
86
60
60
73
complete and the 2-(u-iodoalkyl)-calix[4]arenes (3-I to 5-I) were
isolated in moderate yield by recrystallization from methanol
(Scheme 2; Table 1). These compounds were readily identified by 13C
NMR spectroscopy, with the diagnostic resonance for the methylene
group at the end of the tether (attached to the iodine) appearing at
6.5 ppm in all cases. The NMR spectroscopic data for these com-
pounds in the presence of NaI again showed a cone conformation
with the iodo tether located in an equatorial position. Mass spec-
troscopy further confirmed the synthesis of these compounds with
the observation of [MþNa]þ ions in all cases (electrospray ionization
from a methanol solution with NaI as an internal standard).
The chlorotethers (3-Cl to 6-Cl) were investigated as precursors
to amine-tethered calix[4]arene species. Initial investigations uti-
lized a variety of standard organic (SN2-type) synthetic methodol-
ogies with a wide range of bases, such as hydroxide, carbonate, and
phosphate, etc. It was found that sodium carbonate was most ef-
fective for these reactions, although the overall conversionwas quite
modest and the resulting compounds proved to be rather difficult to
isolate effectively due to their high solubility in most organic
solvents and their oily nature. Although we successfully isolated
three alkylamine-tethered calix[4]arene products (Scheme 3; Table
1), weultimatelyshifted our focus toaryl amines, which proved tobe
much more readily isolated. Specifically, we made two
calix[4]arenes tethered to cyclohexylamine (3-NCy and 5-NCy;
tether lengths of 3 and 5 methylene units) and a calix[4]arene
[3-py]Cl
[4-py]Cl
[5-py]Cl
3-NCy
5-NCy
5-NiPr
3-NiPr
4-NH
NC5Hþ5
NC5Hþ5
NC5Hþ5
NHC6H11
NHC6H11
NHCHMe2
NH-2,6-iPr2C6H3
NHPh
4-NMe
4-NEt
4-NiPr
5-NH
NH-2,6-Me2C6H3
NH-2,6-Et2C6H3
NH-2,6-iPr2C6H3
NHPh
NH-2,6-Me2C6H3
NH-2,6-Et2C6H3
NH-2,6-iPr2C6H3
NH-2,6-Me2C6H3
NH-2,6-Et2C6H3
NH-2,6-iPr2C6H3
NH-2,5-Cl2C6H3
NH-2,5-Cl2C6H3
NH-2,5-Cl2C6H3
5-NMe
5-NEt
5-NiPr
6-NMe
6-NEt
6-NiPr
3-NCl
4-NCl
5-NCl
The NMR spectra of 3-Cl to 6-Cl have some common notable
features. First, the spectra reveal that only a single coordinated
species is present in solution. In the full cone conformation, the two
NaI
- NaCl
(CH2)nCl
2-butanone
n = 3-5
(CH2)nI
R'O
R'O
OR'
OR'
R'O
R'O
OR'
3-Cl - 5-Cl
Scheme 2. The Finkelstein reaction was utilized to produce 2-(
OR'
H
H
3-Cl - 5-I (35-70%)
u
-iodoalkyl)-calix[4]arenes (3-I to 5-I; the number indicates the length of the alkyl tether; R0¼Me).

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M.P. Hertel et al. / Tetrahedron 65 (2009) 8657–8667
H2NAlk
Na2CO3
NaI
n = 3 or 5
NHAlk
(CH2)nCl
(CH2)n
R'O
R'O
OR'
OR'
OR'
R'O
R'O
OR'
H
H
3-Cl or 5-Cl
3-NCy, 5-NCy, or 5-NiPr (30-50%)
Scheme 3. Functionalization of the alkyl tether with an alkylamine resulted in moderate isolated yields for a limited number of substrates (the number indicates the length of the
i
alkyl tether; R0¼Me; Alk¼Cy or Pr).
tethered to isopropylamine through a 5-carbon tether (5-NiPr). For
each of these alkylamine-functionalized compounds, the calix[4]-
arene bridgehead proton was found near 4.6–4.7 ppm, indicative of
its axial orientation. Thus, the amino-terminated alkyl tether was
located in the equatorial position, as with the precursor chloride
compounds. The most notable resonances in the NMR spectra of
these compounds were the 13C peaks attributed to the carbon atoms
adjacent to the amino nitrogen atom. For the two cyclohexyl de-
rivatives, the cyclohexylmethine carbonwas found near57 ppm and
the methylene carbon at the terminus of the linker group resonated
at nearly 44 ppm. For the isopropylamine derivative, these two
carbon atoms were at 50.6 and 44.3 ppm, respectively. Although the
carbon at the end of the tether was only slightly shifted, the ap-
pearance of the new low-field peak was diagnostic for formation of
these alkylamine-functionalized compounds. As with the other
compounds included herein, high-resolution mass spectra also
confirmed the formation of these compounds.
Although various substituted aniline derivatives could be pro-
duced using the amination methodology described above, these
compounds were obtained in very low yields, even under the op-
timized conditions. In an effort to utilize pyridine as base for this
reaction, we found that the amine-terminated tether was not
produced, but rather the pyridinium functionalized calix[4]arene
was formed instead. Thus, 3-Cl to 5-Cl were treated with neat
pyridine at reflux to convert these species to the pyridinium salts
[3-py]Cl to [5-py]Cl in excellent yields (97–98%; Scheme 4; Table 1).
These species were fully characterized and showed spectroscopic
features somewhat similar to 3-Cl to 5-Cl (in NaI-saturated CD3CN).
The compounds again showed approximate mirror symmetry.
The pyridinium resonances were observed in the usual region
(1H: 8.0–9.2 ppm). The most significant difference in the 1H NMR
spectra of these compounds was the appearance of a resonance at
w4.7–4.9 ppm, which integrated as two protons and was assigned
to the methylene unit at the end of the alkyl tether (directly at-
tached to the pyridinium nitrogen atom). This was accompanied by
a disappearance of the peak at w3.4–3.6 ppm, which had pre-
viously been observed for the –CH2Cl protons at the end of the alkyl
chain. In the 13C NMR spectrum, the terminal methylene group,
which had resonated near 45 ppm in the chlorotethered precursors
shifted upfield upon formation of the pyridinium salts, and was
found in the midst of the other alkyl carbon resonances. These
compounds were further identified by high-resolution electrospray
mass spectra, where [MꢁCl]þ peaks were observed in all three
cases.
Overall, we found that installation of aniline derivatives as
secondary amines at the tether’s end in 2-functionalized calix[4]-
arenes required relatively forcing conditions. A more practical
synthesis of this class of compounds was accomplished by reaction
i
of aniline or a 2,6-dialkylaniline (H2N-2,6-R2C6H3; R¼Me, Et, Pr)
with KH in THF. The potassium salt of the aniline derivative was
then treated immediately with 3-Cl to 6-Cl. This reaction was
observed as a slow progression of color changes from yellow, to
orange, to red, to eventually a dark brown color. Upon completion,
the product was quenched with water to destroy any residual
hydride and protonate any product deprotonated by excess KH in
the reaction. An organic workup was used to remove the leftover
salts from the product 2-(u
-anilinoalkyl)-calix[4]arenes (3-NR to
6-NR; R represents the 2,6-substituents of the aniline; Scheme 5).
Residual excess aniline was removed from the product by vacuum
distillation to yield the products as glassy solids upon cooling (Table
1). Again, the use of NaI-saturated NMR solvent revealed spectra
with approximate mirror symmetry. The signal at w3.4–3.6 ppm
assigned to the –CH2Cl protons at the end of the tether in 3-Cl to
6-Cl was no longer present. This methylene group was now
observed at higher field as an apparent quartet (due to coupling to
a methylene group and the N–H proton), although it overlapped
with resonances from other methylene units in the alkyl chain in
several cases. The most diagnostic peak in each NMR spectrum was
the N–H proton, which was nearly always observed as a triplet,
coupling to the terminal methylene unit with 3JHH¼7–8 Hz. 1H NMR
resonances readily attributed to the aryl group from the aniline
moieties were also identified in the isolated products (3-NR to
6-NR). Consistent with 3-Cl to 6-Cl and [3-py]Cl to [5-py]Cl, the
calix[4]arene methylene proton at the bridgehead of the tether was
located at low-field, indicative of its axial orientation and equato-
rially oriented amine-terminated alkyl tether. Further confirmation
of aniline installation was achieved by high-resolution mass spec-
tra, in which the [MþH]þ peak was observed in all cases.
To further characterize the amine-tethered 2-functionalized
calix[4]arene species, we grew X-ray quality crystals of compound
4-NiPr. This species crystallized from acetonitrile at ꢁ25 ꢀC as col-
orless rods (Fig. 3). As expected, the amino tether is located in an
equatorial position and 1 equiv of acetonitrile resides within the
calix[4]arene cavity. Additionally, 4-NiPr was found to crystallize in
the cone conformation exclusively. The metrical parameters within
the molecule are all consistent with previous reports,19,28 and there
are no extraordinary intermolecular interactions beyond the usual
crystal packing forces. The overall structure compares well with the
pyridine
n = 3-5
Cl
N
(CH2)nCl
(CH2)n
R'O
R'O
OR'
OR'
OR'
R'O
R'O
OR'
3-Cl - 5-Cl
u-chloroalkyl)-calix[4]arenes with pyridine yields pyridinium-tethered calix[4]arenes ([3-py]Cl to [5-py]Cl; the number indicates the length of the
H
H
[3-py]Cl - [5-py]Cl (>95%)
Scheme 4. Reaction of the 2-(
alkyl tether; R0¼Me).

M.P. Hertel et al. / Tetrahedron 65 (2009) 8657–8667
8661
KH, H2NAr
- KCl
n = 3-6
NHAr
(CH2)nCl
(CH2)n
R'O
R'O
OR'
OR'
R'O
R'O
OR'
OR'
3-NR - 6-NR (60-90%)
H
H
3-Cl - 6-Cl
Scheme 5. Reaction with potassium anilide derivatives results in installation of secondary aryl amines at the tether’s end (R¼H: Ar¼C6H5; R¼Me: Ar¼2,6-Me2C6H3; R¼Et: Ar¼2,6-
Et2C6H3; R¼iPr: Ar¼2,6-iPr2C6H3; R¼Cl: Ar¼2,5-Cl2C6H3; the number indicates the length of the alkyl tether; R0¼Me).
3. Conclusion
Herein, we have shown that mono-lithiated calix[4]arene 2 is
a useful platform for the attachment of alkyl-tethered functional
groups at a single methylene bridge. The chemoselectivity in the
reaction of these lithiated species with 1,
allows for the clean production of 2-( -chloroalkyl)-calix[4]arenes
with tether lengths of 3–6 methylene units. These chlorotethered
calix[4]arenes can then be further elaborated to produce 2-(
iodoalkyl)-calix[4]arenes, 2-( -pyridiniumalkyl)-calix[4]arenes,
and 2-( -aminoalkyl)-calix[4]arenes. The use of both alkyl and aryl
u-bromochloroalkanes
u
u
-
u
u
amine-functionalized tethers provides a means to potentially
metalate these functionalized calix[4]arenes or link them to a solid
support without compromising the overall calix[4]arene structure.
Efforts to utilize these 2-functionalized calix[4]arenes for advanced
applications remain an ongoing area of pursuit in the Fantini and
Schmidt laboratories.
Figure 3. ORTEP diagram (50% thermal ellipsoids) of 4-NiPr. Hydrogen atoms, disor-
dered tert-butyl group, and 1 equiv of acetonitrile are omitted for clarity. Note the
acetonitrile solvate present within the calixarene cone.
4. Experimental section
4.1. General
other crystallographically characterized calix[4]arenes in which
a single methylene bridge has been functionalized with an organic
group, all of which are also found to crystallize in the cone con-
formation with an equatorial substituent.19,28 Substitution of two or
more of the methylene bridges can sometimes perturb the con-
formational preference away from the cone confirmation with large
groups opposite to each other,30,52 while tetrasubstitution proves
even more complicated.36,37
Compounds 3-I to 5-I, [3-py]Cl to [5-py]Cl, 3-NCy, 5-NCy, and 5-
NiPr were synthesized under ambient atmosphere. Compounds 3-Cl
to 6-Cl and 3-NR to 6-NR were synthesized using standard Schlenk
and dry box techniques. The following materials were purchased
from commercial suppliers and used as received: 1-bromo-3-chlor-
opropane, 1-bromo-4-chlorobutane, 1-bromo-5-chloropentane,
1-bromo-6-chlorohexane, 2-butanone, n-butyllithium (1.6 M in
hexanes), cyclohexylamine, 2,5-dichloroaniline, dichloromethane,
diethylether, isopropylamine, methanol, pentane, potassium
hydride, pyridine, sodium carbonate, and sodium iodide. Tetrahy-
drofuran was purchased from Fisher or VWR and purified by distil-
lation from a purple Na/benzophenone ketyl solution. Aniline,
2,6-dimethylaniline, 2,6-diethylaniline, and 2,6-diisopropylaniline
were dried over calcium hydride, freeze–pump–thawed three times,
distilled under reduced pressure, and stored in the dark. CD3CN and
CDCl3 were purchased from Cambridge Isotope Laboratories or Acros
Organics and used as received. 1H and 13C NMR data were obtained
on a 400 MHz Avance or a 600 MHz Inova NMR spectrometer at
ambient temperature. Unless otherwise specified, NMR spectra were
collected on the 600 MHz Inova spectrometer using CD3CN that had
been presaturated with NaI as solvent. Unless specifically noted, the
Finally, we investigated electron-poor aniline derivatives as
amine functional groups at the end of the alkyl tethers. Having had
some success with reasonably electron-rich alkyl amines and ex-
cellent results with the less basic anilines, the use of chloro-
substituted anilines was explored as a means to further diversify
the amine-tethered calix[4]arenes. Using the reaction conditions
described for the anilines above, 2,5-dichloroaniline was attached
at the end of the 3–5 methylene unit tethers. These reactions
proceeded readily to produce the analogous 2,5-dichloroaniline
functionalized species (3-NCl to 5-NCl; Scheme 5; Table 1). In-
terestingly, in this case after the progression of colors during the
reaction period, the solution was observed as a vibrant purple color
prior to quenching with water. Spectroscopic characterization of
the products again showed approximate mirror symmetry for these
species in NaI-saturated solution, with the alkyl tether oriented in
the equatorial position. The most remarkable change from the
aniline derivatives for these compounds involved the chemical
shifts observed for the protons of the 2,5-dichlorophenyl groups.
These were easily identified in the 1H NMR spectrum in the 6.5–
7.2 ppm region with a characteristic coupling pattern representa-
tive of protons at the 3-, 4-, and 6-positions of the aryl ring. Ad-
ditionally, the effects of the electron withdrawing chlorides were
evident in the 1H NMR chemical shift observed for the amine
protons. The N–H resonances appeared more than 1 ppm down-
field from the chemical shifts observed for the 2,6-dialkylaniline
derivatives. Full spectroscopic characterization and high-resolution
mass spectrometry confirmed the formation of 3-NCl to 5-NCl,
completing our series of secondary amine-tethered calix[4]arenes.
3
reported coupling constants are given for JHH coupling. The NMR
spectra of some compounds were taken in a 3:1 CDCl3/CD3CN
solution containing NaI (1 g per 80 mL solution) as noted in the
individual procedures. 1H NMR shifts are given relative to CD2HCN
(1.96 ppm) or SiMe4 (0.00 ppm) and 13C NMR shifts are given relative
to CD3CN (1.32 ppm) or CDCl3 (77.0 ppm). For IR, liquid samples were
taken neat on a Perkin–Elmer XTL FTIR spectrophotometer, while
solid samples were prepared by dissolving in CH2Cl2, applying a drop
to a KBr plate, and allowing the solvent to evaporate. Infrared spectra
of some solids were recorded with a Bruker Vector 22 using a Pike
Technologies horizontal ATR attachment. High-resolution time-of-
flight or quadrupole mass spectra were obtained using electrospray

8662
M.P. Hertel et al. / Tetrahedron 65 (2009) 8657–8667
ionization by the Mass Spectrometry Laboratory at the University of
Illinois, Urbana, IL or the Campus Chemical Instrument Center-
dMass Spectrometry & Proteomics Facility at The Ohio State Uni-
versity, Columbus, OH. Electrospray samples were prepared by
dissolving in methanol, and in some cases, a NaI internal standard
was used. Elemental analyses were determined by Columbia Ana-
lytical Services, Tucson, AZ. The X-ray structure determination was
performed at the Ohio Crystallographic Consortium housed at The
University of Toledo. Tetrahydroxy-p-tert-butylcalix[4]arene53 and
tetramethoxy-p-tert-butylcalix[4]arene (1)54 were prepared as pre-
viously reported.
4.71 mmol). Yield: 3.34 g (84.6%); 1H NMR:
d 7.24 (s, 4H), 7.22 (d,
4
4
2H, JHH¼2 Hz), 7.18 (d, 2H, JHH¼2 Hz), 4.56 (t, 1H, 8 Hz), 4.17
(d, 3H, 2JHH¼12 Hz), 4.04 (s, 6H), 4.02 (s, 6H), 3.48 (t, 2H, 7 Hz), 3.45
(d, 2H, 2JHH¼12 Hz), 3.44 (d,1H, 2JHH¼12 Hz), 2.09 (q, 2H, 8 Hz), 1.70
(pent, 2H, 7 Hz), 1.46 (pent, 2H, 8 Hz), 1.29 (m, 2H), 1.12 (s, 36H);
13C{1H} NMR:
d 151.7, 149.6, 149.5, 139.1, 135.7, 135.6, 127.2, 127.1,
126.8, 126.7, 123.5, 123.3, 65.6, 65.5, 65.4, 65.3, 46.1, 36.5, 35.2, 35.1,
34.3, 33.0, 31.7, 31.6, 30.5, 30.4, 30.2, 27.7; IR (cmꢁ1): 3413 (w), 3036
(w), 2964 (s), 2874 (m), 2814 (m), 2036 (w), 1749 (w), 1600 (w),
1579 (w), 1481 (s),1460 (m),1427 (m), 1388 (w), 1358 (m), 1296 (w),
1281 (w), 1263 (m), 1242 (m), 1203 (m), 1170 (w), 1116 (m), 1021
(m), 946 (w), 872 (m), 806 (w), 797 (w), 737 (w), 704 (w). Elemental
analysis calculated for C53H73O4Cl$4/3LiBr: C, 68.79; H, 7.95. Found:
C, 68.09; H, 7.98.
4.2. General procedure for the synthesis of 2-(u-chloroalkyl)-
tetramethoxy-p-tert-butylcalix[4]arenes (3-Cl to 6-Cl)
To a solution of 1 (1–3 g) in THF (50 mL) was added 1.15 equiv
n-BuLi (1.53 M in hexanes) via syringe over 5 min at ambient tem-
perature. The solution turned from a clear yellow prior to the
addition of n-BuLi to blood red by the end of the addition. To this
4.2.4. 2-(6-Chlorohexyl)tetramethoxy-p-tert-butylcalix[4]arene (6-Cl).
Reagents:
1 (1.42 g, 2.02 mmol); n-BuLi (1.53 M in hexanes,
1.58 mL, 2.42 mmol); 1-bromo-6-chlorohexane (0.495 g, 0.370 mL,
2.48 mmol). Yield: 1.58 g (83.4%); 1H NMR:
d
7.24 (s, 4H), 7.22 (d, 2H,
4
solution was added 1.15 equiv 1-bromo-
u-chloroalkane via syringe
4JHH¼2 Hz), 7.19 (d, 2H, JHH¼2 Hz), 4.56 (t, 1H, 8 Hz), 4.17 (d, 3H,
2JHH¼12 Hz), 4.04 (s, 6H), 4.02 (s, 6H), 3.49 (t, 2H, 7 Hz), 3.45 (d, 2H,
2JHH¼12 Hz), 3.44 (d, 1H, 2JHH¼12 Hz), 2.08 (m, 2H), 1.66 (m, 2H), 1.36
at ambient temperature. This solution was allowed to stir for 12 h.
Once a yellow solution was observed, a few drops of water were
added to quench any unreacted n-BuLi. The solutionwas filtered and
all volatiles were removed in vacuo. Workup method A: the color-
less solid was crystallized from a mixture of pentane and dieth-
ylether. A halide test with silver nitrate confirmed the presence of
halides in all cases. Elemental analysis indicated the presence of
stoichiometric amounts of LiBr in the crystalline materials. Workup
method B: the colorless solids were redissolved in CH2Cl2 and
washed with brine. After removal of solvent under vacuum,
recrystallization from methanol gave a semi-crystalline white
powder, which was found to be salt-free.
(m, 4H), 1.27 (m, 2H), 1.12 (s, 36H); 13C{1H} NMR:
d 152.1, 149.9, 149.8,
139.5, 136.1, 136.0, 127.6, 127.4, 127.2, 127.1, 123.8, 123.7, 66.0, 65.9,
65.8, 65.7, 46.6, 36.9, 35.6, 35.5, 34.8, 33.5, 32.1, 30.9, 30.8, 30.7, 30.0,
29.8, 27.6; IR (cmꢁ1): 3331 (s), 3248 (s), 3048 (w), 2953 (s), 2863 (s),
1651 (m), 1602 (m), 1584 (m), 1482 (s), 1463 (m), 1438 (m), 1393 (w),
1362 (m), 1300 (w), 1263 (w), 1245 (w), 1205 (m), 1176 (m), 1118 (m),
1021 (w), 999 (m), 947 (w), 870 (w), 805 (w), 732 (w), 703 (w), 647
(w), 619 (w), 610 (w), 585 (w), 565 (w). HRMS calculated for:
C54H76O4Cl [MþH]þ: 823.5432, found: 823.5399. Elemental analysis
calculated for C54H75O4Cl$4/3LiBr: C, 69.04; H, 8.05. Found: C, 69.60;
H, 8.12.
4.2.1. 2-(3-Chloropropyl)tetramethoxy-p-tert-butylcalix[4]arene (3-Cl).
Reagents:
1
(2.58 g, 3.66 mmol); n-BuLi (1.53 M in hexanes,
4.3. General procedure for the synthesis of 2-(u-iodoalkyl)-
2.80 mL, 4.28 mmol); 1-bromo-3-chloropropane (0.669 g, 0.420 mL,
tetramethoxy-p-tert-butylcalix[4]arenes (3-I to 5-I)
4.28 mmol). Yield: 2.15 g (67.6%); 1H NMR:
d 7.24 (m, 6H), 7.20 (d, 2H,
2
4JHH¼2 Hz), 4.59 (t, 1H, 8 Hz), 4.17 (d, 3H, JHH¼12 Hz), 4.04 (s, 6H),
To a mixture of 3-Cl to 5-Cl and finely powdered sodium iodide
was added 2-butanone to afford a homogeneous solution. The re-
action mixture was heated at reflux for 6 days with periodic
monitoring by 1H NMR spectroscopy on evaporated aliquots. After
the reaction was judged to be complete, all volatiles were removed
in vacuo, and the resulting solid was dissolved in dichloromethane
and washed twice with saturated NaCl solution. The organic solu-
tion was dried over MgSO4, filtered, and concentrated to dryness to
yield a white solid. Recrystallization from methanol yielded white
powders.
4.03 (s, 6H), 3.59 (t, 2H, 6 Hz), 3.45 (m, 3H), 2.24 (m, 2H), 1.73 (m, 2H),
1.12 (m, 36H); 13C{1H} NMR:
d 151.1, 149.6, 149.5, 138.3, 135.5, 135.4,
135.3, 126.9, 126.2, 122.6, 65.1, 64.7, 45.5, 35.8, 34.6, 34.4, 31.9, 30.8,
30.7, 30.6, 30.1; IR (cmꢁ1): 3332 (m), 3251 (m), 2960 (s), 2904 (s), 2862
(m), 1651 (w), 1600 (w), 1582 (w), 1483 (m), 1462 (m), 1436 (m), 1393
(w), 1362 (m), 1300 (w), 1284 (w), 1244 (w), 1203 (m), 1176 (w), 1118
(m), 1000 (m), 971 (w), 947 (w), 806 (w), 736 (w), 701 (w), 646 (w).
Elemental analysis calculated for C51H69O4Cl$LiBr: C, 70.54; H, 8.01.
Found: C, 70.42; H, 7.99.
4.2.2. 2-(4-Chlorobutyl)tetramethoxy-p-tert-butylcalix[4]arene (4-Cl).
4.3.1. 2-(3-Iodopropyl)tetramethoxy-p-tert-butylcalix[4]arene (3-I).
Reagents: 3-Cl (0.391 g, 0.500 mmol); 2-butanone (10 mL); NaI
Reagents:
1 (3.00 g, 4.26 mmol); n-BuLi (1.53 M in hexanes,
3.10 mL, 4.74 mmol); 1-bromo-4-chlorobutane (0.818 g, 0.550 mL,
(0.150 g, 1.00 mmol). Yield: 0.291 g (66.7%); 1H NMR (CD3CN/
4.78 mmol). Yield: 3.06 g (78.8%); 1H NMR:
d
7.29–7.26 (m, 8H), 4.62
CDCl3/NaI, 400 MHz):
d
7.29 (d, 2H, JHH¼2 Hz), 7.25 (s, 4H), 7.24
4
(t, 1H, 8 Hz), 4.22 (d, 3H, 2JHH¼12 Hz), 4.09 (s, 6H), 4.08 (s, 6H), 3.59 (t,
(d, 2H, 4JHH¼2 Hz), 4.72 (t, 1H, 8 Hz), 4.30 (d, 3H, 2JHH¼12 Hz), 4.18
2
2H, 7 Hz), 3.50–3.46 (m, 3H), 2.17 (m, 2H), 1.84 (pent, 2H, 8 Hz), 1.46
(s, 6H), 4.17 (s, 6H), 3.49 (d, 2H, JHH¼12 Hz), 3.48 (d, 1H,
(m, 2H), 1.18 (s, 36H); 13C{1H} NMR:
d
151.2, 149.1, 149.0, 138.5, 135.23,
2JHH¼12 Hz), 3.32 (t, 2H, 7 Hz), 2.31 (m, 2H), 1.89 (m, 2H), 1.24 (s,
135.21, 135.1, 126.6, 126.3, 122.9, 65.1, 64.9, 45.4, 36.0, 34.8, 34.6, 33.1,
32.8, 31.2, 31.1, 30.0, 26.3; IR (cmꢁ1): 3847 (w), 3743 (m), 3608 (w),
3338 (s), 3255 (s), 3047 (w), 2944 (s), 2871 (w), 2363 (m), 2238 (w),
1967 (w), 1740 (w), 1652 (m), 1600 (w), 1481 (s), 1362 (m), 1299 (m),
1268 (s), 1200 (s), 1119 (m), 996 (s), 948 (w), 873 (w), 805 (w), 740 (s),
702 (w). Elemental analysis calculated for C52H71O4Cl$4/3LiBr: C,
68.53; H, 7.85. Found: C, 68.67; H, 7.91.
18H), 1.23 (s, 18H); 13C{1H} NMR (CD3CN/CDCl3/NaI, 100 MHz):
d
149.94, 149.93, 148.1, 148.0, 136.8, 133.90, 133.85, 125.35, 125.33,
125.2, 121.6, 64.2, 63.9, 33.9, 33.6, 33.5, 31.7, 30.23, 30.18, 29.1, 28.9,
6.5; IR (cmꢁ1): 2959 (m), 1479 (s), 1204 (m), 1023 (s), 869 (m), 796
(w). HRMS calculated for C51H69O4INa [MþNa]þ: 895.4138, found:
895.4122.
4.3.2. 2-(4-Iodobutyl)tetramethoxy-p-tert-butylcalix[4]arene (4-I).
Reagents: 4-Cl (3.356 g, 4.218 mmol); 2-butanone (25 mL); NaI
4.2.3. 2-(5-Chloropentyl)tetramethoxy-p-tert-butylcalix[4]arene (5-Cl).
Reagents:
1
(3.01 g, 4.27 mmol); n-BuLi (1.53 M in hexanes,
(1.28 g, 8.54 mmol). Yield: 1.375 g (36.7%); 1H NMR (CD3CN/CDCl3/
4
3.10 mL, 4.74 mmol); 1-bromo-5-chloropentane (0.873 g, 0.620 mL,
NaI, 400 MHz):
d
7.24 (d, 2H, JHH¼2 Hz), 7.23 (s, 4H), 7.22 (d, 2H,

M.P. Hertel et al. / Tetrahedron 65 (2009) 8657–8667
8663
4JHH¼2 Hz), 4.66 (t, 1H, 8 Hz), 4.28 (d, 3H, 2JHH¼12 Hz), 4.15 (s, 6H),
4.14 (s, 6H), 3.48 (d, 2H, 2JHH¼12 Hz), 3.46 (d, 1H, 2JHH¼12 Hz), 3.25
(t, 2H, 7 Hz), 2.17 (m, 2H), 1.92 (m, 2H), 1.47 (m, 2H), 1.21 (s, 18H),
701 (m), 685 (m), 646 (w). HRMS calculated for C57H76NO4
[MꢁCl]þ: 838.5774, found: 838.5747.
1.20 (s, 18H); 13C{1H} NMR (CD3CN/CDCl3/NaI, 100 MHz):
d
150.1,
4.3.6. 2-(5-Pyridiniumpentyl)tetramethoxy-p-tert-butylcalix[4]arene
chloride [5-py]Cl. A 50-mL round bottom flask equipped with
a magnetic stir bar and a water-jacketed condenser was charged
with 5-Cl$4/3LiBr (1.372 g, 1.483 mmol) and 40 mL pyridine. The
faint yellow solution was heated to reflux for 12 h at which point
the color had changed to a deep reddish-brown color. All volatiles
were removed in vacuo to produce a brown solid (1.275 g, 96.8%);
148.2, 148.1, 137.3, 134.1, 134.0, 125.5, 125.2, 121.8, 64.4, 64.2,
35.0, 33.8, 33.6, 32.6, 32.1, 30.5, 30.4, 29.3, 29.2, 29.0, 6.5; IR
(cmꢁ1): 2954 (m), 1480 (s), 1204 (m), 1022 (s), 870 (m), 798 (w).
HRMS calculated for C52H71O4INa [MþNa]þ: 909.4295, found:
909.4289.
4.3.3. 2-(5-Iodopentyl)tetramethoxy-p-tert-butylcalix[4]arene (5-I).
Reagents: 5-Cl (0.404 g, 0.499 mmol); 2-butanone (8 mL); NaI
1H NMR:
d 9.05 (d, 2H, 6 Hz), 8.59 (t, 1H, 6 Hz), 8.09 (t, 2H, 6 Hz),
4
4
7.35 (s, 4H), 7.33 (d, 2H, JHH¼2 Hz), 7.27 (d, 2H, JHH¼2 Hz), 4.67
(t, 2H, 7 Hz), 4.57 (t, 1H, 8 Hz), 4.20 (d, 3H, 2JHH¼12 Hz), 4.06 (s, 6H),
4.02 (s, 6H), 3.51 (m, 3H), 2.16 (q, 2H, 8 Hz), 2.00 (pent, 2H, 7 Hz),
1.43 (pent, 2H, 8 Hz), 1.34 (m, 2H), 1.16 (s, 36H); 13C{1H} NMR:
(0.150 g, 1.00 mmol). Yield: 0.224 g (49.8%); 1H NMR (CD3CN/CDCl3/
4
NaI, 400 MHz):
d
7.24 (m, 6H), 7.21 (d, 2H, JHH¼2 Hz), 4.64 (t, 1H,
8 Hz), 4.26 (d, 3H, 2JHH¼12 Hz), 4.14 (s, 6H), 4.12 (s, 6H), 3.48 (d, 2H,
2JHH¼12 Hz), 3.47 (d, 1H, JHH¼12 Hz), 3.20 (t, 2H, 7 Hz), 2.14 (m,
d 151.5, 150.3, 149.9, 148.8, 146.3, 139.1, 135.8, 135.6, 135.5, 128.9,
2
2H), 1.83 (m, 2H), 1.52 (m, 2H), 1.38 (m, 2H), 1.205 (s, 18H), 1.202 (s,
126.9, 126.8, 126.7, 124.7, 123.0, 65.6, 65.0, 36.6, 35.0, 34.9, 34.8,
33.0, 31.5, 31.4, 31.3, 31.2, 31.1, 28.6, 26.4; IR (cmꢁ1): 3388 (br s),
3048 (m), 2959 (s), 2878 (m), 2820 (w), 2736 (w), 2710 (w), 2033
(w), 1741 (w), 1635 (w), 1603 (w), 1584 (w), 1482 (m), 1463 (m),
1432 (w), 1419 (w), 1393 (w), 1362 (w), 1300 (w), 1262 (w), 1245
(w), 1206 (w), 1176 (w), 1123 (w), 1024 (w), 1001 (w), 870 (w), 807
(w), 774 (w), 735 (w), 684 (w). HRMS calculated C58H78NO4
[MꢁCl]þ: 852.5931, found: 852.5909.
18H); 13C{1H} NMR (CD3CN/CDCl3/NaI, 100 MHz):
d 150.0, 148.0,
147.9, 137.3, 133.9, 133.7, 126.1, 125.3, 125.0, 121.6, 64.1, 63.9, 34.8,
33.6, 33.4, 32.9, 32.3, 30.24, 30.17, 29.7, 29.1, 28.9, 26.9, 6.5; IR
(cmꢁ1): 2952 (m), 1480 (s), 1203 (m), 1021 (s), 870 (m), 796 (w).
HRMS calculated for C53H73O4INa [MþNa]þ: 923.4451, found:
923.4430.
4.3.4. 2-(3-Pyridiniumpropyl)tetramethoxy-p-tert-butylcalix[4]ar-
ene chloride [3-py]Cl. A 50-mL round bottom flask equipped with
a magnetic stir bar and a water-jacketed condenser was charged
with 3-Cl$LiBr (1.294 g, 1.490 mmol) and 40 mL pyridine. The faint
yellow solution was heated to reflux for 12 h at which point the
color had changed to a deep reddish-brown. All volatiles were
removed in vacuo to produce a brown solid (1.249 g, 97.4%); 1H
4.4. General procedure for the synthesis of 2-(u-alkylamine)-
tetramethoxy-p-tert-butylcalix[4]arenes
To a mixture of finely powdered sodium iodide, sodium car-
bonate, and 3-Cl or 5-Cl was added THF and an excess of the ap-
propriate alkylamine. The heterogeneous reaction mixture was
heated at reflux for several days with periodic monitoring by 1H
NMR spectroscopy on evaporated aliquots. After the reaction was
judged to be complete, all volatiles were removed in vacuo, and the
resulting solid was dissolved in dichloromethane and washed twice
with saturated NaCl solution. For the cyclohexylamine compounds
(3-NCy and 5-NCy), the organic solution was contacted with 12 M
HCl, then dried over MgSO4, filtered, and concentrated to dryness to
yield the hydrochloride salt as an off-white solid. For the iso-
propylamine compound (5-NiPr), the organic solution was evapo-
rated to dryness and the residue converted to a powder by
treatment with acetonitrile saturated with NaI.
NMR:
d 9.17 (d, 2H, 6 Hz), 8.56 (t, 1H, 6 Hz), 8.06 (t, 2H, 6 Hz), 7.26
(d, 2H, 4JHH¼2 Hz), 7.23 (s, 4H), 7.22 (d, 2H, 4JHH¼2 Hz), 4.88 (t, 2H,
2
7 Hz), 4.60 (t, 1H, 8 Hz), 4.16 (d, 1H, JHH¼12 Hz), 4.15 (d, 2H,
2JHH¼12 Hz), 4.03 (s, 6H), 4.02 (s, 6H), 3.44 (d, 3H, JHH¼12 Hz),
2
2.31 (m, 2H), 1.97 (m, 2H), 1.15 (s, 18H), 1.12 (s, 18H); 13C{1H} NMR:
d
150.2, 150.1, 149.9, 149.2, 148.2, 137.5, 137.4, 129.2, 128.6, 128.5,
127.7,124.9,124.8,122.0,117.6, 69.7, 67.5, 37.5, 33.6, 32.2, 32.0, 25.6,
24.0, 23.0; IR (cmꢁ1): 3396 (br s), 3050 (m), 2956 (s), 2869 (m),
2831 (w), 2818 (w), 2739 (w), 2710 (w), 1635 (m), 1603 (w), 1584
(w), 1482 (s), 1463 (m), 1436 (w), 1394 (w), 1362 (m), 1299 (w),
1264 (w), 1245 (w), 1205 (m), 1177 (m), 1126 (m), 1023 (w), 1000
(m), 944 (w), 890 (w), 871 (w), 807 (w), 773 (w), 735 (w), 684 (w),
645 (w). HRMS calculated for C56H74NO4 [MꢁCl]þ: 824.5618,
found: 824.5598.
4.4.1. 2-(3-Cyclohexylaminopropyl)tetramethoxy-p-tert-butyl-
calix[4]arene (3-NCy). Reagents: 3-Cl (1.02 g, 1.31 mmol); cyclo-
hexylamine (0.44 mL, 3.8 mmol); NaI (0.452 g, 3.01 mmol);
Na2CO3 (0.601 g, 5.67 mmol); THF (7 mL). Yield of [3-NCy]$HCl:
4.3.5. 2-(4-Pyridiniumbutyl)tetramethoxy-p-tert-butylcalix[4]arene
chloride [4-py]Cl. A 50-mL round bottom flask equipped with
a magnetic stir bar and a water-jacketed condenser was charged
with 4-Cl$4/3LiBr (1.049 g, 1.151 mmol) and 40 mL pyridine. The
faint yellow solution was heated to reflux for 12 h at which point
the color had changed to a deep reddish-brown color. All volatiles
were removed in vacuo to produce a brown solid (0.987 g, 98.0%);
0.509 g (44%); 1H NMR of [3-NCy]$HCl (CD3CN/CDCl3/NaI,
4
400 MHz):
d
7.92 (br s, 2H), 7.28 (d, 2H, JHH¼2 Hz), 7.22 (s, 4H),
7.21 (d, 2H, 4JHH¼2 Hz), 4.70 (t, 1H, 8 Hz), 4.27 (d, 3H, 2JHH¼12 Hz),
2
4.16 (s, 6H), 4.13 (s, 6H), 3.47 (d, 2H, JHH¼12 Hz), 3.45 (d, 1H,
2JHH¼12 Hz), 3.17 (m, 1H), 3.10 (m, 2H), 2.30 (m, 2H), 2.20 (m, 2H),
1.85 (m, 1H), 1.73 (m, 4H), 1.24 (m, 5H), 1.22 (s, 18H), 1.20 (s, 18H);
13C{1H} NMR of [3-NCy]$HCl (CD3CN/CDCl3/NaI, 100 MHz):
1H NMR:
d 9.08 (d, 2H, 6 Hz), 8.59 (t, 1H, 6 Hz), 8.09 (t, 2H, 6 Hz),
7.34 (s, 4H), 7.32 (d, 2H, 4JHH¼2 Hz), 7.25 (d, 2H, 4JHH¼2 Hz), 4.67 (t,
d 149.9, 148.2, 148.0, 136.7, 133.9, 133.8, 125.4, 125.2, 121.9, 64.4,
2
2H, 7 Hz), 4.55 (t, 1H, 8 Hz), 4.17 (d, 3H, JHH¼12 Hz), 4.04 (s, 6H),
63.8, 57.1, 43.8, 34.8, 33.7, 33.5, 30.3, 30.2, 29.9, 29.1, 28.9, 27.8,
24.6, 23.9, 23.6. HRMS calculated for C57H82NO4 [MþH]þ:
844.6244, found: 844.6221.
4.00 (s, 6H), 3.50 (m, 3H), 2.15 (q, 2H, 8 Hz), 1.41 (pent, 2H, 7 Hz),
1.32 (m, 2H), 1.15 (s, 18H), 1.14 (s, 18H); 13C{1H} NMR:
d 151.8, 149.7,
149.6, 146.3, 145.3, 138.9, 135.8, 135.6, 128.9, 128.5, 126.7, 126.3,
123.0, 121.8, 117.5, 65.9, 65.4, 36.6, 35.0, 34.9, 34.8, 34.7, 32.8, 32.0,
31.26, 31.20, 31.18, 25.6; IR (cmꢁ1): 3383 (br s), 3046 (m), 2959 (s),
2868 (s), 2822 (m), 2744 (w), 2716 (w), 2591 (w), 2561 (w), 2304
(w), 2039 (w), 1963 (w), 1786 (w), 1740 (w), 1635 (m), 1602 (m),
1583 (m),1482 (s),1463 (m),1434 (m),1417 (m),1394 (m),1362 (m),
1299 (m), 1264 (m), 1245 (m), 1206 (m), 1177 (m), 1123 (m), 1023
(m), 1000 (m), 944 (w), 891 (w), 871 (m), 807 (m), 772 (w), 737 (m),
4.4.2. 2-(5-Cyclohexylaminopentyl)tetramethoxy-p-tert-butyl-
calix[4]arene (5-NCy). Reagents: 5-Cl (1.0 g, 1.2 mmol); cyclohex-
ylamine (0.42 mL, 3.6 mmol); NaI (0.45 g, 3.0 mmol); Na2CO3
(0.61 g, 5.8 mmol); THF (7 mL). Yield of [5-NCy]$HCl: 0.53 g (49%);
1H NMR of [5-NCy]$HCl (CD3CN/CDCl3/NaI, 400 MHz):
d 7.92 (br s,
4
4
2H), 7.25 (d, 2H, JHH¼2 Hz), 7.23 (s, 4H), 7.21 (d, 2H, JHH¼2 Hz),
4.65 (t, 1H, 8 Hz), 4.27 (d, 3H, 2JHH¼12 Hz), 4.13 (s, 6H), 4.12 (s, 6H),

8664
M.P. Hertel et al. / Tetrahedron 65 (2009) 8657–8667
2
2
3.474 (d, 2H, JHH¼12 Hz), 3.465 (d, 1H, JHH¼12 Hz), 3.20 (m, 1H),
2.97 (m, 2H), 2.23 (m, 2H), 2.17 (m, 2H), 1.76 (m, 5H), 1.49 (m, 2H),
1.40 (m, 2H),1.24 (m, 5H),1.211 (s, 18H), 1.205 (s, 18H); 13C{1H} NMR
7 Hz), 4.21 (d, 3H, 2JHH¼12 Hz), 4.07 (s, 6H), 4.05 (s, 6H), 3.51 (d, 2H,
2JHH¼12 Hz), 3.50 (d, 1H, 2JHH¼12 Hz), 3.04 (q, 2H, 7 Hz), 2.20 (m, 2H),
1.66 (m, 2H), 1.40 (m, 2H), 1.18 (s, 18H), 1.17 (s, 18H); 13C{1H} NMR:
of [5-NCy]$HCl (CD3CN/CDCl3/NaI, 100 MHz):
d
149.89, 149.87,
d 151.5, 151.4, 149.7, 149.3, 149.2, 139.0, 135.5, 135.4, 129.5, 126.9, 126.5,
137.3, 133.9, 133.8, 133.6, 125.30, 125.26, 124.88, 121.68, 64.1, 63.8,
57.0, 43.7, 34.8, 33.6, 33.4, 32.9, 30.3, 30.1, 29.0, 28.9, 27.7, 27.4, 26.0,
24.7, 23.9, 23.6. HRMS calculated for C59H85NO4Na [MþNa]þ:
894.6376, found: 894.6368.
123.3,116.6,112.8, 65.2, 65.1, 65.0, 64.9, 43.6, 36.3, 34.9, 34.8, 31.2, 30.0,
29.8, 27.0; IR (cmꢁ1): 3048 (w), 3017 (w), 2958 (s), 2928 (s), 2866 (m),
2820 (m), 2377 (w), 2323 (w), 1603 (w), 1506 (w), 1481 (w), 1463 (w),
1430 (w), 1392 (w), 1361 (w), 1314 (w), 1300 (w), 1286 (w), 1260
(w), 1246 (w), 1206 (w), 1176 (w), 1118 (w), 1024 (w), 871 (w), 797 (w),
747 (w), 691 (w). HRMS calculated for C58H78NO4 [MþH]þ: 852.5931,
found: 852.5930.
4.4.3. 2-(5-Isopropylaminopentyl)tetramethoxy-p-tert-butylcalix[4]-
arene (5-NiPr). Reagents: 5-Cl (1.0 g, 1.2 mmol); isopropylamine
(0.35 mLꢂ12, 4.1 mmol each); NaI (0.45 g, 3.0 mmol); Na2CO3
(0.61 g, 5.8 mmol); THF (7 mL). Over the course of 12 days, 0.35 mL
of isopropylamine was added each day. Yield: 0.323 g (31%); 1H
4.5.3. 2-(4-(2,6-Dimethylanilino)butyl)tetramethoxy-p-tert-butyl-
calix[4]arene (4-NMe). Reagents: 4-Cl$4/3LiBr (0.997 g, 1.09 mmol);
KH (0.176 g, 4.39 mmol); 2,6-dimethylaniline (0.531 g, 0.540 mL,
NMR (CD3CN/CDCl3/NaI, 400 MHz):55
d
7.25 (d, 2H, 4JHH¼2 Hz), 7.23
4
(s, 4H), 7.21 (d, 2H, JHH¼2 Hz), 4.65 (t, 1H, 8 Hz), 4.27 (d, 3H,
4.39 mmol). Yield: 0.656 g (68.1%); 1H NMR:
d 7.36–7.31 (m, 8H),
2JHH¼12 Hz), 4.13 (s, 6H), 4.12 (s, 6H), 3.51 (sept, 1H, 7 Hz), 3.47
6.92 (d, 2H, 7 Hz), 6.72 (t, 1H, 7 Hz), 4.63 (t, 1H, 8 Hz), 4.23 (d, 3H,
2
2
(d, 2H, JHH¼12 Hz), 3.46 (d, 1H, JHH¼12 Hz), 2.96 (m, 2H), 2.17
(m, 2H), 1.93 (m, 2H), 1.55 (m, 2H), 1.48 (d, 6H, 7 Hz), 1.40 (m, 2H),
1.21 (s, 18H), 1.20 (s, 18H); 13C{1H} NMR (CD3CN/CDCl3/NaI,
2JHH¼12 Hz), 4.08 (s, 6H), 4.05 (s, 6H), 3.51 (d, 2H, 2JHH¼12 Hz), 3.50
2
(d, 1H, JHH¼12 Hz), 3.23 (t, 1H, 7 Hz), 2.96 (q, 2H, 7 Hz), 2.20 (m,
8H), 1.62 (pent, 2H, 8 Hz), 1.40 (m, 2H), 1.19 (s, 36H); 13C{1H} NMR:
100 MHz):
d
150.0, 148.1, 148.0, 137.4, 134.0, 133.9, 133.7, 125.42,
d 151.1, 149.0, 148.9, 138.6, 135.2, 135.0, 129.4, 129.3, 129.0, 128.7,
125.39, 125.0, 121.8, 64.2, 63.9, 50.6, 44.3, 34.8, 33.7, 33.5, 33.0, 30.3,
30.2, 29.2, 29.0, 27.5, 26.1, 25.0, 17.9. HRMS calculated for
C56H81NO4Na [MþNa]þ: 854.6063, found: 854.6056.
126.7, 126.4, 126.0, 123.1, 122.8, 121.4, 64.8, 64.7, 64.6, 64.5, 48.1,
36.0, 34.5, 34.4, 33.7, 31.0, 30.9, 30.8, 29.7, 18.2; IR (cmꢁ1): 3382 (w),
3044 (m), 2957 (s), 2866 (s), 2820 (m), 2034 (w), 1751 (w), 1596
(m), 1582 (m), 1480 (s), 1464 (s), 1432 (m), 1392 (m), 1361 (m), 1300
(m), 1286 (m), 1260 (m), 1247 (m), 1206 (m), 1174 (m), 1124 (m),
1100 (m),1023 (m), 951 (w), 922 (w), 871 (m), 800 (m), 764 (m), 739
(m), 704 (w), 643 (w), 614 (w). HRMS calculated for C60H82NO4
[MþH]þ: 880.6244, found: 880.6246. Elemental analysis calculated
for C60H81NO4: C, 81.86; H, 9.27; N, 1.59. Found: C, 80.63; H, 9.02;
N, 1.60.
4.5. General procedure for the synthesis of aniline
derivatives (3-NR to 6-NR)
To a nitrogen-filled Schlenk tube was added 3-Cl to 6-Cl, which
was then placed under vacuum for several hours. To the Schlenk
tube was added w4 equiv KH in a glovebox. After purging back onto
a Schlenk line, THF (15 mL) and w4 equiv aniline or substituted
aniline were added. The yellow suspension immediately began to
evolve H2 and started a slow color transformation to an eventual
dark brown colored solution after 12 h. Several drops of water were
added to quench the unreacted KH and convert any deprotonated
product back to the protio species. All volatiles were removed in
vacuo prior to extraction into pentane. Filtration yielded a light to
dark brown solution, which again had all volatiles removed in
vacuo. Excess aniline was removed by vacuum distillation pro-
ducing beige to dark brown colored glassy solids.
4.5.4. 2-(4-(2,6-Diethylanilino)butyl)tetramethoxy-p-tert-butyl-
calix[4]arene (4-NEt). Reagents: 4-Cl$4/3LiBr (0.842 g, 0.924 mmol);
KH (0.170 g, 4.24 mmol); 2,6-diethylaniline (0.634 g, 0.700 mL,
4.25 mmol). Yield: 0.745 g (88.8%); 1H NMR:
d 7.36–7.30 (m, 8H),
6.97 (d, 2H, 8 Hz), 6.85 (t, 1H, 8 Hz), 4.63 (t, 1H, 8 Hz), 4.23 (d, 3H,
2
2JHH¼12 Hz), 4.08 (s, 6H), 4.06 (s, 6H), 3.51 (d, 2H, JHH¼12 Hz),
3.50 (d, 1H, 2JHH¼12 Hz), 3.14 (t, 1H, 7 Hz), 2.89 (q, 2H, 7 Hz), 2.58
(q, 4H, 8 Hz), 2.20 (m, 2H), 1.66 (m, 2H), 1.41 (m, 2H), 1.19 (s, 18H),
1.18 (s, 18H), 1.13 (t, 6H, 8 Hz); 13C{1H} NMR:
d 151.6, 149.4, 149.3,
146.1, 139.0, 136.9, 135.6, 135.5, 127.3, 127.0, 126.9, 126.7, 126.6,
123.4, 123.3, 122.9, 65.2, 65.0, 50.5, 36.4, 35.0, 34.9, 34.2, 32.3,
31.6, 30.1, 30.0, 27.2, 24.8, 15.2; IR (cmꢁ1): 3041 (w), 2960 (s),
2932 (m), 2869 (m), 2820 (w), 1481 (m), 1460 (w), 1392 (w), 1361
(w), 1301 (w), 1285 (w), 1245 (w), 1206 (w), 1174 (w), 1124 (w),
1024 (w), 870 (w). HRMS calculated for C62H86NO4 [MþH]þ:
908.6557, found 908.6530. Elemental analysis calculated for
C62H85NO4: C, 81.98; H, 9.43; N, 1.54. Found: C, 80.22; H, 9.34;
N, 1.50.
4.5.1. 2-(3-(2,6-Diisopropylanilino)propyl)tetramethoxy-p-tert-butyl-
calix[4]arene(3-NiPr). Reagents: 3-Cl$LiBr (1.052 g,1.211 mmol); KH
(0.190 g, 4.74 mmol); 2,6-diisopropylaniline (0.84 g, 0.89 mL,
4.7 mmol). Yield: 0.913 g (81.7%); 1H NMR:
d
7.35 (s, 4H), 7.34 (d, 2H,
4
4JHH¼2 Hz), 7.27 (d, 2H, JHH¼2 Hz), 7.01 (d, 2H, 7 Hz), 6.94 (t, 1H,
2
7 Hz), 4.61 (t, 1H, 8 Hz), 4.19 (d, 2H, JHH¼12 Hz), 4.18 (d, 1H,
2JHH¼12 Hz), 4.05 (s, 6H), 4.04 (s, 6H), 3.51 (m, 3H), 3.26 (sept, 2H,
7 Hz), 3.04 (t,1H, 7 Hz), 2.84 (q, 2H, 7 Hz), 2.24 (q, 2H, 8 Hz), 1.59 (m,
2H), 1.15 (s, 18H), 1.14 (s, 18H), 1.10 (d, 12H, 7 Hz); 13C{1H} NMR:
d
151.9, 151.8, 149.7, 149.6, 143.8, 142.0, 139.2, 135.9, 132.9, 127.2,
4.5.5. 2-(4-(2,6-Diisopropylanilino)butyl)tetramethoxy-p-tert-butyl-
calix[4]arene (4-NiPr). Reagents: 4-Cl$4/3LiBr (0.869 g, 0.953 mmol);
KH (0.178 g, 4.44 mmol); 2,6-diisopropylaniline (0.77 g, 0.82 mL,
127.1, 126.7, 124.3, 123.4, 118.6, 65.3, 65.0, 53.0, 32.3, 31.55, 31.53,
31.50, 30.4, 30.3, 24.7, 23.3, 14.4; IR (cmꢁ1): 3387 (w), 3045 (m),
2957 (s), 2929 (s), 2868 (m), 2820 (m), 2743 (w), 2713 (w), 2035 (w),
1751 (w),1620 (w),1602 (w),1585 (w),1481 (m),1463 (m),1448 (m),
1392 (w), 1384 (w), 1362 (m), 1300 (w), 1286 (w), 1262 (m), 1247
(w), 1206 (m), 1174 (w), 1124 (w), 1026 (m), 951 (w), 935 (w), 922
(w), 913 (w), 871 (w), 801 (w), 740 (w), 705 (w). HRMS calculated for
C63H88NO4 [MþH]þ: 922.6713, found: 922.6721.
4.4 mmol). Yield: 0.770 g (86.2%); 1H NMR:
d 7.36–7.29 (m, 8H), 7.02
(d, 2H, 8 Hz), 6.96 (t, 1H, 8 Hz), 4.64 (t, 1H, 8 Hz), 4.22 (d, 3H,
2
2JHH¼12 Hz), 4.07 (s, 12H), 3.52 (d, 2H, JHH¼12 Hz), 3.50 (d, 1H,
2JHH¼12 Hz), 3.26 (sept, 2H, 7 Hz), 3.06 (t, 1H, 8 Hz), 2.80 (q, 2H, 7 Hz),
2.20 (m, 2H), 1.69 (pent, 2H, 7 Hz), 1.42 (m, 2H), 1.18 (s, 18H), 1.17 (s,
18H), 1.12 (d, 12H, 7 Hz); 13C{1H} NMR:
d 151.54, 151.50, 151.4, 149.4,
149.3, 143.3, 139.0, 135.8, 135.6, 135.4, 126.9, 126.8, 126.3, 124.2, 124.0,
123.1, 65.0, 64.8, 52.4, 36.3, 34.9, 34.8, 34.2, 31.3, 31.2, 30.1, 29.9, 27.8,
27.2, 24.3; IR (cmꢁ1): 3049 (m), 2939 (s), 2863 (s), 2820 (m), 2742 (w),
2713 (w), 2035 (w), 1751 (w), 1619 (m), 1602 (m), 1584 (m), 1480 (s),
1462 (s), 1446 (s), 1392 (w), 1384 (m), 1362 (m), 1300 (m), 1286 (m),
1265 (m), 1246 (m), 1205 (m), 1174 (m), 1123 (m), 1025 (m), 951 (w),
4.5.2. 2-(4-Anilinobutyl)tetramethoxy-p-tert-butylcalix[4]arene (4-NH).
Reagents: 4-Cl$4/3LiBr (0.917 g, 1.01 mmol); KH (0.160 g, 3.99 mmol);
aniline (0.378 g, 0.370 mL, 4.06 mmol). Yield: 0.701 g (81.7%); 1H NMR:
d
7.35(s,4H),7.33(d, 2H,4JHH¼2 Hz),7.30(d, 2H,4JHH¼2 Hz), 7.06(t, 2H,
8 Hz), 6.56 (d, 2H, 8 Hz), 6.54 (t,1H, 8 Hz), 4.62 (t, 1H, 8 Hz), 4.50 (t, 1H,

M.P. Hertel et al. / Tetrahedron 65 (2009) 8657–8667
8665
934 (w), 923 (w), 871 (m), 800 (m), 740 (m), 705 (w), 645 (w), 614 (w).
2H, 7 Hz), 2.16 (m, 2H), 1.59 (m, 2H), 1.47 (m, 2H), 1.34 (m, 2H), 1.17
(s, 18H), 1.16 (s, 18H), 1.12 (d, 12H, 7 Hz); 13C{1H} NMR:
151.4, 144.4,
HRMS calculated for C64H90NO4 [MþH]þ: 936.6870, found: 936.6840.
d
143.2, 138.9, 135.5, 135.4, 127.0, 126.7, 126.6, 126.4, 124.1, 123.8, 123.3,
123.0, 65.1, 65.0, 64.9, 64.8, 52.3, 36.2, 34.9, 34.7, 31.2, 31.1, 31.0, 29.9,
29.8, 27.8, 27.7, 24.4, 24.3, 24.2, 24.0; IR (cmꢁ1): 3483 (w), 3400 (w),
3044 (m), 2959 (s), 2927 (s), 2867 (m), 2819 (m), 1750 (m), 1619
(w), 1602 (w), 1585 (w), 1482 (m), 1460 (w), 1444 (w), 1392 (w), 1382
(w), 1361 (w), 1300 (w), 1286 (w), 1262 (w), 1246 (w), 1206 (w), 1174
(w), 1124 (w), 1024 (w), 871 (w), 800 (w), 743 (w). HRMS calculated
for C65H92NO4 [MþH]þ: 950.7026, found: 950.7024. Elemental
analysis calculated for C65H91NO4: C, 82.14; H, 9.65; N, 1.47. Found: C,
80.82; H, 9.42; N, 1.66.
4.5.6. 2-(5-Anilinopentyl)tetramethoxy-p-tert-butylcalix[4]arene
(5-NH). Reagents: 5-Cl$4/3LiBr (0.994 g, 1.07 mmol); KH (0.201 g,
5.01 mmol); aniline (0.460 g, 0.450 mL, 4.93 mmol). Yield: 0.562 g
(60.4%); 1H NMR:
d 7.36–7.31 (m, 8H), 7.09–7.06 (m, 2H), 6.57–6.54
(m, 3H), 4.63 (t, 1H, 8 Hz), 4.42 (t, 1H, 7 Hz), 4.22 (d, 3H,
2JHH¼12 Hz), 4.08 (s, 6H), 4.06 (s, 6H), 3.51 (d, 2H, 2JHH¼12 Hz), 3.50
(d, 1H, 2JHH¼12 Hz), 3.02 (q, 2H, 7 Hz), 2.19 (m, 2H), 1.59 (pent, 2H,
8 Hz),1.49 (pent, 2H, 8 Hz),1.36 (m, 2H),1.19 (s, 36H); 13C{1H} NMR:
d
151.6, 149.4, 149.3, 139.1, 135.6, 135.5, 129.8, 129.6, 127.1, 126.9,
126.7, 126.5, 123.5, 123.3, 116.8, 116.7, 113.0, 112.9, 65.3, 65.13, 65.08,
64.9, 43.8, 36.4, 35.0, 34.9, 34.2, 31.3, 31.1, 30.1, 29.3, 29.2; IR (cmꢁ1):
3412 (m), 3049 (m), 3020 (m), 2955 (s), 2927 (s), 2864 (s), 2820 (m),
2739 (w), 2708 (w), 2034 (w), 1755 (w), 1603 (w), 1506 (w), 1481
(w), 1463 (w), 1431 (w), 1392 (w), 1362 (w), 1301 (w), 1263 (w),
1246 (w), 1206 (w), 1177 (w), 1125 (w), 1024 (w), 871 (w), 799 (w),
740 (w), 692 (w). HRMS calculated for C59H80NO4 [MþH]þ:
866.6087, found: 866.6060.
4.5.10. 2-(6-(2,6-Dimethylanilino)hexyl)tetramethoxy-p-tert-butyl-
calix[4]arene (6-NMe). Reagents: 6-Cl$4/3LiBr (0.971 g, 1.03 mmol);
KH (0.160 g, 3.99 mmol); 2,6-dimethylaniline (0.502 g, 0.510 mL,
4.13 mmol). Yield: 0.832 g (88.6%); 1H NMR:
d 7.36 (s, 4H), 7.34
4
4
(d, 2H, JHH¼2 Hz), 7.31 (d, 2H, JHH¼2 Hz), 6.93 (d, 2H, 7 Hz), 6.74
(t, 1H, 7 Hz), 4.64 (t, 1H, 8 Hz), 4.24 (d, 3H, 2JHH¼12 Hz), 4.08 (s, 6H),
4.06 (s, 6H), 3.51 (d, 2H, 2JHH¼12 Hz), 3.50 (d, 1H, 2JHH¼12 Hz), 3.23
(br s, 1H), 2.92 (t, 2H, 7 Hz), 2.21 (s, 6H), 2.18 (m, 2H), 1.55 (m, 2H),
1.47 (m, 2H), 1.39–1.26 (m, 4H), 1.20 (s, 18H), 1.19 (s, 18H); 13C{1H}
4.5.7. 2-(5-(2,6-Dimethylanilino)pentyl)tetramethoxy-p-tert-butyl-
calix[4]arene (5-NMe). Reagents: 5-Cl$4/3LiBr (5.063 g, 5.471 mmol);
KH (0.880 g, 21.9 mmol); 2,6-dimethylaniline (2.66 g, 2.70 mL,
NMR:
d 151.44, 151.42, 149.2, 149.1, 146.1, 138.9, 136.8, 135.5, 135.4,
127.1, 126.90, 126.87, 126.84, 126.54, 126.48, 123.2, 123.1, 122.7, 65.0,
64.9, 50.3, 36.2, 34.9, 34.7, 34.0, 31.2, 30.0, 29.9, 29.8, 29.1, 27.5, 24.6,
15.0; IR (cmꢁ1): 3855 (m), 3746 (m), 3674 (w), 3386 (w), 3045 (m),
2975 (s), 2823 (m), 2362 (m), 2034 (w), 1598 (m), 1477 (s), 1362 (m),
1263 (s), 1207 (s), 1119 (m), 1023 (s), 873 (m), 802 (m), 738 (s). HRMS
calculated for C62H86NO4 [MþH]þ: 908.6557, found: 908.6557.
21.9 mmol). Yield: 4.19 g (85.7%); 1H NMR:
d 7.36–7.30 (m, 8H), 6.93
(d, 2H, 7 Hz), 6.73 (t, 1H, 7 Hz), 4.64 (t, 1H, 8 Hz), 4.24 (d, 3H,
2JHH¼12 Hz), 4.09 (s, 6H), 4.06 (s, 6H), 3.52 (d, 2H, 2JHH¼12 Hz), 3.51
2
(d, 1H, JHH¼12 Hz), 3.21 (t, 1H, 7 Hz), 2.91 (q, 2H, 7 Hz), 2.23–2.16
(m, 8H), 1.55 (pent, 2H, 7 Hz), 1.47 (pent, 2H, 8 Hz), 1.35 (m, 2H), 1.20
(s, 18H), 1.19 (s, 18H); 13C{1H} NMR:
d 151.7, 151.6, 149.5, 149.4, 147.4,
147.3, 139.2, 135.7, 135.5, 129.93, 129.87, 129.3, 127.1, 126.7, 123.4,
122.0, 65.3, 65.2, 65.1, 65.0, 48.6, 48.5, 36.4, 35.1, 35.0, 34.2, 31.4, 31.3,
31.1, 31.0, 30.0, 29.3, 27.7, 18.7; IR (cmꢁ1): 3044 (m), 2956 (s), 2928
(s), 2865 (m), 2820 (m), 2035 (w), 1751 (w), 1597 (m), 1584 (w), 1481
(s), 1463 (s), 1432 (m), 1392 (m), 1361 (m), 1299 (m), 1286 (m), 1265
(m), 1245 (m), 1206 (m), 1174 (m), 1124 (m), 1101 (m), 1024 (s), 950
(w), 922 (w), 871 (m), 798 (w), 763 (m), 739 (m), 705 (w), 644 (w),
614 (w). HRMS calculated for C61H84NO4 [MþH]þ: 894.6400, found:
894.6389. Elemental analysis calculated for C61H83NO4: C, 81.92; H,
9.35; N, 1.57. Found: C, 80.10; H, 9.07; N, 1.61.
4.5.11. 2-(6-(2,6-Diethylanilino)hexyl)tetramethoxy-p-tert-butyl-
calix[4]arene (6-NEt). Reagents: 6-Cl$4/3LiBr (0.968 g, 1.03 mmol);
KH (0.160 g, 3.99 mmol); 2,6-diethylaniline (0.616 g, 0.680 mL,
4.13 mmol). Yield: 0.791 g (82.0%); 1H NMR:
d 7.36 (s, 4H), 7.34 (d,
4
4
2H, JHH¼2 Hz), 7.30 (d, 2H, JHH¼2 Hz), 6.97 (d, 2H, 7 Hz), 6.85 (t,
2
1H, 7 Hz), 4.62 (t, 1H, 8 Hz), 4.23 (d, 3H, JHH¼12 Hz), 4.08 (s, 6H),
4.06 (s, 6H), 3.51 (d, 2H, 2JHH¼12 Hz), 3.50 (d, 1H, 2JHH¼12 Hz), 3.14
(br s, 1H), 2.87 (q, 2H, 8 Hz), 2.62 (q, 4H, 8 Hz), 2.16 (q, 2H, 8 Hz),
1.53 (pent, 2H, 8 Hz), 1.40 (m, 4H), 1.33 (m, 2H), 1.19 (s, 18H), 1.18
(s, 18H), 1.14 (t, 6H, 8 Hz); 13C{1H} NMR:
d 151.6, 151.5, 149.4, 149.3,
146.3, 146.2, 139.1, 137.0, 136.9, 135.5, 127.3, 127.0, 126.6, 123.3,
122.89, 122.87, 65.2, 65.0, 50.6, 36.4, 35.0, 34.9, 34.1, 31.30, 31.27,
30.1, 29.9, 29.3, 27.4, 27.3, 24.8, 24.7 15.2; IR (cmꢁ1): 3390 (m), 3183
(w), 3041 (m), 2958 (s), 2820 (s), 2742 (w), 2713 (w), 2681 (w), 2628
(w), 2562 (w), 2304 (w), 2035 (w), 1914 (w), 1851 (w), 1751 (w),
1621 (w), 1593 (m), 1481 (s), 1458 (s), 1392 (m), 1361 (s), 1299 (m),
1285 (m), 1261 (s), 1244 (s), 1205 (s), 1174 (m), 1124 (s), 1115 (s),
1059 (m), 1024 (s), 951 (w), 922 (w), 914 (w), 871 (m), 799 (w), 756
(m), 740 (m), 705 (m), 644 (w), 614 (w). HRMS calculated for
C64H90NO4 [MþH]þ: 936.6870, found: 936.6869.
4.5.8. 2-(5-(2,6-Diethylanilino)pentyl)tetramethoxy-p-tert-butyl-
calix[4]arene (5-NEt). Reagents: 5-Cl$4/3LiBr (0.995 g, 1.08 mmol);
KH (0.208 g, 5.19 mmol); 2,6-diethylaniline (0.734 g, 0.810 mL,
4.92 mmol). Yield: 0.730 g (73.6%); 1H NMR:
d 7.35–7.28 (m, 8H),
6.96 (d, 2H, 8 Hz), 6.83 (t, 1H, 8 Hz), 4.61 (t, 1H, 7 Hz), 4.21 (d, 3H,
2JHH¼12 Hz), 4.07 (s, 6H), 4.05 (s, 6H), 3.51 (d, 2H, 2JHH¼12 Hz), 3.50
(d, 1H, 2JHH¼12 Hz), 3.11 (t, 1H, 7 Hz), 2.83 (q, 2H, 7 Hz), 2.57 (q, 4H,
7 Hz), 2.16 (m, 2H), 1.57 (pent, 2H, 7 Hz), 1.46 (m, 2H), 1.34 (m, 2H),
1.17 (s, 18H), 1.16 (s, 18H), 1.12 (t, 6H, 7 Hz); 13C{1H} NMR:
d 151.4,
149.2, 149.1, 146.1, 138.9, 136.8, 135.5, 135.4, 127.1, 126.9, 126.8, 126.5,
126.4, 123.2, 123.1, 122.7, 65.1, 65.0, 64.9, 64.8, 50.3, 36.2, 34.9, 34.7,
31.2, 30.8, 30.0, 29.8, 29.1, 27.5, 24.6, 15.1; IR (cmꢁ1): 3392 (w), 3042
(m), 2936 (s), 2863 (s), 2820 (m), 2035 (w), 1751 (w), 1619 (w), 1602
(m), 1594 (m), 1584 (m),1480 (s), 1459 (m),1392 (m), 1300 (m), 1286
(m), 1265 (m), 1245 (m), 1204 (s), 1174 (m), 1124 (m), 1023 (m), 950
(w), 871 (m), 798 (m), 739 (m), 705 (w), 645 (w), 615 (w). HRMS
calculated for C63H88NO4 [MþH]þ: 922.6713, found: 922.6690.
4.5.12. 2-(6-(2,6-Diisopropylanilino)hexyl)tetramethoxy-p-tert-butyl-
calix[4]arene (6-NiPr). Reagents: 6-Cl$4/3LiBr (0.967 g, 1.03 mmol);
KH (0.160 g, 3.99 mmol); 2,6-diisopropylaniline (0.73 g, 0.78 mL,
4.1 mmol). Yield: 0.856 g (86.2%); 1H NMR:
d
7.36 (s, 4H), 7.34 (d, 2H,
4
4JHH¼2 Hz), 7.30 (d, 2H, JHH¼2 Hz), 7.05 (d, 2H, 8 Hz), 6.99 (t, 1H,
2
8 Hz), 4.63 (t, 1H, 8 Hz), 4.23 (d, 3H, JHH¼12 Hz), 4.08 (s, 6H), 4.06
(s, 6H), 3.51 (d, 2H, 2JHH¼12 Hz), 3.50 (d, 1H, 2JHH¼12 Hz), 3.28 (sept,
2H, 8 Hz), 3.05 (br s,1H), 2.78 (m, 2H), 2.17 (q, 2H, 8 Hz),1.56 (pent, 2H,
8 Hz), 1.42 (m, 4H), 1.34 (m, 2H), 1.19 (s, 18H), 1.18 (s, 18H), 1.15 (d, 12H,
4.5.9. 2-(5-(2,6-Diisopropylanilino)pentyl)tetramethoxy-p-tert-butyl-
calix[4]arene (5-NiPr). Reagents: 5-Cl$4/3LiBr (0.999 g, 1.08 mmol);
KH (0.202 g, 5.04 mmol); 2,6-diisopropylaniline (0.87 g, 0.93 mL,
8 Hz); 13C{1H} NMR:
d 151.58, 151.57, 149.4, 149.3, 144.6, 143.4, 143.3,
139.1, 135.6, 135.5, 127.0, 126.6, 124.23, 124.20, 124.1, 123.3, 65.2, 65.0,
52.4, 36.4, 35.0, 34.9, 34.1, 31.31, 31.29, 31.1, 30.1, 30.0, 29.3, 27.9, 27.4,
27.3, 24.4, 24.3; IR (cmꢁ1): 3383 (w), 3183 (w), 3045 (m), 2957 (s),
2925 (s), 2866 (s), 2820 (s), 2741 (w), 2713 (w), 2594 (w), 2559 (w),
2035 (w), 1918 (w), 1858 (w), 1751 (w), 1601 (m), 1585 (m), 1481 (s),
4.9 mmol). Yield: 0.921 g (89.8%); 1H NMR:
d 7.34–7.27 (m, 8H), 7.02
(d, 2H, 8 Hz), 6.93 (t, 1H, 8 Hz), 4.61 (t, 1H, 8 Hz), 4.20 (d, 3H,
2JHH¼12 Hz), 4.06 (s, 6H), 4.05 (s, 6H), 3.50 (d, 2H, 2JHH¼12 Hz), 3.49
2
(d, 1H, JHH¼12 Hz), 3.24 (sept, 2H, 7 Hz), 3.02 (t, 1H, 7 Hz), 2.74 (q,

8666
M.P. Hertel et al. / Tetrahedron 65 (2009) 8657–8667
Table 2
1463 (s), 1445 (s), 1392 (m), 1383 (m), 1362 (s), 1300 (m), 1286 (m),
1262 (s), 1246 (s), 1205 (s), 1175 (m), 1148 (m), 1124 (m), 1114 (m), 1055
(m), 1024 (s), 950 (w), 935 (w), 871 (m), 800 (m), 755 (m), 739 (m),
705 (m), 669 (w), 644 (w), 614 (w). HRMS calculated for C66H94NO4
[MþH]þ: 964.7183, found: 964.7180.
Crystal data and collection parameters
Compound
4-NiPr
Formula
Mr
Space group
T [K]
a [Å]
b [Å]
C64H89NO4$2CH3CN
1018.47
P21/n (#14)
140(2)
12.0770(6)
25.390(1)
19.7979(9)
90
99.752(1)
90
4.5.13. 2-(3-(2,5-Dichloroanilino)propyl)tetramethoxy-p-tert-butyl-
calix[4]arene (3-NCl). Reagents: 3-Cl$LiBr (0.200 g, 0.230 mmol); KH
(0.041 g, 1.0 mmol); 2,5-dichloroaniline (0.165 g, 1.11 mmol). Yield:
c [Å]
0.125 g (59.9%); 1H NMR:
d
7.11 (d, 2H, 4JHH¼2 Hz), 7.09–7.04 (m, 6H),
a
b
g
[ꢀ]
[ꢀ]
[ꢀ]
4
3
7.01 (d, 1H, 8 Hz), 6.66 (d, 1H, JHH¼2 Hz), 6.49 (dd, 1H, JHH¼8 Hz,
4JHH¼2 Hz), 4.55 (t, 1H, 8 Hz), 4.36 (m, 1H), 4.15 (d, 3H, 2JHH¼12 Hz),
4.02 (s, 6H), 4.01 (s, 6H), 3.49 (m, 2H), 3.32 (d, 3H, 2JHH¼12 Hz), 2.17
V [Å3]
5983.0(5)
4
1.131
Z
(m, 2H),1.74 (m, 2H),1.07 (s, 36H); 13C{1H} NMR:
d 150.5,148.7 148.5,
rcalcd [g cmꢁ3
]
Diffractometer
Radiation
Monochromator
Detector
Scan type, width
Scan speed
Siemens SMART
145.8, 144.9, 137.3, 134.40, 134.36, 134.3, 129.5, 127.8, 125.82, 125.80,
125.6, 125.2, 122.1, 116.2, 64.7, 64.4, 45.0, 44.8, 43.2, 34.8, 34.2, 31.0,
30.8, 22.3; IR (cmꢁ1): 3422 (m), 2962 (s), 1764 (m), 1596 (s), 1481 (s),
1362 (s), 1296 (s), 1245 (s), 1206 (s), 1178 (m), 1120 (s), 1005 (s), 872
(s), 807 (s), 738 (s), 703 (m).
Mo K
Graphite
CCD area detector
, 0.3ꢀ
a
(l¼0.71073 Å)
u
30.0 s/frame
Hemisphere
2.6–56.7
No. of reflns measd
2q
range [ꢀ]
4.5.14. 2-(4-(2,5-Dichloroanilino)butyl)tetramethoxy-p-tert-butyl-
calix[4]arene (4-NCl). Reagents: 4-Cl$4/3LiBr (1.093 g, 1.199 mmol);
KH (0.144 g, 3.59 mmol); 2,5-dichloroaniline (0.583 g, 3.60 mmol).
Crystal size [mm]
No. of reflns measd
No. of unique reflns
No. of observations
No. of parameters
R, Rw, Rall
0.26ꢂ0.14ꢂ0.09
68,306
14,929
6282
706
0.0636, 0.1540, 0.1429
0.795
Yield: 0.662 g (60.0%); 1H NMR:
d 7.35–7.33 (m, 6H), 7.28 (d, 2H,
4
4JHH¼2 Hz), 7.15 (d, 1H, 8 Hz), 7.00 (d, 1H, JHH¼2 Hz), 6.67 (dd, 1H,
4
3JHH¼8 Hz, JHH¼2 Hz), 4.73 (m, 1H), 4.60 (t, 1H, 8 Hz), 4.19 (d, 3H,
GOF
2JHH¼12 Hz), 4.04 (s, 12H), 3.60 (m, 2H), 3.53 (d, 3H, JHH¼12 Hz),
2
2.19 (m, 2H), 1.83 (m, 2H), 1.43 (m, 2H), 1.16 (s, 36H); 13C{1H} NMR:
d
151.54, 151.52, 149.51, 149.50, 149.4, 139.9, 135.6, 135.5, 134.4, 130.9,
the X-ray beam, and cooled to 140 K using a nitrogen-flow low-
temperature apparatus that had been previously calibrated by
a thermocouple placed at the same position as the crystal. An
127.0,126.8,126.7,123.4,116.5,115.4,111.3, 65.0, 64.8, 45.7, 43.4, 36.4,
35.0, 31.3, 31.2, 31.0, 30.0, 26.5; IR (cmꢁ1): 3854 (w), 3746 (w), 3674
(w), 3387 (m), 3046 (m), 2959 (s), 2823 (m), 2362 (m), 2033 (w),
1699 (w), 1596 (s), 1480 (s), 1362 (m), 1264 (s), 1206 (s), 1119 (m),
1023 (s), 873 (m), 792 (m), 739 (m). HRMS calculated for
C58H76Cl2NO4 [MþH]þ: 920.5151, found: 920.5141.
arbitrary hemisphere of data was collected using 0.3ꢀ
u
-scans that
were counted for a total of 30 s per frame. The datawas integrated by
SAINT58 to a maximum 2 of 56.7ꢀ, and the final unit cell parameters
were determined by a least-squares refinement of 5207 reflections
with I>10
(I). Data analysis using Siemens XPREP59 gave a primitive
q
s
4.5.15. 2-(5-(2,5-Dichloroanilino)pentyl)tetramethoxy-p-tert-butyl-
calix[4]arene (5-NCl). Reagents: 5-Cl$4/3LiBr (0.925 g, 1.00 mmol);
KH (0.120 g, 3.00 mmol); 2,5-dichloroaniline (0.486 g, 3.00 mmol).
monoclinic cell and based on the successful solution and refinement
of the structure, the space group was determined to be P21/n (#14).
Of the 68,306 reflections that comprised the hemisphere,14,929
were unique (Rint¼0.3096), and all equivalent reflections were av-
eraged. The structure was solved by direct methods using the
SHELXTL60 software package. The unit cell contained two molecules
of acetonitrile. One was located in open space, while the other was
localized within the calix[4]arene cone. All non-hydrogen atoms
were refined anisotropically. Hydrogen atoms were included in
fixed positions. The final cycle of full-matrix least-squares
refinement was based on 6282 observed reflections and 706 vari-
able parameters and converged yielding final residuals: R¼0.0636,
Rall¼0.1429, and GOF¼0.795.
Yield: 0.683 g (73.0%); 1H NMR:
d 7.33–7.30 (m, 6H), 7.21 (d, 2H,
4JHH¼2 Hz), 7.14 (d, 1H, 8 Hz), 6.56 (d, 1H, 4JHH¼2 Hz), 6.51 (dd, 1H,
3JHH¼8 Hz, JHH¼2 Hz), 4.72 (t, 1H, 7 Hz), 4.54 (t, 1H, 7 Hz), 4.14
4
2
(d, 3H, JHH¼12 Hz), 4.01 (s, 6H), 4.00 (s, 6H), 3.49 (d, 3H,
2JHH¼12 Hz), 3.06 (q, 2H, 7 Hz), 2.10 (q, 2H, 7 Hz), 1.54 (pent, 2H,
7 Hz), 1.39 (pent, 2H, 7 Hz), 1.29 (pent, 2H, 7 Hz), 1.11 (s, 18H), 1.10
(s, 18H); 13C{1H} NMR:
d 151.50, 151.47, 151.4, 149.4, 149.34, 149.32,
139.06, 139.03, 135.6, 135.4, 127.0, 126.6, 126.5, 123.4, 123.3, 111.2,
64.84, 64.80, 45.9, 43.4, 36.3, 35.0, 34.8, 32.7, 31.3, 31.2, 31.15, 31.10,
30.0, 27.4; IR (cmꢁ1): 3847 (w), 3746 (w), 3660 (w), 3422 (w), 3172
(w), 3073 (m), 2958 (s), 2819 (m), 2362 (m), 2034 (w), 1740 (w),
1694 (w), 1596 (s), 1479 (s), 1362 (m), 1260 (s), 1206 (s), 1112 (s),
1022 (s), 872 (m), 803 (m), 738 (m). HRMS calculated for
C59H78Cl2NO4 [MþH]þ: 934.5308, found: 934.5269.
Crystallographic data (excluding structure factors) for the
structure in this paper has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC 734236. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
þ44 (0)1223 336033 or email: deposit@ccdc.cam.ac.uk).
4.6. Crystallography
A summary of crystal data and collection parameters for the
crystal structure of 4-NiPr is provided in Table 2. A detailed de-
scription of data collection, as well as data solution, is provided
below. The ORTEP diagram was generated with the ORTEP-3 soft-
ware package.56
Acknowledgements
We gratefully acknowledge The University of Toledo for gener-
ous start-up funding, as well as Dr. Kristin Kirschbaum (University
of Toledo) for assistance with X-ray crystallography. We thank the
Denison University Research Foundation and Denison University
for support of this research. Additionally, we thank Michael J.
Hardman and Ashley M. Thomas for their efforts in the de-
velopment of the synthetic protocols for compounds 3-I to 5-I.
X-ray quality crystals were grown from a solution of acetonitrile
at ꢁ25 ꢀC.
A
colorless crystalline rod with dimensions
0.26ꢂ0.14ꢂ0.09 mm was mounted on a pulled glass fiber using
Paratone-N hydrocarbon oil. The crystal was transferred to a Sie-
mens SMART57 diffractometer with a CCD area detector, centered in

M.P. Hertel et al. / Tetrahedron 65 (2009) 8657–8667
29. Agbaria, K.; Biali, S. E. J. Am. Chem. Soc. 2001, 123, 12495–12503.
8667
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