Do commercially available metal salts mediate calixarene formation via hydrogen-bonded dimers?

Article abstract of DOI:10.1021/jo200927v

In this article we report the first example of a Lewis acid promoted, one-pot, Bronsted acid free, high-yielding synthesis of the calixarene macrocycle from the "monomer" p-tert-butylphenol. We report that when a commercially available metal salt (Lewis acid) is incorporated within the calixarene-forming reaction, a certain amount of control over the size of the calixarenes produced can be gained. Although a detailed mechanistic rationale on how the macrocycle is assembled is unclear, what is evident fro this work is that the metal cation, the counteranion, and the oxidation state of the salt employed are all important contributors to the outcome of the reaction process. Indeed, evidence to date suggests that a subtle "symbiotic" relationship exists between the metal cation, its oxidation state, and the anion that allows the efficient transformation of the "monomeric" p-tert-butylphenol into linear oligomers and, ultimately, into macrocyclic calixarenes. Athough the metal salt mediated process described herein is efficient and high-yielding, what is also fundamentally important is that a comprehensive mechanistic understanding of how the calixarenes are assembled be accrued. Searching for possible indicators or clues, we propose that oligomeric methylene-linked phenolic entities are initially formed and that these, we tentatively suggest, generate metal and/or anion hydrogen-bonded supramolecular intermediates. It is possible that the preorganization of the linear polyphenolic oligomers allows the formation of hydrogen-bonded structures which, critically, result in the formation of supramolecular assemblies that are subsequently "stitched" together, generating the p-tert-butylcalix[n] arenes (n = 4-9) in excellent yields. Substantiating the possibility that hydrogen-bonded entities are generated (and that these subsequently afford metal-templated assemblies), we make reference to a seldom cited 1962 Nature publication that reported the propensity of polyphenolic linear oligomers to form "well-defined intramolecularly hydrogen-bonded conformations".

Full text of DOI:10.1021/jo200927v

ARTICLE
pubs.acs.org/joc
Do Commercially Available Metal Salts Mediate Calixarene Formation
via Hydrogen-Bonded Dimers?
Sean P. Bew* and Sunil V. Sharma
School of Chemistry, University of East Anglia, Norwich, NR4 7TJ, U.K.
S Supporting Information
b
ABSTRACT: In this article we report the first example of a Lewis
acid promoted, one-pot, Brønsted acid free, high-yielding synth-
esis of the calixarene macrocycle from the “monomer” p-tert-
butylphenol. We report that when a commercially available metal
salt (Lewis acid) is incorporated within the calixarene-forming
reaction, a certain amount of control over the size of the
calixarenes produced can be gained. Although a detailed mechan-
istic rationale on how the macrocycle is assembled is unclear,
what is evident from this work is that the metal cation, the
counteranion, and the oxidation state of the salt employed are all
important contributors to the outcome of the reaction process.
Indeed, evidence to date suggests that a subtle “symbiotic” relationship exists between the metal cation, its oxidation state, and the
anion that allows the efficient transformation of the “monomeric” p-tert-butylphenol into linear oligomers and, ultimately, into
macrocyclic calixarenes. Athough the metal salt mediated process described herein is efficient and high-yielding, what is also
fundamentally important is that a comprehensive mechanistic understanding of how the calixarenes are assembled be accrued.
Searching for possible indicators or clues, we propose that oligomeric methylene-linked phenolic entities are initially formed and
that these, we tentatively suggest, generate metal and/or anion hydrogen-bonded supramolecular intermediates. It is possible that
the preorganization of the linear polyphenolic oligomers allows the formation of hydrogen-bonded structures which, critically, result
in the formation of supramolecular assemblies that are subsequently “stitched” together, generating the p-tert-butylcalix[n]arenes
(n = 4ꢀ9) in excellent yields. Substantiating the possibility that hydrogen-bonded entities are generated (and that these
subsequently afford metal-templated assemblies), we make reference to a seldom cited 1962 Nature publication that reported
the propensity of polyphenolic linear oligomers to form “well-defined intramolecularly hydrogen-bonded conformations”.
’ INTRODUCTION
require a sterically encumbered phenol (e.g. 1), a source of
formaldehyde, a suitable solvent, and a catalytic quantity of, for
example, p-toluenesulfonic acid or hydrochloric acid in the case
of (i) and an alkali-metal hydroxide, for example sodium hydro-
xide, for (ii).8 Interestingly it was assumed until relatively recently
(i.e. 1990) that the reaction between p-alkylphenols and for-
maldehyde afforded only high yields of linear oligomers under
acidic conditions.9 However, in a painstaking piece of ground-
breaking research Gutsche et al. demonstrated that employing
a Brønsted acid (PTSA) under specific reaction conditions
afforded a high-yielding, complex mixture of p-tert-butylcalix-
[n]arenes (n = 4ꢀ20).
The first most probable reported synthesis of the calixarene
macrocycle was in 1872 by Albert von Baeyer1 and later by Zinke
in 1944.2 Calixarenes are one of the most studied and widely
utilized synthetic hosts, their interesting structures lending them-
selves to a plethora of applications in synthetic,3 material,4
analytical,5 supramolecular,6 and biological chemistries.7 Further-
more, their use as a versatile platform is enhanced by the ability of
p-tert-butylcalix[4]arene to be transformed, at will, into a cone,
partial cone, or 1,3- or 1,2-alternate conformation and also the ease
with which it is possible to introduce diverse chemical function-
ality to either the lower rim or upper rim or both.
Given the importance of calixarenes, the time they have been
known (viz. 139 years), and their widespread utility, it is
interesting that there is considerable debate on exactly how the
macrocyclic entities are assembled and the driving force for the
chemoselective formation of certain ring sizes: i.e., p-tert-
butylcalix[n]arenes (n = 4, 6, 8) are often generated in preference
to, for example, p-tert-butylcalix[n]arenes (n = 7, 9, 10). Three
protocols are available for calixarene synthesis, utilizing one of
the following: (i) a Brønsted acid, (ii) an alkali-metal hydroxide,
and (iii) a Lewis acid. The first two are one-pot procedures that
Alternatively, depending on the size of the calixarene desired
and utilizing a catalytic quantity of sodium or potassium hydro-
xide in conjunction with defined reaction conditions, the efficient,
high-yielding synthesis of specific p-tert-butylcalix[n]arenes (i.e.
n = 4, 6, 8) is straightforward.8,10
As far as the author is aware, no mechanistic rationale has been
forwarded that attempts to explain macrocycle formation under
Received: May 21, 2011
Published: July 15, 2011
r
2011 American Chemical Society
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|

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ARTICLE
Scheme 1. Synthesis of 2 without the Use of a Brønsted Acid
or Alkali-Metal Hydroxide Salt
Table 1. Investigation of Group 1A and Group IIA Triflate
Salts for Their Ability To Afford Calixarenes
amt, %
entry no., triflate salt
1
linear oligomers
calix[4ꢀ9]arenec
1, Li+a,b
2, Na+a
100
96
4
3, Na+b
4, K+b
26.5
69.5
100
100
13.4
61.2
15.1
11.7
15.4
5, Rb+a,b
6, Cs+a,b
7, Mg2+a
8, Mg2+b
9, Ca2+b
10, Ba2+a,b
Brønsted acid reaction conditions. Furthermore, although there
is somewhat more of an understanding around the cyclooligo-
merization process using basic catalysts, this process is “far from
being well understood”11 with “metal cation template effects” or
“molecular mitosis” assemblies being invoked to account for the
formation of specific calix[n]arenes.
Relative to the Brønsted acid or alkali-metal hydroxide meth-
ods recounted, the application of Lewis acids for p-tert-butylcalix-
[n]arene synthesis has remained relatively dormant, with the
majority of protocols employing titanium(IV) chloride and
directed toward convergent [2 + 2], [2 + 1 + 1], or [3 + 1]
calix[4]arene syntheses. It is difficult to pinpoint exactly why
convergent syntheses are seldom employed, but it may, in part,
be due to the number of “preliminary” reactions required for
constructing the starting materials and the often low to moderate
yields of calixarenes that result.12 Furthermore, similar to
Brønsted acid mediated protocols and the results reported here
(vide infra) a precise mechanistic rationale that fully explains, in
detail, how titanium(IV) chloride mediates calixarene formation
has yet to be reported/elucidated.
Calixarene research in our laboratory focuses on (i) generating
new calixarene motifs with bespoke functionality13 and (ii) dis-
secting and elucidating the mechanisms surrounding the con-
struction of these fascinating macrocyclic entities assembled via
“conventional” (i.e., those that employ alkali-metal hydroxides)
and “nonconventional” procedures. We have, for example,
recently reported that the Lewis acid tin(IV) chloride is a highly
efficient reagent for the synthesis of p-tert-butylcalix[n]arenes
(n = 8, 9) from p-tert-butylphenol.13 In this high-yielding process
these two calixarenes are the major constituents of the reaction
mixture, with the hard to generate p-tert-butylcalix[9]arene being
formed with exceptional ease. It is worth pointing out that in this
one-pot reaction process 18 (for calix[9]arene) and 16 (for
calix[8]arene) new CꢀC bonds are generated! Be that as it may,
a mechanism that explains their formation has yet to be deci-
phered and is still an ongoing concern within our laboratory.
Indeed, it was during our efforts at attempting to understand the
mode of action of tin(IV) chloride, as well as alternative Lewis
acids, in conjunction with our long-term goal of developing an
efficient and generic non-Brønsted acid or non alkali-metal hydro-
xide mediated synthesis of entities based on 2 (Scheme 1) that the
“metal salt effect” outlined here presented itself. Thus, using metal
triflate or tetrafluoroborate salts, trioxane, and microwave irradia-
tion, the efficient, high-yielding, and chemoselective cyclic oligo-
merization of 1 into macrocycles 2 has been achieved (Scheme 1) in
the first example of a Lewis acid promoted, one-pot, Brønsted acid free
synthesis of 2 from “monomer” 1.
1.9
6.5
2.9
84.0
90.4
90.2
3.0
5.5
100
a 20 mol % metal triflate. b 100 mol % metal triflate. c HPLC analysis is
given in the Supporting Information.
and neodymium(III) triflates could mediate the reaction out-
lined in Scheme 1. We envisaged their application as being
multifaceted, acting as bifunctional Lewis acids capable of, in the
first instance, promoting the retrocyclization of trioxane (aiding
in situ formation of formaldehyde) and subsequently as coordi-
nating agents of the precursors to 2 or linear oligomers derived
from 1, allowing a “metal template”14 effect to be established that
aided the formation of 2. Initial results were disappointing.
Subjecting 1, trioxane, and individual catalytic quantities of
zinc(II), ytterbium(III), or neodymium(III) triflate (20 mol %)
to microwave irradiation (120 °C) for 30 min in DCM returned
p-tert-butylphenol (1) with good mass balances.15 Furthermore,
increasing the number of equivalents of trioxane (3 equiv) and
Lewis acid (1 equiv), the temperature (from 80 to 150 °C), and
the reaction time (up to 120 min) all resulted in no detectable
formation of 2 or linear oligomers based on uncyclized 2.
Changing tack, we opted to investigate triflate salts derived
from group IA metals, i.e. lithium, sodium, potassium, cesium,
and rubidium (increasing metal radii and electropositive nature),
and group IIA metals, i.e. calcium, magnesium, and barium
(Table 1). It is known that K+ and in particular Na+ bind well
to the phenolic hydroxyl groups on p-tert-butylcalix[4]arenes (cf.
template effect12).
Employing a catalytic quantity (20 mol %) of lithium triflate or
sodium triflate or a stoichiometric quantity of lithium triflate with
1 and trioxane (1 equiv) afforded only starting material (30 min,
120 °C, microwave, entries 1 and 2, Table 1). When this reaction
was repeated with 1 equiv of sodium triflate, 2 was generated in
11.7% yield (entry 3, Table 1). Although the yield of 2 was low,
we were buoyed by this exciting preliminary result, which
indicated for the first time that p-tert-butylcalix[n]arenes could
indeed be generated in the absence of any Brønsted acid and in a
one-pot reaction process. With a view to probing the mechanistic
nature associated with the formation of 2 and the importance of
the Na+ cation within the condensation reaction, it was repeated
(Scheme 1) using stoichiometric quantities of sodium triflate and
the Na+ complexing agent 15-crown-5. The reaction afforded
only starting material 1, in an almost quantitative yield. Thus, it
seemed the complexing ability of 15-crown-5 for Na+ effectively
shut down the (presumably) initial condensation reaction be-
tween 1 and formaldehyde or its precursor. This being the case, it
was perhaps not too unexpected that the linear oligomerization
’ RESULTS AND DISCUSSION
Initiating our work, we investigated the possibility that com-
mercially available metal triflate salts such as zinc(II), ytterbium(III),
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ARTICLE
and macrocyclization reaction products, i.e. 2, were not observed.
Repeating this reaction using more forcing conditions, i.e. 120 °C
for an extended 60 min time period, did not afford 2. We
pondered the outcome that switching from Na+ to K+ (ionic
radii 1.13 and 1.51 Å, respectively) would have not only on the
yield of 2 but also on the ratios of individual p-tert-butylcalix-
[n]arenes within 2 (vide infra). Exchanging sodium triflate for
potassium triflate (1 equiv) returned 2 in a disappointing 15.4%
yield (entry 4) and a similarly low yield of linear oligomers (i.e.
15.1%. The mass balance of the reaction mixture comprised
starting material 1. From a mechanistic point of view it is
interesting to note the 4:1 ratio difference between the linear
oligomers in entries 3 and 4 (Table 1). Clearly, switching K+ for
Na+ had a significant and detrimental effect on the ability of the
reaction to generate linear oligomers and, presumably, 2. Seeking
an explanation that accounted for the ability of sodium triflate to
generate 61% of linear oligomers (in contrast to potassium
triflate) and the fact that water is generated in transforming 1
into 2 (Scheme 1), we considered the possibility that the Na+
formed hydrated Na+ cations which acted as supramolecular
scaffolds or templates on which linear oligomers and/or calixar-
enes could form. The primary hydration numbers for Li+, Na+,
and K+ are all 4 (others are also possible), and the hydrated radii
of the Na+ and K+ cations are 2.76 and 2.32 Å, respectively. Thus,
given the fact that these cations have identical primary hydration
numbers and similar hydrated radii, it seems unlikely that this
could be invoked to explain the formation of differing ratios of
linear oligomers and yields of calixarenes. Utilizing catalytic or
stoichiometric quantities of rubidium or cesium triflate (entries 5
and 6, Table 1) returned starting material 1 in quantitative yields.
Switching to group IIA triflate salts (M2+ ions are smaller and
considerably less polarized than the isoelectronic M+ ions),
magnesium triflate (entry 7, Table 1, 20 mol %) afforded 2 in a
significantly enhanced 84% yield, with only 1.9% of linear
oligomers and 13% of 1. Gratifyingly, increasing the amount of
magnesium triflate still further to 1 equiv afforded an excellent
90% yield of 2 (entry 8, Table 1).
Similar to the case for magnesium triflate, switching to calcium
triflate afforded 2 in an excellent 90% yield (entry 9, Table 1).
Thus, it seemed that the M2+ (M = group IIA) triflate salts (ionic
radii of 0.71 Å for Mg2+ and 1.14 Å for Ca2+) are more effective
than group IA triflate salts at generating macrocycles based on 2.
Barium triflate consistently returned starting material 1.
Given that the solubility of magnesium or calcium triflate in
dichloromethane is likely to be very low, even at 120 °C, it seems
reasonable to assume that the reaction process which generates,
very effectively, linear oligomers and 2 using these salts is
heterogeneous in nature. Thus, the lack of barium triflate
solubility in DCM does not appear to be a likely reason for the
observed lack of reaction: i.e., no linear oligomers or 2 formed
when barium triflate is employed. At this point in time it is
unclear why barium triflate does not afford any linear oligomers
or 2. Furthermore, speculating that the lack of reaction can be
attributed to the large ionic radius of Ba2+ (i.e. 1.49 Å) makes it
hard to explain why K+, with a similar ionic radius (i.e. 1.51 Å),
affords a reasonable yield of linear oligomer and 2.
Table 2. HPLC Analysis of 2 Synthesized using Group IA and
IIA Metal Triflates
amt, %
entry no., triflate salt
[4]c
[5]c
[6]c
[7]c
[8]c
[9]c
1, Na+b
2, K+b
3, Mg2+a
4, Mg2+b
5, Ca2+b
1.2
5.7
3.0
0.2
1.2
3.5
1.2
1.8
2.8
2.2
0.7
3.5
6.0
32.8
24.8
6.6
6.6
4.2
39.2
40.2
40.0
11.5
8.2
2.2
8.2
15.5
18.8
a 20 mol % metal triflate. b 100 mol % metal triflate. c HPLC analysis is
given in the Supporting Information.
reaction the group IA Na+ cation, which is generally considered a
good “template” for p-tert-butylcalix[4]arene synthesis,12 is in-
ferior to a group IIA Mg2+ cation, which affords substantially
larger percentages of p-tert-butylcalix[4]arene within 2 (cf. 1.2%
for Na+). Worthy of particular note is the contrast between the
hard, oxophilic Mg2+ and the Ca2+ cation. Mg2+ (when present in
catalytic or stoichiometric quantities; entries 3 and 4, respec-
tively) affords substantially larger percentages of p-tert-butylcalix-
[4]arene within 2 than does Ca2+ (cf. 6.6%). Indeed, under
catalytic reaction conditions magnesium triflate afforded the
highest percentage of p-tert-butylcalix[4]arene of any of the
group IA and IIA salts. Furthermore, employing either catalytic
(20 mol %) or stoichiometric quantities of magnesium triflate
returned p-tert-butylcalix[8]arene in 39.2% and 40.2% yields,
respectively, both of which are essentially identical with the
percentage generated using calcium triflate. Worthy of note are
the increased percentages of p-tert-butylcalix[n]arene (n = 7, 9;
18.8% and 8.2%, respectively, entry 5, Table 2) afforded using
calcium triflate in comparison with the percentages generated
using magnesium triflate (cf. entries 3 and 4, Table 2). It is
interesting to contrast Mg2+ with the more electro(di)positive
and larger Ca2+ (extra 3p6 and 4s2 shells) in their abilities to
coordinate longer linear oligomers and thus afford (generally)
larger percentages of p-tert-butylcalix[n]arenes (n = 6ꢀ9).
We were concerned that the hydrolysis of a triflate salt
(perhaps via 1) could afford triflic acid that may, via a Brønsted
acid mediated process, afford 2.9 Investigating this, we reacted
p-tert-butylphenol (1) and trioxane with (i) stoichiometric and
(ii) catalytic quantities of triflic acid. Major decomposition
was observed when a stoichiometric quantity of triflic acid
was employed. Likewise, with 20 mol % of triflic acid a dark
precipitate formed and significant decomposition was observed.
Repeating the triflic acid mediated catalytic reaction (20 mol %)
at ambient temperature (6 h) returned unreacted 1 in an 80%
yield and p-tert-butylcalixarenes 2 in a poor 10% yield. Given
these results, i.e. dark reaction mixtures, significant decomposi-
tion, copious amounts of precipitation, and low yields, it seemed
unlikely that our efficient reaction process could be attributed to
in situ triflic acid synthesis that, subsequently, mediates forma-
tion of 2. Thus, the evidence to date seemed to suggest that the
metal salt mediated process was proceeding via a template effect
and that different metal cations derived from within group IA or
IIA and between groups IA and IIA have a significant influence on
the chemoselectivity of the reaction process that generates 2.
Intrigued by these positive results, we felt compelled to
explore alternative, readily available metal salts derived from
copper, lanthanum, and the group IVb element tin. Of specific
When 3, 4, and 7ꢀ9 were subjected to HPLC analysis
(Table 2), several observations were evident.16 Of particular
note is the substantial difference in p-tert-butylcalix[n]arene
(n = 4, 8) composition in entries 1 and 2 (derived from Na+
and K+ group IA salts, respectively; Table 2) and entries 3ꢀ5
(Mg2+ and Ca2+ group IIA salts; Table 2). Evidently in this
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Table 3. Investigating Metal Triflate Salts 11ꢀ14 for Their
Ability To Promote the Efficient Synthesis of 2
Table 5. Investigation of Salts 15ꢀ17 for Their Ability To
Promote the Synthesis of 2
amt, %
amt, %
entry no., triflate salt ORP, e
1
linear oligomer b calix[4ꢀ9]areneb
entry no., salt
1
linear oligomer b
calix[4ꢀ9]areneb
11, CuOTf a
+0.52
7.3
7.5
4.2
0.6
2.5
84.3
84.5
93.6
94.7
15, Zn(BF4)2
1.0
3.8
7.8
23.0
17.4
46.5
75
a
a
a
12, Cu(OTf)2
+0.15 10.4
16, CuBF4
77.6
45.5
a
a
13, Sn(OTf)2
ꢀ0.24
ꢀ2.52
5.6
3.0
17, Pb(BF4)2
14, La(OTf)3
a 100 mol % metal triflate. b HPLC analysis is given in the Supporting
Information.
a
a 20 mol % metal triflate. b HPLC analysis is given in the Supporting
Information.
Table 6. HPLC Analysis of 2 Synthesized via Metal Tetra-
fluoroborate Salts 15ꢀ17
Table 4. HPLC Analysis of 2 Synthesized using Metal Triflate
Salts 11ꢀ14
amt, %
amt, %
entry no., BF4 salt
[4]
[5]
[6]
[7]
[8]
[9]
entry no., triflate salt
[4]b
[5]b
[6]b
[7]b
[8]b
[9]b
1, Zn2+
2, Cu+
3, Pb2+
7.7
8.3
5.7
4.8
0.5
15.1
16.2
7.2
21.9
21.6
1.6
15.9
17.5
19.4
6.7
9.2
1, Cu+a
2, Cu2+a
3, Sn2+a
4, La3+a
29.2
32.4
21.4
21.7
4.8
3.2
4.7
3.8
12.2
6.4
7.6
4.0
9.6
9.1
29.5
38.5
42.0
47.0
1.0
16.8
13.9
10.9
2.0
2.2
(n = 6, 7) as the copper(II) triflate, while the percentage of p-tert-
butylcalix[4]arene generated was, more or less, the same for both
copper(I) and copper(II) triflates (compare entries 1 and 2,
Table 4). Second, of all the salts tested, lanthanum(III) triflate
returned the largest percentage, i.e., 47% of p-tert-butylcalix-
[8]arene, via a reaction that afforded the highest yield of 2, i.e.
95% (entry 4, Table 4). With this latter observation in mind, it is
worth noting the general trend for larger amounts of p-tert-
butylcalix[8]arenes (entries 1ꢀ4, Table 4, descending order
observed for the [8] column) as the redox potentials of the
metal triflate salts decrease, i.e. 29.5% Cu+ +0.52e, 38.5% Cu2+
+0.15e, 42% Sn2+ ꢀ0.24e, and 47% La3+ ꢀ2.52e, as well as for
the formation of smaller percentages of p-tert-butylcalix[4]arene.
Repeating our standard reaction (Scheme 1) with a stoichio-
metric quantity of zinc(II), copper(I), or lead(II) tetrafluorobo-
rate (Table 5) afforded 2 in moderate (i.e. ∼45%) to good (i.e.
∼77%) yields. Of the three tetrafluoroborate salts tested, copper-
(I) tetrafluoroborate (entry 16, Table 5) afforded the highest
yield of 2 and lowest percentage yield of linear oligomers.
Furthermore, of particular note is the aptitude of zinc(II) (15)
and lead(II) tetrafluoroborate (17) to afford 2 at all. Indeed, the
ability of 15 and 17 (Table 5) to afford 2, albeit both in lower
yield than when 16 was employed, was in sharp contrast to the
case for zinc(II) triflate, which afforded only starting material 1.
Intriguingly, this observation suggests the possibility that a subtle
anion recognition effect is operating, with a successful reaction
dependent on not only the type of cation employed but also the
anion associated with the cation. It is interesting to note the
difference in yields between zinc(II) triflate (cf. 0%) and zinc(II)
tetrafluoroborate which, under otherwise identical reaction con-
ditions, afford 2 in 75% yield.
a 20 mol % metal triflate. b HPLC analysis is given in the Supporting
Information.
interest was the feasibility of increasing any chemoselective
nature displayed by these salts such that we enhance the
formation of specific p-tert-butylcalix[n]arenes: cf. our previous
report using tin(IV) chloride for the synthesis of p-tert-butylcalix-
[n]arene (n = 8, 9).13c Thus far, all successful applications had
explored the use of single metal salt species in only one oxidation
state: i.e., +1 (group 1A) or +2 (group IIA). Changing tack, we
considered the possibility of incorporating one metal salt that was
readily available in two oxidation states. Copper(I) and copper(II)
triflates are both commercially available and are ideally suited to
probing the effect that a decreasing ionic radius (Cu+ (0.74 Å) to
Cu2+ (0.71 Å)) and different oxidation states would have, if any,
on the formation of 2. Gratifyingly, catalytic quantities of either
copper(I) or copper(II) triflate afforded essentially identical
yields of 2: i.e. 83.3% and 84.5% (entries 11 and 12, respectively,
Table 3). Similarly, tin(II) triflate (ionic radius 1.12 Å) returned a
93.6% yield of 2 (entry 13), while lanthanum triflate (ionic radius
1.17Å) returned 2 in an excellent 94.7% yield (entry 14,
Table 3). Worthy of note is the fact that, broadly speaking, the
ionic radii of these metal salts are similar to those of Mg2+ and
Ca2+ and that collectively all of these salts afforded excellent
yields of 2. Furthermore, as the redox potentials (ORP) of the
metal salts in 11ꢀ14 decrease, i.e. Cu(I) +0.52e, Cu(II) +0.15e,
Sn(II) ꢀ0.24e, and La(III) ꢀ2.52e (Table 3), the yields of 2
steadily increase from ∼84% to ∼95%. These interesting and
unoptimized results suggest that perhaps the size of the metal
cation and its oxidation state play a key role in the efficient
formation of 2.
HPLC analysis of the calixarenes resulting from 15ꢀ17 are
outlined in Table 6. On comparison of these results with those in
Table 4 derived from the triflate salts it is evident that zinc(II) or
copper(I) tetrafluoroborate (Table 6, entries 1 and 2, respec-
tively) afford a near 3- to 4-fold decrease in the percentage of
p-tert-butylcalix[4]arene generated when 11ꢀ14 (stoichiometric
quantities) were employed. This is in stark contrast to the signi-
ficant 2.5ꢀ5.5-fold increase in p-tert-butylcalix[7]arene generated
HPLC analysis of 11ꢀ14 (Cu+, Cu2+, Sn2+, and La3+,
respectively) are outlined in Table 4. As a first observation, it is
interesting to note the difference in the percentages of p-tert-
butylcalix[n]arene (n = 6, 7) when stoichiometric quantities of
copper(I) and copper(II) triflate are employed. The copper(I) trif-
late afforded approximately twice as much p-tert-butylcalix[n]arene
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Scheme 2. Possible Synthesis of “Dimer” 22 via a Lewis Acid Assisted Reaction Process
using zinc(II) tetrafluoroborate 15 (i.e. 21.9%; entry 1, Table 6)
or copper(I) tetrafluoroborate 16 (i.e. 21.6%; entry 2, Table 6):
cf. 4% using copper(II) triflate (entry 2, Table 4). Furthermore,
there is a 6ꢀ9-fold increase in p-tert-butylcalix[9]arene when 15
or 16 is used: i.e., compare entries 1 and 2 in Table 4 with entries
1 and 2 in Table 6. Turning our attention to lead(II) tetrafluor-
oborate, 17 mediated the formation of a very low percentage of
p-tert-butylcalix[n]arene (n = 5, 7), i.e. 0.5 and 1.6% (entry 3,
Table 6); furthermore, in comparison to 15 and 16, 17 generated
a significantly higher 16.8% of p-tert-butylcalix[4]arene.
At the present time it is unclear exactly how the calixarenes are
assembled. However, clues can be gleaned from the literature on
the synthesis and properties of methylene-linked polyphenols.
Of particular relevance, Casnati et al. has reported the regiose-
lective synthesis of o-hydroxymethylene-substituted phenols via
a template-driven reaction between aryloxymagnesium bromides
and formaldehyde.17 With this and the work of Casiraghi et al.18
in mind, it seems likely the first step toward generating 2 is the
synthesis of a linear “dimer” and “trimer” based on 22 and 23
(Scheme 2). Presumably the Lewis acid acts as a bifunctional
catalyst, facilitating in situ formaldehyde synthesis via activation
and retrocyclization of trioxane (19, boxed part in Scheme 2), but
also enables subsequent coordination of the formaldehyde and
the p-tert-butylphenol, allowing them to react and generate a
metal chelate complex similar to 20 (Scheme 2). Subsequent
rearrangement of 20 affords a reactive o-quinone methide species
(i.e. 21) that reacts with 1, generating dimer 22. Utilizing 22 as
the “core oligomer” starting material and repeating this sequence
of reaction events allows the formation of homologated trimers:
i.e., 23, tetramer, pentamer, etc. With these “core” building
blocks in place, their subsequent transformation into calixarenes
based on 2 can occur.
22 and 23 into hydrogen-bonded dimers 24 and 25, respectively,
to be a viable, potentially important process that in conjunction
with cationic and or anionic recognition processes (vide infra)
may offer a possible rationale for the formation of 2.
Our preliminary results suggest that the efficient formation of
2 is dependent on the metal cationic center and to a certain
extent the anion associated with the cation of the Lewis acid
employed. Searching for a possible mechanistic rationale for the
formation of 2, it is interesting to note that single and multiple
cationic metal centers are known to coordinate with phenols
such as 22 and 23. For example Vicens and Masci et al. have
reported21 that multiphenolic ligands similar to 22 and 23
efficiently bind, in some cases multiple, metal cations, affording
large cyclic complexes that are held together via hydrogen
bonding and metalꢀheteroatom coordination (see Figure 5 in
ref 21).
With the propensity for oligomeric phenols to undergo
hydrogen bond dimerization (cf. Figure 1) as well as their ability
to efficiently coordinate cationic metals in mind, it seems plau-
sible that if these two processes were combined, then a possible
explanation for the efficient formation of 2 could be invoked. By
way of example, incorporating 22 or its ortho-bis(hydroxy-
methylated) analogue may result in a [2 + 2] metal-chelated/
hydrogen-bonded complex similar to 26 (Figure 3). The forma-
tion of a complex based on 26 allows the proposed and important
“methylene stitching” event that joins the four hydrogen-bonded
metal-coordinated spatially constrained aryl groups into close
proximity, thus allowing p-tert-butylcalix[4]arene formation. Invok-
ing a similar intramolecular hydrogen bond, metal-mediated self-
assembly process, the synthesis of p-tert-butylcalix[n]arenes
(n = 5, 6) via [2 + 3] and [3 + 3] assemblies: i.e., 27 and 28
respectively could be envisaged (Figure 3).
Eglinton and Cairns19 have described how oligomeric methy-
lene-linked phenolic species based on 22 and 23 generate
intramolecular hydrogen-bonded complexes: i.e., 24 and 25
(Figure 1). Similarly, Yamagishi et al. reported that entities
similar to 22 and 23 self-assemble via intramolecular and
intermolecular hydrogen bonds, generating bimolecular aggre-
gates that assume “pseudo-cyclic conformations analogous to
p-tert-butylcalix[4]arene and p-tert-butylcalix[6]arenes”. Thus,
in the absence of structural data we propose the preorganization of
The synthesis of p-tert-butylcalix[n]arenes (n = 6ꢀ8) can be
accommodated by invoking a broadly similar but multimetal
mediated reaction process. Thuꢀery and Nierlich reported that a
hexameric o-methylene-linked phenolic species effectively coor-
dinated two uranyl ions (UO2+), each one to a trimeric phenol
component within a hexameric phenol; it is interesting to note
(given our observed triflate and tetrafluoroborate anion effect,
vide supra) that the assembly is held in place via a central
double chelated NO3ꢀ anion (Figure 2).22 Invoking a similar
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Figure 1. Dimerization of 22 and 23 generates calixarene like supramolecular architectures i.e. 24 and 25.
Figure 2. X-ray crystal structure of a uranyl (UO2+) complex that
incorporates an acyclic bis(hydroxymethyl)phenolic hexamer and an
unusual bridging nitrate anion.22
assembly/reaction process, the formation of [3 + 3], [3 + 4], and
[4 + 4] complexes (i.e. 15ꢀ17) would afford, after macrocycliza-
tion via “methylene” stitching, the desired p-tert-butylcalix-
[n]arenes (n = 6ꢀ8).
After a relatively slow start, the use of synthetic hosts for anion
recognition/complexation is becoming an increasingly impor-
tant theme in chemistry. Nabeshima and co-workers23 have
recently described a p-tert-butylcalix[4]arene motif capable of
binding a cation (i.e. Na+ or Ag+) and either a CF3SO2ꢀ or BF4
ꢀ
Figure 3. Proposed supramolecular assemblies for p-tert-butylcalix-
[n]arene (n = 4ꢀ8) 26ꢀ33 synthesis.
anion; furthermore, Ito et al. has described a 2,20-dihydroxy-1,10-
dinaphthyl-1-methane species (similar to 22) that has an affiꢀnit2y4
for anions such as HSO4ꢀ, NO3ꢀ, H2PO4ꢀ, and CH3CO2
.
With this in mind, it seems plausible that a hydrogen-bond-
mediated self-assembly process (Figure 1) in conjunction with
CF3SO3ꢀ or BF4ꢀ coordination may be a driver for macrocycli-
zation of oligomers based on 22 or 23 and their subsequent
transformation into calixarenes 2.
or cation coordination and trimeric, tetrameric, etc. phenol
systems allows the supramolecular assembly of differently sized
calixarenes to be envisaged.
With the work of Thuꢀery and Nierlich22 in mind, an alternative
route for the formation of the larger calixarenes appears viable.
Thus, generating a supramolecular complex that incorporates
multiple cationic centers, i.e. Cu2+, Sn2+, or La3+ (for example
30ꢀ32, Figure 3), and one anionic species encapsulated by two
ortho-linked methylene tetrameric phenols affords a supramole-
cular complex based on 33 (Figure 3). It is interesting to note
that in a recent full paper Shibasaki et al. reported25 the formation
of a novel binuclear [La2Li4(binaphthoxide)5] complex that
incorporates five (R)-BINOL motifs (structural similarities to
ꢀ
Thus, encapsulation of the CF3SO3 anion within a hydro-
gen-bonded [2 + 2] dimer would afford a self-assembled supra-
molecular complex based on 27 (presumably anion complexes
based on 28 and 29 are also possible; not shown) which is
analogous to the cationic dimer 26 (Figure 3). Following a
similar macrocyclization pathway (outlined for 26), subsequent
“CH2 stitching” generates the desired p-tert-butylcalix[4]arene.
Again, using similar molecular recognition events such as anion
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22), thus demonstrating the feasibility of the La3+ cation to
acccomodate large numbers of multicyclic phenol motifs. Sub-
sequent “CH2 stitching” of a complex based on 33 should result
in a p-tert-butylcalix[8]arene macrocycle. The formation and
possible intermediacy of an entity based on 33 could help explain
the symbiotic relationship observed between certain metal centers
and the anion of the salt and their preference for the formation of
larger p-tert-butylcalixarenes.
rate of 2 mL/min. Eluent A was MeCN with 1% AcOH, and eluent B was
a mixture of CH2Cl2 and tert-butyl methyl ether (12:9 ratio) with 1%
AcOH. An isocratic run using an 80:20 mixture of A and B for 15 min was
found suitable for separation of calix[n]arenes (n = 4ꢀ12). (Note: a
significant shift in retention times was observed as a function of the
variable room temperature; higher retention times were noticed under
cold conditions.)
5,11,17,23-Tetrakis(1,1-dimethylethyl)-25,26,27,28-tetra-
hydroxycalix[4]arene:8. mp 335ꢀ340 °C; FT-IR 3152, 2953, 2864,
1479, 1199 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 10.33 (br s, 1H), 7.03
(s, 2H), 4.22 (d, 1H, J = 14.0 Hz), 3.46 (d, 1H, J = 14.0 Hz), 1.23 (s, 9H);
MS (APCI) m/z calcd for C44H56O4 648.9, found 649.3.
’ CONCLUSION
In summary, we report the first and only example of a one-pot
calixarene synthesis from a ‘monomeric’ phenol that does not
utilize base or acid. Although an exact mechanistic rationale for
the generation of 2 is unclear, it may be possible that hydrogen-
bonded dimers are formed and that these encapsulate cationic
and or anionic species and may play an important role in
calixarene formation. By way of substantiating the possibility
that the formation of a supramolecular assembly be important,
we refer to a 1962 Nature publication by Cairns and Eglinton
(cited 18 times). Interestingly, given the continued debate on
calixarene formation, this communication has, by and large, been
overlooked by the calixarene chemistry community; it may be the
case that hydrogen bond entities are formed and their involve-
ment in calixarene synthesis is more important than might be
apparent at first. This and other additional mechanistic features of
the reaction are currently under investigation in our laboratories.
The possibility of “fine-tuning' our metal salt mediated reaction such
that the inclusion of a simple metal salt affords a specific p-tert-
butylcalix[n]arene is of significant interest and promise. Results
from these studies will be published in due course.
5,11,17,23,29-Pentakis(1,1-dimethylethyl)-35,36,37,38,39-
pentahydroxycalix[5]arene:8. mp 285ꢀ288 °C; FT-IR 3262, 2957,
2868, 1484, 1201 cmꢀ1; 1H NMR (CDCl3ꢀpyridine-d5, 10%, 400 MHz)
δ 8.64 (br s, 1H), 7.15 (s, 2H), 3.75 (br s, 2H), 1.18 (s, 9H); 13C NMR
(CDCl3, 400 MHz) δ 147.8, 144.2, 128.0, 125.9, 34.1, 31.7, 31.6; MS
(APCI) m/z calcd for C55H70O5 811.1, found 811.2.
5,11,17,23,29,35-Hexakis(1,1-dimethylethyl)-37,38,39,40,
41,42-hexahydroxycalix[6]arene:8. mp >350 °C; FT-IR 3134,
2957, 2866, 1482, 1200 cmꢀ1; 1H NMR (CDCl3ꢀpyridine-d5, 10%, 400
MHz) δ 10.44 (br s, 1H), 7.10 (s, 2H), 3.82 (br s, 2H), 1.20 (s, 9H); 13C
NMR (CDCl3, 400 MHz) δ 147.5, 144.5, 127.2, 126.4, 34.2, 33.5, 31.7;
MS (APCI) m/z calcd for C66H84O6 973.4, found 973.4.
5,11,17,23,29,35,41-Heptakis(1,1-dimethylethyl)-43,44,45,
46,47,48,49-heptahydroxy calix[7]arene:8. mp 235ꢀ238 °C
(reported 249ꢀ251 °C); FT-IR 3143, 2956, 2883, 1483, 1200 cmꢀ1
;
1H NMR (CDCl3ꢀpyridine-d5, 10%, 400 MHz) δ 7.15 (s, 2H), 3.88 (br
s, 2H), 1.24 (s, 9H); 13C NMR (CDCl3, 400 MHz) δ 147.5, 144.6,
127.6, 126.3, 34.2, 33.1, 31.7; MS (APCI) m/z calcd for C77H98O7
1135.5, found 1135.5.
5,11,17,23,29,35,41,47-Octakis(1,1-dimethylethyl)-49,50,
51,52,53,54,55,56-octahydroxy calix[8]arene:8. mp >360 °C;
1
FT-IR 3191, 2953, 2348, 1485, 1201; H NMR (CDCl3, 400 MHz)
’ EXPERIMENTAL SECTION
δ 9.62 (br s, 1H), 7.17 (s, 2H), 4.35 (d, 1H, J = 12.8 Hz), 3.48 (d, 1H,
J = 12.8 Hz), 1.24 (s, 9H); 13C NMR (CDCl3, 400 MHz) δ 146.8, 144.9,
128.9, 125.7, 34.2, 32.5, 31.7; MS (MALDI) m/z calcd for C88H112O8Na
1320.8, found 1320.8.
General Protocols. All reactions requiring anhydrous conditions
were conducted in flame-dried glass apparatus under an atmosphere of
argon. All commercially available chemicals, reagents, and salts were
used as supplied. Microwave syntheses were performed on an Emrys
Creator.
5,11,17,23,29,35,41,47,53-Nonakis(1,1-dimethylethyl)-55,
56,57,58,59,60,61,62,63-nonahydroxycalix[9]arene: mp 302ꢀ
1
304 °C; FT-IR 3194, 2955, 2360, 1484, 1202; H NMR (CDCl3ꢀ
General Procedure. p-tert-Butylphenol (PTBP, 150 mg, 1 mmol),
trioxane (90 mg, 1 mmol), and magnesium triflate (1 mmol) were added
to dichloromethane (4 mL) in a microwave vial of 2.0ꢀ5.0 mL capacity.
This heterogeneous mixture was heated (after sealing with an aluminum
crimp cap with a PTFE-lined rubber seal) in the microwave synthesizer
at 120 °C for 30 min. After this time, HPLC analysis of the reaction
mixture indicated complete consumption of the starting material
(PTBP) and the formation of a mixture of p-tert-butylcalix[n]arenes
(90%). The reaction mixture was diluted with dichloromethane (10 mL)
and filtered to remove solid magnesium sulfate. The insoluble solid was
washed with dichloromethane (5 mL). The combined organic extracts
were washed with dilute sodium bicarbonate solution (5 mL, 10%) and
brine, respectively. The organic layer was dried using anhydrous
magnesium sulfate and filtered and the solvent removed under reduced
pressure, affording a white solid. The individual calix[n]arenes (n =
4ꢀ9) were isolated (in 85ꢀ99% HPLC purity) by gradient flash
chromatography using a cyclohexaneꢀtolueneꢀethanol (90:10:00 to
60:48:2 in 120 min using 2 mL/min flow rate) solvent system (moni-
tored by HPLC).
pyridine-d5, 10%) δ 7.09 (d, 2H, J = 3.3), 3.84 (br s, 2H), 1.17 (s, 9H);
13C NMR (CDCl3) δ 147.2, 144.5, 128.0, 125.9, 34.2, 32.6, 31.5; MS
(MALDI) m/z calcd for C99H126O9Na 1482.9, found 1483.0.
’ ASSOCIATED CONTENT
S
Supporting Information. Analytical HPLC and NMR
b
spectra for the compounds discussed in this manuscript can be
found in the Supporting Information. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: s.bew@uea.ac.uk.
’ ACKNOWLEDGMENT
S.P.B. and S.V.S. acknowledge the financial assistance of the
University of East Anglia, the EPSRC, and Dr. R. Bruggraber of
Biotage for the advice and loan of a Biotage Initiator Sixty. The
EPSRC National Mass Spectroscopy Service Centre at Swansea
is acknowledged for undertaking mass spectral analysis.
HPLC Procedure. HPLC analysis was performed on a Pursuit RP
C18 column (4.6 mm i.d., 250 mm) packed with 5 μm reverse-phase
silica. The analysis procedure followed was similar to that reported by
Gutsche et al.9a The HPLC separation of calix[n]arenes (n = 4ꢀ9) was
achieved using a mixture of two eluents (at 280 nm), A and B, at a flow
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