Path to Industrial Production of Calix[8 and 4]arenes

Article abstract of DOI:10.1021/acs.joc.9b02692

A highly selective and high yield synthesis for the production of calix[8]arenes in concentrated reaction masses is described. Obtained purities are >98% and yields of >80%, with isolation by simple filtration. The developed approach allows for subsequent

Full text of DOI:10.1021/acs.joc.9b02692

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Article
A Path To Industrial Production of Calix[8 & 4]arenes
Cornelius Heinz Werner Haase
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02692 • Publication Date (Web): 16 Dec 2019
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A Path To Industrial Production of Calix[8 & 4]arenes
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Cornelius Heinz Werner Haase*
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SI Group, Inc., 2750 Balltown Road, Schenectady, NY 12301, USA.
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Cornelius.haase@siigroup.com
R
R
R
OH
New Synthesis: 80% yield,
Highly Concentrated,
Highly Selective,
OH
OH
OH
HO
HO
HO
R
R
Work-up by Simple Filtration
R = tert.-Butyl-, tert.-Amyl, tert.-Octyl-
OH
R
R
R
Abstract:
Highly selective and high yield synthesis for production of calix[8]arenes in concentrated reaction
masses is described. Obtained purities are > 98% having yields > 80%, with isolation by simple filtration.
The developed approach allows for subsequent ‘in-situ’ formation of calix[4]arenes. The syntheses are
amenable to large scale manufacturing.
Kinetic observations during the formation of calix[4]arenes from calix[8]arenes are included.
Furthermore, details related to ‘soluble’ calix[4]arene are described.
Introduction:
C
alixarenes are cyclic condensation products of para-substituted alkylphenols with formaldehyde (s.
e.g. Schemes 1 and 2). When considering such calixarenes, three procedures for the preparative
synthesis of main calixarenes with four, six and eight aromatic ring units in Organic Synthesis1 - 3 may be
considered benchmark preparations and are exemplified for the historically most prominent three tert.-
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butylcalixarene species 4. The utilized catalysts are sodium hydroxide (for [8 & 4]) respectively, and
potassium hydroxide (for [6]). When reviewing the strengths and weaknesses of the calix[8 & 4]arene
syntheses, the following should be recognized: tert.-butylcalix[8]arene 2b formation is worked with less
than 18% (wght.) para-tert.-butylphenol 1b. While the reaction occurs rapidly, it is not entirely selective
and gives about 10% of a mix of [4] and [6]. For a pure 2b, a recrystallization is desired, which may be a
challenge due to its poor solubility with the overall yield being 64%3. While other para-substituted
phenol derivatives are mentioned4,5, the selectivities or yields are limited.
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It is tert.-butylcalix[4]arene 3b, which not only includes a detrimental dilution, but also creates a
technical challenge for large scale production. When 1b and aqueous 37% formaldehyde solution are
heated without the presence of any solvent and above the boiling point of water, a thick slurry or
frothing results which multiplies the loaded volume. Then it is diluted, heated to 260oC (with water still
to be eliminated), and finally, the desired product is obtained in a poor space yield but with 61%
theoretical yield, prior to re-crystallization. The re-crystallized yield is described at 49%1.
Nevertheless, with all the technical difficulties which limit 2b and 3b production to pilot quantities,
these compounds or substituted derivatives, have found their way into published technical applications,
where they are added in small quantities. Their special features enhance performance and offer
significant value for specific applications. Examples include polymerization accelerators in cyanoacrylate-
based super glues6, and charge control additives in toner resin7. A highly substituted calix[4]arene in its
1,3-alternate conformation even presents a solution for significant end-of-lifecycle issues of nuclear
power fuels8.
Results and Discussion:
This note presents a general approach which overcomes the described difficulties for production of
calix[8 & 4]arenes. Outlined in Scheme 1 is a calix[8]arene synthesis, starting from para-tert.-amylphenol
1a:
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Scheme 1:
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8
a
tert.-amyl
para-alkylphenol
1
2
b
c
d
e
f
tert.-butyl
tert.-octyl
sec.-butyl
para-cumyl
iso-propyl
alkylcalix[8]arene
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OH
base, A-150
OH
OH
HO
HO
a) 6 hrs @ 115oC
b) 5 - 10 hrs 145oC
8 HCHO + 8
aqueous
formaldehyde, 50%
OH
HO
- 8 H2O
OH
para-tert.-amylphenol
OH
1a
Base:
+
OH-
N
tert.-amylcalix[8]arene
isolated yield: 81.3%
HPLC (281 nm): 99.0%
2a
Tetramethylammonium hydroxide
(TMAH)
Under these reaction conditions, side reactions were minimized, and formaldehyde is given time to
react with the alkyphenol. In Scheme 1, tetramethyl ammonium hydroxide (TMAH, 2 mol% in relation to
alkylphenol) was found to catalyze the reaction with 50% aqueous formaldehyde, although other
formaldehyde sources work as well. The reaction times are longer compared to benchmark cases. When
working with aqueous formaldehyde, it is distinguished between a reflux and a distillation phase. The
reflux phase can be between 6 to 12 hours and builds mostly linear precursors. It is then taken to 145oC
for 5 to 10 hours to remove the water and cyclize to the calix[8]arene with high selectivity. Even
following a lengthy reflux phase, free formaldehyde can be detected in the aqueous distillate from this
distillation step. While industrial solvent aromatic-150® (A-150) is described in Scheme 1, other solvents
work as well. It can be very concentrated as one only needs enough solvent to be able to stir the
obtained suspension of the final calix[8]arene. The solvent amount is specific to the alkyl-substituent in
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the para-position for each calix[8]arene example. In the example of Scheme 1 (Example 1 of Table 1)
one needed only 90 g A-150 for 123 g 1a, which equals ~ 58% (wt.) solid content of alkylphenol in
solvent. In this example, 115 mol % formaldehyde was used.
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[8], 86.0%
[4], 0.7%
system
‘linears’
peak
Figure 1: HPLC (281 nm) of Crude [8] Reaction Mass 2a (Example 1, Table 1)
Figure 1 displays the HPLC (area % detected at 281 nm) of the final crude reaction mass of the reaction
in Scheme 1, showing selectivity toward the calix[8]arene over other ring sizes. Work-up is a simple
filtration with a subsequent wash with solvent to remove the ‘linears’, un-reacted alkylphenol and
catalyst. By this wash, the unreacted alkylphenol can be brought below 0.1%, which is a critical level for
impurity in an industrial context. It was dried and a light powdery product obtained. The yield in this
example was above 81% of the theoretical yield, with an HPLC-purity of 99.0%. The HPLC method does
not quantify the remaining solvent and unreacted monomer.
Chart 1:
N
OH-
N
+
N
N
N
Tetraethylammonium hydroxide 4-(Dimethylamino)-pyridine
Diazabicyclo[5.4.0]undec-7-ene
(DBU)
(TEAH)
(DMAP)
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Chart 1 provides additional well working catalyst examples for this synthesis but is not exhaustive. DBU
is a cyclic amine and DMAP is an amino-substituted aromatic heterocycle, demonstrating that it must
not be an ammonium hydroxide derivative which provides the solution. Different nitrogen-containing
bases work to varying degrees and their comprehensive actions are not yet fully understood.
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Table 1: Examples for calix[8]arene Syntheses
Example-
#
Phenolic
starting
compound
Aldehyde
source /
mol %
Solvent
Cata-
lyst
Reflux
phase
time
Distillation
phase time
[hrs]
Isolated
yield [%
of
theory] /
product
HPLC-
purity
[area%
at 281
nm]a
Free
phenolic
monomer
in final
product
[% (wt.)]
0.44
Theoretical
solid
[8]-
compound
previously
referenced
contentb
HCHO
[hrs]
1
2
3
4
5
1a
1a
1a
1b
1b
aqueous
HCHO, 50%
/ 114.1
aqueous
HCHO, 50%
/ 114.1
aqueous
HCHO, 50%
/ 113.9
aqueous
HCHO, 50%
/ 100.1
A-150
TMAH
TMAH
DMAP
DBU
6 (at
10
10
10
6.5
10
81.3 / 2a
81.2 / 2a
79.9 / 2a
n.d.d
99.0
98.8
99.0
58.2
5a
115oC)
Diphenyl-
ether /
xylenec
A-150
12
12
< 0.05
0.18
-
40.6
(including
xylene)
44.9
A-150
15.25
12.5
(~
56.6 (too
viscous for
filtration)
35.7
(without
xylene as it
was added
for
95.5%
[8])e
aqueous
HCHO, 50%
/ 114.9
Diphenyl-
ether /
TEAH
81.2 / 2b
98.1
0.07
13
5a
xylenec
distillation
step)
47.6
6
7
1c
1d
1e
1f
aqueous
HCHO, 50%
/ 114.9
aqueous
HCHO, 50%
/ 99.9
aqueous
HCHO, 37%
/ 115.5
aqueous
HCHO, 50%
/ 115.1
Hexa-
decane
TEAH
TMAH
TMAH
TMAH
TMAH
12
12
12
12
-
10
10
10
10
10f
79.4 / 2c
66.3 / 2d
61.2 / 2e
73.7 / 2f
79.5 / 2a
97.0
99.2
91.0
98.1
98.5
0.13
< 0.05
0.99
A-150
A-150
A-150
A-150
36.1
47.2
35.1
60.0
8
14
5a
9
< 0.05
0.18
10
1a
paraform,
95% / 105.8
aHPLC method does not capture remaining solvent nor residual starting monomer, which are determined by GC
b’Theoretical solid content’ is defined as weight-% of starting substituted phenol mass in the mass of the applied solvent (approximately the
amount of solvent needed to keep final obtained reaction mass in manageable slurry)
cXylene added as an azeo-carrier for water in the distillation step
dReaction mass too thick to be filtered; a preparative column chromatography showed ~ 80% (wt.) calixarenes in the solids
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eIn the calixarene fraction from preparative column chromatography the [8]arene made 95.5% (area-% HPLC at 281 nm) of all calixarene
4
5
derivatives
6
7
fWith paraform no ‘reflux-phase’
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The approach with these catalysts is universal. Table 1 illustrates examples with different para-
substituted phenols, different solvents, different catalysts, and different sources of formaldehyde. The
last five columns display the results. The isolated yields are shown in the eighth column, which are in the
~ 80% range for the major alkylphenols, tert.-butyl 1b, tert.-amyl 1a and tert.-octyl 1c. The ninth column
gives purity determined by HPLC analysis at 281 nm of the final, isolated product. The information in the
eleventh column is the ‘theoretical solid content’, defined as the weight-% of starting monomer in the
applied amount of solvent only, which still permitted an acceptable stirring of the obtained final product
suspension. Therefore, the table shows that e.g. for 1b (example 5) the obtained suspension of the final
reaction mass reaches above ~ 38 weight % of starting monomer in the solvent, already a suspension
that is difficult to stir, while e.g. 1c (example 6) can be managed just below 50% (wt.).
Due to the chiral carbon atom in 1d, the product 2d represents a mixture of diastereomers.
Various sources of formaldehyde can be used, for example paraform (Example 10, Table 1). Use of this
source precludes a reflux phase.
While the purity of the calixarene products could be brought above 98% (HPLC, 281 nm), this was not
true for the para-cumyl[8] 2e, which remained at 91% even after several washes with double the
amount of solvent volume. This was not caused by lack of selectivity toward the calix[8]arene, but rather
by ‘linear’ impurities, which are potentially less prone to be removed by the washing solvent, due to the
influence of the second aromatic group of the cumyl-phenol moiety. HPLC and 1H-NMR of the isolated
product of 2e14 are displayed in the supporting information.
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Table 1 illustrates two solvents for the calix[8]arene synthesis with a boiling point above 250oC. If one
has calix[8]arene in a high concentration, as it is in a thick reaction mass from the described [8]-
synthesis, one can obtain calix[4]arene in meaningful space yields following David Gutsche’s method,
described in ‘Pathways for the Reversion of p-tert.-Butylcalix[8]arene to p-tert.-Butylcalix[4]arene’9. One
only needs to switch the catalyst and add some sodium hydroxide to the ‘in-situ’ [8]-reaction mass, and
then heat to 250 - 260oC as indicated in Scheme 2.
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Scheme 2:
NaOH
in diphenylether
TMAH
in diphenylether
OH
OH HO
OH
'in-situ' tert.-amyl[8]
8 HCHO + 8
~ 62% yield
~ 82% yield
2a
OH
1a
a
b
c
tert.-amyl
para-alkylphenol
1
3
tert.-butyl
tert.-octyl
sec.-butyl
tert.-amylcalix[4]arene
alkylcalix[4]arene
3a
d
overall yield 50.9%,
purity: 98+%
Therefore, the first part of the reaction is the same as described for the production of calix[8]arenes.
However, there is no work-up and it is continued ‘in-situ’ to the next step. It should be noted that at the
time the NaOH catalyst is added, and prior to the increased heating to 250 - 260oC, all water from the
condensation reactions has been removed, making for a safer heating step, compared to the benchmark
approach1.
Table 2: Examples of calix[4]arene Syntheses
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Example-
#
Monomer,
type of
conversion
Solvent
Catalyst:
Reflux phase, then
distillation phase
time [hrs]
Time at Isolated
HPLC-purity
[area% at 281
nm]a
Theore-
tical
[4]
Compound
previously
referenced
1 step toward
‘in-situ’ [8] / 2
step for [4]arene
250 –
260oC
[hrs]
yield [%
of
theory]
/
solid
contentb
product
50.9 /
3a
45.0 /
3a
1
2
1a -> ‘in-
situ’ [4]
1a -> ‘in-
situ’ [4]
Diphenyl-
ether
Diethylene
glycol
dibutyl
ether
TMAH / NaOH
(10.9 mol%)
TMAH / NaOH
(32 mol%)
Like example 2 table
1c
3
2
98.1% [4]
(1.2% [8])
96.0% [4]
(3.3% [8])
24.2%
44.9%
5a
Like example 2 table
1 but with diethylene
glycol dibutyl ether
instead of diphenyl-
ether c
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3
4
1b -> ‘in-
situ’ [4]
2a -> 3a
Diphenyl-
ether
Diethylene NaOH (17 mol%)
glycol
dibutyl
ether
Diphenyl-
ether /
TMAH / NaOH
(14.3 mol%)
Like example 5 table
3
5
50.1 /
3b
69.6 /
3a
98.5% [4]
99.7% [4]
~ 25%
11.2%
13
11
1c
not applicable
5
1d -> ‘in-
situ’ [4]
TEAH / NaOH (32
mol%)
Like example 2 table
1 but with 1d instead
of 1a and 30% more
solvent
1
33.4 /
94.6% [4]
(4.7% [8]) – 1.
distillation, 2.
acetone
isolation due
to solubility of
sec.-bu[4] –
not yet
33.5%
3d
xylene
optimized
96.7%
6
1c -> [4] ‘in-
Hexa-
decane
TEAH / NaOH (16
mol%)
as for example 6 in
table 1
4
43.2 /
50.7%
5a
situ’
3c
aHPLC method does not capture remaining solvent nor residual starting monomer; they are determined by GC
b’Theoretical solid content’ is defined as weight-% of starting monomer mass in the mass of the applied solvent together with the mass of the
‘anti-solvent’, where applicable
cFor these early attempts, xylene was not yet added as an azeo-carrier for the water removal in the distillation step for the ‘in-situ’-calix[8]arene
formation
Table 2 gives an overview of selected examples for the [8] -> [4] ring contraction using 50% aqueous
formaldehyde. The amount of sodium hydroxide catalyst (‘mol-%’) was calculated by assuming that all
the starting alkylphenol would become calix[8]arene. The mass of added sodium hydroxide is considered
in relation to such hypothetical amount of calix[8]arene, to result in the given mol-% numbers.
For these examples the published procedure from Prof. Gutsche was followed9, except that it was more
concentrated during the 260oC hot phase. Following this reflux phase, after cooling, an ‘anti-solvent’
(e.g. ethylacetate) was added to exhaustively precipitate the desired calix[4]arenes. The final product
was then filtered through a Büchner funnel and washed with anti-solvent. The free phenolic monomer in
the final product was below 0.05% (wt.) by GC.
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Considering these examples, one can appreciate why it is preferable to work with the tert.-amyl
variants. Their suspensions can be handled in more concentrated form than e.g. for tert.-butyl and one
can therefore achieve better space-yields with tert.-amylcalix[8 & 4]arenes.
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Examining the purity (HPLC, 281 nm) of the [4]arenes indicates that the main impurity is the
unconverted calix[8]arene. This purity depends on completion of conversion of [8] but concentration
from which [4] is precipitated out of the solution also plays a factor. The more dilute, the remaining
calix[8]arene was kept in solution the better and the higher the [4]-purity.
In diethylenglycol dibutyl ether (b.p. 256oC) the isolated yield (Example 2, Table 2) is not as high,
because lower amounts of ‘in-situ’ calix[8]arene are formed in the first reaction step. However, a higher
‘space-yield’ can be achieved, as no ‘anti solvent’ is needed to precipitate the calix[4]arene.
The same is true for hexadecane as solvent for ‘in-situ’ 2c (Example 6, Table 2). The theoretical solid
content in this example is above 50%. Such paraffinic solvents have already been suggested in EP
0447977A110.
The isolation of p-sec.-butylcalix[4]arene is considered in Example 5, Table 2. Conversion of the ‘in-situ’
formed 2d was straightforward, but even with large amounts of ‘anti-solvent’ the in the HPLC clearly
visible 3d did not precipitate.
Such a compound had an unusual solubility for a butylcalix[4]arene and isolation required a different
strategy. The employed solvent, diphenylether, was reduced via vacuum distillation and all by-products
were dissolved in acetone from the obtained resin. Then, at room temperature, the remaining solid 3d
(and remaining 2d) could be filtered off. The 2d content in the obtained material was reduced by
dissolving in hot acetone solution and filtering hot. A product with an HPLC-purity (281 nm) of 98+%
quality was achieved (s. Supporting Information).
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Graph 1:
5
6
7
8
9
Solubilities of 3b (small markers; full lines) and
3d (large markers; dotted lines)
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16.0%
14.0%
12.0%
10.0%
8.0%
6.0%
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2.0%
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Dissolution Temperature (°C)
A-150 3d
Diglybe 3b
toluene 3b
A-150 3b
xylene 3d
Xylene 3b
Diglybe 3d
toluene 3d
Graph 1 illustrates the solubility characteristics of 3d and compares it to 3b. While the latter is insoluble
at room temperature in toluene, 3d is soluble with almost 14% (wt.). Some interesting applications of a
soluble butylcalix[4]arene scaffold are to be expected. It is recognized that due to the chiral carbon
atom in the side chain of the starting monomer, the obtained 3d is a mixture of diastereomers (s.
Supporting Information), which might explain the unusual solubility in contrast with the other calixarene
species studied.
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Figure 2: HPLC (at 281 nm) of Crude Reaction Mass for Synthesis of 3a in DPE at 240oC
Referencing the publication ‘Pathways for the Reversion of p-tert.-Butylcalix[8]arene to p-tert.-
Butylcalix[4]arene’9 by David Gutsche, the author described the reaction of a mixture of regular and fully
deuterated p-tert.-butylcalix[8]arene in a 1 : 1 ratio (by weight) and then considered the deuterium-
substituted product distribution of the obtained [4]arenes. He wanted to check if ‘Molecular Mitosis’
would occur and split each [8]-molecule in half. It appears that the obtained species were not pure un-
deuterated or fully deuterated, but were rather mixtures, indicating an un-symmetrical path to the
reaction products.
Figure 2 supports Gutsche’s observation. It shows an HPLC-chromatogram of a p-tert.-amylcalix[8]arene
reaction mass while being heated to 260oC. The figure is a snapshot of when 240oC was reached. In
Figure 3, sharp individual signals can be seen. These signals represent different ring-sized calixarenes.
Therefore, it appeared that initially all kinds of calixarenes were formed, including larger ones such as
[9], [10] or potentially even larger. In the end of the 260oC phase, they fell mostly back to the
thermodynamic [4] product.
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Figure 3: 1H-NMR (500 MHz, CDCl3) of Crude Reaction Mass of 3a at 240oC
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[7] + Na+
[8] + Na+
1608.198, [9] + Na+
1784.305, [10] + Na+
Figure 4: MALDI of Crude Reaction Mass of 3a at 240oC
Figure 3 shows the corresponding proton NMR spectrum (in CDCl3) to this HPLC reaction mass, it shows
tiny singlets on the right side of the phenolic proton of the tert.-amylcalix[8]arene (at 9.65 ppm). While
this is the tert.-amyl-case, and not all members of the tert.-amylcalix[n]arene family are yet isolated and
characterized, one may still draw an analogy to the tert.-butyl-case and compare to the proton-NMR (in
CDCl3) of the isolated different ring-sizes Stewart and Gutsche had published in their JACS paper from
199912. The [9, 10, 11, …] show the phenolic protons at 20oC at the locations where they are observed
here for the amyl-case.
The MALDI spectrum in Figure 4 supports the assumptions. Since not all tert.-amylcalix[n]arenes are yet
characterized, some assignments in Figures 2 and 3 are indicated with a question mark.
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Conclusion:
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Based on the presented technology, the production of the calix[8 & 4]-species can be simplified, and
previous technical challenges, can be overcome. [8]-arenes can be made highly selective and in high
concentrated reaction masses with isolation by simple filtration and no need for re-crystallization.
Utilizing the ‘in-situ’ [8]-reaction masses, one can safely proceed to [4]-arene syntheses and obtain [4] in
much higher space yields. Therefore, the synthesis of such materials does not need to be limited to pilot
scale quantities anymore. Simplified manufacturing processes should also allow for greater availability
of desired materials, and eventually the benefits of larger volume of production that provide to ultimate
end-users in diverse industries.
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Experimental Section:
All chemicals were reagent grade and were used without further purification. The reaction products in
above examples were characterized by various methods, including 1H- and 13C{1H}-NMR, GPC, HPLC, and
MALDI. In all examples, heating was provided using electric heating mantles controlled by
thermocouples and J-Kem boxes. Preparative column chromatography for Example 4, Table 1, was
performed on silica gel (Aldrich, high purity grade, pore size 60 Ångström, 200 - 400 mesh particle size).
Solvent system was plain chloroform for the calixarene fraction (appeared first) and a mixture of
acetone : methanol : chloroform (1 : 1 : 1 by volume) to evaluate the linear components.
1H NMR spectra were recorded on a Bruker Avance HD (500 MHz) spectrometer and are reported in
ppm using solvent as the internal standard (CDCl3 at 7.27 ppm). Data are reported as: (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br: broad, coupling constant(s) in Hz, integration). 13C
NMR spectra were recorded on a Bruker Avance HD (126 MHz) spectrometer. Chemical shifts are
reported in ppm with the solvent resonance employed as the internal standard (CDCl3 at 77.0 ppm).
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MALDI mass spectra were obtained on Bruker Autoflex speed MALDI ToF-ToF spectrometer using the
thin layer method using 1 µL of a saturated α-Cyano-4-hydroxycinnamic acid (HCCA) acetone solution as
the initial layer on a stainless-steel plate and placing 1 µL of a calixarene chloroform solution on top of
the dried matrix. Mass spectra were calibrated externally using the peptide calibration standard mixture
from Bruker (a mass range between ~1000 and 3500 Da).
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GC analysis for calixarene solvent and remaining monomer analysis was done on an Agilent 5890 Series
II gas chromatograph with a split injection and FID detection using a standard (5%-Phenyl)-
methylpolysiloxane column. When a sample contained both 1a and diphenyl ether, a DB-1701 column
was needed for separation. An external standard method of calculation was used. The analysis was done
using tetrahydrofuran solvent.
High-Performance Liquid Chromatography (HPLC) was done on a Hewlett Packard 1100 Series HPLC
System using Agilent InfinityLab Poroshell 120 EC-C18 HPLC columns 3.0 x 150 mm, 2.7 µm
(Agilent Technologies) and a UV detector set at 281 nm. HPLC grade solvents were used. Samples were
dissolved in stabilized chloroform. To obtain a high peak resolution for calixarene compounds with
varying ring sizes, particularly from ring size 4 to ring size 8, the following combinations of solvents,
gradients, and flow rates were used:
Flow rate:
Gradient
0.4 ml/minute
Time (min)
% C
90
90
80
40
%D
10
10
20
60
0
5
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C = 99/1 acetonitrile/glacial acetic acid; D=12:9:1 MeCl2:MTBE (methyl tert.-butyl ether):glacial acetic
acid
para-tert.-Amylcalix[8]arene 2a:
Example 2 in Table 1:
A 500 ml round bottom flask with overhead stirrer, thermocouple, overhead addition tank, moisture
trap (could be switched to allow reflux), and condenser was loaded with 123.2 g (0.25 mol) 1a
briquettes, 90.2 g diphenylether and 10.2 g xylene. A gentle nitrogen breathing was applied to go over
the surface of the reaction mass and it was heated to ~ 90oC. When all the 1a and the DPE/xylene had
formed a clear solution, 5.5 g (2.0 mol%) of a 25% solution of tetramethylammonium hydroxide in
methanol was added dropwise. Within 25 minutes, a total of 52.2 g (0.855 mol, 114.0 mol%) of aqueous
formaldehyde (49.2%) was added.
After the end of the formaldehyde addition, the reaction was kept at 90oC for 1 hour and then heated to
reflux (beginning at 96oC) for a total of 12 hours. At the end the reaction, the mass had a temperature of
about 100oC. At this point, the reaction mass was diluted with 60.1 g more DPE and 20.1 g more xylene
solvent. The purpose of the added xylene was to be able to consistently remove the formed water to
avoid potential boil-over episodes, as it was now the goal to finish the polycondensation; and, therefore
the reaction temperature slowly raised to 145oC and the water trap switched to remove water. It was
kept for 10 hours at 145oC until a total of 34.5 g of lower layer were removed. This aqueous layer
contained 6.4% (wght.) formaldehyde. A pot sample showed 1.02% (wt.) remaining 1a. The reaction was
interrupted at night.
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It was cooled to 60oC and the reaction mass filtered easily through a Büchner funnel. The filter cake was
successively washed with portions of xylene (together 106.2 g) to result after drying in a vacuum oven at
130oC in 2a with < 0.05% (wt.) free 1a and 2.78% (wt.) DPE and an HPLC purity of 98.8% (281 nm). The
isolated yield was 110.0 g (81.2% of the theory on dry base).
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Example 1 in Table 1 (more forceful reflux-phase and more concentrated in a different solvent):
A 500 ml round bottom flask equipped as in the previous example was loaded with 123.2 g (0.75 mol) 1a
briquettes and 88.6 g A-150. A very gentle nitrogen breathing was applied, heated and 5.5 g (2.0 mol%)
of a 25% solution of tetramethylammonium hydroxide in methanol added dropwise. At 90oC, within 7
minutes a total of 51.0 g (0.855 mol, 114.1 mol%) of the aqueous formaldehyde solution (50.4%) was
added.
After the end of the formaldehyde addition, the reaction was kept at 90oC for one hour. The reaction
was set to reflux conditions and forcefully heated, while allowing the distillate to return into the
reaction flask. With this strong heating (it took 17 minutes from room temperature to 100oC), the pot
temperature could be raised within 60 min from 100 - 108oC. During the next 60 minutes it climbed to
even 111oC to reach after 4.5 hours after the start a pot temperature of 115oC. It was then held at 115oC
for an additional 1.5 hours. A sample showed 0.52% free formaldehyde and 8.93% unreacted
alkylphenol. It was switched to distillation and the reaction mass brought to 145oC and held there for 10
hours, while the water and the excess formaldehyde were distilled out. The final reaction mass showed
86.0% (HPLC, area at 281 nm) 2a and 1.98% (wt.) 1a.
In the 38.5 g of aqueous distillate a total of 2.50 g of formaldehyde could be detected.
It was cooled to ~ 60oC and easily filtered through a Büchner funnel. The filter cake was successively
washed with A-150 to result after drying (vacuum oven at 130oC) in 108.8 g of 2a with 0.44% (wt.) free
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1a and 1.17% (wt.) A-150 and an HPLC purity of 99.0% (281 nm). The isolated yield was 81.3% (of the
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Example 10 from Table 1 (with paraform as formaldehyde source):
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A 500 ml round bottom flask equipped as in the previous example was loaded with 149.8 g (0.91 mol) 1a
briquettes, 99.9 g A-150 and 30.5 g (0.965 mol ‘HCHO’, 105.8 mol%) paraform (95%). It was slowly
stirred and a very gentle nitrogen breathing applied and 6.74 g (2.0 mol%) of a 25% solution of
tetramethylammonium hydroxide in methanol added dropwise.
It was warmed and at 83oC the reaction mass cleared up. The temperature was raised within 10 min to
91oC, in further 15 min to 102oC, and then subsequently in 60 more minutes gradually to 145oC. From
120oC, on condensate collected in the Dean-Stark-trap. As the batch got thicker the stirrer speed was
increased up to 250 rpm. It was kept for a total of 10 hours at 145oC.
26.8 g of aqueous distillate were obtained. It was cooled to 80oC and the thick reaction mass was
transferred with 55.6 g A-150 into a Büchner funnel and rinsed with 45.2 g A-150 to give after drying in a
vacuum oven at 130oC 128.2 g 2a with 98.5% HPLC-purity (281 nm), 0.25% A-150 (wt.) and 0.18% (wt.)
1a in a yield of 79.5% (of the theory on dry base).
para-sec.-Butylcalix[8]arene 2d (mixture of diastereomers):
2d was prepared as 2a in Example 1 in Table 1. It was started with 112.7 g (0.75 mol) 1d. Isolated yield
was 80.7 g (66.3% yield) of a white powder of 2d with < 0.05% (wt.) 1d and < 0.05% (wt.) A-150. HPLC-
purity was 99.2% (281 nm).
1H-NMR (500 MHz, chloroform-d):  = 9.58 (s, 1H), 6.98 (s, 2H), 4.39 (d, J = 13.5 Hz, 1H), 3.49 (d, J = 13.5
Hz, 1H), 2.50 (s, 1H), 1.86 – 1.30 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H).
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13C{1H}-NMR (126 MHz, CDCl3):  = 146.9, 141.1, 129.0, 127.1, 40.9, 32.1, 31.6, 30.9, 22.4, 21.7, 12.2,
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MALDI in ‘Supporting Information’.
para-tert.-Amylcalix[4]arene 3a:
Example 1 in Table 2:
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For the ‘in-situ’ 2a formation it was worked as described as for Example 2 in Table 1 except that here no
xylene was yet added. Loads were 122.9 g (0.75 mol) 1a briquettes, 115.1 g diphenylether, 5.5 g (2.0
mol%) of a 25% solution of tetramethylammonium hydroxide in methanol and 50.8 g (0.846 mol, 113.1
mol%) of the formaldehyde (50%).
After the end of the reflux phase, 86.3 g more diphenylether solvent was added and within 2.5 hours
heated to 145oC. Without xylene around, this up-heating had to be carefully monitored while adjusting
the nitrogen stream to remove the released water. It took about 2.5 hours to reach 145oC in the pot.
After 10 hours at this temperature, the reaction mass was cooled and 0.82 g (0.01 mol) of an aqueous
NaOH solution (50%) added and gradually heated to a temperature of 250 - 260oC over the course of 3
hours. Stirring was monitored to avoid caking. The reaction mass became a clear dark liquid. Then it was
kept for 3 hours at ~ 260oC and then cooled.
At room temperature, 184.1 g ethylacetate were added, which caused the product to precipitate. It was
filtered through a Büchner funnel and washed in three portions with a total of 155.6 g ethylacetate.
After extended suction, 69.4 g dry filter cake of 3a with < 0.05% (wt.) free 1a, 1.3% (wt.) ethylacetate
and 2.1% (wt.) diphenylether in a theoretical yield of 50.9% (of the theory on dry base) was obtained.
The HPLC purity (at 281 nm) was 98.0% with 1.2% 2a.
Example 2 in Table 2 (no ‘anti-solvent’ necessary):
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It was worked as in Example 1 in Table 2 except that the solvent was diethylene glycol dibutyl ether.
Because no xylene was added as azeo-carrier, caution was observed when after the end of the reflux-
phase, the temperature had to be increased to 145oC. The following amounts were used: initially 123.2 g
(0.75 mol) 1a briquettes in 100.1 g diethylene glycol dibutyl ether with 8.2 g (0.3 mol%) of a 25%
solution of tetramethylammonium hydroxide in methanol and a total of 65.8 g (0.975 mol, 130.0 mol%)
of the aqueous formaldehyde (44.5%).
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Prior to the distillation phase, the reaction mass diluted with 51.2 g more diethylene glycol dibutyl ether.
It took about 2.5 hours to go from 100oC to 145oC in the pot. After 10 hours at 145oC, 48.7 g lower layer
were removed from the Dean-Stark trap. It contained 22.8% formaldehyde (11.1 g = 0.36975 mol =
37.9% of the starting load of formaldehyde). A reaction mass showed 1.92% (wt.)1a.
Then 2.4 g (0.03 mol) of an aqueous NaOH solution (50%) was added and gradually heated over 2 hours
to a temperature of 250 - 260oC. Stirring was monitored to avoid caking. It was kept for 2 hours at ~ 250
- 260oC.
It was cooled down, and the obtained suspension was filtered through a Büchner funnel and washed
with a total of 100.7 g ethylacetate. After drying under vacuum at 130oC, 59.7 g 3a was obtained. It had
< 0.05% (wt.) free 1a, < 0.05% (wt.) ethylacetate and 0.31% (wt.) diethylene glycol dibutyl ether. The
HPLC purity (at 281 nm) was 96.0% 3a and 3.3% 2a. The yield was 45.0% (of the theory on dry base).
Associated Content:
Supporting Information
HPLC, GC (remaining solvent), 1H-, 13C{1H}-NMR and MALDI of compounds 2a (example 2 in table 1), 3a
(example 1 in table 2), 2d, 3d, 2e and 2f as well as HPLC and GC (remaining solvent) of compounds 2a
(example 1 in table 1), 2b, 3b, 2c and 3c. Background for all MALDI in the supporting information.
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Author information:
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*E-mail: Cornelius.haase@siigroup.com
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Funding
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This work was paid for by SI Group, Inc.
Notes:
SI Group, Inc. has a financial interest in this work15, 16. Cornelius Haase is an employee of SI Group, Inc.
Acknowledgements:
Many thanks go to Professor Placido Neri for the fruitful conversations on this topic as well as to Dr.
Kristopher Kolonko, Director of the SAInT Center of Analytics at Siena College, Loudonville, NY for the
helpful analytical discussions and proof-reading of the manuscript. Further thanks extended for the
contribution of the underlying research, to Ricky Biittig, Allyson Stanton, Jeff Hiscock, Philip David
Atwood, Rebekah Beer, Jim Webb, and Kelly Chichak.
References:
1) Gutsche, C. D.; Iqbal, M. ’p-tert-Butylcalix[4]arene’ Org. Synth. 1990, 68, 234-237.
2) Gutsche, C. D.; Dhawan, B.; Leonis, M.; Stewart, D. ’p-tert-Butylcalix[6]arene’ Org. Synth. 1990, 68,
238-242.
3) Munch, J. H.; Gutsche, C. D. ’p-tert-Butylcalix[8]arene’ Org. Synth. 1990, 68, 243-246.
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4) Neri, P.; Sessler, J. L.; Wang, M.-X. in ‘Calixarenes and Beyond’, Springer, Switzerland, 2016, e.g. page
5
6
142.
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8
9
5) for p-isopropyl-, p-tert.-amyl-, p-tert.-octylcalix[8]arene nonselective; needs re-crystallization: (a)
Dhawan, B.; Chen, S.-I; Gutsche, C. D. ‘Studies of the formation of calixarenes via condensation of p-
alkylphenols and formaldehyde’ Makromol. Chem. 1987, 188, 921-950; for p-phenylcalix[8]arene: (b)
Gutsche, C. D.; Pagoria, P. F. ‘Functionalized Calixarenes: The Direct Substitution Route’ J. Org. Chem.
1985, 50, 5795-5802.
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6) Harris, S. J.; McKervey, M. A.; Melody, D. P.; Woods, J.; Rooney, J. M., Loctite, ‘Instant Adhesive
Composition Utilizing Calixarene Accelerators’ US 4,556,700; improved synthesis for 5,11,17,23-tetra-
tert.-butyl-25,26,27,28-tetra(2-oxo-2-ethoxy)ethoxy calix[4]arene in JP5248132 B2 (by Suruga, T.;
Miyagi, K.; Tamaoki, M., Sugai Chemical Ind. Co. Ltd.).
7) e.g. in Yamanaka, S.-I; Sukuta, K., Orient Chemical Industries, ‘Calixarene Charge Control Agent and
Toner for Developing Electrostatic Images’ US 5,952,145.
8) Peterman, D. R.; Meikrantz, D. H.; Law, J. D.; Riddle, C. L.; Todd, T. A.; Greenhalgh, M. R.; Tillotson, R.
D.; Bartsch, R. A.; Moyer, B. A.; Delmau, L. H.; Bonnesen, P. V., Battelle Energy Alliance, LLC, ‘Extractant
Compositions for Co-Extracting Cesium and Strontium, a Method of Separating Cesium and Strontium
from an Aqueous Feed, Calixarene Compounds, and an Alcohol Modifier’ US 8,158,088 B2.
9) Gutsche, C. D.; Johnston Jr., D. E.; Stewart, D. R. ‘Pathways for the Reversion of p-tert.-
Butylcalix[8]arene to p-tert.-Butylcalix[4]arene’ J. Org. Chem. 1999, 64, 3747-3750.
10) Görmer G.; Seiffarth, K.; Schulz, M., Leuna-Werke, ‘Verfahren zur Herstellung von p-
alkylcalix[4]arenen’ EP 0447977A1, March 1990.
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The Journal of Organic Chemistry
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11) A synthesis of 3d starting from unsubstituted calix[4]arene via Friedel-Crafts alkylation is described
in Talipov, S. A.; Yuldashev, A. M.; Gapparov, Kh. L.; Ibragimov, B. T.; Aripov, T. F. ‘Substituted
Calix[n]arenes, p-sec-Butylcalix[4]arene, Synthesis and Structure of Its Clathrate with Toluene’ Russ. J.
Org. Chem. 1996, 33, 1176-1178.
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12) Stewart, D. R.; Gutsche, C. D. ‘Isolation, Characterization, and Conformational Characteristics of p-
tert-Butylcalix[9-20]arenes’ J. Am. Chem. Soc. 1999, 121, 4136-4146.
13) Gutsche, C. D.; Dhawan, B.; No, K. H.; Muthukrishnan, R. ‘The Synthesis, Characterization, and
Properties of the Calixarenes from p-tert-Butylphenol’ J. Am. Chem. Soc. 1981, 103, 3782-3792; Araki,
K.; Iwamoto, K.; Shinkai, S.; Matsuda, T. ‘’pKa’ of Calixarenes and Analogs in Nonaqueous Solvents’ Bull.
Chem. Soc. Jpn. 1990, 63, 3480-3485.
14) Assigned CAS-#: 131957-03-4, mentioned in patent publication numbers: JP 1990201378A (Orient
Chem Ind LTD) and JP 1993127426A (Minolta Camera KK); no characterization.
15) Haase, C.; Biittig, R.; Staats, A.; Atwood, P. D.; Webb, J.; Chichak, K., SI Group, Inc., ‘Processes for
Preparing Calixarenes’, US 2019/0248721 A1, WO 2019157357 A1.
16) Haase, C.; Hiscock, J.; Atwood, P. D., SI Group, Inc., ‘Processes for Preparing Calix[4]arenes from
Calix[8]arenes’, US 2019/0248722 A1, WO 2019157368 A1.
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