Fragmentation Reaction via an Ipso-Attack in the Multistep Synthesis of Regioselectively Functionalized Calix[8]arene

Article abstract of DOI:10.1021/ol006195x

The acid-catalyzed convergent synthesis of a calix[8]arene containing a regioselectively functionalized upper rim has been investigated through the isolation and identification of cyclic and acyclic byproducts. Theoretical calculations demonstrated that t

Full text of DOI:10.1021/ol006195x

ORGANIC
LETTERS
2
000
Vol. 2, No. 20
071-3074
Fragmentation Reaction via an
Ipso-Attack in the Multistep Synthesis of
Regioselectively Functionalized
Calix[8]arene
3
Hirohito Tsue,* Kazutaka Enyo, and Ken-ichi Hirao
DiVision of Material Science, Graduate School of EnVironmental Earth Science,
Hokkaido UniVersity, Sapporo 060-0810, Japan
tsue@ees.hokudai.ac.jp
Received June 13, 2000
ABSTRACT
The acid-catalyzed convergent synthesis of a calix[8]arene containing a regioselectively functionalized upper rim has been investigated through
the isolation and identification of cyclic and acyclic byproducts. Theoretical calculations demonstrated that the synthetic process involves
two types of reaction mechanisms, one of which leads to the favorably constructed framework, while the other causes undesirable fragmentation
via ipso-substitution. A possible rationale is proposed to explain the overall reaction pathways which derive the calix[8]arene along with the
byproducts.
3
“
Calixarene” is a general term for a series of macrocyclic
rim. However, the latter methodology is usually associated
with long and tedious reaction steps, which cause poor
overall yields and also present a large barrier to its
conventional use, although this method has permitted the
synthesis of regioselectively substituted calixarenes with
well-defined molecular structures. We have previously
reported the successful application of the latter methodology
phenol condensates, which are linked via methylene bridges
and which play an important role in host-guest chemistry.
1
Synthetic strategies for the construction of such frameworks
are generally classified into two main groups, i.e., (1) one-
step and (2) multistep syntheses.1c The former has been
extensively utilized for preparing calixarenes with uniformly
functionalized upper rims, and systematic and extensive
studies by Gutsche enable the ring size to be controlled by
4
to the preparation of calix[8]arene 1, in which the upper
rim is regioselectively functionalized by two different types
of substituents. However, contrary to prior expectations, a
variety of linear and cyclic byproducts including a ring-
2
simply adjusting the reaction conditions used. On the other
hand, the latter has mainly been applied to the synthesis of
calixarenes which contain different substituents at the upper
(2) (a) Gutsche, C. D.; Iqbal, M. Org. Synth. 1990, 68, 234. (b) Gutsche,
(
1) (a) Gutsche, C. D. Calixarenes ReVisited; Stoddart, J. F., Ed.;
C. D.; Dhawan, B.; Leonis, M.; Stewart, D. Org. Synth. 1990, 68, 238. (c)
Munch, J. H.; Gutsche, C. D. Org. Synth. 1990, 68, 243.
(3) See, for example: (a) B o¨ hmer, V.; Marschollek, F.; Zetta, L. J. Org.
Chem. 1987, 52, 3200. (b) Zetta, L.; Wolff, A.; Vogt, W.; Platt, K.-L.;
B o¨ hmer, V. Tetrahedron 1991, 47, 1911. (c) No, K.; Kim, J. E.; Kwon, K.
M. Tetrahedron Lett. 1995, 36, 8453.
Monographs in Supramolecular Chemistry, No. 6; The Royal Society of
Chemistry: Cambridge, 1998. (b) Calixarenes: A Versatile Class of
Macrocyclic Compounds; Vicens, J., B o¨ hmer, V., Eds.; Kluwer: Dordrecht,
991. (c) Gutsche, C. D. Calixarenes; Stoddart, J. F., Ed.; Monographs in
Supramolecular Chemistry, No. 1; The Royal Society of Chemistry:
Cambridge, 1989.
1
(4) Tsue, H.; Ohmori, M.; K, Hirao J. Org. Chem. 1998, 63, 4866.
1
0.1021/ol006195x CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/07/2000

shrunken calix[6]arene were found as contaminants in the
synthesis of 1. This finding prompted us to isolate and
identify these side reaction products and to investigate the
reaction mechanism by which they are produced. In this
Letter, we describe the molecular structures of the byproducts
and the key reaction mechanism via ipso-substitution, which
appears to be commonly involved in the multistep synthesis
of calixarenes.
Chart 1. Schematic representation of the reaction products
which have acyclic molecular structuresa
a
Black and white dots represent 4-ethoxycarbonylphenol-2,6-diyl and
4
-tert-bytylphenol-2,6-diyl groups, respectively. b Yields in the reaction 2
+
3 f 4.
homooxacalix[3]arene 15 were obtained, along with the
recovered heptamer 4 and the desired calix[8]arene 1. Very
interestingly, in these two reactions, the linear byproducts
were constructed of only an odd number of aryl residues,
except for benzyl alcohols 9 and 10, whereas the cyclic
molecules contained an even number of the residues, with
the single exception of 15. An important point in these two
reactions is that the starting materials 2, 3, and 4 would not
be expected to afford compounds such as 5, 6, 7, 8, 10, 11,
12, and 13, although the formations of homooxacalix[3]arene
4
According to the previous report, calix[8]arene 1 was
prepared by the application of a convergent “7 + 1” fragment
condensation, which was an extension of B o¨ hmer’s “3 + 1”
methodology. Starting from the acid-catalyzed condensation
of 2 and 3, the resultant “7” fragment 4 (20%) was allowed
to react with the “1” fragment 3 in the presence of a catalytic
amount of p-TsOH to afford the desired calix[8]arene 1
3
5
6
(8.5%). The fairly low yields in these two steps are reflected
in the fact that both steps were accompanied by the formation
of a variety of side reaction products, which were purified
by repeatitive flash column chromatography and identified
on the basis of spectral and microanalytical data (see
Supporting Information). Charts 1 and 2 schematically
summarize the molecular structures of the byproducts which
were isolated from the two reaction steps.
Chart 2. Schematic representation of the reaction products
with cyclic molecular structuresa
In the initial step 2 + 3 f 4, a total of 82 wt % of the
reaction products was recovered and identified, and all the
compounds which are depicted in Charts 1 and 2 were
obtained with the sole exception of homooxacalix[3]arene
15. Acyclic products consisted of trimer 5, two types of
pentamers 6 and 7, two types of heptamers 4 and 8, and two
types of terminally hydroxymethylated condensates 9 and
10, along with the unreacted 2, while the cyclic molecules
were comprised of two types of calix[8]arenes 1 and 11, two
calix[6]arene derivatives 12 and 13, and calix[4]arene 14.
On the other hand, in the second step 4 + 3 f 1, a total of
54 wt % of the reaction mixture was identified, and only
cyclic byproducts such as ring-shrunken calix[6]arene 12 and
a
Black and white dots represent 4-ethoxycarbonylphenol-2,6-diyl and
b
(
5) Dhawan, B.; Gutsche, C. D. J. Org. Chem. 1983, 48, 1536.
4-tert-bytylphenol-2,6-diyl groups, respectively. Yields in the initial step
2 + 3 f 4. c Yields in the second step 4 + 3 f 1.
(6) Zinke, A.; Ott, R.; Leggewie, E.; Hassanein, A.; Zankl, G. Monatsh.
Chem. 1956, 87, 552; Chem. Abstr. 1957, 51, 2845c.
072
3
Org. Lett., Vol. 2, No. 20, 2000

15 from 3 and of calix[4]arene 14 from 2 and 3 are easily
understandable.
Scheme 1. A Competitive Fragmentation Pathway via
To further explore the mechanism for this reaction, the
acid-lability of 1, 2, and 4 was examined by exposing each
compound to acidic conditions, which were essentially
identical with that used for the acid-catalyzed condensation
reactions 2 + 3 f 4 and 4 + 3 f 1. However, these
compounds were recovered quantitatively and revealed no
detectable changes, indicating that they are stable under these
conditions. It is thus reasonable to assume that none of the
byproducts are generated directly from molecules 1, 2, and
Ipso-Substitution
4
1
. It is particularly interesting to note that calixarenes 12-
4 are not formed through the direct [8]-to-[6] or [8]-to-[4]
shifts of 1 at least under the reaction conditions examined
7
herein, although Mendoza reported the direct transformation
of a calix[6]arene into a calix[4]arene under acidic conditions,
8
and Gutsche also reported a similar interconversion from
p-tert-butylcalix[8]arene to the bimolecular p-tert-butylcalix-
[4]arene in the presence of NaOH. In contrast to the stability
of 1, 2, and 4, the similar treatment of a byproduct 9 under
the same acidic condition resulted in the formation of a
complicated reaction mixture. Considering the synthetic
processes of the target compound 1 and the intermediate 4,
the results of this experiment clearly suggest that the benzyl
alcohol moiety present in 3, 9, and 10 serves as a trigger for
inducing side reactions, from which the byproducts shown
in Charts 1 and 2 are derived.
With this in mind, an aromatic electrophilic substitution
reaction between phenol condensate 2 and benzyl cation 16,
which could be generated in situ from benzyl alcohol 3 and
an acid catalyst of p-TsOH, was analyzed as a typical case
mixture. On the other hand, the 4-position in 2 was calculated
to be the highest reactive cite and the tert-butyl cation would
be expected to be a good leaving group. Nevertheless, the
electrophilic attack at the 4-position appears not to occur,
mainly due to the steric hindrance arising from the bulky
tert-butyl group. Indeed, none of the corresponding byprod-
ucts were involved in the reaction products. Consequently,
the formation of the various side reaction products can be
attributed to the participation of an additional reaction
pathway, which would result from the newly formed benzyl
alcohol 10 and benzyl cation 17 which are capable of reacting
with other molecules present in the same reaction system.
of such a reaction by using a semiempirical molecular orbital
calculation based on MOPAC PM39 according to the
Klopman’s general perturbation equation.10 The theoretical
calculations clearly showed that the orbital coefficients of
the highest occupied molecular orbital (HOMO) in 2 ap-
peared only in one of the terminal phenol rings, the carbon
atoms of which are numbered in Scheme 1, and that the
ortho- and para-positions of the ring were susceptible to
attack by the electrophile 16. The regioselectivity was
Scheme 2 shows a possible explanation for the complete
reaction diagram, which shows that the synthetic pathways
11
estimated to increase in the order of 6- < 2- < 4-positions.
In other words, the point of this theoretical prediction is that
a reaction at the 6-position would favorably extend the linear
structure of the product, whereas that at the 2-position leads
to an undesirable fragmentation reaction through a Meisen-
heimer complex, to give a benzyl alcohol 10 and a benzyl
cation 17, as illustrated in Scheme 1. This prediction is in
reasonable agreement with the experimental fact that com-
pound 10 was isolated as a byproduct from the reaction
Scheme 2. A Possible Explanation of All the Reaction
Pathways. The Presence of Fragmentation Reaction via
Ipso-Attack Is Designated as Branched Arrows
(
7) de Mendoza, J.; Nieto, P. M.; Prados, P.; S a´ nchez, C. Tetrahedron
990, 46, 671.
8) (a) Gutsche, C. D.; Iqbal, M.; Stewart, D. J. Org. Chem. 1986, 51,
42. (b) Dhawan, B.; Chen, S.-I.; Gutsche, C. D. Makromol. Chem. 1987,
88, 921.
1
(
7
1
(
9) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209.
(
10) (a) Klopman, G. In Chemical ReactiVity and Reaction Paths;
Klopman, G., Ed.; Wiley & Sons: New York, 1974; pp 55-165. (b) Houk,
K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem. Soc. 1973, 95,
7
301.
11) Perturbation energies at the 2-, 4-, and 6-positions were estimated
(
to be 0.48, 0.84, and 0.36 eV, respectively.
Org. Lett., Vol. 2, No. 20, 2000
3073

leading to calix[8]arene 1 are associated with numerous
competitive side reactions. The formation of 1, 4, 9, 14, and
although consideration must also be given to steric hindrance
as a factor. In light of our present result and those reported
by B o¨ hmer, who obtained a calix[4]arene as the exclusive
product in the attempted synthesis of a calix[5]arene using
15 can be easily understood, while it is likely that the other
molecules are formed as above through undesirable frag-
mentation reactions via ipso-attack. Although the side
reactions in Scheme 2 remain to be proved by actually
examining the reactions of each byproduct, the scheme is a
reasonable one, since the key intermediates 4, 7, and 8 in
the formation of calixarenes 11, 12, and 13 were theoretically
predicted to have reactivities similar to 2. The orbital
coefficients of the HOMOs in these molecules were found
only in the one terminus, and the regioselectivities of the
aromatic electrophilic substitution reactions with benzyl
1
4
“3 + 2” methodology, it seems quite likely that a
fragmentation reaction via ipso-attack is frequently involved
in the multistep preparation of calixarenes especially under
1
5
acidic conditions. To locate a method for suppressing the
undesirable pathways, the nature and generality of the
reaction are being investigated in our laboratory.
Acknowledgment. We thank the GC-MS and NMR
Laboratory, Faculty of Agriculture, Hokkaido University, for
FDMS measurements. We are also grateful to Ms. Hiroko
Matsumoto and Ms. Akiko Maeda at the Center for Instru-
mental Analysis, Hokkaido University, for the measurement
of elemental analysis. This research was supported, in part,
by Grant-in-Aid for Encouragement of Young Scientists
cation 16 were calculated to increase in the same order as
that predicted for 2.12 In particular, from the mechanistic
point of view, the results of the theoretical calculations are
1
3
in good agreement with Gutsche’s recent study of the
reaction mechanism which involves ipso-substitution in the
acid-induced one-step formation of calix[n]arenes (n )
(Nos. 09740456 and 12740334) from the Ministry of
Education, Science, Sports and Culture, Japan.
4-20) from linear oligomers of p-tert-butylphenol and
formaldehyde. Accordingly, judging from the above, it seems
reasonable to presume that Scheme 2 represents a plausible,
though inconclusive, interpretation for explaining the com-
plete reaction pathways leading to calix[8]arene 1 along with
the observed byproducts.
In conclusion, it follows from the present study that the
formation of calix[8]arene 1 is very sensitive to regioselec-
tivity in the aromatic electrophilic substitution reactions,
Supporting Information Available: Experimental pro-
cedures, characterization data, and H NMR spectra of all
new compounds, and the results of theoretical calculations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
OL006195X
(
14) B o¨ hmer, V.; Marschollek, F.; Zetta, L. J. Org. Chem. 1987, 52,
200.
(15) A similar ipso-substitution reaction under neutral condition was
3
(12) Perturbation energies at the 2- and 6-positions were estimated to
be 0.51 and 0.36 eV for 4, 0.51 and 0.36 eV for 7, and 0.51 and 0.36 eV
for 8, respectively.
supposed in the heat-induced synthesis of calix[5]arenes. See: Biali, S. E.;
B o¨ hmer, V.; Columbus, I.; Ferguson, G.; Gr u¨ ttner, C.; Grynszpan, F.; Paulus,
E. F.; Thondorf, I. J. Chem. Soc., Perkin Trans. 2 1998, 2261.
(13) Stewart, D. R.; Gutsche, C. D. J. Am. Chem. Soc. 1999, 121, 4136.
3074
Org. Lett., Vol. 2, No. 20, 2000