Chapter 15
Molecular Recognition by Azacalix[3]arenes Philip D. Hampton, Si Wu, Panadda Chirakul, Zsolt Bencze, and Eileen N. Duesler
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Department of Chemistry, University of New Mexico, Albuquerque, NM 87131
The azacalix[3]arene macrocycles 1 are ideal hosts for the binding of metal ions and alkylammonium ions due to the presence of heteroatoms in the macrocycle ring and the ease of modifying their structure through the R, R', and R" substituents. Synthetic routes to the azacalix[3]arene macrocycles will be discussed from the perspective of their ability to generate the azacalix[3]arenes 1 free from the corresponding azacalix[4]arenes 2. Azacalix[3]arene macrocycle 1a exhibits the ability to bind trivalent metal ions and form complexes where the macrocycle is either a neutral (H L) or a trianionic (L ) donor. Crystal structures of well-defined yttrium(III) [3: Y ( H L ) C l ] and lanthanum(III) [4: La(L)] complexes are reported. Molecular recognition studies have been performed on the azacalix[3]arenes 1. In contrast with the O-unsubstituted macrocycles (1, R"= H) which exhibit no detectable binding of alkali or ammonium ions, the O-methylated macrocycle 1j is observed to extract alkali metal and alkylammonium picrates. 3
3-
3
3
The hexahomotriazacalix[3]arene macrocycles 1 (Figure 1), abbreviated to azacalix[3]arenes in this paper, are interesting targets for molecular recognition and ion separation studies since their structure can be modified at not only the upper-rim (R) and lower-rim (R"), but also within the macrocycle cup at the inner-rim (R') (/- 4). The azacalix[3]arenes have received only limited attention for their molecular recognition behavior; this is probably due to the difficulty of synthesizing the macrocycles free from the corresponding cyclic tetramers, the azacalix[4]arenes 2 (/). Takemura and co-workers first reported that the azacalix[3]arenes lb-e could be synthesized (Eq. 1) by heating 2,6-bis(hydroxymethylphenols) 5 in the presence of a primary amine in refluxing toluene (2-4). The azacalix[3]arenes were reported to be isolated without contamination by the corresponding azacalix[4]arenes 2. They also reported that azacalix[3]arene lb could be O-alkylated with picolyl chloride to yield macrocycle If but the cone vs. partial-cone selectivity of this reaction was not discussed (4). Macrocycle lb was reported to extract U 0 from aqueous solutions. 2 +
2
© 2000 American Chemical Society
In Calixarenes for Separations; Lumetta, G., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
195
196 M
l a : R= C H , R'= C H C 0 C H , R — Η 3
2
2
3
l b : R = C H , R'= C H P h , R"= Η 3
2
le: R= t-Bu, R'= C H P h , R"= H 2
Id: R = C H , R - ( 5 > < : H ( C H ) P h , R"= H 3
3
le: R = C H , K= CH (2-pyridyl), R"= H 3
α
.Ν R"
N
2
If: R = C H , R'= C H P h , R"= CH (2-pyridyl)
V
3
R"
2
2
l g : R = C H , R'= C H C H ( C H ) , R"= H 3
2
3
2
Downloaded by UNIV OF MICHIGAN ANN ARBOR on February 18, 2015 | http://pubs.acs.org Publication Date: July 20, 2000 | doi: 10.1021/bk-2000-0757.ch015
M
l h : R= C H , R'= C H C H = C H , R — H 3
2
2
l i : R = C H , R - H, R"= H l j : R = C H , R'= C H P h , R — C H 3
M
3
2
3
Figure 1. Structures of Azacalix[3]arene Macrocycles la-j
H
L J
R'NH
2
toluene, 135° R
lb-e
(Eq. 1)
5
Several years later, we developed an alternative approach to the azacalix[3]arenes 1 which is compatible with volatile amines that involves a cyclooligomerization reaction between 2,6-bis(chloromethyl)phenols 6 and primary amines at 60° in D M F (7). The use of glycine methyl ester as the primary amine resulted in a mixture of azacalix[3]arene l a , and the corresponding azacalix[4]arene 2 which could be separated by recrystallization. The crystal structure of this azacalix[3]arene exhibited a coneshaped conformation where the three nitrogen R ' groups are on the same face of the macrocycle and within the cone of the cupped macrocycle ligand. With all other primary amines that we examined, inseparable mixtures of the azacalix[3]arene 1 and azacalix[4]arene 2 macrocycles were obtained. Azacalix[3]arene l a exhibited no significant extraction of alkali metal or ammonium picrates. The absence of molecular recognition exhibited by these macrocycles was attributed to strong, intramolecular hydrogen-bonding which prevented both the phenolic oxygens and amines from participating in molecular recognition processes.
In Calixarenes for Separations; Lumetta, G., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
197
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The difficulties associated with these syntheses led us to develop new routes to the azacalix[3]arene macrocycles 1 which would provide the macrocycles in high purity, free from contamination by azacalix[4]arenes 2, and with the ability to easily modify the R, R ' , and R " substituents. In this paper, we describe several synthetic approaches to the azacalix[3]arene macrocycles 1 and studies of their molecular recognition behavior.
Results and Discussion Synthetic Routes to the Azacalix[3]arenes Four cyclooligomerization approaches to the azacalix[3]arene macrocycles 1 have been examined: (1) reaction of monomers 5 with primary amines (Eq. 1), (2) reaction of the monomers 6 with primary amines (Eq. 2), (3) condensation of the aminomethyl-chloromethyl monomers 7 (Eq. 3), and (4) cyclization of the aminomethyl-salicylaldehyde 8 (Eq. 4). The first route (Eq. 1), which was reported by Takemura and co-workers to yield only azacalix[3]arenes 1, in our hands resulted in inseparable mixtures of the azacalix[3]arene 1 and azacalix[4]arene 2 macrocycles. Similar results were obtained with the second (Eq. 2) and third (Eq. 3) routes (5).
(Eq. 4)
+ other cyclic oligomers + polymeric material
In Calixarenes for Separations; Lumetta, G., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
198 The fourth approach (Eq. 4), the cyclization of monomer 8 to form the iminocalix[3]arene 9, was examined as a route to the N-unsubstituted azacalix[3]arenes 1 ( R R"= H) which we believed would be ideal precursors to a wide range of TV-substituted azacalix[3]arenes If. Modification of the secondary amines in 1 f by Michael addition, alkylation, reductive alkylation could be used to introduce R ' substituents on the nitrogen atoms. Unfortunately, this cyclooligomerization reaction yielded mostly polymeric material and low yields of macrocycles (
