Chapter 8
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Synthesis of Novel Azamacrocyclic Metal Ion Receptors Using a Modified Mannich Aminomethylation Reaction 1
2
Jerald S. Bradshaw, Andrei V. Bordunov , Xian Xin Zhang, Victor N. Pastushok , and Reed M. Izatt Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602
A modified Mannich aminomethylation reaction was used to prepare a series of N-substituted-phenol-containing azacrown ether ligands. Ligands synthesized include aza-15-crown-5, aza-18-crown-6, azapyridino-18crown-6, diaza-18-crown-6, diaza-21-crown-7 and diaza-24-crown-8 containing various substituted phenols, salicylaldehyde, and 5-chloro-8hydroxyquinoline (CHQ) groups as side arms. The modified Mannich reaction was also used to prepare bi- and tricyclic azamacroheterocycles containing phenol units, benzoazacrown ethers, benzocryptands, and cryptohemispherands. The phenol- and CHQ-substituted azacrown ligands interact more strongly with metal ions than do the parent unsubstituted azacrown ethers. Bis-CHQ-substituted diaza-18-crown-6, wherein the CHQ groups are attached through their 7 positions, are particularly selective for K over other alkali metal ions and for Ba over all other metal ions studied. +
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Current address: Department of Chemistry, California Institute of Technology, Pasadena, C A 91125. Current address: A.V. Bogatsky Physico Chemical Institute, National Academy of Sciences of Ukraine, Odessa 270080, Ukraine.
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©1999 American Chemical Society
In Metal-Ion Separation and Preconcentration; Bond, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
133
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134 A Mannich aminomethylation reaction, where an amine is reacted with an aldehyde and a C-H or N-H acid to form aminomethyl derivatives, has wide use in organic synthesis (1). We have explored this type of interaction for the synthesis of supramolecular metal ion complexing agents (2). This general approach to substituted azacrown ethers simplifies existing synthetic methodologies and, in contrast to conventional methods, allows the preparation of azamacrocyclic ligands in good to excellent yields in mostly one or two steps. The modified Mannich reaction expands considerably the functional and structural variety of synthesized azamacrocycles and facilitates their large-scale synthesis, particularly in the case of azacrown ethers and cryptands containing phenolic units. The modified Mannich reaction was also used to prepare bi- and tricyclic azamacroheterocycles, benzo- and bisazacrown ethers and cryptands. Lariat ether ligands synthesized include aza-15-crown-5, aza-18-crown-6, azapyridino-18-crown-6, diaza- 18-crown-6, diaza-21-crown-7 and diaza-24-crown-8 lariat ether macrocycles functionalized with various substituted phenols, heterocycles, amides, imides, and sulfamides. This synthetic method eliminates the need for benzyl halides or phenylacyl chlorides as starting building blocks for coupling with nitrogen-containing fragments. Aromatic azamacrocyclicframeworkscan be constructed by Mannich-type condensation between iV-methoxymethylamines and phenolic substances that are readily available or easily synthesized. Furthermore, Mannich condensation does not require protecting groups for the phenolic hydroxide under normal conditions. This reaction also allows benzylamine bond formation between phenols and secondary amines in the presence of other unprotected functional groups which can be used in further chemical transforma tions. Thus, phenolic hydroxides as well as carbonyl groups of aromatic fragments attached to the azamacrocylic rings have been exploited to prepare ligands containing a greater number of rings (3) and Schiff base lariat azacrown ethers (4). The basic idea of combining macrocyclicfragmentswith molecules of phenolcontaining analytical reagents to improve the strength and, especially, selectivity of metal ion binding was realized via Mannich condensation of ΑΓ-methoxymethylazacrown ethers with 5-chloro-8-hydroxyquinoline (CHQ) (5). A number of novel UV/fluorescent active metal ion receptors exhibit extremely high complexing ability and specificity upon binding cations. Highly specific reagents for K and Ba and chromogenic ligands for Mg and Zn have been found among CHQ-modified azacrown macrocycles (5,6). Several pyridinocrown ethers functionalized with phenol side arms show very high specificity towards Ag over other monovalent cations (7). This chapter reviews the work done in our laboratory on the synthesis of macroheterocyclic ligands using the modified Mannich reaction. The interaction of some of these new ligands with various metal ions is also reviewed. +
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Phenol and 5-Chloro-8-hydroxyqumoline Armed Azacrown Ethers
A number of phenol-containing lariat azacrown ethers has been reported as selective chromogenic reagents for the extraction of alkali and alkaline earth metal ionsfromwater to an organic phase (8,9). The usual method to prepare these lariat ethers is to react a hydroxy-substituted benzyl halide with the unsubstituted azacrown ether. The need to prepare suitable starting benzyl halides and the necessity to protect their phenolic
In Metal-Ion Separation and Preconcentration; Bond, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
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135 hydroxy groups (10) often make this alkylation reaction difficult and time consuming. On the other hand, the aminomethylation reaction allows the preparation of iV-phenolsubstituted azacrown ethers in one step from inexpensive and accessible phenols containing electron donating as well as electron withdrawing groups on the substituent phenolic ring (11). Figure 1 shows the structures of some lariat ether metal ion receptors synthesized in our laboratory using the modified Mannich aminomethylation reaction. iV-Methoxymethylazacrown ethers have been used as key intermediates in all chemical transformations leading to these materials. Scheme 1 shows the typical synthesis of iV-methoxymethyl derivatives of the azacrown ethers via treatment of the azamacroeycle with formaldehyde in methanol (12,13). iV-Methoxymethylazacrown ethers were obtained in almost quantitative yields. The N-methoxymethyl-substituted azacrowns were then treated with phenolic compounds in non-polar solvents. Ligand 20, for example, was prepared as follows (13,14). A solution of 1 g (3.8 mmol) of l,10-diaza-18-crown-6 in 3 mL of pure methanol was added to a mixture of 0.23 g (7.6 mmol) of paraformaldehyde in 3 mL of methanol that was purified by refluxing in the presence of a trace of potassium hydroxide. The resulting methanol solution was left to stand for 12 h at 20 °C. The methanol was removed and the residue was dissolved in 5 mL of pure ether and the mixture was filtered. Thefiltratewas concentrated to 2 mL and cooled to -50 °C. The resulting crystals were rapidlyfilteredto give 0.83 g of iV,AP-bis(methoxymethyl)diaza-18-crown6; mp 36-37 °C. A further 0.26 g of product was obtainedfromthefiltratemaking a total of 1.09 g (82%) (13). A^A -Bis[(5-chloro-8-hydroxyquinolin-7-yl)methyl]-diaza-18-crown-6 (20) was prepared by treating 1 g (2.9 mmol) of the above A^iV-bisimethoxmethy^diaza-lScrown-6 with 1 g (5.6 mmol) of 5-chloro-8-hydroxyquinoline in 30 mL of refluxing benzene for 10 h. The hot solution wasfilteredand thefiltratewas evaporated under reduced pressure. The residue was mixed with 15 mL of a hot mixture of benzene and THF (1:1). Ligand 20 crystallized when the solution stood for 24 h to give 1.2 g (67%); mp 140-141 °C (14). The aza- and diazacrown ethers are available but expensive. They can be prepared by a number of methods as we have outlined in a recent book (15). Neverthe less, the high yields for iV-methoxymethylation and subsequent aminomethylation of the phenol make this method useful for the preparation of phenol-substituted azacrown ethers. Unsubstituted phenols generally react in the
3
v
H3Q /
C
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- C f \-N H3C
N
\ /
0
\ CH3
w ^ Ο Ν—^ f
' ^ CH 32 71%
3
Scheme 5. Synthesis of benzoazamacrocyles.
In Metal-Ion Separation and Preconcentration; Bond, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
141
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Log Κ Values for the Interaction of Azacrown Ethers Containing Hydroxyaromatic Sidearms With Various Metal Ions in Methanol at 25.0 °C.
Table 1.
log If Downloaded by UNIV OF MICHIGAN ANN ARBOR on October 11, 2014 | http://pubs.acs.org Publication Date: February 11, 1999 | doi: 10.1021/bk-1999-0716.ch008
Ligand
Na
Ba
2+
Cu
2+
Tl
+
Ag
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1.70
1.60
30
2
3.32
2.71
4
3.00
3.17
3 b
4.28
29
7.88
30
A18C6
2.69
5
3.11
4.07
6
3.60
4.47
4.08
9.44
29
7
3.98
5.42
6.20
5.52
29
b
4
7
PyA18C6
c
8
3.06
3.17
4.20
>8.5
7
9
3.10
3.27
4.22
>9
7
10
3.29
3.41
4.29
>9
7
11
3.49
3.53
4.34
>9
7
12
3.59
3.62
4.40
>9
7
13
3.21
3.40
14
3.85
4.01
4.12
8.12
29
4.20
5.16
5.49
3.72
29
DA18C6
c
1.83
6.12
8.48
18
2.85
2.76
3.52
4.14
5
20
2.89
3.39
3.60
10.1
5
21
3.74
6.61
12.2
4.7
5
15 b
b
K
+
A15C5
b
a
+
4
3.06
30
Values determined by calorimetric titration. A15C5 = aza-15-crown-5, A18C6 = aza-18-crown-6, PyA18C6 = pyridinoaza-18-crown-6, D A 1 8 C 6 = l,10-diaza-18-crown-6.
°No measurable heat.
In Metal-Ion Separation and Preconcentration; Bond, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
142 However, ligands 8-15 with different phenol, salicylaldehyde, and CHQ arms complex Na with log Κ values of 3.06-4.20. CHQ modified azamcrocycles show especially interesting properties in terms of the correlation between binding ability and structures of ligands studied. Compounds 3, 6, 14, and 20 form very stable complexes with transition metal ions (log Κ values for Cu are shown as an example in Table 1). The enhanced copper binding specificity compared to the alkali and alkaline earth metal ions is due to participation of the CHQ moieties in complex formation. Ligand 18, containing only chlorophenol sidearms, exhibits smaller log Κ values for interactions with metal ions. Ligand 18 forms a less stable complex with Cu than does 20 by six orders of magnitude. In addition, 18 shows no special selectivity among the metal ions studied. The position of attachment of the CHQ groups to the macroring has a significant effect on cation complexation. Ligands 3, 6,14, and 20 have CHQ attached through its 7 position (next to the OH group) and form more stable complexes with Cu than with Na , K and Ba (5, 29). However, when CHQ is attached through its 2 position (next to the quinoline nitrogen), the resulting ligands 7,15, and 21 exhibit strong interactions with Na , K and Ba but decreased interactions with Cu . Such reversed complexing ability is caused by different mutual positions of the quinoline OH groups and aliphatic nitrogen atoms of the azamacrocycles in 2-CHQ-substitututed (7, 15, and 21) and 7CHQ-substituted (6, 14, and 20) ligands. Compounds 6, 14, and 20 having hydroxy groups and azacrown nitrogens in a close proximity form less stable complexes with alkali metal ions and Ba because of the deactivation of aliphatic nitrogen atoms through intramolecular hydrogen bonds with the quinoline OH groups (5). The hydroxy group also causes the soft nitrogen atom of the quinoline to be in a pseudo axial position and, thus, the nitrogen atom would not be available to metal ions complexed in the macroring. Bis-CHQ-substituted 21 exhibits high selectivity for K and Ba over Na and Cu . Log Κ values for the formation of K and Ba complexes with 21 are larger than those for K and Ba complexes with all other lariat ethers (30). The log Κ value for the 21-Ba complex (12.2 in MeOH) is the same magnitude as that of the cryptand [2.2.2]Ba complex (12.9 in MeOH (29)). Selectivity factors for Ba over other alkaline-earth cations and for K over Na are >10 and ~10 , respectively (Table 1), which are the highest factors ever reported for lariat ethers. Moreover, the selectivity of 21 for Ba is larger than that of any cryptand studied to date. The special complexing properties of 21 are related to its peculiar molecular structure. Through coordination with K and Ba , the two CHQ substitutents of 21 can overlap each other through π-π interaction so that a pseudo second macroring is formed. This effect results in a cryptate-like structure and, therefore, highly stable complexes (5,6). High selectivity of CHQ-containing metal ion receptors is combined with their ability to perform UV/fluorescence response upon complexation. Ligand 20, having high Mg selectivity over other alkaline-earth, alkali metal, and zinc ions, also has a very specific absorption at 265 nm when it is bound to Mg (5). Moreover, 20 fluoresces strongly in the presence of Zn , but not with Na or K . The chromogenic features of 20 allow the application of this receptor for the measurement of Mg and Zn concentra tions in very dilute solutions and in mixtures with other metal ions. Phenol-substituted pyridinoazacrown ethers 8-12 form stable complexes with Na , K , Tf, and Ag in MeOH and show high selectivity for Ag over the other cations studied. In each case, the log Κ values for complex formation increase in the order +
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Downloaded by UNIV OF MICHIGAN ANN ARBOR on October 11, 2014 | http://pubs.acs.org Publication Date: February 11, 1999 | doi: 10.1021/bk-1999-0716.ch008
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7
3
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In Metal-Ion Separation and Preconcentration; Bond, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
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