The Aza α-aminophosphonate macrocycle

Article abstract of DOI:10.1080/10426500902947823

In order to combine the properties of aza-macrocycles and aminophosphonates, a new tetraaminophosponic macrocyclic molecule has been synthesized. This potential receptor for organic molecules as well as for metal cations was obtained by condensation, hydr

Full text of DOI:10.1080/10426500902947823

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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The Aza-α-aminophosphonate
Macrocycle
Piotr Młynarz a , Agata Rydzewska a , Sylwia
Śliwińska a & Monika Szymczyk a
a Department of Chemistry , Wrocław University of
Technology , Wrocław, Poland
Published online: 06 Jun 2009.
To cite this article: Piotr Młynarz , Agata Rydzewska , Sylwia Śliwińska
& Monika Szymczyk (2009) The Aza-α-aminophosphonate Macrocycle,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:6, 1496-1501, DOI:
10.1080/10426500902947823
To link to this article: http://dx.doi.org/10.1080/10426500902947823
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Phosphorus, Sulfur, and Silicon, 184:1496–1501, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902947823
The Aza-α-aminophosphonate Macrocycle
´
´
Piotr Mlynarz, Agata Rydzewska, Sylwia Sliwinska,
ꢀ
and Monika Szymczyk
Department of Chemistry, Wroclaw University of Technology,
ꢀ
Wroclaw, Poland
ꢀ
In order to combine the properties of aza-macrocycles and aminophosphonates,
a new tetraaminophosponic macrocyclic molecule has been synthesized. This po-
tential receptor for organic molecules as well as for metal cations was obtained
by condensation, hydrophosphonylation, and deprotection. The second synthetic
step was performed using di(trimethylsilyl) phosphite, which enabled us to ob-
tain the final product in high yield. NMR studies strongly suggested that the
α-aminophosphonate macrocycle was reached as a symmetric meso-derivative.
Keywords Macrocyclic ligands; NMR spectroscopy
INTRODUCTION
The discovery of a family of macrocyclic compounds was a milestone
in chemistry and opened new frontiers in the synthesis of supramolec-
ular host molecules. This group of compounds has been recognized
as a source of receptors for many chemical species, such as metal
cations, inorganic and organic anions, and structurally variable organic
molecules.1 Therefore they are widely used for construction of metal se-
questering agents, selective sensors, mimetics of enzymes, or carriers
for transport through membranes.2−10 On the other hand, aminophos-
phonates have been found to be not only good enzyme inhibitors, but
also a promising group of metal ion chelators, and as such, they are
used in many branches of industry (e.g., agricultural, pharmaceutical,
Received 8 January 2008; accepted 3 March 2008.
Dedicated to Professor Marian Mikolajczyk, CBMiM PAN in Lo´dz´, Poland, on the
ꢀ
ꢀ
occasion of his 70th birthday.
The project was financially supported by Polish Ministry of Science and Higher Edu-
cation (Grant R05 016 01).
Address correspondence to Piotr Mlynarz, Department of Chemistry, Wroclaw Uni-
ꢀ
ꢀ
versity of Technology, Wybrzez˙e Wyspian´skiego 27, Wroclaw 50-370, Poland. E-mail:
piotr.mlynarz@pwr.wroc.pl
ꢀ
1496

The Aza-α-aminophosphonate Macrocycle
1497
and chemical industry).1 The tandem structure of macrocyclic polyaza
groups including phoshonate entities recently has been extensively in-
vestigated as potential contrast agents for MRI spectroscopy.11 Recently
we have shown that some di(aminomethylphosphonic)phenylenes com-
pounds exhibit interesting properties towards basic amino acids (Lys,
Arg) and metal ions,12,13
RESULTS AND DISCUSSION
In this article, we present the synthesis of a new group of aza-α -
aminophosphonate macrocycles represented by compound 2, which
combines features of both macrocyclic and phosphonic entities
(Scheme 1). As a substrate recently described, macrocyclic compound 1
was used based on the assumption that the introduction of four phos-
phonic groups placed into a carefully tailored cavity should result in
the new synthetic receptor of possible use in chelation of biologically
important molecules and metal ions.2
SCHEME 1

1498
P. M lynarz et al.
ꢀ
The macrocycle 1 was synthesized according to a standard [2+2]
condensation reaction that gave the desired Schiff base in a satisfac-
tory yield.14 When applying the standard procedure for the addition
of diethylphosphite to this Schiff base 1, the course of reaction was
non-satisfactory, most likely due to its low solubility in organic sol-
vents and leading to a mixture of many organophosphorus products.
Therefore another agent, trimethylsilyl phosphite, generated in situ,
was used.15,16
However, after only one purification step, a single and narrow sig-
nal is present in the 31P NMR spectra of the obtained moiety (see
Figures 1 and 2). This is really surprising when considering the rela-
tively high yield of the final product at 95%. This may suggest conver-
sion of kinetically controlled products into a thermodynamically stable
meso-stereoisomer. The inspection of 13C NMR spectra for α - CH and
CH2 groups of the purified compound reveal the presence of one major
stereoisomer accompanied by minute amounts of minor stereoisomers
(Figure 2), which supports predominant formation of a meso-derivative.
A similar assumption was reached from inspection of the 1H NMR spec-
tra. However, the addition of R (+) methylbenzylamine to compound 2
shows the presence of two small signals at 14.78 and 15.83 ppm and one
main at 15.51 ppm in 31P NMR spectra, which suggests the formation
of meso forms. Additional confirmation of the suggested meso form of
compound 2 is a capillary electrophoresis diagram in which only one
signal is visible.
FIGURE 1 The 31P NMR spectrum of a crude compound 2.

1499

1500
P. M lynarz et al.
ꢀ
It is worth stressing that the obtained macrocycle 2, in contrast to
simple aminophosphonic acids, is weakly soluble in water at neutral
pH. In order to increase solubility of this compound in water, its con-
version into salts is required either by addition of an amine (e.g., ben-
zylamine) or by transformation the acid into its sodium or ammonium
salt. The MS studies performed for macrocycle 2 sodium salt revealed
a complete dissociation of sodium ions and species of molecular masses
of 729 [M-H]− and 364 [M-2H]2− was observed, indicating the presence
of mononegative and dinegative anionic forms of the compound 2.
In conclusion, the simple synthesis of aza-α -aminophosphonate com-
pound, a promising agent in supramolecular chemistry, was described.
EXPERIMENTAL
Preparation of a Macrocyclic Schiff Base 1
This compound was synthesized according to the procedure in the
literature.14 The solution of terephthal-aldehyde (22 mmol, 3 g) in
370 mL of CH3CN was added dropwise to the solution of diethylen-
etriamine (22 mmol, 2.42 mL) in 630 mL of CH3CN. The mixture was
stirred for 24 h at room temperature, and a white precipitate was
formed. It was filtered off and washed with 10 mL of CH3CN and 3
× 10 mL of diethyl ether. The 1H NMR spectra of the isolated product
revealed chemical shifts that are in a good agreement with the data in
the literature.14
Yield: 34%; 1.54 g; 0.0038 mol; 1H NMR (300 MHz, CDCl3): 1.87 (s,
2H, NH); 3.00 (t, 8H, CH2 NH); 3.79 (t, 8H, CH2 N C); 7.55 (s, 8H,
Ar); 8.31 (s, 4H, CH N).
Preparation of a Macrocyclic Compound 2
A mixture of trimethyl phosphite (0.65 mL, 0.678 g, 5,5 mmol) and
trimethylsilyl bromide (3.3 mL, 3.278 g, 24.84 mmol) in 30 mL of dried
CHCl3 was cooled to –5◦C and stirred for 45 min. The solution became
yellow and clear. In a separate flask, a Shiff base 1 (0.500 g, 1.242
mmol) was suspended in 15 mL of dried CHCl3 and also cooled to –
5◦C. After 45 min, it was added to the above solution. The mixture
was stirred for 48 h in a room temperature. After that, all volatiles
were evaporated, and next the orange residue was treated with 30 mL
of methanol containing 5% of water and stirred overnight to give a
pale precipitate. A crude product was filtered off and dissolved in 1M
solution of sodium hydroxide. Then a 3M hydrochloric acid was dropped
in until the white precipitate was formed, which was next filtered off

The Aza-α-aminophosphonate Macrocycle
1501
and washed with diethyl ether to yield a yellow solid, 95%, 0.860 g, mp
255–257◦C.
1H NMR (300 MHz, D2O + NaOH): 1.81–1.92 (m, 16H, CH2); 3.20
(d, 4H, α CH, J = 17.3 Hz); 6.89 (s, 8H, Ar); 31P NMR (300 MHz, D2O
+ NaOH) δ ppm: 16.15 (s, P CH). ESI-MS (-): m/z = 729 [M-H]−; 364
[M-2H]2−
.
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