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NH2
2. Results and discussion
The encapsulating ligand 1-methyl-8-amino-3,13,16-trithia-
6,10,19-triazabicyclo[6.6.6]icosane (AMN3S3sar) was isolated after
removal of the metal ion from the complex [Co(AMN3S2sar)]2+ with
sodium cyanide [33–36]; the free ligand was crystallized from
dilute HClO4 and characterized crystallographically. The structure,
shown in Fig. 3, consists of the protonated ligand, two perchlorate
anions and two water molecules, AMN3S3sar.2ClO4.2H2O. There is
some disorder around the perchlorate anions. The cationic ligand
displays the typical three dimensional arrangements of the ligand
strands around the potentially encapsulating cavity. Two of the
amines are protonated, consistent with an earlier potentiometric
study of the ligand which determined that the di-protonated form
of the ligand was predominant over the pH range 3–9 (pKa1 = 2.5,
pKa2 = 5.74, pKa3 = 9.70) [37]. The sites of the protonation were
assigned based on a previous report which suggested that for hex-
NHNH NH
NHNH NH
HN
NH2
ammine cage molecules the0 protonated NAC bond distances were
0
appreciably longer (1.505 ÅA) than unprotonated (1.462 ÅA) [38].
Fig. 2. 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1,8-dia-
mine (SarAr).
Thus the bond distances for N(2)AC(10) and N(2)AC(13)
0
(1.502(4) and 1.486(4) ÅA, respectively) and N(3)AC(11) and
0
N(3)AC(14) (1.488(4) and 1.505(4) ÅA, respectively) suggest that
N(2) and N(3) are protonated when compared with analogous
bond distances for N(1)AC(9), N(1)AC(12) and N(4)AC(15)
0
0
(1.472(4) ÅA, 1.470(4) and 1.467(4) ÅA, respectively). There was no
evidence from the X-ray crystal structure of either the counterions
or the water molecules within the cavity of the ligand. AMN3S3sar
has been employed to prepare a range of transition metal com-
plexes; the copper(II) complexes displaying variable coordination
modes depending on the anion, and solvent [39–41]. With ClO4ꢀ
the hexadentate complex [Cu(AMN3S3sar)](ClO4)2 forms; however,
in the presence of bromide in DMSO the five-coordinate bromido
complex [Cu(AMN3S3sar)Br]+ was characterized, exhibiting a tetra-
dentate (N2S2)-coordinated form of the ligand [39–42].
Previously encapsulating ligands such as 1,8-diamine-3,6,
10,13,16,19-octaazabicyclo[6.6.6]icosane (diAMsar) have been
structurally modified to add functional groups to both the primary
and secondary amines. Examples of these reactions include, the
reaction of ortho- and meta-hydroxybenzaldehyde and subsequent
reduction with sodium cyanoborohydride resulting in mono- and
dialkylated derivatives of the starting cage complexes, attachment
of carboxymethyl groups to sarcophagine type ligands, and reac-
tions with benzoyl chloride, phthalic anhydride, and a range of
aldehydes [24–28].
Fig. 3. ORTEP plot of the (AMN3S3sarH2)2+ cation. Hydrogen atoms and the ClOꢀ4
anions omitted for clarity.
We have chosen to explore the reactions of the apical primary
amine of the cage ligand AMN3S3sar with carboxylic acids.
Coupling of a primary amine with a carboxylic acid to form an
amide has reportedly been readily achieved employing the coupling
agent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
chloride (DMT-MM). DMT-MM prepared by reaction of N-methyl-
morpholine and 2-chloro-4,6-dimethoxy-1,3,5-triazine (Scheme 1),
is stable on standing and readily promotes amide formation in eth-
anol solution, without requiring rigorously dry solvent conditions
[31,32].
NH2
NH2
Reaction of AMN3S3sar with 4-nitrobenzoic acid in the presence
of DMT-MM resulted in the isolation, in reasonable yield, of
N3S3amideSarArNO2, the ligand characterized through NMR, MS
and microanalysis. The 13C NMR spectrum displayed a total of
twelve resonances attributed to the product, as expected, suggest-
ing that the coupling had occurred at the terminal primary amine,
and not at a secondary amine, of the cage ligand. The resonance
attributed to the amide carbon atom was present at d 171.25 ppm.
Reaction of the cage ligand and the protected amine 4-(1,3-
dioxoisoindolin-2-yl)benzoic acid (Scheme 1) [43] in the presence
of DMT-MM in ethanol resulted in isolation of the protected amide
4-(1,3-dioxoisoindolin-2-yl)-N-(1-methyl-3,13,16-trithia-6,10,19-
N
NH
NH
NH NH NH
NH
NH
NH
NH
NH
NH
NH
NH
S
S
S
NH
N
NH
CH3
NH2
(a)
(b)
(c)
triazabicyclo[6.6.6]icosan-8-yl)
benzamide
(P-N3S3amideSa-
Fig. 1. (a) 1-Methyl-8-amino-3,13,16-trithia-6,10,19-triazabicyclo[6.6.6]icosane
(AMN3S3sar); (b) 1,3,6,8,10,13,16,19-octaazabicyclo[6.6.6]icosane (sep); (c) 1,8-
diamine-3,6, 10,13,16,19-octaazabicyclo[6.6.6]icosane (diAMsar).
rArꢁ3H2O) (Scheme 2). The 13C NMR of this product displayed six-
teen resonances suggesting that the primary amine of the cage