Synthesis of a [2.2.2] cryptand containing reactive functional groups

Article abstract of DOI:10.3390/molecules14093600

The functional group- containing potassium ionophore 195, 245 dibromo-4,7,13,16,20,23-hexaoxa-1,10 diaza-19(1,2), 24(1,2 dibenzabicyclo[8.8.6] tetracosaphane has been synthesized.

Full text of DOI:10.3390/molecules14093600

Molecules 2009, 14, 3600-3609; doi:10.3390/molecules14093600
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of a [2.2.2] Cryptand Containing Reactive Functional
Groups
Yousry M.A. Naguib †
Faculty of Education, Suez Canal University, El-Arish, Egypt; Email: yousryn@gmail.com
†
Current address: 19 E Newman Ave, Arcadia, CA 91006, USA.
Received: 10 August 2009; in revised form: 3 September 2009 / Accepted: 14 September 2009 /
Published: 15 September 2009
Abstract: The functional group-containing potassium ionophore 195,245-dibromo-
4,7,13,16,20,23-hexaoxa-1,10-diaza-19(1,2),24(1,2)-dibenzabicyclo[8.8.6]tetracosaphane
has been synthesized.
Keywords: dibenzocryptand [2.2.2]; ionophore; potassium
Introduction
Potassium (K+) is a major cationic constituent of living cells; its concentration in intercellular living
cells is around 150 mmol·dm-3, whilst its extracellular levels are typically around 4 mmol·dm-3.
Potassium level measurements of are importance in the fields of cell physiology and clinical medicine [1,2].
Fluoroionophores based on a fluorescent coumarin group probe and the ionophore 1,10-diaza-18-
crown-6 chelating group (abbreviated by the acronym CD18), which is selective for K+ ions, and
capable of measuring K+ in an aqueous physiological environment have been reported [3].
Fluoroionophore sensors possess a guest binding site (ionophore) having a heteroatom with
nonbonding electron pairs such as nitrogen, and a photon-interaction site (fluorophore) capable of
accepting electrons. In the absence of a cation that binds selectively in the cavity of ionophore, when
the fluorophore is excited by a photon, electron transfer from the ionophore to the fluorophore results
in fluorescence quenching. In the presence of a cation which selectively binds to the ionophore and
hence inhibits the electron transfer process, the fluorescence of fluorophore is switched on.
In order to attain high, yet selective binding of a potassium ion chelator some rigidity in the system
was considered necessary compared to the selective binder CD18. Hence, the 1,10-diaza-18-crown-6

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chelating group in CD18 was replaced by the bicyclic ionophore “cryptand [2.2.2]” which resulted in a
selective, high affinity fluoresecent probe for K+ abbreviated CD222 [4].
Cryptands are cavities containing macromolecules which form stable complexes with alkali metal
ions. For a given cation, the stability constant is largest for the cation which fits best into the cavity of
the ligand. Thus stability maxima are found for Li[2.1.1]+, Na[2.2.1]+, and K[2.2.2]+, respectively [5].
A similar fluoroionophore based on the ionophore cryptand [2.2.2] (abbreviated MCC) for measuring
potassium, namely, 6,7-(4-methyl)coumaro-[2.2.2] cryptand, was also reported [6]. Other potassium
fluoroionophores based on triazocryptands have been reported [7, 8]. The cavity size of the cryptand
[2.2.2] (2.8 Å in diameter) closely matches the size of potassium cation (2.66 Å). This paper describes
the synthesis of a bromo-derivative of the ionophore dibenzo-cryptand [2.2.2] which serves as a
precursor of potential fluoroionophores for potassium ions [9]. The fluorophore can be introduced by,
for example, reacting the bromodibenzocryptand [2.2.2] with t-butyl lithium, followed by reaction with
a 2,7-dichloroxanth-9-one derivative to give a fluoroscein type fluoroionophore.
Results and Discussion
The synthesis of the dibenzocryptand [2.2.2] derivative; namely 195,245-dibromo-4,7,13,16,20,23-
hexaoxa-1,10-diaza-19(1,2),24(1,2)-dibenzabicyclo[8.8.6]tetracosaphane (VIII) is outlined in
Scheme 1. The commercially available compound 2-nitrophenol (I) was chosen as a starting material.
Treatment of two equivalents of (I) with 1,2-dibromoethane and potassium carbonate in dimethyl
formamide (DMF) afforded 1,2-bis(2-nitrophenoxy)ethane (II). Reduction of II with 10% palladium-
on-charcoal as the catalyst produced the diamino derivative III. The diamine III was next reacted in
tetrahydrofuran under high dilution conditions [10] with 3,6-dioxaoctanedioyl dichloride (1,2-
ethylene-O,O-diglycolic acid chloride) to gave the lactam IV. The lactam IV was reduced with lithium
1
aluminum hydride (LiAlH4) in THF to give the azacrown V [11]. Figure 1 shows the complete H-
NMR spectrum of V and the insert shows the 6.4–7.2 ppm region, and the assignment of spectral data
are given in the Experimental section.
Subsequent treatment of V with 1,2-ethylene-O,O-diglycolic acid chloride gave VI which upon
reduction with diborane in tetrahydrofuran [12] furnished the cryptand VII. Calo et al. have reported a
simple method for monobromination of aromatic amines predominantly or exclusively in the para-
position utilizing 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one [13]. A similar procedure is also
described in Organic Syntheses [14] for the preparation of para-brominated aromatic amines in high
yield, for example bromination of ortho-anisidine (closely related to compounds V and VII) with
2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one yielded 85% of the corresponding para-bromo-derivative
[14]. These data support the expected para-bromination with 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-
one of compound VII to the dibromocryptand VIII, and of V to X.
1
Figure 2 shows the complete H-NMR spectrum of VIII and the insert shows the 6.7–7.3 ppm
region. Figure 3 shows the FAB (fast atom bombardment) mass spectrum of VIII, which displays a
[M+Na]+ ion at m/z 651 (based on 79Br) and this gives M = 628, consistent with molecular formula of
VIII. The isotope pattern reflects a dibromo composition. The ions at m/z 307 and 329 are [2M+H]+
and [2M+Na]+ respectively for the nitrobenzyl alcohol used as the FAB matrix.

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Scheme 1. Synthesis of bromodibenzocryptand [2.2.2].
Figure 1. 1H-NMR (300 MHz, CDCl3) of V.

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Figure 2. 1H-NMR (400 MHz, CDCl3) of VIII.
Figure 3. Mass spectrum (FAB) of VIII.
The dibromocryptand VIII was also prepared by an alternative reaction sequence starting with
azacrown V. Bromination of V with bromine afforded both monobromo azacrown IX and dibromo
azacrown X. Compound X was also prepared by the treatment of diamine V with 2,4,4,6-tetrabromo-
1
2,5-cyclohexadien-1-one. Figures 4 and 5 show the H-NMR spectra of IX and X, respectively.
Treatment of X with 3,6-dioxaoctanedioyl dichloride afforded XI (195,245-Dibromo-4,7,13,16,20,23-
hexaoxa-1,10-diaza-19(1,2)24(1,2)-dibenzabicyclo[8.8.6]tetracosaphane-2,9-dione) which upon reduc-
tion with borane in THF gave the dibromocryptand VIII.
1
The H-NMR compound X (Figure 5) displays signals at δ 6.44 (d, J = 8.7 Hz, 2H, 13-H, 63-H),
6.86 (d, J = 2 Hz, 2H, 16-H, 66-H), 6.99 (dd, J = 2 and 8.7 Hz, 2H, 14-H, 64-H) assigned to 15,65-
dibromo-2,5,10,13-tetraoxa-7,16-diaza-1(1,2),6(1,2)-benzenecyclohexadecaphane. Comparison of the

Molecules 2009, 14
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spectral data of X with those of the diamine V reveals that bromination para- to the amino group
results in an upfield shift (0.18 ppm) of 13-H (from 6.62 to 6.44 ppm), a downfield shift (0.11 ppm) of
14-H (from 6.88 to 6.99 ppm), and a downfield shift (0.08 ppm) of 16-H (from 6.78 to 6.86 ppm).
These chemical shift changes are in agreement with the predicted values [15] of closely related
compounds, as will be shown below.
The following signals of Figure 5 could also be assigned to 14,64-dibromo-2,5,10,13-tetraoxa-7,16-
diaza-1(1,2),6(1,2)-benzenecyclohexadecaphane: δ 6.44 (d, J = 8.7 Hz, 2H, 16-H, 66-H), 6.86 (d,
J = 2 Hz, 2H, 13-H, 63-H), 6.99 (dd, J = 2 and 8.7 Hz, 2H, 15-H, 65-H). Comparison of these spectral
data with those of the diamine V reveals that bromination para- to the oxygen group results in a
downfield shift (0.24 ppm) of 13-H (from 6.62 to 6.86 ppm), downfield shift (0.31 ppm) of 15-H (from
6.68 to 6.99 ppm), and an upfield shift (0.34 ppm) of 16-H (from 6.78 to 6.44 ppm). These chemical
shift changes are different from the predicted values of closely related compounds, as discussed below.
The predicted chemical shifts of aromatic protons of 2-methoxy-N-methylaniline are δ 6.31, 6.47,
6.55, and 6.60 ppm for 6-H, 4-H, 3-H, and 5-H, respectively. The predicted chemical shifts of the
aromatic protons of 4-bromo-2-methoxy-N-methylaniline are δ 6.20, 6.72, and 6.77 ppm for 6-H, 3-H,
and 5-H, respectively. These data indicate that para-bromination of the amino group results in an
upfield shift (0.11) of 6-H, a downfield shift (0.17 ppm) of 3-H, and a downfield shift (0.17) of 5-H.
These chemical shift changes are close to those of the corresponding protons in compound X.
The predicted chemical shifts of the aromatic protons of 5-bromo-2-methoxy-N-methylaniline are δ
6.43, 6.48, and 6.64 ppm for 3-H, 6-H, and 4-H, respectively. These data indicate that bromination
para- to the oxygen group results in an upfield shift (0.12 ppm) of 3-H, a downfield shift (0.17) of
6-H, and a downfield shift (0.17) of 4-H. These chemical shift changes are different than those of 14,
64-dibromo derivative indicating bromination of the diamine V proceeds via para-bromination of the
amino group.
Figure 4. 1H-NMR (300 MHz, CDCl3) of IX.

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Figure 5. 1H-NMR (300 MHz, CDCl3) of X.
Experimental
General
All purifications by flash chromatography were performed on silica gel 230-400 mesh (Merck).
1
Thin layer chromatography (TLC) was performed on silica gel IB-F (J.T. Baker). H-NMR spectra
were recorded on either Varian 300 MHz or Bruker 400 MHz spectrometers. Resonances are reported
as (solvent); δ = shift in ppm from tetramethyl silane (TMS) at 0 ppm and the multiplicity of signals as
s, singlet; d, doublet; dd, double doublet; t, triplet; m, multiplet; br, broad; J values are in Hz. The
numbering system used is shown in the schemes. IR spectra were measured on Nicolet FT-IR Impact
400D as KBr discs. UV-Visible spectra were obtained on a Hitachi U2000 spectrometer. FAB mass
spectra were carried out using m-nitrobenzyl alcohol as matrix. Melting points were measured on a
Laboratory Devices (Cambridge, MA) Mel-Temp apparatus and are uncorrected. High dilution
reactions of acid chlorides with amines were carried out using infusion pump model 975 from Harvard
Apparatus (MA, USA).
1,2-Bis (2-nitrophenoxy)ethane (II): A mixture of 2-nitrophenol (13.3 g, 96 mmol), 1,2-dibromoethane
(10 g, 53 mmol) and K2CO3 (15.2 g, 110 mmol) in dimethylformamide (50 mL) was refluxed
overnight. Additional 1,2-dibromoethane (10 g) was added and then refluxed for 2 hrs. The reaction
was cooled to room temperature and water (50 mL) was added and the mixture stirred for 30 minutes.
The resulting light brown precipitate was collected, washed with water, and recrystallized from
acetone to afford yellow crystals (10.4 g, 71%); m.p.163-165 °C; IR (KBr): υmax 1,606, 1,525, 1,490,
1
1,445, 1,364, 1,254, 1,163, 937, 858, 777, 752 cm-1; H-NMR (DMSO-d6): δ 4.52 (s, 4H,
OCH2CH2O), 7.13 (t, J = 7.4, 2H, 4-H), 7.42 (d, J = 8.4, 2H, 6-H), 7.64 (dt, J = 1.6 and 8.0 Hz, 2H,
5-H), 7.84 (dd, J = 1.8 and 8.4 Hz, 2H, 3-H).

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1,2-Bis (2-aminophenoxy)ethane (III): A suspension of II (14.7 g, 48 mmol), 10% palladium on
carbon (0.7 g) in methanol (400 mL) and ethyl acetate (50 mL) was hydrogenated overnight at
atmospheric pressure and room temperature. The reaction mixture was filtered and the solvent
removed in vacuo leaving a white solid, which was recrystallized from ethyl acetate to yield white
crystals (9.5 g, 81%), m.p. 122-125 °C; IR (KBr): υmax 3,446 and 3,361 (NH), 1,610, 1,504, 1,461,
1
1,275, 1,213, 1,082, 947, 746, 737 cm-1; H-NMR (DMSO-d6): δ 4.26 (s, 4H, OCH2CH2O), 4.68 (s,
4H, NH2), 6.5 (dt, J = 2.0 and 8.0 Hz, 2H, 5-H), 6.65 (dt, J = 1.6 and 8.5 Hz, 2H, 4-H), 6.70 (dd,
J = 1.2 and 7.4 Hz, 2H, 3-H), 6.85 (dd, J = 1.0 and 7.6 Hz, 2H, 6-H).
2,5,10,13-Tetraoxa-7,16-diaza-1(1,2),6(1,2)-benzacyclohexadecaphane-8,15-dione (IV): To a two liter
three necked flask was added a solution of triethylamine (3.5 g, 35 mmol) in anhydrous toluene
(400 mL) maintained at 0 °C with stirring. The bisamine (III) (3.06 g, 12.5 mmol) in THF (150 mL)
and the diacid chloride, 2,6-dioxaoctanedioic acid chloride (2.69 g, 12.5 mmol) in toluene (150 mL)
were added dropwise simultaneously through Teflon syringe needles (16 gauge, 24 inch length with
KEL-Fluerhub) attached to 50 mL syringes which were controlled by an infusion pump (Harvard
Apparatus, model 975). The addition proceeded at a rate of 0.3 mL/min. After the addition was
complete, stirring was continued for a further two days at room temperature and the reaction mixture
was filtered to remove the salts. Removal of the solvent in vacuo left a white solid which was
recrystallized from ethyl acetate to afford white crystals of the diamide IV (3.1 g, 64%), m.p.
183-187 °C; IR (KBr): υmax 3,372, 3,356, 1,648, 1,607, 1,596, 1,460, 1,250, 1,121, 748 cm-1; 1H-NMR:
(DMSO-d6) δ 3.80 (s, 4H, 11-CH2, 12-CH2), 4.11 (s, 4H, 9-CH2, 14-CH2), 4.47 (s, 4H, 3-CH2, 4-CH2),
6.93 (t, J = 6.5 Hz, 2H, 14-H, 64-H), 7.05 (t, J = 7.6 Hz, 2H, 15-H, 65-H), 7.90 (d, J = 8.0 Hz, 2H, 16’-H,
66-H), 8.4 (d, J = 7.4 Hz, 2H, 13-H, 63-H), 9.5 (s, 2H, -NH).
2,5,10,13-Tetraoxa-7,16-diaza-1(1,2),6(1,2)-benzacyclohexadecaphane (V): To the diamide IV (0.4 g,
1.0 mmol) was added LiAlH4 in THF (1.0 M, 10 mL) dropwise with stirring at room temperature. The
reaction mixture was heated under reflux overnight. The excess of LiAlH4 was destroyed by the
successive dropwise addition of water (0.4 mL), NaOH (15%, 0.4 mL) and water (1.2 mL). The
reaction mixture was filtered and the filtrate was evaporated to dryness to leave a solid which was
recrystallized from ethyl acetate/hexane to afford white crystals (0.24 g, 67%), m.p. 165-167 °C; IR
(KBr): υmax 3,422, 1,597, 1,523, 1,448, 1,253, 1,222, 1,120, 941, 733, 715 cm-1; 1H-NMR (CDCl3): δ
3.33 (m, 4H, 8-CH2, 15-CH2), 3.60 (s, 4H, 11-CH2, 12-CH2), 3.71 (t, J = 4.7 Hz, 4H, 9-CH2, 14-CH2),
4.38 (s, 4H, 3-CH2, 4-CH2), 4.80 (br s, 2H, NH), 6.62 (dd, J = 1.43 and 7.80 Hz, 2H, 13-H, 63-H), 6.68
(dt, J = 1.53 and 7.70 Hz, 2H, 15-H, 65-H), 6.78 (dd, J = 1.4 and 7.95 Hz, 2H, 16-H, 66-H), 6.88 (dt,
J = 1.40 and 7.62 Hz, 2H, 14-H, 64-H).
4,7,13,16,20,23-Hexaoxa-1,10-diaza-19(1,2)24(1,2)-dibenzabicyclo[8.8.6]tetracosaphane-2,9-dione
(VI): To a stirred solution of triethylamine (2.61 g, 25.8 mmol) in toluene (500 mL) maintained at 0°C
was added the bisamine V (3.0 g, 8.4 mmol) in THF (200 mL) and the diacid chloride, 3,6-
dioxaoctanedioic acid chloride (2.1 g, 9.8 mmol) in toluene (200 mL), simultaneously using 50 mL
syringes. The rate of addition (0.3 mL/min) was controlled by an infusion pump. After addition was
completed, the mixture was stirred at room temperature overnight. Removal of the solvent in vacuo

Molecules 2009, 14
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left a semisolid which was crystallized from ethyl acetate to give white crystals (1.6 g, 40%), m.p.
1
186-189 °C; IR (KBr): υmax 1,672, 1,499, 1,452, 1,275, 1,132, 933, 755 cm-1; H-NMR (CDCl3): δ
3.05-4.75 (m, 24H), 6.96-7.16 (m, 6H), 7.25-7.40 (m, 12H).
4,7,13,16,20,23-Hexaoxa-1,10-diaza-19(1,2)24(1,2)-dibenzabicyclo[8.8.6]tetracosaphane (VII): To a
solution of diamide VI (0.2 g, 0.4 mmol) in THF (2 mL) was added borane in THF (1 M, 2 mL,
2 mmol), and the mixture was heated under reflux for 2 hrs, cooled and water (0.5 mL) carefully added
followed by aqueous HCl (6 M, 4 mL). The solution was concentrated in vacuo and the resulting
yellow solution was brought to pH 8 with aqueous LiOH. The aqueous layer was extracted with
chloroform and dried over sodium sulfate. Removal of the solvent yielded a yellow oil which was
triturated with ethyl acetate to give a white powder, m.p.141-143 °C; IR (KBr): υmax 1,593, 1,505,
1
1,449, 1,341, 1,250, 1,230, 1,135, 1,115, 1,056, 975, 940, 732 cm-1 ; H-NMR (CDCl3): δ 3.12 (m,
4H), 3.54 (m, 16H), 3.81 (m, 4H), 4.37 (s, 4H, 2CH21, 2CH22), 6.92 (m, 8H, aromatic).
195,245-Dibromo-4,7,13,16,20,23-hexaoxa-1,10-diaza-19(1,2)24(1,2)-dibenzabicyclo[8.8.6]tetra-
cosaphane (VIII): To a stirred solution of diamine VII (116 mg, 0.25 mmol) in CH2Cl2 (5 mL) kept at
-78 °C was added portion-wise 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one (0.25 g, 0.61 mmol). The
mixture was allowed to warm to room temperature and stirred overnight. The resulting yellow solution
was extracted with aqueous NaOH (2 N, 10 mL), water and the organic layer was dried over sodium
sulfate. Removal of the solvent afforded a yellow oil which was chromatographed using silica gel and
methylene chloride and methanol (up to 5%) to give white solid which was recrystallized from ethyl
acetate to yield white crystals (31 mg, 20 %), m.p. 204-206 °C; IR (KBr): υmax 1,580, 1,489, 1,232,
1
1,125, 959, 848, 817 cm-1; H-NMR (CDCl3): δ 3.09-3.16 (m, 4H), 3.36-3.42 (m, 4H), 3.46-3.52 (m.
4H), 3.58-3.66 (m, 8H), 3.76-3.83 (m, 4H), 4.48 (s, 4H, 2CH21, 2CH22), 6.78 (d, J = 8.0 Hz, 2H, 193-H,
243-H), 7.04 (dd, J = 8.0 and 2.4 Hz, 2H, 194-H, 244-H), 7.06 (d, J = 2.4 Hz, 2H, 196-H, 246-H); m/z
(FAB) 651 (M+Na+).
15-Bromo-2,5,10,13-tetraoxa-7,16-diaza-1(1,2),6(1,2)-benzenecyclohexadecaphane (IX): To a stirred
solution of diamine V (150 mg, 0.4 mmol) and pyridine (98 mg, 1.2 mmol) in CH2Cl2 (10 mL) and
kept at -78 °C was added slowly 0.78 M bromine solution in CH2Cl2 (1.3 mL). The mixture was
allowed to warm to room temperature. The reaction mixture was washed with aqueous Na2CO3 and
dried over sodium sulfate. Removal of the solvent yielded a residue which was chromatographed on a
TLC plate (200 µm layer of silica gel IB-F, 1% CH3OH in CH2Cl2 as solvent) to give two major
products: the monobromo-derivative IX (22 mg, 13%), m.p. 158-161 °C; IR (KBr): υmax 3,405, 1,603,
1
1,520, 1,453, 1,261, 1,202, 1,141, 1,096, 942, 838, 799, 724 cm-1; H-NMR (CDCl3): δ 3.31 (m, 4H,
8-CH2, 15-CH2), 3.60 (s, 4H, 11-CH2, 12-CH2), 3.70 (m, 4H, 9-CH2, 14-CH2), 4.36 (m, 4H, 3-CH2,
4-CH2), 4.76 (br s, 2H, NH), 6.44 (d, J = 8.8 Hz, 1H, 13-H), 6.61 (d, J = 7.5 Hz, 1H, 63-H), 6.68 (t,
J = 7.5 Hz, 1H, 65-H), 6.78 (d, J = 7.5 Hz, 1H, 66-H), 6.86 (d, J = 2.0 Hz, 1H, 16-H), 6.90 (t,
J = 7.5 Hz, 1H, 64-H), 6.98 (dd, J = 2 and 8.7 Hz, 1H, 14-H); and the dibromo derivative X (20 mg,
10%), m.p. 210-214 °C; IR (KBr): υmax 3,405, 1,598, 1,509, 1,463, 1,406, 1,346, 1,217, 1,203, 1,146,
1
1,097, 939, 843, 794 cm-1; H-NMR (CDCl3): δ 3.29 (q, J = 5 Hz, 4H, 8-CH2, 15-CH2), 3.60 (s, 4H,
11-CH2, 12-CH2), 3.69 (t, J = 5 Hz, 4H, 9-CH2, 14-CH2), 4.33 (s, 4H, 3-CH2, 4-CH2), 4.73 (br t,

Molecules 2009, 14
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J = 5 Hz, 2H, NH), 6.44 (d, J = 8.7 Hz, 2H, 13-H, 63-H), 6.86 (d, J = 2 Hz, 2H, 16-H, 66-H), 6.99 (dd,
J = 2 and 8.7 Hz, 2H, 14-H, 64-H).
15,65-Dibromo-2,5,10,13-tetraoxa-7,16-diaza-1(1,2),6(1,2)-benzenecyclohexadecaphane (X): To a
stirred solution of of diamine V (1.4 g, 4 mmol) in CH2Cl2 (50 mL) maintained at -78 °C was added
finely powdered 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one (3.4 g, 8 mmol). After addition was
completed, the reaction mixture was allowed to warm to room temperature and stirred overnight. The
resulting yellow solution was extracted with aqueous 2N sodium hydroxide. The organic layer was
washed with water and dried over sodium sulfate. Removal of the solvent afforded a yellow solid
which was recrystallized from ethyl acetate to yield white flakes (1.6 g, 78%), m.p. 212-215 °C,
1H-NMR spectral data were identical to those given above.
195,245-Dibromo-4,7,13,16,20,23-hexaoxa-1,10-diaza-19(1,2)24(1,2)-dibenzabicyclo[8.8.6]tetra-
cosaphane-2,9-dione (XI): To a stirred solution of triethylamine (1.45 g, 14.3 mmol) in toluene
(300 mL) maintained at 0 οC were added the bisamine X (1.4 g, 2.7 mmol) in THF (100 mL), and
3,6-dioxa-octanedioic acid chloride (0.6 g, 2.8 mmol) in toluene (100 mL), simultaneously at a rate of
0.3 mL/min with the aid of an infusion pump. After the addition was completed, the mixture was
stirred at room temperature overnight. The mixture was filtered and removal of solvent in vacuo gave
an oil which was chromatographed using silica and CH2Cl2 and methanol (10%) to yield a white solid
ο
(0.27 g,15%), m.p. 282-289 C (decomposition); IR (KBr): υmax1,684, 1,586, 1,494, 1,403, 1,273,
1
1,134, 1,102, 952, 853, 739 cm-1; H-NMR (CDCl3): δ 3.25-4.75 (m, 24H), 6.94-7.03 (m, 2H),
7.10-7.20 (m, 4H).
Conversion of XI to VIII: To a solution of diamide XI (200 mg, 0.3 mmol) in THF (4 mL) was added
borane in THF (1 M, 3 mL), and the mixture heated under reflux for 2 hrs. The reaction mixture was
worked up as described above to yield white solid, which showed IR (KBr) and 1H-NMR data similar
to those of VIII reported above.
Conclusions
In summary, the dibromdibenzocryptand [2.2.2] VIII, a potential potassium ionophore, has been
synthesized. The bromo derivatives of the benzocryptand are likely be linked to a fluorophore, such as
those described by McGimpsey in [16].
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3. Crossley, R.; Goolamali, Z.; Gosper, J.J.; Sammes P.G. Synthesis and spectral properties of new
fluorescent probes for potassium. J. Chem. Soc. Perkin Trans. 2 1994, 513-518.

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Sample Availability: Samples of the compounds are available from the author.
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