Synthesis and liquid membrane transport properties of photolabile molecular clips based on dithiane-spiro-crown ethers

Article abstract of DOI:10.1021/ol016309k

(Equation presented) Synthesis of novel dithiane-spiro-crown ethers starting from 5,5-di(hydroxymethyl)-1,3-dithiane is developed. These compounds can be used as building blocks to assemble photolabile bis-crown ethers via addition to dicarbonyl-containing tethers, e.g., isophthalic aldehyde. It is found that unlike their mono-crown precursors such bidentate bis-crowns are capable of efficient liquid membrane transport of, for example, methyl viologen. The transport can be interrupted photochemically, providing a basis for developing smart light-responsive membranes.

Full text of DOI:10.1021/ol016309k

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2633-2635
Synthesis and Liquid Membrane
Transport Properties of Photolabile
Molecular Clips Based on
Dithiane-spiro-crown Ethers
Loren A. Barnhurst and Andrei G. Kutateladze*
Department of Chemistry and Biochemistry, UniVersity of DenVer,
DenVer, Colorado 80208-2436
akutatel@du.edu
Received June 20, 2001
ABSTRACT
Synthesis of novel dithiane-spiro-crown ethers starting from 5,5-di(hydroxymethyl)-1,3-dithiane is developed. These compounds can be used
as building blocks to assemble photolabile bis-crown ethers via addition to dicarbonyl-containing tethers, e.g., isophthalic aldehyde. It is
found that unlike their mono-crown precursors such bidentate bis-crowns are capable of efficient liquid membrane transport of, for example,
methyl viologen. The transport can be interrupted photochemically, providing a basis for developing smart light-responsive membranes.
Tethered bis-crown ethers have found extensive use in
various membrane applications due to their unique ionophoric
properties.1 We suggest that linking two crown moieties with
a photolabile tether carries the additional benefit of control-
ling their complexation ability. In this Letter we report on
our progress toward development of carriers for smart
membranes: synthesis of novel dithiane-spiro-crown ethers
5-7 and their reaction with isophthalic aldehyde to produce
tweezers-shaped bis-crown ethers 8-10 capable of photo-
induced fragmentation.2
tected via cyclic acetal formation with formaldehyde and then
reacted with potassium thioacetate, affording 1,3-dioxane 3.
The critical feature of this synthetic sequence was that during
the next, acid-catalyzed step (3 f 4) no extra formaldehyde
was added and therefore the deprotection of the diol and
formation of the dithiane ring occurred via methylenic trans-
fer from oxygen to sulfur atoms (59% yield, Scheme 1).
Recognizing the fact that diol 4 allows for direct coupling
of dithiane and crown ether moieties through a spiro
The key starting material, 5,5-di(hydroxymethyl)-1,3-
dithiane 4, was synthesized from commercially available 2,2-
bis(bromomethyl)-1,3-propanediol (1), which was first pro-
Scheme 1
(1) For selected examples of bis-crown-based ionophores, see: Bu¨hl-
mann, P.; Pretsch, E.; Bakker, E. Chem. ReV. 1998, 98, 1593.
(2) Photoinduced cleavage in hydroxy- or amino-alkyl dithianes: (a)
McHale, W. A.; Kutateladze, A. G. J. Org. Chem. 1998, 63, 9924. (b) Wan,
Y.; Mitkin, O.; Barnhurst, L.; Kurchan, A.; Kutateladze, A. Org. Lett. 2000,
2, 3817. (c) Vath, P.; Falvey, D. E.; Barnhurst, L. A.; Kutateladze, A. G.
J. Org. Chem. 2001, 66, 2886. (d) Mitkin, O. D.; Kurchan, A. N.; Wan,
Y.; Schiwal, B. F.; Kutateladze, A. G. Org. Lett. 2001, 3, 1841.
10.1021/ol016309k CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/27/2001

connection, we synthesized dithiane-bearing crowns 5-7 via
the alkylation of 4 with (poly)ethylene glycol ditosylates in
DMF in the presence of sodium hydride (Scheme 2).3
bond cleavage in the generated cation-radical. The benzophe-
none anion-radical generally accelerates the second step by
deprotonating the hydroxy group.5
To evaluate the liquid membrane transport properties and
the possibility of photochemically shutting off the transport,
we chose methyl viologen as a guest molecule. In addition
to structural considerations, our choice of guest was influ-
enced by our finding that methyl viologen itself can sensitize
C-C bond cleavage in dithiane-carbonyl adducts. We found
that bis-crown 10 (based on 19-crown-6) transported methyl
viologen with greater efficiency than either the 16-crown-5
host 9 or 13-crown-4 host 8. Figure 1 shows this efficient
Scheme 2
Crown ethers 5-7 were purified by column chromatog-
raphy and then utilized as building blocks to assemble bis-
crown ethers 8-10 (Scheme 3). First, the corresponding
Scheme 3
Figure 1. Methyl viologen transport through the liquid (chloro-
form) membrane assisted by 10 (9). The efficiency of transport
by irradiated 10 is significantly reduced (2). Poor mono-crown
carrier 7 is shown for comparison (b).
transport from the donor aqueous phase to the receiving
aqueous phase through the chloroform solution of bis-crown
dithiane anions were generated with butyllithium at -20 °C
in THF. The lithiodithianes were then quenched with
isophthalic aldehyde at -78 °C to furnish bis-crowns 8-10
(60-80%).4
As expected from our earlier studies on photoinduced C-C
bond cleavage in R-hydroxyalkyldithianes, bis-crowns 8-10
undergo efficient photofragmentation in the presence of an
external ET-sensitizer, benzophenone. The general mecha-
nism for cleavage, exemplified by the photoinduced C-C
bond scission in a parent compound, the dithiane-benzal-
dehyde adduct, is shown in Scheme 4. After initial excitation,
(3) Typical procedure: 8,11,14,17-Tetraoxa-2,4-dithiaspiro[5.12]-
octadecane (5). A solution of 5,5-di(hydroxymethyl)-1,3-dithiane 4 (0.40
g, 2.2 mmol) in 40 mL of DMF was stirred under a nitrogen atmosphere.
This solution was treated with hexane-washed NaH (0.21 g, 8.8 mmol).
After 15 min of stirring, tri(ethylene glycol) di-p-tosylate (0.96 g, 2.1 mmol)
was added and allowed to stir at room temperature overnight. The resulting
mixture was carefully treated with NH4Cl and then extracted into ether.
The ethereal layer was washed 4× with NH4Cl and 2× with water to remove
all DMF, dried, and concentrated. Flash column chromatography (1:1 ethyl
acetate:hexanes) gave 0.54 g of a light yellow oil (88%): 1H NMR (CDCl3,
400 Hz) 3.64-3.72 (m, 18H), 2.72 (s, 4H); MS (EI) m/z (relative intensity)
294 (M+, 30), 144 (60), 98 (100), 85 (60).
(4) Compounds 8-10 were purified by column chromatography without
separating individual diastereomers. Typical procedure: {3-[Hydroxy-
(8,11,14,17-tetraoxa-2,4-dithiaspiro[5.12]octadec-3-yl)methyl]phenyl}-
(8,11,14,17-tetraoxa-2,4-dithiaspiro[5.12]octadec-3-yl)methanol (8). A
solution of 5 (0.130 g, 0.44 mmol) in 10 mL of freshly distilled THF was
cooled to -20 °C, and 1.6 M n-butyllithium (0.41 mL, 0.66 mmol) was
added while stirring under a N2 atmosphere. The reaction mixture was stirred
at this temperature for 2 h, after which the reaction was further cooled to
-78 °C, and isophthalaldehyde (0.030 g, 0.22 mmol) in 2 mL of THF was
added via syringe. The resulting mixture was allowed to slowly warm to
room temperature over a period of 2 h and then stirred overnight. The
resulting yellow solution was washed 2× with 10 mL of saturated NH4Cl,
extracted into ether, dried, and concentrated. Flash column chromatography
(1:50 MeOH:CHCl3) gave 0.150 g of a clear oil (94%): 1H NMR (CD3-
CN, 400 Hz) 7.41 (b, 1H), 7.30 (d, J ) 1.2 Hz, 3H), 4.82 (m, 2H), 4.16
(dd, J1 ) 1.6 Hz, J2 ) 6.8 Hz, 2H), 3.53-3.62 (m, 32H), 3.44 (s, 2H),
2.70-2.78 (m, 4H), 2.52-2.58 (m, 4H).
Scheme 4
triplet benzophenone is quenched via single electron transfer
from the dithiane moiety, followed by the mesolytic C-C
(5) For further mechanistic details of the photocleavage, see refs 2a,c.
2634
Org. Lett., Vol. 3, No. 17, 2001

10.6 In contrast, the chloroform solution of the corresponding
mono-crown 7, twice as concentrated for fair comparison,
does not transport methyl viologen appreciably. Irradiation
of the chloroform solution containing the host-guest com-
plex (10‚methyl viologen) led to a significant decrease in
transport efficiency as evidenced by the leveling off optical
density of the receiving aqueous phase.7
Similar photochemically induced disruption of liquid
membrane transport was observed with benzophenone as an
external sensitizer. It should be noted that the addition of
benzophenone had a negligible effect on the transport rate
by 10, while the transport rate by the less efficient bis-crown
carriers 8 and 9 was improved in the presence of benzophe-
none. Clearly, in the latter case, benzophenone additionally
stabilizes the weaker complex of methyl viologen with 8 or
9, thus serving the dual function of a co-complexing
sensitizer. As expected, the rate of viologen transport by the
corresponding mono-crown ethers 5, 6, and 7 was insignifi-
cant and the addition of benzophenone caused only a minor
enhancement.
Figure 2. PM3 geometry of 10‚methyl viologen (hydrogen atoms
are not shown for clarity).
fit accounting for the efficient transport by the bis-crown
carrier. Obviously, analogous trimolecular-sandwiched com-
plexes with two mono-crown ethers are less favorable due
to entropic factors.
To summarize, we have developed a simple modular
approach to photolabile bis-crown ethers allowing us to
photochemically interrupt transport through liquid mem-
branes.
Figure 2 shows a PM3-optimized geometry of the complex
between methyl viologen and 10. It helps visualize a nice
(6) The photochemically interrupted transport experiments were carried
out in a Pyrex U-tube (300 nm cutoff), while slowly stirring the central
chloroform solution with a magnetic stirrer. Irradiations were performed
with a medium-pressure mercury lamp. The temperature was maintained
by immersing the tube into a regulated water bath. Initial concentration of
viologen in the donor solution was 1 mM. Carrier concentration: 5.1 mM
for 10 or 10.4 mM for 7. Donor solution volume: 4 mL. Receiving solution
volume: 4 mL. Carrier solution volume: 12 mL. Interface area: 1.77 cm2.
pH of 8 in both the donor and the receiving solutions was maintained by
10 mM K2HPO4. The progress was monitored by the increase in UV
absorption of the receiving solution at λ ) 256 nm.
(7) Judging by NMR, the photofragmentation was driven to >90%
conversion. At this point we can only speculate on the nature of the residual
transferability by irradiated 10. One possibility is that overoxidation of the
dithiane moiety in the released mono-crown ether 7 produces a small amount
of a better complexing byproduct.
Acknowledgment. Support of this research by the
National Institutes of Health (GM6277301) is gratefully
acknowledged.
Supporting Information Available: Experimental de-
tails. This material is available via the Internet at http:
//pubs.acs.org
OL016309K
Org. Lett., Vol. 3, No. 17, 2001
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