Improved Syntheses of Benzyl Hydraphile Synthetic Cation-Conducting Channels

Article abstract of DOI:10.1055/s-0034-1378345

The tris(macrocycle)s that function in bilayer membranes as ion channels have recently shown versatile new applications such as antibiotic synergists and as agents for direct injection chemotherapy. This report records the development of new and versatile approaches to these molecules that produce significantly better overall yields for a group of previously reported hydraphiles having spacer chains ranging from octylene to hexadecylene.

Full text of DOI:10.1055/s-0034-1378345

PAPER
▌2771
paper
Improved Syntheses of Benzyl Hydraphile Synthetic Cation-Conducting
Channels
Hydraphile Syntheses
Nichole S. Curvey,a,c Sarah E. Luderer,a,b John K. Walker,a,b George W. Gokel*a,b,c,d
a
Center for Nanoscience, University of Missouri–St. Louis, 1 University Blvd., St. Louis, MO 63121, USA
b
Medicinal Chemistry Group, University of Missouri–St. Louis, 1 University Blvd., St. Louis, MO 63121, USA
c
Department of Chemistry & Biochemistry, University of Missouri–St. Louis, 1 University Blvd., St. Louis, MO 63121, USA
d
Department of Biology, University of Missouri–St. Louis, 1 University Blvd., St. Louis, MO 63121, USA
Fax +1(314)5165342; E-mail: gokelg@umsl.edu
Received: 08.04.2014; Accepted after revision: 29.05.2014
field of study: numerous synthetic ion channels are now
known.6
Abstract: The tris(macrocycle)s that function in bilayer mem-
branes as ion channels have recently shown versatile new applica-
tions such as antibiotic synergists and as agents for direct injection
chemotherapy. This report records the development of new and ver-
satile approaches to these molecules that produce significantly bet-
ter overall yields for a group of previously reported hydraphiles
having spacer chains ranging from octylene to hexadecylene.
Synthetic ion channels have often been described as chan-
nel models. To be sure, they are channel models, but they
are more than that. In many cases they selectively conduct
alkali metal cations or anions such as chloride across lipo-
somal and natural bilayer membranes. These amphiphiles
insert into bilayer membranes from the bulk aqueous
phase and they show the open–close behavior that is char-
acteristic of natural protein channels. The cation channels
exhibit selectivities for one alkali metal over another and
larger metals block their function just as is observed in
protein channels.
Key words: acylation, benzylation, macrocycles, reduction, supra-
molecular chemistry
The advent of synthetic ion channels can be traced to stud-
ies by Tabushi and his coworkers, who attached hydro-
phobic chains to β-cyclodextrin.1 Subsequent to that, the
results of three separate efforts to develop synthetic ion
channels appeared almost simultaneously. In the first of
these, Jullien and Lehn attached multiple, polar-group-
terminated chains to an 18-crown-6 unit.2 A similar struc-
tural element was used by Fyles and coworkers.3 The hy-
draphile synthetic ion channels developed in the author’s
lab also incorporated a macrocycle as a central unit, but it
was 4,13-diaza-18-crown-6 rather than a tetracarboxyl-
18-crown-6 derivative.4 The logic of using a diazacrown
followed the experience gained from study of the lariat
ethers.5 When residues are attached to all-oxygen crowns,
there is a stereochemical issue and the residues must re-
main on only one side of the macrocycle. When chains are
linked through nitrogen atoms within the macrocycle, the
system retains a high degree of flexibility and, owing to
nitrogen’s invertibility, does not experience stereochemi-
cal limitations. Of course, these initial examples led to a
Extensive studies defined the biophysics of the hydraphile
channels and these results have been reported both in a se-
ries of papers and in summary form.7 Recently, a number
of new applications have been discovered for hydraphiles.
These include antibiotic activity,8 antibiotic synergy,9 and
direct injection chemotherapy.10 Owing to the applica-
tions under study, we revisited our initial approach to
these compounds in an attempt to develop simpler, more
reliable, and versatile syntheses of hydraphiles. Our need
was both for different spacer chain lengths and varied side
chains. The essential hydraphile core structure is illustrat-
ed in Figure 1. In much of our previous work, we have
sought to obtain compounds primarily for biological test-
ing and the efficacy of the synthetic approach was a sec-
ondary consideration.
The overall symmetry of a hydraphile molecule is fraught
with the problem that each macrocycle has identical nitro-
O
O
O
O
O
O
O
O
O
O
O
O
(CH2)n
N
N
R
R
N
N
(CH2)n
N
N
1
Figure 1 General structure of tris(macrocycle) hydraphile synthetic ion channels; n = 8, 10, 12, 14, 16; R = n-dodecyl, benzyl
SYNTHESIS, 46, 2771–2779
Advanced online publication: 30.07.2014
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0
3
9
-
7
8
8
1
1
4
3
7
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2
1
0
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DOI: 10.1055/s-0034-1378345; Art ID: SS-2014-m0201-OP
© Georg Thieme Verlag Stuttgart · New York

2772
N. S. Curvey et al.
PAPER
gen connection points although each nitrogen atom is at-
tached to a different residue. The two distal macrocycles
differ only slightly from the medial macrocycle. This sub-
tle symmetry issue must be addressed in any viable syn-
thetic approach. Moreover, the ideal approach would
exhibit versatility in the functional groups that could be
present in the product hydraphiles, the chains attached to
the distal macrocycles, and the range of lengths that could
be prepared.
O
O
O
O
N
HOOC(H2C)10OC
N
CO(CH2)10COOH
minor product
O
O
O
O
O
Several approaches to the hydraphiles can be readily envi-
sioned. Essential to any strategy is to desymmetrize 4,13-
diaza-18-crown-6 by monosubstituting a nitrogen with
the incipient side arm. Symmetrical substitution of the
central macrocycle can be accomplished in several ways.
The diazacrown can be treated with an ω-haloacyl halide,
O
O
N
N
(CH2)10
(CH2)10
N
O
O
HO
O
O
HN
O
major product
which will result in
a
structure such as
X(CH2)nCO<N18N>CO(CH2)nX, where <N18N> rep-
resents the diaza-18-crown-6 core element. An alternative
would be to treat H<N18N>H with a lactone, which
would afford a similar structure in which the terminal
groups are hydroxyl rather than halide. Yet another ap-
proach is to dialkylate H<N18N>H with a dihalide and
separate X(CH2)n<N18N>(CH2)nX from the various other
possible products. This could then be treated with
H<N18N>CH2Ph, as obtained below.
Figure 2 Minor (expected) and major product obtained from the re-
action of the presumed cyclic anhydride of dodecanedioic acid and
4,13-diaza-18-crown-6
diaza-18-crown-6 to give hydraphile 1 with R = n-do-
decyl, n = 12 (Figure 1).
Many of the hydraphiles we have prepared and studied re-
quired N-benzyl-4-aza-18-crown-6 (3; Scheme 1), as a
starting material. Alkylation of 4,13-diaza-18-crown-6 (2)
with benzyl bromide affords a mixture of mono- (3) and
disubstituted (4) products, as shown in Scheme 1. Our ini-
tial approach was to treat 2 with slightly less than one
equivalent of benzyl bromide. The reaction was conduct-
ed in butyronitrile in the presence of sodium carbonate
and potassium iodide. A mixture was obtained that afford-
ed, after chromatography, 18% of dibenzylcrown 4 and
33% of monobenzyl crown 3.6a The two compounds sep-
arate readily by chromatography and dibenzylcrown 4 can
be hydrogenolyzed in essentially quantitative yield and
recycled. The cost of this reaction is in the loss of nearly
half of the starting diazacrown 2, although some recovery
was possible.
A further strategy that appeared at the outset to be both ef-
ficient and flexible was the formation of a cyclic anhy-
dride that could be ring-opened by H<N18N>H. This
intermediate would then be converted into the fully elab-
orated tetraamide possessing all three diazacrown rings.
Reduction of the four amide groups would then afford the
hydraphile. Dodecanedioic acid anhydride was prepared
according to the literature.11 We heated the diacid with
acetic anhydride and both IR and NMR spectroscopy con-
firmed that the anhydride had formed after acetic acid
distilled out. We then heated the product that we pre-
sumed was the cyclic anhydride with 4,13-diaza-18-
crown-6 in tetrahydrofuran expecting to isolate
HOOC(CH2)10CO<N18N>CO(CH2)10COOH. The di-
azacrown diamide diacid was obtained in only modest
yield. The major product, identified only by HPLC and
LC-MS, was the bis-adduct shown in Figure 2.
An alternative method, developed by Cuevas, Prados, and
de Mendoza13 begins with N,N′-dibenzyl-4,13-diaza-18-
crown-6 (4), which is now commercially available.14 It
can also be prepared reliably by using an Organic Synthe-
ses procedure.15 The Cuevas et al. approach partially hy-
drogenates dibenzyl compound 4. The hydrogenation uses
palladium-on-carbon and is conducted in ethanol at ambi-
ent temperature (Scheme 1). Compound 3 is isolated in
40% yield by chromatography and the unchanged materi-
al is recycled.
The surprising outcome of this reaction should have been
anticipated on the basis of the early work of Hill and
Carothers,12 who conducted extensive studies of the reac-
tion between various diacids and acetic anhydride. They
found that the anhydrides produced were open chained
polymeric materials rather than the expected cyclic anhy-
drides. Thus, the non-cyclic anhydrides were activated for
reaction at both ends producing a material that was not
useful for further hydraphile synthesis.
The first hydraphile preparation4 began with 4,13-diaza-
18-crown-6. This was treated with 1-bromododecane to
form N-n-dodecyldiaza-18-crown-6. This single-armed
macrocycle was then treated with 1,12-dibromododecane
to form Me(CH2)11<N18N>(CH2)12Br. Two equivalents
of this distal crown module were then treated with 4,13-
A third approach involves a reductive amination of di-
azacrown 2 with benzaldehyde (this work; Scheme 2).
Thus, diazacrown 2 and benzaldehyde are stirred in di-
chloromethane at ambient temperature for twelve hours in
the presence of 1.5 equivalents of sodium triacetoxyboro-
hydride. As before, chromatography is required, but the
yields of mono- (3) and dibenzylated (4) crowns are 30%
and 65%, respectively. This is a significant improvement,
Synthesis 2014, 46, 2771–2779
© Georg Thieme Verlag Stuttgart · New York

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Hydraphile Syntheses
2773
of these molecules16 and to extend it to a range of overall
chain lengths.17 The compounds whose syntheses are de-
scribed here all have the general structure shown in Figure
1, where R = Bn. The spacer chain lengths vary and in-
clude n-octylene (5; n = 8), n-decylene (6; n = 10), n-do-
decylene (7; n = 12), n-tetradecylene (8; n = 14), and n-
hexadecylene (9; n = 16).
O
O
O
O
H
N
N
H
2
PhCH2Br
PhCH2Br
We have previously reported an amide-based approach to
Me(CH2)11<N18N>(CH2)12<N18N>(CH2)12<N18N>(CH
2)11Me (1, R = n-dodecyl, n = 12).18 In this method, 2 was
acylated with n-decanoyl chloride. This resulted in only a
10% isolated yield of the monoacylated material. We sur-
mised that the acylation to form a tertiary amide was sim-
ply too rapid to show any selectivity.
H2, Pd/C
H2, Pd/C
O
O
O
O
O
O
PhCH2Br
H2, Pd/C
N
N
H
N
N
O
O
3
4
The same reference describes the reaction of methyl 12-
bromododecanoate with 2, to give a dialkylated macrocy-
cle. The alkylation afforded 59% of the desired product.
Hydrolysis with aqueous sodium hydroxide gave the di-
acid in 93% yield for a two-step yield of 55% to
HO2C(CH2)11<N18N>(CH2)11CO2H. This compound was,
in turn, converted into the diacid dichloride and coupled with
H<N18N>CO(CH2)10Me to give the tris(macrocyclic) tetraamide,
Me(CH2)10CO<N18N>CO(CH2)11<N18N>(CH2)11CO<N-
18N>CO(CH2)10Me. Unfortunately, this compound was
found to be a relatively poor mediator of sodium cation
transport from within synthetic liposomes into the bulk
aqueous phase.8
Scheme 1 Conversion of 4,13-diaza-18-crown-6 into mono- and
dibenzylated derivatives by three different synthetic approaches (see
text)
especially considering that dibenzyl crown 4 can readily
be hydrogenolyzed and recovered.
O
O
O
HN
O
O
N
O
PhCHO (1 equiv)
NaBH(OAc)3
(1.5 equiv)
CH2Cl2, r.t., 12 h
NH
NH
O
O
A strategy for a general tetraamide synthesis, to provide
various tetraamide hydraphiles, is to mono-protect a di-
acid, couple it to diaza-18-crown-6 to form the two-armed
diamide, and then further couple this with monobenzyl di-
azacrown 3. The monobenzyl ester of dodecanedioic acid
is prepared by forming the potassium salt and alkylating
with benzyl bromide. This procedure has been described
previously.18 The monobenzyl ester is coupled to diaza-
2
3 65%
O
O
O
N
N
O
+
4 30%
18-crown-6 (2) by using O-(benzotriazol-1-yl)-N,N,N′,N′-
–
Scheme 2 Reductive amination of diazacrown 2 to give a mixture of tetramethyluronium tetrafluoroborate (TBTU, or the PF6
3 and 4
salt HBTU) and N,N-diisopropylethylamine (DIPEA;
Hünig’s base) (Scheme 3). This sequence affords a crown
diamide diester. The benzyl ester groups are then removed
by hydrogenolysis to afford the corresponding diamide di-
acid in an overall yield of 76% (Scheme 3).
The initial strategy for the preparation of the C12 benzyl
hydraphile 7 was to prepare Br(CH2)12<N18N>(CH2)12Br
and to couple it to monobenzylated diazacrown 3.6a This
procedure worked well enough to explore the biophysics
O
O
O
O
O
O
O
O
O
O
1. TBTU (2.2 equiv)
DIPEA, CH2Cl2
BnO
N
N
OBn
10
HO
OBn
10
10
2. diaza-18-crown-6
r.t., 2 h, 85%
(2.1 equiv)
O
O
O
O
O
O
O
H2, Pd/C
HO
N
N
OH
10
10
MeOH, r.t., 18 h
90%
O
Scheme 3 Preparation of the diamide diacid side-chained diaza-18-crown-6 module
© Georg Thieme Verlag Stuttgart · New York
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N. S. Curvey et al.
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O
O
O
O
Ph
NH
N
3
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
OH
N
N
OH
10
10
10
10
TBTU, DIPEA
CHCl2, r.t., 2 h, 75%
Ph
Ph
O
O
O
O
O
O
O
O
O
BH3•THF (16.0 equiv)
THF, r.t., 24 h, 60%
(CH2)12
N
N
N
N
(CH2)12
N
N
O
O
O
7
Scheme 4 General ‘tetraamide’ scheme for the formation of dibenzyl hydraphiles, illustrated for C12 benzyl hydraphile 7
At this point, it remains only to couple the diacid side hydraphile, the yields obtained are within experimental
chains to the previously prepared monobenzyl crown 3 error. The octylene compound was obtained in the highest
and to reduce the resulting tetraamide to the hydraphile yield of these closely related substances, but a slightly dif-
(Scheme 4). The coupling step is accomplished by the ferent synthetic approach than that published was utilized.
same type of reaction used to form the diamides. The The repeated yield is more realistic and more consistent
tetraamide product is formed cleanly in 75% yield and is among the several compounds reported. Superior yields
purified by precipitation from acetone. Reduction is ac- were obtained by the current method in all cases relative
complished by treatment with excess borane–tetrahydro- to our own repetition. The unusually high yield of the
furan complex in tetrahydrofuran solution for 24 hours at hexadecylene compound is the result of its ability to crys-
room temperature. The isolated yield of product in this tallize from the reaction mixture.
step is 60%; this suggests that each of the four amide re-
duction steps occurred in nearly 90% yield (Scheme 4).
data obtained in the study reported here. Superior yields
The third column of Table 1, method B, summarizes the
This method has been compared with the previous ap- were obtained by the current method in all cases relative
proach. In previous studies,19 we prepared a range of ben- to our own repetition. The unusually high yield of the
zyl hydraphiles by what appears to be a simpler approach. hexadecylene compound is the result of its ability to crys-
Generally, the procedure required monobenzyl diaza- tallize from the reaction mixture.
crown 3 as the starting material. As noted above, 3 was
Table 1 Comparison of Hydraphile Yields
obtained in 33% yield. The second step involved alkyl-
ation using 1,12-dibromododecane. This afforded
Br(CH2)12<N18N>(CH2)12Br in 61% yield. The next step
Overall yield (%)a
Hydraphile Spacer chain
Published19 Method Method
was reaction of the latter compound with
PhCH2<N18N>H (3) to give the benzyl C12 hydraphile in
38% yield after chromatography.19 The three steps (0.33 ×
0.61 × 0.38) give an overall yield of 7.6%. The present
method, although involving two more steps, gives an
overall yield of 22% (0.65 × 0.85 × 0.90 × 0.75 × 0.60).
Ab
Bc
5
6
7
8
9
octylene (CH2)8
10
2
8
7
16
12
22
32
46
decylene (CH2)10
dodecylene (CH2)12
tetradecylene (CH2)14
hexadecylene (CH2)16
8
12
11
7
The tetraamide approach described here was applied to
the preparation of the five hydraphiles 5–9 (R = Bn, n = 8,
10, 12, 14, 16, respectively). The overall yields reported
previously for these compounds and those for the proce-
dures used herein are recorded in Table 1.
6
3
a Yield of hydraphile prepared from 4,13-diaza-18-crown-6.
b Published sequence19 reproduced by using MeCN and DIPEA (see
text).
The first column of yields in Table 1 is taken from the lit-
erature. The procedures used varied, as they were accom-
plished and reported at different times. The column
designated method A shows the yield obtained in recent
work, by using the approach to which the previous column
corresponds. With the exception of the octylene spacer
c This work.
Three features of the present work are notable. First,
monobenzyl diazacrown 3, a key starting material for ben-
zyl hydraphiles, can be prepared conveniently in good
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Hydraphile Syntheses
2775
13C NMR (75 MHz, CDCl3): δ = 26.06, 26.85, 27.22, 28.14, 28.72,
29.25, 32.82, 34.17, 53.68 53.93, 55.43, 59.77, 68.47, 69.97, 70.67,
127.05, 128.30, 128.95, 139.35.
yield by reductive amination. Material obtained from
over-reaction can be recycled by hydrogenation. Second,
the formation of diamides and their subsequent acylation
reactions are clean, high-yielding, and convenient to con-
duct. Third, the reduction of the various tetraamides, ex-
pected to be problematic, occurred in good yield as well.
Thus, the overall sequence is slightly longer than previ-
ously reported, but it is more convenient and better-yield-
ing overall.
Hydraphile 5, Method A
A mixture of Br(CH2)8<N18N>CH2Ph (0.27 g, 0.50 mmol), diaza-
18-crown-6 (2; 0.060 g, 0.23 mmol), and DIPEA (0.13 mL, 0.69
mmol) in MeCN (20 mL) was heated to reflux for 48 h under argon.
The solvent was evaporated. The remaining oil was redissolved in
CH2Cl2 (20 mL), the solution was washed with H2O (3 × 5 mL) and
dried (MgSO4), and then chromatography followed (silica gel,
MeOH–CHCl3, 0:100 to 25:75) to afford a yellow oil; yield: 0.090
g (33%). The spectroscopic properties were identical to those previ-
ously published.19
1H NMR spectra of samples in CDCl3 were recorded at 300, 400, or
600 MHz and are reported in ppm (δ) downfield from internal TMS.
13C NMR spectra of samples in CDCl3 were recorded at 75 MHz un-
less otherwise stated. IR spectra were recorded on a Perkin-Elmer
1710 Fourier Transform Infrared Spectrophotometer and were cali-
brated against the 1601 cm–1 band of polystyrene. Melting points of
samples in open capillaries were determined on a Thomas Hoover
apparatus and are uncorrected. TLC analyses were performed on
aluminum oxide 60 F-254 neutral (Type E) with a 0.2 mm layer
thickness or on silica gel 60 F-254 with a 0.2 mm layer thickness.
Preparative chromatography columns were packed with activated
aluminum oxide (MCB 80–325 mesh, chromatographic grade, AX
611) or with Kieselgel 60 (70–230 mesh). All reactions were con-
ducted under anhydrous N2 unless otherwise stated. All reagents
were the best (non-LC) grade commercially available and were dis-
tilled, recrystallized, or used without further purification, as appro-
priate.
Octylene-Spacer Benzyl Hydraphile 5
[PhCH2<N18N>(CH2)8<N18N>(CH2)8<N18N>CH2Ph]; Method B
Octanedioic Acid Monobenzyl Ester [PhCH2O2C(CH2)6CO2H]
This compound was prepared as described for PhCH2O2C(CH2)12CO2H.18
Octanedioic acid (2.92 g, 16.8 mmol), 10% KOH (1.00 g, 17.8
mmol) in MeOH, TBAB (0.56 g, 1.7 mmol), and PhCH2Br (2.86
mL, 24.1 mmol) afforded a white solid; yield: 2.88 g (65%). The
spectroscopic properties were identical to those previously pub-
lished.20
PhCH2O2C(CH2)6CO<N18N>CO(CH2)6CO2CH2Ph
A mixture of octanedioic acid monobenzyl ester (1.87 g, 7.09
mmol), HBTU (2.70 g, 7.12 mmol), and DIPEA (7.31 mL, 42.0
mmol) in CH2Cl2 (50 mL) was stirred at r.t. for 10 min. Diaza-18-
crown-6 (2; 0.837 g, 3.19 mmol) was added in one portion and the
mixture was allowed to stir at r.t. for 18 h. The reaction mixture was
washed with H2O (3 × 50 mL) and dried (MgSO4); chromatography
(silica gel; MeOH–CHCl3, 0:100 to 10:90) afforded a yellow oil;
yield: 2.22 g (92%).
4,13-Diaza-18-crown-6 (2; H<N18N>H)
Compound 2 was obtained by hydrogenolysis15 of N,N′-dibenzyl-
4,13-diaza-18-crown-6 (4).
1H NMR (300 MHz, CDCl3): δ = 0.98 (br s, 8 H), 1.28 (br s, 8 H),
N-Benzyl-4,13-diaza-18-crown-6 (3)
A mixture of 4,13-diaza-18-crown-6 (2; 2.76 g, 10.51 mmol),
NaBH(OAc)3 (1.67 g, 7.88 mmol), benzaldehyde (0.54 mL, 5.3
mmol), and CH2Cl2 (135 mL) was stirred overnight at r.t. and then
quenched with MeOH (3 mL) and dried (MgSO4). The off-white
residue was mixed with Et2O (100 mL) and filtered, after which it
was chromatographed (dry loaded, silica gel, NH4OH–MeOH–
CH2Cl2, 0.5:2:97.5 to 0.5:5:94.5). Dibenzyl crown 4 eluted first and
was obtained as an off-white solid; yield: 0.70 g (30%). Monoben-
zyl diazacrown 3 eluted next and was obtained as a yellow oil; yield:
1.21 g (65%).
1.99 (m, 8 H), 3.10–3.24 (m, 24 H), 4.75 (s, 4 H), 6.48–7.02 (m, 10
H).
13C NMR (75 MHz, CDCl3): δ = 23.89, 24.22, 28.01, 28.10, 31.93,
33.17, 46.13, 46.21, 47.93, 48.01, 64.94, 68.87, 68.94, 69.20, 69.54,
69.68, 69.81, 69.94, 127.19, 127.63, 135.42, 172.04, 172.26.
HO2C(CH2)6CO<N18N>CO(CH2)6CO2H
PhCH2O2C(CH2)6CO<N18N>CO(CH2)6CO2CH2Ph (2.99 g, 3.96
mmol) was dissolved in EtOH (50 mL). The flask was evacuated
and backfilled with argon three times and then Pd/C (90 mg, 10%
activated Pd/C) was added. The flask was evacuated and backfilled
with H2 (3×) and then two H2 balloons were attached to the flask.
The reaction mixture was stirred at r.t. for 18 h, then filtered through
a 1 inch pad of Celite, washed with EtOAc (100 mL) and MeOH
(100 mL), and dried to afford an off-white solid (2.16 g, 95%)
which was taken onto the next step without further purification. The
spectroscopic properties were identical to those previously report-
ed.21
1H NMR (300 MHz, CDCl3): δ = 2.71–2.83 (m, 8 H), 3.56–3.68 (m,
16 H), 3.69 (s, 2 H), 7.33–7.12 (m, 5 H).
N,N′-Dibenzyl-4,13-diaza-18-crown-6 (4)
Compound 4 was obtained from Sigma-Aldrich and used as re-
ceived or synthesized following published methods.15
Octylene-Spacer Benzyl Hydraphile 5
[PhCH2<N18N>(CH2)8<N18N>(CH2)8<N18N>CH2Ph]; Meth-
od A
PhCH2<N18N>CO(CH2)6CO<N18N>CO(CH2)6CO<N18N>CH2Ph
A mixture of HO2C(CH2)6CO<N18N>CO(CH2)6CO2H (1.60 g,
2.78 mmol), TBTU (2.22 g, 5.85 mmol), DIPEA (2.91 mL, 16.7
mmol), and CH2Cl2 (50 mL) was stirred at r.t. for 10 min. Monoben-
zyl diaza-18-crown-6 (3; 2.27 g, 6.43 mmol) was added in one por-
tion and the mixture was stirred at r.t. for 24 h, washed with H2O (3
× 50 mL), and dried (MgSO4). Purification was done by HPLC.
MeOH (6.0 mL) was added to create a homogeneous solution which
was then purified by using reverse-phase chromatography on a Tar-
ga C18 5 μM 150 × 20 mm column by using a Gilson 4000 Instru-
ment. A gradient (20 mL/min) was run, starting with a 5 min hold
at MeCN–H2O, 5:95 (0.5% TFA), then increasing over 20 min to
MeCN–H2O, 60:40 (0.5% TFA) while monitoring at 210 nm. The
product eluted between 16.8 and 19.1 min. The collected fractions
were neutralized (pH 7) with a sat. aq NaHCO3 solution, extracted
Br(CH2)8<N18N>CH2Ph
A mixture of 1,8-dibromooctane (0.63 mL, 3.4 mmol), N-benzyl-
4,13-diaza-18-crown-6 (3; 1.09 g, 1.3 mmol), and DIPEA (0.86 mL,
4.6 mmol) was heated to reflux for 24 h in MeCN (30 mL) under ar-
gon. The solvent was evaporated. The remaining oil was redis-
solved in CH2Cl2 (60 mL), the solution was washed with H2O (3 ×
10 mL) and dried (MgSO4), and then chromatography followed (sil-
ica gel, MeOH–CHCl3, 0:100 to 25:75) to afford a yellow oil; yield:
0.64 g (38%).
1H NMR (300 MHz, CDCl3): δ = 1.12–1.48 (m, 8 H), 1.53 (br s, 2
H), 1.77 (q, J = 7 Hz, 2 H), 2.76 (m, 6 H), 2.98 (br s, 4 H), 3.33 (t,
J = 7 Hz, 2 H), 3.48–3.60 (m, 12 H), 3.61 (s, 2 H), 3.69 (br s, 4 H),
7.10–7.30 (m, 5 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2771–2779

2776
N. S. Curvey et al.
PAPER
with CH2Cl2 (3 × 50 mL), and dried (MgSO4) to afford an oil; yield:
1.53 g (47%).
1H NMR (300 MHz, CDCl3): δ = 1.03 (br s, 16 H), 1.33 (br s, 8 H),
1.60–2.16 (m, 8 H), 3.35 (br s, 24 H).
1H NMR (300 MHz, CDCl3): δ = 1.14 (br s, 8 H), 1.52 (br s, 8 H),
1.52 (m, 8 H), 2.21 (t, J = 7 Hz, 8 H), 2.70 (m, 8 H), 3.38–3.61 (m,
68 H), 7.05–7.20 (m, 10 H).
13C NMR (75 MHz, CDCl3): δ = 13.73, 24.32, 24.77, 28.45, 28.50,
28.72, 32.43, 33.53, 33.67, 46.61, 48.39, 48.48, 59.54, 69.00, 69.19,
69.45, 69.55, 69.82, 69.95, 70.17, 70.28, 173.17, 175.91.
13C NMR (75 MHz, CDCl3): δ = 24.96, 29.06, 32.76, 46.66, 46.75,
48.56, 53.42, 53.49, 59.63, 69.39, 69.45, 69.67, 69.87, 70.05, 70.18,
70.32, 70.41, 70.68, 126.68, 127.93, 128.59, 139.06, 172.87,
127.90.
PhCH2<N18N>CO(CH2)8CO<N18N>CO(CH2)8CO<N18N>C
H2Ph
This compound was prepared similarly to PhCH2<N18N>
CO(CH2)6CO<N18N>CO(CH2)6CO<N18N>CH2Ph. A mixture of
HO2C(CH2)8CO<N18N>CO(CH2)8CO2H(1.99 g, 3.15 mmol),
HBTU (2.59 g, 6.83 mmol), DIPEA (3.30 mL, 18.9 mmol), and
monobenzyl diaza-18-crown-6 (3; 2.57 g, 7.29 mmol) afforded a
colorless oil; yield: 1.59 g (41%).
Hydraphile 5, Method B
BH3·THF (15.5 mL, 15.5 mmol, 1.0 M in THF) was added dropwise
to
a
solution of anhydrous THF (15.5 mL) and
PhCH2<N18N>CO(CH2)6CO<N18N>CO(CH2)6CO<N18N>CH2P
h (1.21 g, 0.973 mmol) at 0 °C under argon, and the mixture was al-
lowed to stir at r.t. for 3 d. Aq HCl (15.5 mL, 1 M) was added to
quench the reaction. Purification by HPLC was carried out as de-
scribed above; this afforded a colorless oil; yield: 0.67 g (58%). The
spectroscopic properties were identical to those previously pub-
lished.19
1H NMR (300 MHz, CDCl3): δ = 1.19 (br s, 16 H), 1.49 (br s, 8 H),
2.14–2.21 (m, 8 H), 2.64–2.72 (m, 8 H), 3.32–3.60 (m, 68 H), 7.05–
7.26 (m, 10 H).
13C NMR (75 MHz, CDCl3): δ = 25.14, 29.16, 29.23, 32.92, 46.73,
48.63, 53.61, 59.73, 69.44, 69.51, 69.80, 69.90, 69.98, 70.05, 70.25,
70.36, 70.39, 70.49, 70.70, 70.77, 126.71, 127.99, 128.65, 139.25,
173.06, 173.10.
Decylene-Spacer Benzyl Hydraphile 6
[PhCH2<N18N>(CH2)10<N18N>(CH2)10<N18N>CH2Ph];
Method A
Hydraphile 6, Method B
This compound was prepared similarly to hydraphile 5, method B.
BH3·THF (15.1 mL, 15.1 mmol, 1 M in THF) and PhCH2<N18N>
CO(CH2)8CO<N18N>CO(CH2)8CO<N18N>CH2Ph (1.23 g, 0.946
mmol) afforded a colorless oil; yield: 0.62 g (53%). The spectro-
scopic properties were identical to those previously published.19
Br(CH2)10<N18N>CH2Ph
This compound was prepared similarly to Br(CH2)8<N18N>
CH2Ph. 1,10-Dibromodecane (1.13 g, 3.8 mmol), monobenzyl di-
aza-18-crown-6 (3; 1.21 g, 3.4 mmol), and DIPEA (0.95 mL, 5.2
mmol) afforded a yellow oil; yield: 0.66 g (34%). The spectroscopic
properties were identical to those previously published.19
Dodecylene-Spacer Benzyl Hydraphile 7
[PhCH2<N18N>(CH2)12<N18N>(CH2)12<N18N>CH2Ph];
Method A
Hydraphile 6, Method A
This compound was prepared similarly to hydraphile 5, method A.
Br(CH2)10<N18N>CH2Ph (0.46 g, 0.80 mmol), diaza-18-crown-6
(2; 0.095 g, 0.36 mmol), and DIPEA (0.20 mL, 1.1 mmol) afforded
a yellow oil; yield: 0.055 g (31%). The spectroscopic properties
were identical to those previously published.19
Br(CH2)12<N18N>CH2Ph
This compound was prepared similarly to Br(CH2)8<N18N>
CH2Ph. 1,12-dibromododecane (0.55 g, 1.7 mmol), monobenzyl di-
aza-18-crown-6 (3; 0.53 g, 1.5 mmol), and DIPEA (0.42 mL, 2.3
mmol) afforded a yellow oil; yield: 0.32 g (35%). The spectroscopic
properties were identical to those previously published.19
Decylene-Spacer Benzyl Hydraphile 6
[PhCH2<N18N>(CH2)10<N18N>(CH2)10<N18N>CH2Ph];
Method B
Hydraphile 7, Method A
This compound was prepared similarly to hydraphile 5, method A.
Br(CH2)12<N18N>CH2Ph (0.42 g, 0.70 mmol), diaza-18-crown-6
(2; 0.086 g, 0.33 mmol), and DIPEA (0.20 mL, 1.1 mmol) afforded
an off-white solid; yield: 0.22 g (55%). The spectroscopic proper-
ties were identical to those previously published.6a
Decanedioic Acid Monobenzyl Ester [PhCH2O2C(CH2)8CO2H]
This compound was prepared similarly to PhCH2O2C(CH2)6CO2H.
Dodecanedioic acid (2.90 g, 14.3 mmol), 10% KOH (0.85 g, 15.1
mmol) in MeOH, TBAB (0.48 g, 1.49 mmol), and PhCH2Br (2.47
mL, 20.8 mmol) afforded a white solid; yield: 2.76 g (66%). The
spectroscopic properties were identical to those previously pub-
lished.22
Dodecylene-Spacer Benzyl Hydraphile 7
[PhCH2<N18N>(CH2)12<N18N>(CH2)12<N18N>CH2Ph];
Method B
PhCH2O2C(CH2)8CO<N18N>CO(CH2)8CO2CH2Ph
Dodecanedioic Acid Monobenzyl Ester
This compound was prepared similarly to PhCH2O2C(CH2)6CO
<N18N>CO(CH2)6CO2CH2Ph. Decanedioic acid monobenzyl ester
(2.23 g, 7.62 mmol), HBTU (2.89 g, 7.62 mmol), DIPEA (7.85 mL,
45.1 mmol), and diaza-18-crown-6 (2; 0.900 g, 3.43 mmol) afford-
ed a colorless oil; yield: 2.50 g (90%).
[PhCH2O2C(CH2)10CO2H]
This compound was prepared similarly to PhCH2O2C(CH2)6CO2H.
Dodecanedioic acid (10.0 g, 43.6 mmol), 10% KOH (2.70 g, 48.1
mmol) in MeOH, TBAB (1.40 g, 4.34 mmol), and PhCH2Br (8 mL,
67.5 mmol) afforded a white solid; yield: 5.16 g (37%); mp 67.5–
68.2 °C. The spectroscopic properties were identical to those previ-
ously published.18
1H NMR (300 MHz, CDCl3): δ = 0.99 (br s, 16 H), 1.31 (br s, 8 H),
2.03 (m, 8 H), 3.18–3.36 (m, 24 H), 6.89–7.07 (m, 10 H).
13C NMR (75 MHz, CDCl3): δ = 24.11, 24.49, 28.22, 28.32, 28.50,
28.53, 32.19, 33.33, 37.73, 46.21, 46.29, 48.03, 48.11, 65.02, 68.94,
69.07, 69.32, 69.63, 69.77, 69.91, 70.04, 127.27, 127.69, 135.49,
172.25, 172.27, 172.39.
PhCH2O2C(CH2)10CO<N18N>CO(CH2)10CO2CH2Ph
This compound was prepared similarly to PhCH2O2C(CH2)6CO<
N18N>CO(CH2)6CO2CH2Ph. Dodecanedioic acid monobenzyl es-
ter (0.93 g, 2.9 mmol), TBTU (0.92 g, 2.9 mmol), DIPEA (1.4 mL,
1.0 mmol), and diaza-18-crown-6 (2; 0.35 g, 1.31 mmol) afforded
an off-white solid; yield: 0.97 g (85%). The spectroscopic proper-
ties were congruent with previously published methods.18
HO2C(CH2)8CO<N18N>CO(CH2)8CO2H
This compound was prepared similarly to HO2C(CH2)6CO<N18N>
CO(CH2)6CO2H. PhCH2O2C(CH2)8CO<N18N>CO(CH2)8CO2CH2Ph
(2.70 g, 3.33 mmol) and Pd/C (80 mg, 10% activated Pd/C) afforded
an off-white solid; yield: 2.05 g (98%), mp 78.9–80.9 °C.
HO2C(CH2)10CO<N18N>CO(CH2)10CO2H
This compound was prepared similarly to HO2C(CH2)6CO
<N18N>CO(CH2)6CO2H.
PhCH2-
Synthesis 2014, 46, 2771–2779
© Georg Thieme Verlag Stuttgart · New York

PAPER
Hydraphile Syntheses
2777
CO(CH2)10CO<N18N>CO(CH2)10CO2CH2Ph (0.97 g, 1.1 mmol)
and Pd/C (113 mg, 10% activated Pd/C) afforded an off-white solid;
yield: 0.69 g (90%). The spectroscopic properties were identical to
those previously published.18
Hydraphile 8, Method A
This compound was prepared similarly to hydraphile 5, method A.
Br(CH2)14<N18N>CH2Ph (1.16 g, 1.8 mmol), diaza-18-crown-6 (2;
0.22 g, 0.8 mmol), and DIPEA (0.46 mL, 2.5 mmol) afforded an off-
white solid after precipitation from hot acetone; yield: 0.63 g (55%).
The spectroscopic properties were identical to those previously
published.19
PhCH2<N18N>CO(CH2)10CO<N18N>CO(CH2)10CO<N18N>C
H2Ph
This
compound
was
prepared
similarly
to
PhCH2<N18N>CO(CH2)6CO<N18N>CO(CH2)6CO<N18N>CH2P
h. HO2C(CH2)10CO<N18N>CO(CH2)10CO2H (0.65 g, 0.95 mmol),
HBTU, DIPEA (3.0 mL, 2.2 mmol), and monobenzyldiaza-18-
crown-6 (3; 0.71 g, 2.0 mmol) afforded an off-white solid after pre-
cipitation from hot acetone; yield: 0.97 g (75%). The spectroscopic
properties were identical to those previously published.18
Tetradecylene-Spacer Benzyl Hydraphile 8
[PhCH2<N18N>(CH2)14<N18N>(CH2)14<N18N>CH2Ph];
Method B
Tetradecanedioic Acid Monobenzyl Ester
[PhCH2O2C(CH2)12CO2H]
This compound was prepared similarly to PhCH2O2C(CH2)6CO2H.
Tetradecanedioic acid (1.71 g, 6.62 mmol), 10% KOH (0.408 g,
7.27 mmol) in MeOH, TBAB (0.213 g, 0.661 mmol), and PhCH2Br
(0.90 mL, 7.6 mmol) afforded a white solid; yield: 1.27 g (55%); mp
77.2–77.8 °C.
Hydraphile 7, Method B
This compound was prepared similarly to hydraphile 5, method B.
BH3·THF (1.18 mL, 1.18 mmol,
1 M in THF) and
PhCH2<N18N>CO(CH2)10CO<N18N>CO(CH2)10CO<N18N>CH
2Ph (0.10 g, 0.074 mmol) afforded a colorless oil; yield: 0.058 g
(60%). The spectroscopic properties were identical to those previ-
ously published.6a
1H NMR (300 MHz, CDCl3): δ = 1.26 (br s, 16 H), 1.64 (m, 4 H),
2.35 (m, 8 H), 5.13 (s, 2 H), 7.22–7.37 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 25.14, 29.23, 29.30, 29.41, 29.60,
29.71, 34.26, 34.52, 66.27, 128.35, 128.72, 136.30, 173.97, 180.34.
Tetradecylene-Spacer Benzyl Hydraphile 8
[PhCH2<N18N>(CH2)14<N18N>(CH2)14<N18N>CH2Ph];
Method A
PhCH2O2C(CH2)12CO<N18N>CO(CH2)12CO2CH2Ph
This
compound
was
prepared
similarly
to
Dimethyl Tetradecanedioate [MeO2C(CH2)12CO2Me]23
Thionyl chloride (3.5 mL, 49 mmol) was added dropwise to the
commercial diacid (5.05 g, 20 mmol) in MeOH (250 mL) and the
mixture was allowed to stir for 24 h. The solvent was removed to
afford a white solid; yield: 5.6 g (~100%).
PhCH2O2C(CH2)6CO<N18N>CO(CH2)6CO2CH2Ph. Tetradecane-
dioic acid monobenzyl ester (0.0873 g, 0.251 mmol), HBTU
(0.0935 g, 0.247 mmol), DIPEA (0.260 mL, 1.49 mmol), and diaza-
18-crown-6 (2; 0.286 g, 0.109 mmol) afforded a yellow oil; yield:
0.90 g (89%).
1H NMR (300 MHz, CDCl3): δ = 1.25 (br s, 32 H), 1.64 (m, 8 H),
2.34 (m, 8 H), 3.51–3.67 (m, 24 H), 5.11 (s, 4 H), 7.26–7.37 (m, 10
H).
13C NMR (75 MHz, CDCl3): δ = 25.06, 25.46, 25.50, 29.24, 29.36,
29.55, 29.62, 29.67, 29.70, 33.24, 33.30, 34.44, 46.98, 47.13, 48.84,
48.97, 66.67, 69.67, 70.13, 70.18, 70.55, 70.64, 70.86, 71.01,
128.27, 128.65, 136.24, 173.48, 173.54, 173.82.
1H NMR (300 MHz, CDCl3): δ = 1.08 (br s, 16 H), 1.41 (br s, 4 H),
2.09 (m, 4 H), 3.45 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 24.47, 28.69, 28.83, 29.00, 29.10,
33.51, 173.41.
1,14-Tetradecanediol [HO(CH2)14OH]
A 1 M solution of LAH in THF (60 mL, 60 mmol) was added to an-
hydrous THF (50 mL) in a flask preflushed with argon at 0 °C.
MeO2C(CH2)12CO2Me (3.44 g, 12 mmol) in anhydrous THF (30
mL) was then added dropwise and the mixture was allowed to stir
for 5 h and heated under reflux for 16 h. The reaction mixture was
cooled to r.t., quenched with EtOAc (15 mL) then H2O (50 mL) un-
til no more gas evolved. The mixture was shaken with a 1 M aq
solution of sodium potassium tartrate (100 mL) for 5 min. The top
organic layer was collected and evaporated to afford a white solid;
yield: 2.62 g (95%). The spectroscopic properties were identical to
those previously published.24
HO2C(CH2)12CO<N18N>CO(CH2)12CO2H
This compound was prepared similarly to HO2C(CH2)6CO<N18N>
CO(CH2)6CO2H. PhCH2O2C(CH2)12CO<N18N>CO(CH2)12CO2CH2Ph
(1.48 g, 1.1 mmol) and Pd/C (40 mg, 10% activated Pd/C) afforded
an off-white solid; yield: 1.17 g (98%); mp 118.0–119.2 °C.
1H NMR (300 MHz, CDCl3): δ = 1.12–1.35 (m, 16 H), 1.58 (m, 8
H), 2.29 (m, 8 H), 3.46–3.68 (m, 24 H).
PhCH2<N18N>CO(CH2)12CO<N18N>CO(CH2)12CO<N18N>C
H2Ph
1,14-Dibromotetradecane [Br(CH2)14Br]
This compound was prepared similarly to PhCH2<N18N>
CO(CH2)6CO<N18N>CO(CH2)6CO<N18N>CH2Ph. HO2C(CH2)12CO
<N18N>CO(CH2)12CO2H (0.34 g, 0.46 mmol), HBTU (0.76 g, 2.0
mmol), DIPEA (0.48 mL, 2.8 mmol), and monobenzyldiaza-18-
crown-6 (3; 0.373 g, 1.06 mmol) afforded a yellow oil; yield: 0.60
g (93%).
Aq HBr (48%, 7 mL, 42 mmol) was added dropwise to Ac2O (12
mL, 126 mmol) at 0 °C. To this solution, HO(CH2)14OH (0.44 g, 1.9
mmol) was added and the mixture was brought to reflux for 24 h.
After the mixture had cooled to r.t., the dihalide was extracted with
hexanes and was then washed with excess H2O to remove the re-
maining AcOH, leaving an off-white solid; yield: 0.65 g (95%). The
spectroscopic properties were identical to those previously pub-
lished.25
1H NMR (300 MHz, CDCl3): δ = 1.21 (m, 32 H), 1.57 (m, 8 H), 2.26
(m, 8 H), 2.75 (m, 8 H), 3.42–3.68 (m, 68 H), 7.09–7.29 (m, 10 H).
13C NMR (75 MHz, CDCl3): δ = 25.32, 29.43, 29.55, 33.09, 46.87,
48.77, 53.67, 53.77, 59.90, 69.64, 69.98, 70.15, 70.24, 70.39, 70.53,
70.64, 70.92, 126.83, 128.12, 128.77, 139.44, 173.26, 173.31.
Br(CH2)14<N18N>CH2Ph
This
compound
was
prepared
similarly
to
Br(CH2)8<N18N>CH2Ph. 1,14-Dibromotetradecane (2.73 g, 2.7
mmol), monobenzyl diaza-18-crown-6 (3; 2.00 g, 5.7 mmol), and
DIPEA (2.1 mL, 11 mmol) afforded a yellow oil; yield: 1.17 g
(33%). The spectroscopic properties were identical to those previ-
ously published.19
Hydraphile 8, Method B
This compound was prepared similarly to hydraphile 5, method B.
BH3·THF (2.67 mL, 2.67 mmol, 1.0
M in THF) and
PhCH2<N18N>CO(CH2)12CO<N18N>CO(CH2)12CO<N18N>CH
2Ph (0.236 g, 0.167 mmol) afforded a white solid; yield: 0.14 g
(62%). The spectroscopic properties were identical to those previ-
ously published.19
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2771–2779

2778
N. S. Curvey et al.
PAPER
Hexadecylene-Spacer Benzyl Hydraphile 9
[PhCH2<N18N>(CH2)16<N18N>(CH2)16<N18N>CH2Ph];
Method A
36.75, 69.88, 70.00, 70.06, 70.17, 70.32, 70.42, 70.61, 70.69,
126.61, 127.89, 128.54, 139.24, 173.00, 173.05.
Hydraphile 9, Method B
This compound was prepared similarly to hydraphile 5, method B.
1,16-Dibromohexadecane [Br(CH2)16Br]
This compound was prepared similarly to Br(CH2)14Br. Aq HBr
(48%, 63 mL, 380 mmol), Ac2O (108 mL, 1.1 mol), and
HO(CH2)16OH (4.47 g, 17 mmol) afforded an off-white solid; yield:
6.55 g (99%). The spectroscopic properties were identical to those
previously published.26
BH3·THF (7.40 mL, 7.40 mmol, 1.0
M in THF) and
PhCH2<N18N>CO(CH2)14CO<N18N>CO(CH2)14CO<N18N>CH
2Ph (0.650 g, 0.443 mmol) afforded a white solid; yield: 0.609 g
(97%). The spectroscopic properties were identical to those previ-
ously published.19
Br(CH2)16<N18N>CH2Ph
This compound was prepared similarly to Br(CH2)8<N18N>
CH2Ph. 1,16-Dibromohexadecane (6.70 g, 17.4 mmol), monoben-
zyl diaza-18-crown-6 (3; 5.50 g, 15.6 mmol), and DIPEA (4.32 mL,
25.0 mmol) afforded a yellow oil; yield: 4.18 g (41%). The spectro-
scopic properties were identical to those previously published.19
Acknowledgment
We thank the NSF for grants (CHE 0957535 and CHE 1307324)
that supported this work.
Hydraphile 9, Method A
Supporting Information for this article is available online
This compound was prepared similarly to hydraphile 5, method A.
Br(CH2)16<N18N>CH2Ph (4.18 g, 6.37 mmol), diaza-18-crown-6
(2; 0.76 g, 2.9 mmol), and DIPEA (1.76 mL, 10.1 mmol) afforded
an off-white solid; yield: 1.14 g (28%). The spectroscopic proper-
ties were identical to those previously published.19
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunogIpimrfiantoSuIpg
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fonirtat
ori
References
Hexadecylene-Spacer Benzyl Hydraphile 9
[PhCH2<N18N>(CH2)16<N18N>(CH2)16<N18N>CH2Ph];
Method B
(1) Tabushi, I.; Kuroda, Y.; Yokota, K. Tetrahedron Lett. 1982,
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(2) Jullien, L.; Lehn, J.-M. Tetrahedron Lett. 1988, 29, 3803.
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Hexadecanedioic Acid Monobenzyl Ester
[PhCH2O2C(CH2)14CO2H]
This compound was prepared similarly to PhCH2O2C(CH2)6CO2H.
Hexadecanedioic acid (4.93 g, 17.2 mmol), 10% KOH (1.06 g, 18.9
mmol) in MeOH, TBAB (0.555 g, 1.71 mmol), and PhCH2Br (2.25
mL, 18.9 mmol) afforded a white solid; yield: 2.71 g (42%); mp
83.1–84.4 °C. The spectroscopic properties were identical to those
previously published.27
(5) (a) Gokel, G. W.; Dishong, D. M.; Diamond, C. J. J. Chem.
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Soc. Rev. 2007, 36, 378. (d) Matile, S.; Vargas Jentzsch, A.;
Montenegro, J.; Fin, A. Chem. Soc. Rev. 2011, 40, 2453.
(e) Chui, J. K.; Fyles, T. M. Chem. Soc. Rev. 2012, 41, 148.
(7) Gokel, G. W.; Daschbach, M. M. Coord. Chem. Rev. 2008,
252, 886.
(8) Weber, M. E.; Wang, W.; Steinhardt, S. E.; Gokel, M. R.;
Leevy, W. M.; Gokel, G. W. New J. Chem. 2006, 30, 177.
(9) Atkins, J. L.; Patel, M. B.; Cusumano, Z.; Gokel, G. W.
Chem. Commun. 2010, 46, 8166.
(10) (a) Smith, B. A.; Daschbach, M. M.; Gammon, S. T.; Xiao,
S.; Chapman, S. E.; Hudson, C.; Suckow, M.; Piwnica-
Worms, D.; Gokel, G. W.; Leevy, W. M. Chem. Commun.
2011, 47, 7977. (b) Smith, B. A.; Gammon, S. T.; Xiao, S.;
Wang, W.; Chapman, S.; McDermott, R.; Suckow, M. A.;
Johnson, J. R.; Piwnica-Worms, D.; Gokel, G. W.; Smith, B.
D.; Leevy, W. M. Mol. Pharm. 2011, 8, 583.
PhCH2O2C(CH2)14CO<N18N>CO(CH2)14CO2CH2Ph
This
compound
was
prepared
similarly
to
PhCH2O2C(CH2)6CO<N18N>CO(CH2)6CO2CH2Ph. Hexadecane-
dioic acid monobenzyl ester (0.202 g, 0.536 mmol), HBTU (0.205
g, 0.541 mmol), DIPEA (0.560 mL, 3.22 mmol), and diaza-18-
crown-6 (2; 0.632 g, 0.241 mmol) afforded a yellow oil; yield:
0.201 g (85%).
1H NMR (300 MHz, CDCl3): δ = 1.27 (br s, 40 H), 1.64 (m, 8 H),
2.33 (m, 8 H), 3.50–3.68 (m, 24 H), 5.11 (s, 4 H), 7.25–7.36 (m, 10
H).
HO2C(CH2)14CO<N18N>CO(CH2)14CO2H
This compound was prepared similarly to HO2C(CH2)6CO<N18N>
CO(CH2)6CO2H. PhCH2CO(CH2)14CO<N18N>CO(CH2)14CO2CH2Ph
(0.34 g, 0.35 mmol) and Pd/C (20 mg, 10% activated Pd/C) afforded
an off-white solid (0.27 g, 97%, mp = 118.5–119.9 °C).
1H NMR (300 MHz, CDCl3): δ = 1.23 (br s, 40 H), 1.60 (br s, 8 H),
2.31 (m, 8 H), 3.41–3.68 (m, 24 H).
PhCH2<N18N>CO(CH2)14CO<N18N>CO(CH2)14CO<N18N>C
H2Ph
(11) Zusi, F. C.; Marathe, S. A.; Tramposch, K. M. US Patent
4731382, 1988.
(12) Hill, J. W.; Carothers, W. H. J. Am. Chem. Soc. 1933, 55,
5023.
(13) de Mendoza J.; Cuevas F.; Prados P. personal
communication.
This
compound
was
prepared
similarly
to
PhCH2<N18N>CO(CH2)6CO<N18N>CO(CH2)6CO<N18N>CH2P
h. HO2C(CH2)14CO<N18N>CO(CH2)14CO2H (0.700 g, 0.876
mmol), HBTU (0.84 g, 2.2 mmol), DIPEA (0.92 mL, 5.3 mmol),
and monobenzyl diaza-18-crown-6 (3; 0.713 g, 2.02 mmol) afford-
ed a yellow oil; yield: 1.16 g (90%).
(14) de Mendoza, J.; Cuevas, F.; Prados, P.; Meadows, E. S.;
Gokel, G. W. Angew. Chem. Int. Ed. 1998, 37, 1534.
(15) Gatto, V. J.; Miller, S. R.; Gokel, G. W. Org. Synth. 1989,
68, 227.
1H NMR (300 MHz, CDCl3): δ = 1.14 (m, 40 H), 1.49 (m, 8 H), 2.21
(m, 8 H), 2.65–2.73 (m, 8 H), 3.32–3.58 (m, 68 H), 7.00–7.22 (m,
10 H).
13C NMR (75 MHz, CDCl3): δ = 25.10, 29.20, 29.23, 29.25, 29.36,
32.85, 38.34, 46.68, 48.58, 53.34, 53.49, 53.58, 59.69, 69.38, 36.45,
(16) Gokel, G. W. Chem. Commun. 2000, 1.
Synthesis 2014, 46, 2771–2779
© Georg Thieme Verlag Stuttgart · New York

PAPER
Hydraphile Syntheses
2779
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Soc. 2005, 126, 636.
(24) (a) Manske, R. H. Org. Synth. 1943, 2, 154. (b) Mori, K.
Tetrahedron 2008, 64, 4060.
(18) Wang, W.; Yamnitz, C. R.; Gokel, G. W. Heterocycles 2007,
73, 825.
(25) Taffa, D.; Kathiresan, M.; Walder, L. Langmuir 2009, 25,
5371.
(19) Murray, C. L.; Gokel, G. W. J. Supramol. Chem. 2001, 1, 23.
(20) Keller, M.; Teng, S.; Bernhardt, G.; Buschauer, A.
ChemMedChem 2009, 4, 1733.
(21) Kotzyba-Hibert, F.; Lehn, J. M.; Vierling, P. Tetrahedron
Lett. 1980, 21, 941.
(26) (a) Yuen, A. K. L.; Heinroth, F.; Ward, A. J.; Masters, A. F.;
Maschmeyer, T. Microporous Mesoporous Mater. 2012,
148, 62. (b) Chuit, P.; Hausser, J. Helv. Chim. Acta 1929, 12,
850.
(27) Zhang, X.-X.; Prata, C. A. H.; Berlin, J. A.; McIntosh, T. J.;
Barthelemy, P.; Grinstaff, M. W. Bioconjugate Chem. 2011,
22, 690.
(22) Iso, Y.; Shindo, H.; Hamana, H. Tetrahedron 2000, 56,
5353.
(23) Cardinale, G.; Laan, J. A. M.; Van Der Steen, D.; Ward, J. P.
Tetrahedron 1985, 41, 6051.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2771–2779