Synthesis of 7-deoxycholic amides or cholanes containing distinctive ion-recognizing groups at C3 and C12 and evaluation for ion-selective ionophores

Article abstract of DOI:10.1016/j.tet.2008.12.023

Tweezer-type ionophores containing C3-bipyridyl and C12-dithiocarbamoyl groups, or C3-bithiophenyl with C12-dithiocarbamoyl groups on a 7-deoxycholic amide or cholane derivatives were designed and synthesized. Potentiometric evaluation of the PVC membrane

Full text of DOI:10.1016/j.tet.2008.12.023

Tetrahedron 65 (2009) 1415–1423
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 7-deoxycholic amides or cholanes containing distinctive ion-
recognizing groups at C3 and C12 and evaluation for ion-selective ionophores
Jeung Hoon On, Kui Tae Cho, Youngjin Park, Sunmi Hahm, Wook Kim, Joo Young Cho, Ji Hyeon Hwang,
*
*
Young Moo Jun, Guen Sig Cha, Hakhyun Nam , Byeong Hyo Kim
Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 October 2008
Received in revised form 5 December 2008
Accepted 5 December 2008
Available online 13 December 2008
Tweezer-type ionophores containing C3-bipyridyl and C12-dithiocarbamoyl groups, or C3-bithiophenyl
with C12-dithiocarbamoyl groups on a 7-deoxycholic amide or cholane derivatives were designed and
synthesized. Potentiometric evaluation of the PVC membranes containing those deoxycholic amides/
cholanes linked with unsymmetrically substituted tweezer-type bipyridyl or bithiophenyl with dithio-
carbamoyl moieties proved their good affinity and selectivity for silver(I) ion. Especially, ionophores with
bithiophenyl moiety on the 3a-position and diphenylaminothioxomethylthioacetyloxy group on 12a-
position of cholan-24-amide or cholane reveal the most excellent result with a theoretical slope value of
59 mV/decade.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
magnesium, anions, and transition metal ions, including silver ion
with the same frame.5 Most known transition metal-selective
Ion-selective electrodes (ISEs) are a distinctive example of
chemical sensors that use the principle of molecular recognition
chemistry. For this reason, new molecular tweezer-type neutral
carriers based on a cholic acid backbone (CAB) have been designed,
synthesized, and successfully utilized to yield highly selective
ionophores for carbonate, chloride, silver, and calcium by us in
recent years.1–6 The CAB-based carriers are relatively easy to design
and straightforward to synthesize. Moreover, previous examples
show that the CAB frame is as versatile as calix[n]arenes for the
development of selective ionophores. The selective ion-tweezing
ability of a CAB-based neutral carrier can be controlled by changing
the several factors; (1) variation in cavity size between two binding
sites by changing the length of the linking chain between the
substituent and the hydroxyl linker; (2) differentiation of the steric
hindrance between C3 and C12 carbons of the backbone, and
modification of ion-recognizing functional groups. Thus, many
different CAB-based neutral carriers can be designed by substitut-
ing various types of ion-recognizing groups to the two hydroxyl
linkers, which are approximately parallel at the C3 and C12 carbons
of the frame and about 6 Å apart that is a reasonable distance for
tweezing the various ions.7
ionophores, such as silver ion-selective ionophores, possess sulfur
and/or nitrogen atoms in their proposed binding sites.8 Therefore,
bipyridyl moieties containing nitrogen atoms4 or dithiocarbamoyl
moieties containing sulfur atoms6 as a binding site for the silver
ion-selective ionophores were adopted to 7-deoxycholic amide
previously and showed reasonable affinity and selectivity to sil-
ver(I) ions over other metal cations.
Up to the present, all the CAB-based neutral carriers we have
reported have the same ion-recognizing groups at C3 and C12 be-
cause introducing the different functional groups at C3 and C12 was
hardly possible. Fortunately, we recently found a synthetic method
for introducing different functional groups in a step-by-step fash-
ion at C3 and C12 on CAB, which could be a cornerstone for de-
veloping diverse types of CAB-based neutral carriers with different
ion-recognizing groups in the same molecule. Consequently, un-
symmetrically substituted tweezer-type CAB-based ionophores,
that is, the nitrogen atom-binding site containing moiety at C3 and
sulfur atom-binding site containing moiety at C12, or sulfur atom-
binding site containing moieties with different functional groups,
such as C3-bithiophenyl and C12-dithiocarbamoyl moieties were
designed and synthesized. Newly synthesized unsymmetrically
substituted tweezer-type CAB-based ionophores showed excellent
affinity and selectivity to silver(I) ions over alkali, alkaline earth,
and other transition metal ions. Herein, we report on the synthesis
and application to ionophores of CAB-based ionophores that have
substituted with different ion-recognizing functional groups at C3
and C12 of 7-deoxycholic amide or cholane.
Our initial success in several CAB-based neutral carriers has
encouraged us to develop ion-selective ionophores for calcium,
* Corresponding authors. Fax: þ82 2 942 4635.
E-mail addresses: namh@kw.ac.kr (H. Nam), bhkim@kw.ac.kr (B.H. Kim).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.023

1416
J.H. On et al. / Tetrahedron 65 (2009) 1415–1423
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
(b)
(a)
CO2H
CO2H
CON(C8H17)2
OH
OCHO
OCHO
1
OH
OCHO
OCHO
(d)
(c)
H
H
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
(e), (f)
OH
CO2Me
CON(C8H17)2
OH
OH
OMOM
OH
OH
OMOM
(j)
(g), (h)
H
Me
Me
Me
H
Me
H
Me
Me
Me
Me
CON(C8H17 2
)
(i)
O
O
OH
OMOM
O
O
Cl
2 (80%)
OH
OMOM
Cl
(j)
(k)
H
H
Me
Me
Me
Me
Me
Me
3a; R1 = CON(C8H17)2, R2 = C2H5 (75%)
3b; R1 = CON(C8H17)2, R2 = i-C4H9 (78%)
(k)
R1
O
O
O
O
a
3c; R1 = CON(C8H17)2, R2 = Ph (73%)
5a; R1 = CH3, R2 = C2H5 (71%)
5b; R1 = CH3, R2 = i-C4H9 (87%)
O
O
OH
Cl
S
4 (93%)
S
NR2
Cl
a
5c; R1 = CH3, R2 = Ph (74%)
Scheme 1. (a) HCOOH, Ac2O, 55 ꢀC, 1.5 h, 99%; (b) ClCOOMe, NEt3, HN(C8H17)2, 0 ꢀC, 3 h, 89%; (c) K2CO3, MeOH, THF, 0 ꢀC, 24 h, 98%; (d) AcCl, MeOH, 0 ꢀC, 20 h, 86%; (e) CH2(OCH3)2,
CF3SO3H, CH2Cl2, rt, 5 h; (f) LAH, Et2O, rt, 2 h, 88% (for two steps); (g) TsCl, Py, 75 ꢀC, 1.5 h; (h) LAH, Et2O, 0 ꢀC, 1 h, 73% (for two steps); (i) HCl, MeOH, CH2Cl2, 50 ꢀC, 2 days, 96%; (j)
ClCH2COCl, CaH2, Bu4NBr, Tol, 90 ꢀC, 5 h; (k) (i) NaSC(S)NR2, EtOH, 70 ꢀC, 12 h, (ii) saturated LiOH (aq) 2 mL, 5 min (a3c, a5c; saturated LiOH (aq) 10 mL, 10 min).
2. Results and discussion
occurred. Although a more sterically hindered secondary alkoxy
group of 12 -position is safe for trans-esterification in EtOH, the
relatively less hindered secondary alkoxy group of 3 -position is
a
2.1. Synthesis of ionophores
a
cleaved to the hydroxyl group via a trans-esterification reaction
even in the neutral condition.
To improve the time-consuming trans-esterification reaction
condition, several control experiments were carried out in this
As mentioned earlier in the introduction, our previously repor-
ted CAB-based neutral carriers have the same ion-recognizing
groups at C3 and C12 because introducing the different functional
groups at C3 and C12 independently was not easy to control.
study. As a result, we found that hydrolysis of 3a-position was ac-
However, recently we found that 3
dioctyl-5 -cholan-24-amide (2) could be transformed into mono-
substituted 5 -cholan-24-amides, 3a–3c, instead of di-substituted
-cholan-24-amide using the modified procedure.6 Although 2
a
,12
a
-bis(chloroacetoxy)-N,N-
celerated the reaction to completion appropriately by adding
aqueous LiOH to the reaction mixture (Scheme 1, step k), which
improved the reaction time and handiness compared with the re-
sults from the previous trans-esterification method. As it has a free
b
b
5
b
and sodium N,N-di-R-dithiocarbamate (R¼ethyl, isobutyl, phenyl)
3
a
-hydroxy group, it can be used as a precursor for the synthesis of
tweezer-type CAB-based ionophores that has a different ion rec-
ognition group on 3 - and 12 -position, respectively, which would
be a valuable precursor for developing a new type of ionophores.
In addition to optimizing ion recognition groups on 3 - and 12
position, the evaluation of lipophilic characteristics of the 5 -side
chain is also important.6 Therefore, the preparation of 5
-cholan-
24-amides with long alkyl chains on the amide group and 5
cholane derivatives with an alkyl chain should likewise be optimized
in order to obtain the best ionophore. Thus, to prepare 5 -cholane
precursors, the similar reaction condition was applied to 3 ,12
in THF at reflux (bath temp, 70 ꢀC) produced di-R-substituted
5
b
-cholan-24-amide, such as N,N-dioctyl-3
thioxomethyl]thio]acetyl]oxy]-5
-cholan-24-amide (R¼ethyl, isobutyl,
phenyl), 2 and sodium N,N-di-R-dithiocarbamate (R¼ethyl, isobutyl,
phenyl) in EtOH at 70 ꢀC produced
-hydroxy-N,N-dioctyl-
12 -[[[[(di-R-amino)thioxomethyl]thio]acetyl]oxy]-5 -cholan-24-
amides (3a–3c) with good yields. In EtOH, the formation of
N,N-dioctyl-3 ,12 -bis[[[[(di-R-amino)thioxomethyl]thio]acetyl]oxy]-
-cholan-24-amide was observed first, which is similar to the
reaction in THF. However, 3 -hydroxy-N,N-dioctyl-12 -[[[[(di-R-
thioxomethyl]thio]acetyl]oxy]-5 -cholan-24-amide (3) gradually
appeared and increased as the reaction proceeded. After 24 h,
N,N-dioctyl-3 ,12 -bis[[[[(di-R-amino)thioxomethyl]thio]acetyl]oxy]-
-cholan-24-amide disappeared and 3 was obtained as a final
product. It seemed that highly selective trans-esterification had
a
,12
a
-bis[[[[(di-R-amino)-
a
a
b
a
a-
3a
b
a
b
b
b-
a
a
5b
b
a
a
a
a-
b
bis(chloroacetoxy)-5
12 -[[[[(di-R-amino)thioxomethyl]thio]acetyl]oxy]-5
(5a–5c, R¼ethyl, isobutyl, phenyl) as well (Scheme 1, step l). Ac-
cordingly, 3a–3c and 5a–5c, containing 12 -dithiocarbamoyl
groups on a 7-deoxycholic amide or cholane derivatives were
b-cholane (4) and it produced 3
a
-hydroxy-
a
b-cholanes
a
a
5b
a

J.H. On et al. / Tetrahedron 65 (2009) 1415–1423
1417
H
Me
Me
Me
3; R1 = CON(C8H17)2,
R2 = C2H5, i-C4H9, Ph
5; R1 = CH3,
R1
O
O
R2 = C2H5, i-C4H9, Ph
OH
Cl
S
R2
S
N
R2
O
O
Cl
S
N
S
b
a
N
H
Me
H
Me
Me
Me
Me
R2
Me
R1
R1
O
O
O
O
O
O
O
S
S
O
R2
S
N
S
N
S
R2
R2
N
N
S
9a; R1 = CON(C8H17)2, R2 = C2H5 (41%)
9b; R1 = CON(C8H17)2, R2 = i-C4H9 (47%)
7a; R1 = CON(C8H17)2, R2 = C2H5 (69%)
7b; R1 = CON(C8H17)2, R2 = i-C4H9 (69%)
7c; R1 = CON(C8H17)2, R2 = Ph
(66%)
9c; R1 = CON(C8H17)2, R2 = Ph
(40%)
8a; R1 = CH3, R2 = C2H5 (56%)
8b; R1 = CH3, R2 = i-C4H9 (77%)
10a; R1 = CH3, R2 = C2H5 (44%)
10b; R1 = CH3, R2 = i-C4H9 (53%)
8c; R1 = CH3, R2 = Ph
(52%)
10c; R1 = CH3, R2 = Ph
(46%)
Scheme 2. (a) 6a, DMAP, TEA, CH2Cl2, rt, 24 h, (b) 6b, pyridine, reflux, 12 h.
prepared from 7-deoxycholic acid (1) as described in Scheme 1,
which used as precursors in this study.
performance among four different plasticizers (NPOE, DOS, DOA,
and BBPA) when used for the preparation of transition metal ion-
selective electrodes.5 Membranes consisting of 1:2 ratio of PVC and
DOA were prepared as described in the Experimental section and
all 12 ionophores were then evaluated with the DOA-plasticized
PVC membranes. No further efforts were made to improve the
potentiometric performance of each membrane to compare the
effect of structural variations in the binding properties of CAB-
based ionophores under the same conditions. The transition metal
ion selectivities of all ionophores were evaluated for 10 different
ions (Agþ, Mn2þ, Fe2þ, Co2þ, Ni2þ, Cu2þ, Zn2þ, Pb2þ, Cd2þ, and
Hg2þ), and the results are compared with respect to the Agþ.
Figures 1 and 2 show the typical calibration plots of the elec-
trodes based on ionophores 7a–7c and 8a–8c (Fig.1) and 9a–9c and
10a–10c (Fig. 2), respectively. The plots include only silver ion re-
sponses of the electrodes for clarity, and the responses were
measured in the 10ꢁ9 to 10ꢁ3 M range. Responses to other transi-
tion metal ions were negligible except for Hg2þ in case of the
electrodes based on 9a–10c. The selectivity coefficients with re-
spect to silver ions were determined by the matched potential
method; the concentration of the primary ion that brings about the
same response potential corresponding to 10ꢁ2 M of interfering
ions was determined and their activities were compared. Tables 1
and 2 summarize the potentiometric characteristics (response
slopes, detection limits, and selectivity coefficients) of all mem-
brane electrodes prepared with the ionophores 7a–10c.
After the preparation of precursors, 3a–3c and 5a–5c, the esteri-
fication of the 3a-hydroxy group was performed with proper car-
bonyl chloride to transform the 3a-hydroxy to the proper ester group
that has ion-recognizing functional groups such as bithiophenyl or
bipyridyl moiety. Thus, 3a–3c or 5a–5c was treated with [2,20-
bithiophene]-5-carbonyl chloride (6a) in the presence of DMAP and
TEA in CH2Cl2 at room temperature for 24 h to produce 12
[[[[(di(alkyl, aryl)amino)thioxomethyl]thio]acetyl]oxy]-3
-[[[2,20-
bithiophen]-5-yl]carboxy]-N,N-dioctyl-5 -cholan-24-amides (7a–7c)
or 12 -[[[[(di(alkyl, aryl)amino)thioxomethyl]thio]acetyl]oxy-3
[[[2,20-bithiophen]-5-yl]carboxy]-5
-cholanes (8a–8c) correspondingly
(Scheme 2, (a)). Likewise, 12 -[[[[(di(alkyl, aryl)amino)thioxome
thyl]thio]acetyl]oxy]-3
-[[[2,20-bipyridin]-5-yl]carboxy]-N,N-dioc-
tyl-5 -cholan-24-amides (9a–9c) or 12 -[[[[(di(alkyl, aryl)amino)-
thioxomethyl]thio]acetyl]oxy-3
-[[[2,20-bipyridin]-5-yl]carboxy]-
-cholanes (10a–10c) were obtained by treating 3a–3c or 5a–5c
a-
a
b
a
a-
b
a
a
b
a
a
5
b
with [2,20-bipyridine]-5-carbonyl chloride (6b) in pyridine at reflux
for 12 h, respectively (Scheme 2, (b)). Hence,12 different prospective
ionophores, (i.e., 7a–7c, 8a–8c, 9a–9c, and 10a–10c) were synthe-
sized successfully and their structures were fully identified with 1H
NMR,13C NMR, FTIR, and FAB MASS (7b, 7c, 9b, and 9c) or HRMS (3a–
3c, 5a–5c, 7a, 8a–8c, 9a, and 10a–10c).
2.2. Potentiometric properties of ionophores
The ISEs prepared with the ionophores 7a–8c with bithiophenyl
moiety on 3
a-position and dithiocarbamoyl moiety on 12a-posi-
DOA was chosen as the plasticizer for the preparation of ion-
selective membranes; it provided the best potentiometric
tion exhibited near Nernstian response to Agþ, resulting in the

1418
J.H. On et al. / Tetrahedron 65 (2009) 1415–1423
7a
7b
7c
8a
300
8b
300
250
200
150
100
50
8c
250
200
150
100
50
0
0
-9
-8
-7
-6
log [Ag+]
-5
-4
-3
-9
-8
-7
-6
log [Ag+
-5
-4
-3
]
Figure 1. Calibration plots of the electrodes based on ionophores 7a–8c. Only the representative responses are presented for clarity. Responses to other transition metal ions
(Mzþ¼Zn2þ, Pb2þ, Ni2þ, Co2þ, Cd2þ, Fe2þ, Cu2þ, and Mn2þ) are negligible ðlogK
< ꢁ5:5Þ.
POT
Agþ ;Mþ
400
9a
400
350
300
250
200
150
100
10a
10b
10c
9b
350
300
250
200
150
100
9c
-8
-7
-6 -5
log [Ag+]
-4
-3
-2
-8
-7
-6 -5
log [Ag+]
-4
-3
-2
Figure 2. Calibration plots of the electrodes based on ionophores 9a–10c. Only the representative responses are presented for clarity. Responses to other transition metal ions
(Mzþ¼Zn2þ, Pb2þ, Ni2þ, Co2þ, Cd2þ, Fe2þ, Cu2þ, and Mn2þ) are negligible ðlogK
< ꢁ5:0Þ.
POT
Agþ ;Mþ
slopes of 42–59 mV/decade and the detection limits of 10ꢁ7 to
10ꢁ8 M. It is interesting to note that the ISEs based on compounds
7c and 8c exhibit ideal response, 59 mV/decade. Both ionophores
ISEs based on 9c and 10c that contain the same type of phenyl
groups on R2 as those in 7c and 8c also show theoretical response
slopes to Agþ.
contain diphenylaminothioxomethylthioacetyloxy group on 12
a
-
However, ISEs based on bipyridine containing ionophores,
compounds 9a–10c, exhibited substantially increased responses to
Hg2þ compared with those based on bithiophene, 7a–8c, resulting
in reduced Agþ selectivity over that of Hg2þ. It appears that the
bidentate ligand, bipyridine, provides a favorable binding site to
Hg2þ compared with bithiophene, which may be explained by
Pearson’s hard and soft acid base classification. The ISE results
provide some insights on the role of the functional groups in
compounds 7a–10c. The sensitive variations in the Agþ response
characteristics with the change in the R2 functional group on
position of cholan-24-amide (7c) and cholane (8c). Presumably,
resonance participation of phenyl groups (R2 in Scheme 2) on
dithiocarbamoyl moiety of 7c and 8c may reduce the electron
density of the sulfur atom, resulting in sulfur atoms softer than that
of compounds 7a, 7b, 8a, and 8b that have hyperconjugative
e-donating groups on R2. It could result in ISE membranes with
improved silver ion responses, which is indicative of increased in-
teraction with silver ions. A similar tendency was observed in
ionophores, 9a–10c, which has bipyridyl moiety on the 3
a
-position
and dithiocarbamoyl moiety on the 12a-position (Table 2). That is,
Table 2
Table 1
Potentiometric properties of silver ion-selective electrodes based on ionophores
containing bipyridine moiety
Potentiometric properties of silver ion-selective electrodes based on ionophores
containing bithiophene moiety
Compound
Slopea
Detection limitb
Selectivity
Compound
Slopea
Detection limitb
c
c
POT
POT
Selectivity coefficient ðlogK
2þ Þ
coefficient ðlogK
Þ
Agþ ;Hg2þ
Ag þ ;Hg
7a
7b
7c
8a
8b
8c
42.9
53.5
58.1
49.5
45.5
58.6
ꢁ7.2
ꢁ7.6
ꢁ7.6
ꢁ7.5
ꢁ7.6
ꢁ7.7
ꢁ4.7
ꢁ4.1
ꢁ4.5
ꢁ5.0
ꢁ3.5
ꢁ3.6
9a
9b
9c
10a
10b
10c
48.8
52.2
58.6
53.0
48.9
54.4
ꢁ5.8
ꢁ5.8
ꢁ5.3
ꢁ5.6
ꢁ5.8
ꢁ5.9
ꢁ0.2
ꢁ0.9
ꢁ1.7
ꢁ0.7
ꢁ0.7
ꢁ1.3
a
a
Range : 10ꢁ7 to 10ꢁ3 M, mV/decade.
Range : 10ꢁ7 to 10ꢁ2 M, mV/decade.
b
c
b
c
log[Agþ], M.
log[Agþ], M.
Mþ
¼
The sliver ion selectivity overall other transition metal ions ðlogK
;
Agþ ;Mþ
Mþ
¼
POT
POT
The sliver ion selectivity overall other transition metal ions ðlogK
;
Agþ ;Mþ
Zn2þ
;
Pb2þ; Ni2þ; Co2þ; Cd2þ; Fe2þ; Cu2þ; Mn2þÞ tested is less than ꢁ5.5.
Zn2þ; Pb2þ; Ni2þ; Co2þ; Cd2þ; Fe2þ; Cu2þ; Mn2þÞ tested is less than ꢁ5.0.

J.H. On et al. / Tetrahedron 65 (2009) 1415–1423
1419
Hb
Hb
N(C8H17 2
)
O
O
S
O
O
S
Hc
O
Hc
Hd
He
Hd
He
O
O
O
O
Hg
Hg
Hg
Hg
Hf
Hf
Ha
Ha
Ha
S
N
S
N
Hg
S
S
S
S
2
Ha
Ha
Ha
2
7a
8c
Ha
Ha
<7a>
Ha
Hb
Hc
He
Hd
Hf
(A)
(B)
(C)
8
7
5
4
<8c>
Ha & Hg
Hb
He
Hc
Hd
(D)
(E)
(F)
8
7
5
4
Figure 3. 1H NMR spectra (400 MHz) of the ionophores, (A) free 7a measured in methanol-d4/acetone-d6 (v/v¼5:1), (B) 7a after addition of 1 equiv of AgNO3, (C) 7a after addition of
2 equiv of AgNO3, (D) free 8c measured in methanol-d4/acetone-d6 (v/v¼5:6), (E) 8c after addition of 1 equiv of AgNO3, and (F) 8c after addition of 2 equiv of AgNO3.
dithiocarbamoyl moiety but not with the type of ligands on 3
a
-
co-solvent. Among the NMR titration experiments we were carried
out, two representative results of NMR titrations (7a and 8c) are
shown in Fig. 3; one (7a) is that showed a minimally good result
from ISE test and the other (8c) is that exhibited the most excellent
result with a theoretical slope value of 59 mV/decade.
position indicate that the sulfur atom in the thiocarbamoyl moiety
is mostly responsible for the silver ion recognition. On the other
hand, the functional groups of bithiophene and bipyridine on the
3
a-position, which are introduced as the tweezers of 7a–8c and 9a–
10c on the 12 -position together with the dithiocarbamoyl group,
seem to affect the silver binding ability secondarily.
a
1H NMR spectra of free ionophores, 7a and 8c shown in Figure 3
A and D, were altered with the Agþ ion addition; following the
addition of 1 equiv of AgNO3 to the ionophore in methanol-d4/ac-
etone-d6 solution, changes in chemical shifts of several peaks were
clearly observed by the influence of Agþ ion Fig. 3 B and E. While
significant downfield shifts of the He peak (diastereotopic proton
2.3. NMR titration experiments of ionophores with AgD ion
To confirm the recognition properties of the newly synthesized
silver ion-selective ionophores toward Agþ ion, 1H NMR titration
experiments were examined. Titrations were done with the iono-
phore and AgNO3 in methanol-d4/acetone-d6 (v/v¼5:1 to 5:6)
that is on the same plane with adjacent carbonyl
dithiocarbamoyl moiety and the 12 -Hc peaks were observed, rel-
atively small shifts of the Ha peaks on bithiophene moiety were
p-bond), the Hf on
b

1420
J.H. On et al. / Tetrahedron 65 (2009) 1415–1423
noted. Definitely, these changes in NMR peaks are attributed to the
complexation between Agþ ion and hetero atoms in dithiocarba-
moyl and bithiophene moiety. However, the extent of downfield
shifts of the Ha peaks on bithiophene moiety of 7a and 8c differed.
While there were some observable downfield shifts of the Ha peaks
on bithiophene moiety of 8c, there were insignificant downfield
shifts observed for that of 7a. However, in the case of 7c that was as
good as 8c as an ionophore, comparable downfield shifts for the Ha,
Hc, He, and Hf peaks were observed from NMR titration experi-
ments similar to 8c. This proves that the effective tweezer-type ion
capture by dithiocarbamoyl and bithiophene moieties is important
for ISEs even though bithiophene moiety appears to have a rela-
tively small effect compared to dithiocarbamoyl moiety.
Overall, the results strongly imply that the sulfur and oxygen
atoms in the dithiocarbamoyl moiety are mostly responsible for the
silver ion recognition together with an assist of the sulfur atoms in
bithiophene. Increase in the amount of AgNO3 up to 2 equiv did not
notably influence the chemical shifts of the Ha, Hc, Hd, and He peaks
anymore for both 7a and 8c (Fig. 3 C and F). Certainly, this indicates
thationophores, both7aand8c, forma1:1 complex withtheAgþ ion.
4.2. Synthesis
4.2.1. General procedure for the preparation of 12a-[[[[(di(alkyl,
aryl)amino)thioxomethyl]thio]acetyl]oxy]-3
-cholan-24-amides 3a–3c
solution of N,N-dioctyl-3
a
-hydroxy-N,N-dioctyl-
5b
A
a
,12
a
-bis(chloroacetoxy)-5b-
cholan-24-amide (2, 218 mg, 0.27 mmol) and sodium N,N-
di(alkyl, aryl)dithiocarbamate (1.36 mmol) in 10 mL of EtOH
was refluxed for 12 h and then saturated LiOH(aq) (2–10 mL)
was added to reaction mixture and stirred for 5–10 min. It was
filtered through a pad of Celite (5 g) after cooling. The Celite
was washed with dichloromethane (200 mL) and the combined
filtrate and washings were collected and evaporated in vacuo.
The residue was diluted with CH2Cl2 (150 mL), extracted with
saturated NaHCO3(aq) (2ꢂ150 mL), washed with water
(1ꢂ150 mL), dried over MgSO4, and evaporated in vacuo. The
residue was purified by chromatography on silica gel with
ethyl acetate/hexane as an eluent to yield 3a–3c as waxy
liquids.
4.2.1.1. 12
a
-[[[[(Diethylamino)thioxomethyl]thio]acetyl]oxy]-3
a-hy-
3. Conclusion
droxy-N,N-dioctyl-5
b
-cholan-24-amide (3a). Waxy liquid; TLC (sil-
ica gel, 50% ethyl acetate/hexane) Rf 0.45; 1H NMR (300 MHz,
In this article, we synthesized uniquely designed silver ion-selec-
tive ionophores based on unsymmetric tweezer-type ionophores
containing bithiophenyl or bipyridyl moiety on the C3-position and
dithiocarbamoyl groups on a 7-deoxycholic amide or cholane de-
rivative. Their potentiometric properties were evaluated with the PVC
membrane-based electrodes. Newly synthesized unsymmetrically
substituted tweezer-type CAB-based 12 ionophores linked with
unsymmetric tweezer-type bipyridyl, bithiophenyl, and dithiocarba-
moyl moieties showed excellent affinity and selectivity to silver(I) ion
over alkali, alkaline earth, and other transition metal ions. Overall,
most ionophores showed slopes that were near Nernstian responses
with 10ꢁ6 to 10ꢁ7 M detection limit. Especially, ionophores 7c and 8c
CDCl3)
d
5.13 (1H, br s, 12
b
-H), 4.39 (1H, d, J¼16.5 Hz, RSCH2CO2R0),
4.19 (1H, d, J¼16.5 Hz, RSCH2CO2R0), 4.12–3.90 (2H, m,
RCSN(CH2R0)2), 3.90–3.70 (2H, m, RCSN(CH2R0)2), 3.62–3.48 (1H, m,
3b
-H), 3.29–3.19 (4H, m, RCON(CH2R0)2), 2.34–0.72 (72H, m); 13C
NMR (75 MHz, CDCl3)
d 193.34, 172.91, 167.96, 77.58, 71.70, 50.11,
49.07, 47.96, 47.44, 46.88, 45.82, 45.17, 42.02, 39.13, 36.51, 35.65,
35.25, 35.04, 34.18, 34.05, 31.76, 31.72, 31.43, 30.61, 30.03, 29.36,
29.31, 29.21, 29.18, 27.75, 27.41, 27.03, 26.89, 26.06, 25.28, 23.50,
22.94, 22.58, 17.74, 14.05, 12.57, 12.20, 11.51; IR (KBr) nmax 3425,
3056, 2985, 1727, 1627, 1488, 1263 cmꢁ1
C47H84N2O4S2 m/z 804.5873, found 804.5895.
; HRMS calcd for
that have bithiophene moiety on the 3
nothioxomethylthioacetyloxy group on the 12
a
-position and diphenylami-
4.2.1.2. 3
acetyl]oxy]-N,N-dioctyl-5
TLC (silica gel, 40% ethyl acetate/hexane) Rf 0.49; 1H NMR
a
-Hydroxy-12
a
-[[[[(diisobutylamino)thioxomethyl]thio]-
a-position of cholan-
b-cholan-24-amide (3b). Waxy liquid;
24-amide(7c)orcholane(8c)revealthemostexcellentresultwiththe
theoretical slope value of 59 mV/decade. Compounds with bipyridyl
moiety and diphenylaminothioxomethylthioacetyloxy group also
showed similarproperties, but, exhibited reduced Agþ selectivityover
that of Hg2þ. The results show that the sensitive variations in the re-
sponses to silver ion are the most sensitive to the change in
substituted functional groups on the dithiocarbamoyl moiety.
(300 MHz, CDCl3)
d 5.12 (1H, br s, 12b-H), 4.45 (1H, d,
J¼16.7 Hz, RSCH2CO2R0), 4.15 (1H, d, J¼16.7 Hz, RSCH2CO2R0),
3.95–3.74 (2H, m, RCSN(CH2R0)2), 3.71–3.48 (3H, m, 3
b-H and
RCSN(CH2R0)2), 3.37–3.13 (4H, m, RCON(CH2R0)2), 2.53–2.11 (4H,
m, RCH2CONR02 and RCSN(CH2CHR02)2), 1.95–0.72 (76H, m); 13C
NMR (75 MHz, CDCl3)
d 194.94, 172.80, 167.82, 77.58, 71.67,
63.89, 61.05, 49.10, 47.90, 47.44, 45.76, 45.08, 42.97, 39.23,
36.52, 35.55, 35.26, 34.92, 34.09, 33.98, 31.69, 31.65, 31.35,
30.59, 29.95, 29.29, 29.24, 29.11, 27.69, 27.26, 26.96, 26.84,
26.18, 25.95, 25.18, 23.45, 22.83, 22.45, 20.32, 20.20, 17.67,
13.98, 12.16; IR (KBr) nmax 3420, 3052, 2956, 1727, 1631, 1469,
1273 cmꢁ1; HRMS calcd for C51H92N2O4S2 m/z 860.6499, found
860.6508.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded at 300 (Bruker) or 400
(Jeol) and 75 or 100 MHz, respectively. Chemical shifts are reported
in parts per million relative to residual solvent as an internal
standard. High-resolution mass was recorded mostly on a JEOL
JMS-DX303 mass spectrometer. Infrared (IR) spectra were recorded
using MB104 FTIR (ABB Bomem Inc.).
4.2.1.3. 3
yl]thio]acetyl]oxy]-5
(silica gel, 40% ethyl acetate/hexane) Rf 0.40; 1H NMR (300 MHz,
a-Hydroxy-N,N-dioctyl-12a-[[[[(diphenylamino)thioxometh-
b
-cholan-24-amide (3c). Waxy liquid; TLC
Chemical reagents were purchased from Aldrich unless noted
otherwise and were used without purification in most cases. Sol-
vents were purchased and dried using the usual laboratory tech-
niques. All anhydrous reactions were carried out under nitrogen
atmosphere. Poly(vinyl chloride) (PVC) and bis(2-ethylhexyl) adi-
pate (DOA) were purchased from Fluka Chemie AG (Buch, Swit-
zerland). All other chemicals for analytical experiments were
analytical-reagent grade. Standard solutions and buffers were
CDCl3) d 7.58–7.30 (10H, m, Ph), 5.10 (1H, br s, 12b-H), 4.36 (1H,
d, J¼16.8 Hz, RSCH2CO2R0), 4.04 (1H, d, J¼16.8 Hz, RSCH2CO2R0),
3.52–3.39 (1H, m, 3b
-H), 3.37–3.07 (4H, m, RCON(CH2R0)2),
2.25–0.73 (66H, m); 13C NMR (75 MHz, CDCl3)
d 199.41, 172.66,
167.34, 129.54, 128.41, 127.76, 77.59, 71.51, 49.26, 47.84, 47.47,
45.78, 45.16, 41.96, 39.84, 36.55, 35.60, 35.18, 34.81, 34.14, 33.97,
31.68, 31.63, 31.24, 30.56, 29.74, 29.28, 29.18, 29.12, 29.07, 29.00,
27.70, 27.37, 26.95, 26.78, 26.12, 25.16, 23.52, 22.81, 22.50, 17.64,
13.98, 12.13; IR (KBr) nmax 3450, 3052, 2964, 1711, 1628,
1252 cmꢁ1; HRMS calcd for C55H84N2O4S2 m/z 900.5873, found
900.5867.
prepared with freshly deionized water (18 MU cm). Compounds 2
and 4 were prepared from 7-deoxycholic acid (1) using our pre-
vious method as shown in Scheme 1.4–6

J.H. On et al. / Tetrahedron 65 (2009) 1415–1423
1421
4.2.2. General procedure for the preparation of 12
a
-[[[[(di-
were collected and evaporated in vacuo. The residue was diluted
with CH2Cl2 (150 mL), extracted with saturated NaHCO3(aq)
(2ꢂ150 mL), washed with water (1ꢂ150 mL), dried over MgSO4, and
evaporated in vacuo. The crude was purified by chromatography
on silica gel with ethyl acetate/hexane (1:3) as an eluent to yield 7a–
7c as waxy liquids.
(alkyl, aryl)amino)thioxomethyl]thio]acetyl]oxy]-3
a
-hydroxy-5b-
cholanes 5a–5c
A solution of 3a,12a-bis(chloroacetoxy)-5b-cholane (4, 121 mg,
0.24 mmol) and sodium N,N-di(alkyl, aryl)dithiocarbamate
(1.18 mmol) in 10 mL of EtOH was refluxed for 12 h and then sat-
urated LiOH(aq) (2–10 mL) was added to reaction mixture and
stirred for 5–10 min. It was filtered through a pad of Celite (5 g)
after cooling. The Celite was washed with dichloromethane
(200 mL) and the combined filtrate and washings were evaporated
in vacuo. The residue was diluted with CH2Cl2 (150 mL), extracted
with saturated NaHCO3(aq) (2ꢂ150 mL), washed with water
(1ꢂ150 mL), dried over MgSO4, and evaporated in vacuo. The resi-
due was purified by chromatography on silica gel with ethyl ace-
tate/hexane as an eluent to give 5a–5c as colorless waxy liquids.
4.2.3.2. 12
octyl-3
-[[[2,20-bithiophen]-5-yl]carboxy]-5
Waxy liquid; TLC (silica gel, 40% ethyl acetate/hexane) Rf 0.58; 1H
NMR (300 MHz, CDCl3)
7.73 (1H, d, J¼3.8 Hz, Th), 7.35–7.20 (2H,
m, Th), 7.12 (1H, d, J¼3.8 Hz, Th), 7.10–7.01 (1H, m, Th), 5.15 (1H, br s,
a
-[[[[(Diethylamino)thioxomethyl]thio]acetyl]oxy]-N,N-di-
a
b-cholan-24-amide (7a).
d
12
b
-H), 5.00–4.83 (1H, m,
3
b
-H), 4.44 (1H, d, J¼16.5 Hz,
RSCH2CO2R0), 4.25 (1H, d, J¼16.5 Hz, RSCH2CO2R0), 4.10–3.93 (2H,
m, RCSN(CH2R0)2), 3.90–3.72 (2H, m, RCSN(CH2R0)2), 3.40–3.10 (4H,
m, RCON(CH2R0)2), 2.40–0.68 (71H, m); 13C NMR (75 MHz, CDCl3)
4.2.2.1. 12
a
-[[[[(Diethylamino)thioxomethyl]thio]acetyl]oxy]-3
a
-hy-
d 193.16, 172.76, 167.86, 161.56, 143.66, 136.38, 133.85, 132.44,
droxy-5 -cholane (5a). Waxy liquid; TLC (silica gel, 50% ethyl
b
127.93, 125.74,124.92, 123.69, 77.33, 75.17, 50.00, 48.97, 47.86, 47.37,
46.64, 45.72, 45.08, 41.76, 39.08, 35.57, 34.93, 34.74, 34.11, 34.02,
32.16, 31.67, 31.63, 31.32, 29.94, 29.28, 29.22, 29.12, 29.09, 27.68,
27.29, 26.94, 26.80, 26.59, 25.86, 25.32, 23.38, 22.83, 22.49, 17.65,
13.97, 12.59, 12.14, 11.37; IR (KBr) nmax 3078, 2952, 1703, 1638, 1452,
1420, 1270 cmꢁ1; HRMS calcd for C56H88N2O5S4 m/z 996.5576,
found 996.5570.
1
acetate/hexane) Rf 0.43; H NMR (300 MHz, CDCl3)
d 5.13 (1H, br s,
12
b
-H), 4.38 (1H, d, J¼16.4 Hz, RSCH2CO2R0), 4.20 (1H, d, J¼16.4 Hz,
RSCH2CO2R0), 4.10–3.98 (2H, m, RCSN(CH2R0)2), 3.87–3.72 (2H, m,
RCSN(CH2R0)2), 3.62–3.48 (1H, m, 3
(75 MHz, CDCl3) 193.41, 167.88, 77.65, 71.71, 50.06, 49.04, 47.53,
b
-H),1.86–0.71 (45H,m);13C NMR
d
46.79, 45.06, 42.00, 39.17, 38.02, 36.49, 35.62, 35.22, 34.97, 34.15,
34.01, 30.60, 27.44, 27.01, 26.04, 25.20, 23.44, 22.88,19.11,17.76,14.44,
12.51, 12.10, 11.46; IR(KBr) nmax 3460, 3057, 2989, 1720, 1262 cmꢁ1
HRMS calcd for C31H53NO3S2 m/z 551.3467, found 551.3454.
;
4.2.3.3. 12
dioctyl-3
-[[[2,20-bithiophen]-5-yl]carboxy]-5
Waxyliquid;TLC(silicagel,30%ethylacetate/hexane) Rf 0.68;1H NMR
(300 MHz, CDCl3)
7.74 (1H, d, J¼3.9 Hz, Th), 7.35–7.25 (2H, m, Th),
a-[[[[(Diisobutylamino)thioxomethyl]thio]acetyl]oxy]-N,N-
a
b-cholan-24-amide (7b).
4.2.2.2. 3
a
-Hydroxy-12
a
-[[[[(diisobutylamino)thioxomethyl]thio]-
d
acetyl]oxy]-5
b
-cholane (5b). Waxy liquid; TLC (silica gel, 30% ethyl
7.12 (1H, d, J¼3.9 Hz, Th), 7.03 (1H, dd, J¼5.0, 3.8 Hz, Th), 5.15 (1H, br s,
acetate/hexane) Rf 0.43; 1H NMR (300 MHz, CDCl3)
d
5.11 (1H, br s,
12
b
-H), 5.00–4.85 (1H, m, 3
b
-H), 4.50 (1H, d, J¼16.8 Hz, RSCH2CO2R0),
12
b
-H), 4.48 (1H, d, J¼16.5 Hz, RSCH2CO2R0), 4.13 (1H, d, J¼16.5 Hz,
4.22(1H, d,J¼16.8 Hz, RSCH2CO2R0), 3.93–3.75(2H, m, RCSN(CH2R0)2),
RSCH2CO2R0), 3.96–3.76 (2H, m, RCSN(CH2R0)2), 3.72–3.48 (3H, m,
3.70–3.52 (2H, m, RCSN(CH2R0)2), 3.40–3.12 (4H, m, RCON(CH2R0)2),
3
b
-H and RCSN(CH2R0)2), 2.57–2.30 (2H, m, RCSN(CH2CHR02)2),
2.52–0.70 (79H, m);13C NMR(75 MHz, CDCl3)
d 194.83,172.72,167.79,
1.91–0.76 (51H, m); 13C NMR (75 MHz, CDCl3)
d
195.06, 167.82,
161.55, 143.60, 142.44, 136.41, 133.84, 132.47, 127.89, 127.01, 125.66,
124.86, 123.99, 123.64, 77.32, 75.10, 63.91, 60.94, 49.08, 47.87, 47.41,
45.72, 45.06, 41.76, 39.30, 35.56, 34.88, 34.77, 34.08, 34.00, 32.09,
31.66,31.62,31.33,29.94,29.26, 29.21, 29.08,27.68,27.22, 26.93,26.80,
26.59, 26.16, 25.82, 25.32, 23.39, 22.81, 22.48, 20.17,17.64,14.05,13.96,
12.18; IR (KBr) nmax 3054, 2960,1700,1630,1453,1422,1261 cmꢁ1; MS
(FAB) m/z 1051 (Mþ), 790 (MþꢁOCOCH2SC(S)N(C6H5)2), 580
(MþꢁOCOCH2SC(S)N(C6H5)2, OCOC8H5S2).
77.71, 71.77, 64.00, 61.12, 49.21, 47.49, 45.06, 42.04, 39.34, 38.04,
36.58, 35.60, 35.32, 34.92, 34.14, 34.02, 30.66, 27.74, 27.40, 27.00,
26.23, 26.00, 25.20, 23.47, 22.86, 20.22, 19.00, 17.76, 14.48, 12.14; IR
(KBr) nmax 3425, 3052, 2961, 1727, 1469, 1268 cmꢁ1; HRMS calcd
for C35H61NO3S2 m/z 607.4093, found 607.4084.
4.2.2.3. 3
tyl]oxy]-5
acetate/hexane) Rf 0.31; 1H NMR (300 MHz, CDCl3)
a
-Hydroxy-12
-cholane (5c). Waxy liquid; TLC (silica gel, 30% ethyl
7.54–7.25
a-[[[[(diphenylamino)thioxomethyl]thio]ace-
b
d
4.2.3.4. N,N-Dioctyl-12
yl]oxy]-3
-[[[2,20-bithiophen]-5-yl]carboxy]-5
(7c). Waxy liquid; TLC (silica gel, 30% ethyl acetate/hexane) Rf 0.66;
1H NMR (300 MHz, CDCl3)
7.56 (1H, d, J¼3.9 Hz, Th), 7.43–7.22
a
-[[[[(diphenylamino)thioxomethyl]thio]acet-
(10H, m, Ph), 5.10 (1H, br s, 12
b
-H), 4.38 (1H, d, J¼16.7 Hz,
a
b
-cholan-24-amide
RSCH2CO2R0), 4.03 (1H, d, J¼16.7 Hz, RSCH2CO2R0), 3.52–3.40 (1H,
m, 3
b
-H), 1.98–0.72 (39H, m); 13C NMR (75 MHz, CDCl3)
d
199.56,
d
167.40, 145.1, 129.55, 128.44, 127.83, 77.73, 71.62, 49.32, 47.60,
45.12, 42.00, 39.91, 38.00, 36.58, 35.62, 35.22, 34.97, 34.19, 34.01,
30.62, 27.55, 27.04, 26.16, 25.17, 23.56, 22.86, 19.06, 17.71, 14.48,
(12H, m, Th and Ph), 7.10–7.05 (2H, m, Th), 5.13 (1H, br s, 12b-H),
4.92–4.82 (1H, m, 3
b
-H), 4.41 (1H, d, J¼16.6 Hz, RSCH2CO2R0), 4.12
(1H, d, J¼16.6 Hz, RSCH2CO2R0), 3.38–3.02 (4H, m, RCON(CH2R0)2),
12.11; IR (KBr) nmax 3423, 3056, 2933, 1722, 1490, 1264 cmꢁ1
HRMS calcd for C39H53NO3S2 m/z 647.3467, found 647.3466.
;
2.30–0.72 (66H, m); 13C NMR (75 MHz, CDCl3)
d 199.38, 172.75,
167.45, 161.65, 143.69, 136.60, 134.03, 132.57, 129.56, 128.39, 128.08,
127.86, 125.81, 125.05, 123.80, 77.57, 75.07, 49.43, 47.95, 47.59,
45.91, 45.28, 41.81, 40.14, 35.72, 34.90, 34.20, 34.09, 32.13, 31.80,
31.75, 31.34, 29.83, 29.41, 29.31, 29.25, 29.19, 29.13, 27.84, 27.50,
27.09, 26.90, 26.63, 26.06, 25.38, 23.60, 22.89, 22.62, 17.76, 14.09,
4.2.3. General procedure for the preparation of 12
aryl)amino)thioxomethyl]thio]acetyl]oxy]-N,N-dioctyl-3
bithiophen]-5-yl]carboxy]-5 -cholan-24-amides 7a–7c
a
-[[[[(di(alkyl,
a
-[[[2,20-
b
12.30; IR (KBr) nmax 3069, 2955, 1697, 1635, 1493, 1452, 1284 cmꢁ1
;
4.2.3.1. 12
a
-[[[[(Diethylamino)thioxomethyl]thio]acetyl]oxy]-3
a
-hy-
MS (FAB) m/z 1093 (Mþ), 790 (MþꢁOCOCH2SC(S)N(C6H5)2), 580
droxy-N,N-dioctyl-5b-cholan-24-amide (3a). Compound 3a (175 mg,
(MþꢁOCOCH2SC(S)N(C6H5)2, OCOC8H5S2).
0.22 mmol), 4-(dimethylamino)pyridine (32 mg, 0.26 mmol), and
[2,20-bithiophene]-5-carbonyl chloride (152 mg, 0.66 mmol) were
dissolved in dichloromethane (10 mL) at room temperature. TEA
4.2.4. General procedure for the preparation of 12
aryl)amino)thioxomethyl]thio]acetyl]oxy]-N,N-dioctyl-3
bithiophen]-5-yl]carboxy]-5 -cholanes 8a–8c
a
-[[[[(di(alkyl,
a
-[[[2,20-
(93
which was stirred for 24 h. The reaction mixture was filtered
through pad of Celite (5 g). The Celite was washed with
dichloromethane (200 mL) and the combined filtrate and washings
mL, 0.66 mmol) was slowly added to the reaction mixture,
b
a
4.2.4.1. 12
hydroxy-5
a
-[[[[(Diethylamino)thioxomethyl]thio]acetyl]oxy]-3
a-
b-cholane (5a). Compound 5a (68 mg, 0.12 mmol),

1422
J.H. On et al. / Tetrahedron 65 (2009) 1415–1423
4-(dimethylamino)pyridine (18 mg, 0.15 mmol), and [2,20-bithio-
phene]-5-carbonyl chloride (84 mg, 0.37 mmol) were dissolved in
[[[[(Diethylamino)thioxomethyl]thio]acetyl]oxy]-3
a-hydroxy-N,N-di-
octyl-5 -cholan-24-amide (3a, 210 mg, 0.26 mmol) was dissolved in
b
dichloromethane (6 mL) at room temperature. TEA (50
mL,
pyridine (10 mL) and was added to the reaction mixture at 0 ꢀC,
which was stirred for 12 h at reflux. The reaction mixture was fil-
tered through a pad of Celite (5 g). The Celite was washed with
dichloromethane (200 mL) and the combined filtrate and washings
were collected and evaporated in vacuo. The residue was diluted
with CH2Cl2 (150 mL), extracted with saturated NaHCO3(aq)
(2ꢂ150 mL), washed with 1 N HCl (2ꢂ150 mL), washed with water
(1ꢂ150 mL), dried over MgSO4, and evaporated in vacuo. The crude
was purified by chromatography on silica gel with ethyl acetate/
hexane (4:6) as eluent to yield 9a–9c as waxy liquids.
0.37 mmol) was slowly added to the reaction mixture, which was
stirred for 24 h. The reaction mixture was filtered through a pad of
Celite (5 g). The Celite was washed with dichloromethane (150 mL)
and the combined filtrate and washings were collected and evap-
orated in vacuo. The residue was diluted with CH2Cl2 (100 mL),
extracted with saturated NaHCO3(aq) (2ꢂ100 mL), washed with
water (1ꢂ100 mL), dried over MgSO4, and evaporated in vacuo. The
crude was purified by chromatography on silica gel with ethyl ac-
etate/hexane (1:4) as an eluent to yield 8a–8c as waxy liquids.
4.2.4.2. 12
[[[2,20-bithiophen]-5-yl]carboxy]-5
(silica gel, 20% ethyl acetate/hexane) Rf 0.50; 1H NMR (300 MHz,
CDCl3)
7.74 (1H, d, J¼3.9 Hz, Th), 7.31–7.26 (2H, m, Th), 7.12 (1H, d,
a
-[[[[(Diethylamino)thioxomethyl]thio]acetyl]oxy]-3
a
-
4.2.5.1. 3
thioxomethyl]thio]acetyl]oxy]-N,N-dioctyl-5
Waxy liquid; TLC (silica gel, 40% ethyl acetate/hexane) Rf 0.22; 1H
NMR (400 MHz, CDCl3) 9.31–9.33 (1H, m, Py), 8.71–8.69 (1H, m,
Py), 8.51–8.47 (3H, m, Py), 7.84 (1H, td, J¼7.8, 1.8 Hz, Py), 7.35 (1H,
a
-[[[2,20-Bipyridin]-5-yl]carboxy]-12
-cholan-24-amide (9a).
a-[[[[(diethylamino)-
b-cholane (8a). Waxy liquid; TLC
b
d
d
J¼3.9 Hz, Th), 7.04 (1H, dd, J¼5.0, 3.7 Hz, Th), 5.15 (1H, br s, 12
b-H),
4.97–4.86 (1H, m, 3
b
-H), 4.45 (1H, d, J¼16.3 Hz, RSCH2CO2R0), 4.24
ddd, J¼7.8, 4.8, 1.2 Hz, Py), 5.14 (1H, br s, 12
b-H), 5.05–4.99 (1H, m,
(1H, d, J¼16.3 Hz, RSCH2CO2R0), 4.01 (2H, q, J¼7.0 Hz, RCSN-
3
b
-H), 4.50 (1H, d, J¼16.5 Hz, RSCH2CO2R0), 4.19 (1H, d, J¼16.5 Hz,
(CH2R0)2), 3.79 (2H, q, J¼7.1 Hz, RCSN(CH2R0)2), 2.12–0.70 (44H, m);
RSCH2CO2R0), 4.06–3.95 (2H, m, RCSN(CH2R0)2), 3.78 (2H, m,
RCSN(CH2R0)2), 3.35–3.15 (4H, m, RCON(CH2R0)2), 2.38–2.04 (2H, m,
RCH2CONR02), 2.38–0.71 (68H, m); 13C NMR (100 MHz, CDCl3)
13C NMR (75 MHz, CDCl3)
d 193.38, 167.98, 161.72, 143.77, 136.51,
133.97, 132.60, 128.06, 125.84, 125.05, 123.82, 77.56, 75.33, 60.34,
50.11, 49.10, 47.61, 46.74, 45.14, 41.91, 39.30, 38.10, 35.70, 35.05,
34.87, 34.26, 34.15, 32.30, 27.52, 26.98, 26.71, 25.98, 25.42, 23.50,
22.97, 21.01, 19.23, 17.83, 14.54, 14.18, 12.69, 12.21, 11.50 ppm; IR
(KBr) nmax 3070, 2952, 1703, 1489, 1452, 1270 cmꢁ1; HRMS calcd for
C40H57NO4S4 m/z 743.3170, found 743.3176.
d
193.17, 172.77, 167.97, 164.86, 159.01, 155.14, 150.59, 149.21, 138.06,
136.91, 126.30, 124.26, 121.76, 120.25, 77.41, 75.43, 50.12, 48.97,
47.89, 47.49, 46.67, 45.78, 45.14, 41.83, 39.02, 35.62, 35.01, 34.82,
34.12, 32.15, 31.72, 31.69, 31.36, 30.04, 29.32, 29.28, 29.18, 29.15,
29.10, 27.72, 27.36, 26.99, 26.86, 26.57, 25.89, 25.32, 23.43, 22.88,
22.55,17.70, 14.02, 12.60, 12.17, 11.40; IR (KBr) nmax 3053, 2925,1716,
4.2.4.3. 12
[[[2,20-bithiophen]-5-yl]carboxy]-5
(silica gel, 20% ethyl acetate/hexane) Rf 0.49; 1H NMR (300 MHz,
CDCl3)
7.75(1H, d,J¼3.8 Hz,Th), 7.28(1H, d,J¼5.0 Hz, Th),7.26(1H, d,
J¼3.7 Hz, Th), 7.11 (1H, d, J¼3.8 Hz, Th), 7.03 (1H, dd, J¼5.0, 3.7 Hz, Th),
a
-[[[[(Diisobutylamino)thioxomethyl]thio]acetyl]oxy]-3
a
-
1639, 1462, 1271 cmꢁ1
986.6353, found 986.6370.
; HRMS calcd for C58H90N4O5S2 m/z
b-cholane (8b). Waxy liquid; TLC
d
4.2.5.2. 3
thioxomethyl]thio]acetyl]oxy]-N,N-dioctyl-5
Waxy liquid; TLC (silica gel, 30% ethyl acetate/hexane) Rf 0.22; 1H
NMR (400 MHz, CDCl3) 9.35–9.33 (1H, m, Py), 8.71–8.70 (1H, m,
Py), 8.51–8.47 (3H, m, Py), 7.84 (1H, td, J¼7.8, 1.8 Hz, Py), 7.35 (1H,
a
-[[[2,20-Bipyridin]-5-yl]carboxy]-12
-cholan-24-amide (9b).
a-[[[[(diisobutylamino)-
b
5.14 (1H, br s,12
b
-H), 4.98–4.85 (1H, m, 3
b
-H), 4.57 (1H, d, J¼16.5 Hz,
RSCH2CO2R0), 4.17 (1H, d, J¼16.5 Hz, RSCH2CO2R0), 3.92–3.76 (2H, m,
RCSN(CH2R0)2), 3.60 (2H, d, J¼7.5 Hz, RCSN(CH2R0)2), 2.52–2.32 (2H,
m, RCSN(CH2CHR02)2), 2.10–0.70 (50H, m); 13C NMR (75 MHz, CDCl3)
d
ddd, J¼7.7, 4.9, 1.2 Hz, Py), 5.15 (1H, br s, 12
b-H), 5.06–4.96 (1H, m,
d
194.97, 167.88, 161.69, 143.68, 136.52, 133.94, 132.60, 127.96, 125.72,
3b
-H), 4.57 (1H, d, J¼16.8 Hz, RSCH2CO2R0), 4.15 (1H, d, J¼16.8 Hz,
124.96, 123.73, 77.49, 75.23, 64.06, 61.05, 49.18, 47.49, 45.06, 41.87,
39.44, 38.06, 35.64, 34.95,34.85,34.18,34.10,32.17, 27.77, 27.42,26.93,
26.65, 26.26, 25.90, 25.37, 23.46, 22.91, 20.24,19.04,17.75,14.50,14.13,
12.19;IR (KBr)nmax 3070, 2957,1703,1456,1282 cmꢁ1; HRMS calcd for
C44H65NO4S4 m/z 799.3796, found 799.3819.
RSCH2CO2R0), 3.86–3.79 (2H, m, RCSN(CH2R0)2), 3.60–3.59 (2H, m,
RCSN(CH2R0)2), 3.34–3.18 (4H, m, RCON(CH2R0)2), 2.54–0.70 (79H,
m); 13C NMR (100 MHz, CDCl3)
d 194.76, 172.78, 167.95, 164.90,
159.98, 155.15, 150.65, 149.22, 138.09, 136.91, 126.28, 124.28, 121.74,
120.23, 77.41, 75.44, 64.12, 61.11, 49.05, 47.91, 47.53, 45.79, 45.11,
41.84, 39.24, 35.61, 34.95, 34.84, 34.15, 32.08, 31.74, 31.70, 31.36,
30.02, 29.34, 29.29, 29.19, 29.13, 27.78, 27.73, 27.28, 26.99, 26.88,
26.59, 26.19, 25.88, 25.35, 23.46, 22.89, 22.56, 20.32, 20.21, 17.71,
4.2.4.4. 12
[[(2,20-bithiophen)-5-yl]carboxy]-5
(silica gel, 20% ethyl acetate/hexane) Rf 0.49; 1H NMR (300 MHz,
CDCl3)
7.57 (1H, d, J¼3.9 Hz, Th), 7.49–7.23 (12H, m, Th and Ph),
7.08 (1H, d, J¼3.9 Hz, Th), 7.05 (1H, dd, J¼5.1, 3.7 Hz, Th), 5.12 (1H, br
a
-[[[[(Diphenylamino)thioxomethyl]thio]acetyl]oxy]-3
a-
b
-cholane (8c). Waxy liquid; TLC
14.05, 12.24; IR (KBr) nmax 3058, 2955, 1716, 1637, 1466, 1280 cmꢁ1
;
d
MS (FAB) m/z 1044 (Mþ), 781 (MꢁOCOCH2SC(S)N(i-C4H9)2), 580
(MꢁOCOCH2SC(S)N(i-C4H9)2, OCOC10H7N2).
s, 12
b
-H), 4.92–4.79 (1H, m,
3
b
-H), 4.44 (1H, d, J¼16.6 Hz,
RSCH2CO2R0), 4.10 (1H, d, J¼16.6 Hz, RSCH2CO2R0), 2.00–0.72 (38H,
4.2.5.3. 3
thioxomethyl]thio]acetyl]oxy]-N,N-dioctyl-5
Waxy liquid; TLC (silica gel, 30% ethyl acetate/hexane) Rf 0.22; 1H
NMR (400 MHz, CDCl3) 9.18–9.16 (1H, m, Py), 8.75–8.72 (1H, m,
a
-[[[2,20-Bipyridin]-5-yl]carboxy]-12
-cholan-24-amide (9c).
a-[[[[(diphenylamino)-
m); 13C NMR (75 MHz, CDCl3)
d
199.44, 167.42, 161.64, 143.64,
b
136.56, 134.01, 132.55, 129.47, 128.32, 128.04, 127.86, 125.76, 125.01,
123.78, 77.60, 75.07, 49.39, 47.65, 45.17, 41.79, 40.14, 38.05, 35.67,
35.04, 34.80, 34.19, 34.06, 32.11, 27.62, 26.92, 26.59, 26.01, 25.32,
23.56, 22.87, 19.13, 17.73, 14.50, 12.18; IR (KBr) nmax 3062, 2952,
1739, 1695, 1452, 1266 cmꢁ1; HRMS calcd for C48H57NO4S4 m/z
839.3170, found 839.3166.
d
Py), 8.51 (1H, d, J¼8.1 Hz, Py), 8.43 (1H, dd, J¼8.1, 0.7 Hz, Py), 8.29
(1H, dd, J¼7.9, 2.1 Hz, Py), 7.88 (1H, ddd, J¼7.9, 7.7, 1.8 Hz, Py), 7.45–
7.19 (11H, m, Py and Ph), 5.13 (1H, br s, 12b-H), 4.98–4.88 (1H, m, 3b-
H), 4.47 (1H, d, J¼16.8 Hz, RSCH2CO2R), 4.07 (1H, d, J¼16.8 Hz,
RSCH2CO2R), 3.35–3.01 (4H, m, RCON(CH2R0)2), 2.30–0.73 (65H, m);
4.2.5. General procedure for the preparation of 12
aryl)amino)thioxomethyl]thio]acetyl]oxy]-N,N-dioctyl-3
a
-[[[[(di(alkyl,
13C NMR (100 MHz, CDCl3)
d 199.29, 172.66, 167.46, 164.80, 158.89,
a
-[[[2,20-
155.27, 150.70, 149.28, 138.20, 137.00, 129.55, 127.85, 126.26, 124.30,
121.79, 120.26, 77.54, 75.20, 60.34, 49.40, 47.90, 47.56, 45.88, 45.27,
41.78, 39.84, 35.69, 34.80, 34.18, 34.14, 31.98, 31.78, 31.72, 31.25,
29.69, 29.39, 29.28, 29.22, 29.18, 29.08, 27.82, 27.48, 27.05, 26.93,
26.88, 26.50, 26.05, 25.31, 23.60, 22.84, 22.59, 17.71, 14.07, 12.24; IR
bipyridin]-5-yl]]carboxy]-5b-cholan-24-amides 9a–9c
[2,20-Bipyridine]-5-carboxylic acid (100 mg, 0.50 mmol) was
dissolved in thionyl chloride (5 mL, 68.85 mmol), which was stirred
for 3 h. The reaction mixture was evaporated in vacuo. 12a-

J.H. On et al. / Tetrahedron 65 (2009) 1415–1423
1423
(KBr) nmax 3057, 2923, 1714, 1638, 1590, 1491, 1279 cmꢁ1; MS (FAB)
m/z 1084 (Mþ), 781 (MꢁOCOCH2SC(S)N(C6H5)2), 580 (MꢁOCO
CH2SC(S)N(C6H5)2, OCOC10H7N2).
126.34, 124.34, 121.87, 120.34, 77.65, 75.29, 49.45, 47.69, 45.24,
41.85, 39.91, 38.09, 35.74, 35.03, 34.88, 34.26, 34.19, 32.04, 27.67,
26.99, 26.54, 26.07, 25.32, 23.63, 22.89, 19.07, 17.75, 14.56, 12.20; IR
(KBr) nmax 3066, 2956, 1713, 1587, 1281 cmꢁ1; HRMS calcd for
C50H59N3O4S2 m/z 829.3947, found 829.3954.
4.2.6. General procedure for the preparation of 12
aryl)amino)thioxomethyl]thio]acetyl]oxy]-3
-[[[2,20-bipyridin]-5-
yl]carboxy]-5
a-[[[[(di(alkyl,
a
b-cholanes 10a–10c
4.3. Preparation and evaluation of polymer membranes
[2,20-Bipyridine]-5-carboxylic acid (100 mg, 0.50 mmol) was
dissolved in thionyl chloride (5 mL, 68.85 mmol), which was stirred
The ion-selective membranes were prepared with 12 different
ionophores (composition of membrane cocktails: 2 mg of iono-
phore, 66 mg of PVC and 132 mg of plasticizer [DOA]). The cocktail
solutions dissolved in 1.0 mL THF were then poured into a glass ring
(i.d. 22 mm) placed on a slide glass and dried for a day at room
temperature. After curing, 5.5 mm-diameter disks were punched
out of the master membrane and placed in Philips electrode bodies
for 3 h. The reaction mixture was evaporated in vacuo. 12
a-
[[[[(Diethylamino)thioxomethyl]thio]acetyl]oxy]-3 -hydroxy-5 -chol-
a
b
ane (5a, 170 mg, 0.31 mmol) was dissolved in pyridine (10 mL) and
was added to the reaction mixture at 0 ꢀC, which was stirred for
12 h at reflux. The reaction mixture was filtered through a pad of
Celite (5 g). The Celite was washed with dichloromethane (200 mL)
and the combined filtrate and washings were collected and evap-
orated in vacuo. The residue was diluted with CH2Cl2 (150 mL),
extracted with saturated NaHCO3(aq) (2ꢂ150 mL), washed with 1 N
HCl (2ꢂ150 mL), washed with water (1ꢂ150 mL), dried over MgSO4,
and evaporated in vacuo. The crude was purified by chromatogra-
phy on silica gel with ethyl acetate/hexane (2:8) as an eluent to
yield 10a–10c as waxy liquids.
¨
(IS-561) (Glasbla¨serei MOller, Zu¨rich, Switzerland). The inner filling
solutions were 0.1 M KCl for evaluation of the ionophores. An Orion
(Cambridge, MA, USA) sleeve-type double-junction Ag/AgCl elec-
trode (Model 90–02) was used as the external reference. The po-
tential differences between the silver ISEs and the reference
electrode were measured using an IBM AT-type computer equipped
with a custom-built high-impedance input 16-channel analog-to-
digital converter. Beforebeing used, all electrodes werepresoaked in
0.01 M (or 0.001 M at times and deionized water) magnesium ace-
tate buffer (pH 4.5). Dynamic response curves and calibration plots
for transition metal ions in the 10ꢁ9 to 10ꢁ3 M range were obtained
by adding calculated volume of standard solutions stepwise to
200 mL of background electrolyte (0.01 M Magnesium acetate, pH
4.5) at room temperature. The solutions were magnetically stirred
during the recording of all potential measurement. The selectivity
coefficients were determined by using the matched potential
method;9–11 the concentration of the primary ion that brings about
the same response potential corresponding to 10ꢁ2 M interfering
ion was determined and their activities have been compared. The
detection limits of the electrodes were obtained from the calibration
curves, as described in the references.10,11
4.2.6.1. 3
thioxomethyl]thio]acetyl]oxy]-5
(silica gel, 20% ethyl acetate/hexane) Rf 0.20; 1H NMR (400 MHz,
CDCl3)
9.33 (1H, dd, J¼1.9, 1.1 Hz, Py), 8.72–8.68 (1H, m, Py), 8.51–
8.42(3H, m, Py), 7.84(1H, td, J¼7.7, 1.7 Hz, Py), 7.35(1H, ddd, J¼7.7, 4.9,
a
-[[[2,20-Bipyridin]-5-yl]carboxy]-12
-cholane (10a). Waxy liquid; TLC
a-[[[[(diethylamino)-
b
d
1.2 Hz, Py), 5.14 (1H, br s,12b-H), 5.08–4.96 (1H, m, 3b-H), 4.50 (1H, d,
J¼16.5 Hz, RSCH2CO2R0), 4.19 (1H, d, J¼16.5 Hz, RSCH2CO2R0), 4.15–
3.93 (2H, m, RCSN(CH2R0)2), 3.78 (2H, q, J¼7.1 Hz, RCSN(CH2R0)2),
2.17–0.73 (44H, m); 13C NMR (100 MHz, CDCl3)
d 193.31, 168.00,
164.91, 159.01, 155.18, 150.64, 149.23, 138.11, 136.94, 126.34, 124.29,
121.79, 120.27, 77.54, 75.48, 60.32, 50.13, 49.01, 47.57, 46.66, 45.09,
41.87, 39.11, 38.06, 35.66, 34.96, 34.85, 34.18, 34.16, 32.18, 27.46,
26.93, 26.59, 25.93, 25.34, 23.45, 22.92,19.15,17.77,14.50,14.14,12.61,
12.14, 11.43; IR (KBr) nmax 3057, 2926, 1715, 1636, 1269 cmꢁ1; HRMS
calcd for C42H59N3O4S2 m/z 733.3947, found 733.3919.
Acknowledgements
4.2.6.2. 3
thioxomethyl]thio]acetyl]oxy]-5
(silica gel, 20% ethyl acetate/hexane) Rf 0.20; 1H NMR (400 MHz,
CDCl3) 9.35–9.33 (1H, m, Py), 8.71–8.69 (1H, m, Py), 8.52–8.45 (3H,
m, Py), 7.84 (1H, td, J¼7.7, 1.7 Hz, Py), 7.35 (1H, ddd, J¼7.6, 4.8,1.1 Hz,
a
-[[[2,20-Bipyridin]-5-yl]carboxy]-12
-cholane (10b). Waxy liquid; TLC
a-[[[[(diisobutylamino)-
Financial supports from the RRC program of Ministry of Com-
merce, Industry & Energy and Kwangwoon University in the year
2008 are greatly acknowledged.
b
d
References and notes
Py), 5.13 (1H, br s, 12b-H), 5.08–4.97 (1H, m, 3b-H), 4.63 (1H, d,
J¼16.7 Hz, RSCH2CO2R0), 4.12 (1H, d, J¼16.7 Hz, RSCH2CO2R0), 3.90–
3.76 (2H, m, RCSN(CH2R0)2), 3.60 (2H, d, J¼7.3 Hz, RCSN(CH2R0)2),
2.55–2.30 (2H, m, RCSN(CH2CHR02)2), 2.18–0.69 (50H, m); 13C NMR
1. Lee, H. J.; Yoon, I. J.; Yoo, C. L.; Pyun, H.; Cha, G. S.; Nam, H. Anal. Chem. 2000, 72,
4694–4699.
2. Choi, Y. S.; Lvova, L.; Shin, J. H.; Oh, S. H.; Lee, C. S.; Kim, B. H.; Cha, G. S.; Nam, H.
Anal. Chem. 2002, 74, 2435–2440.
3. Lee, M. H.; Yoo, C. L.; Lee, J. S.; Cho, I. S.; Kim, B. H.; Cha, G. S.; Nam, H. Anal.
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4. Kim, B. H.; Lee, C. S.; Shim, J. H.; Hong, H. P.; Cha, G. S.; Jun, Y. M.; Nam, H.
Talanta 2003, 61, 393–401.
5. Shim, J. H.; Jeong, I. S.; Hong, H. P.; On, J. H.; Kim, K. S.; Kim, H. S.; Kim, B. H.;
Cha, G. S.; Nam, H. Talanta 2004, 63, 61–71.
6. Kim, B. H.; Hong, H. P.; Choi, K. T.; On, J. H.; Jun, Y. M.; Jeong, I. S.; Cha, G. S.;
Nam, H. Talanta 2005, 66, 794–804.
7. Forrepresentativeexamples, see: (a) Davis, A. P. Chem. Soc. Rev.1993, 243–253; (b)
Bonar-Law, R. P.; Sanders, J. K. M. J. Am. Chem. Soc. 1995, 117, 259–271; (c) Bonar-
Law, R. P.; Mackay, L. G.; Walter, C. J.; Marvaud, V.; Sanders, J. K. M. Pure Appl. Chem.
1994, 66, 803–810; (d) Maitra, U.; Balasubramanian, S. J. Chem. Soc., PerkinTrans.1
1995, 83–88; (e) Bonar-Law, R. P.; Sanders, J. K. M. J. Chem. Soc., PerkinTrans.11995,
3085–3096; (f) D’Souza, L. J.; Maitra, U. J. Org. Chem. 1996, 61, 9494–9502.
8. (a) Chung, S.; Kim, W.; Park, S. B.; Kim, D. Y.; Lee, S. S. Talanta 1997, 44, 1291–
1298; (b) Lee, S. S.; Ahn, M. K.; Park, S. B. Analyst 1998, 123, 383–386; (c) Kim,
H.-S.; Bae, S.-Y.; Kim, K. S.; Choi, J.-H.; Choi, H. J.; Shim, J. H.; Cha, G. S.; Nam, H.
Bull. Korean Chem. Soc. 2008, 29, 417–421.
(100 MHz, CDCl3)
d 194.94, 167.95, 164.39, 155.81, 153.14, 150.60,
147.16, 139.59, 138.88, 127.27, 125.02, 123.13, 121.47, 77.49, 75.85,
64.22, 61.14, 60.32, 49.12, 47.44, 45.04, 41.88, 39.27, 38.04, 35.63,
34.86, 34.16, 32.05, 27.77, 27.39, 26.93, 26.54, 26.24, 25.87, 25.35,
23.44, 22.89, 20.32, 20.21, 18.92, 17.75, 14.52, 14.12, 12.17; IR (KBr)
nmax 3052, 2956, 1715, 1594, 1280 cmꢁ1
C46H67N3O4S2 m/z 789.4573, found 789.4566.
; HRMS calcd for
4.2.6.3. 3
thioxomethyl]thio]acetyl]oxy]-5
(silica gel, 20% ethyl acetate/hexane) Rf 0.21; 1H NMR (400 MHz,
CDCl3) 9.19–9.17 (1H, m, Py), 8.77–8.70 (1H, m, Py), 8.52 (1H, d,
a
-[[[2,20-Bipyridin]-5-yl]carboxy]-12
-cholane (10c). Waxy liquid; TLC
a-[[[[(diphenylamino)-
b
d
J¼8.1 Hz, Py), 8.43 (1H, d, J¼8.1 Hz, Py), 8.29 (1H, dd, J¼8.0, 2.2 Hz,
Py), 7.87 (1H, ddd, J¼8.0, 7.7, 1.8 Hz, Py), 7.47–7.17 (11H, m, Py and
9. Gadzekpo, V. P. Y.; Christian, G. D. Anal. Chim. Acta 1984, 164, 279–282.
10. IUPAC recommendations for nomenclature of ion-selective electrodes,
Pure Appl. Chem. 1994, 66, 2527–2536.
Ph), 5.12 (1H, br s, 12b-H), 5.00–4.79 (1H, m, 3b-H), 4.50 (1H, d,
J¼16.8 Hz, RSCH2CO2R), 4.05 (1H, d, J¼16.8 Hz, RSCH2CO2R), 2.05–
0.70 (48H, m); 13C NMR (100 MHz, CDCl3)
199.49, 167.50, 164.87,
158.82, 155.28, 150.72, 149.26, 138.27, 137.08, 129.52, 128.37, 127.94,
d
11. IUPAC selectivity coefficients for ion-selective electrodes: recommended
POT
AB
methods for reporting K
values, Pure Appl. Chem. 1995, 67, 507–518.