Towards the Discrimination of Carboxylates by Hydrogen-Bond Donor Anion Receptors

DOI: 10.1002/chem.201405858

Full Paper

&

Carboxylate Receptors

Towards the Discrimination of Carboxylates by Hydrogen-Bond

Donor Anion Receptors

[

a]

[a]

[b]

[a]

Sandip A. Kadam, Kerli Martin, Kristjan Haav, Lauri Toom, Charly Mayeux,

[a]

[c]

Astrid Pung, Philip A. Gale, Jennifer R. Hiscock, Simon J. Brooks, Isabelle L. Kirby,

Nathalie Busschaert, and Ivo Leito*

[c]

[a]

Abstract: The binding constants (logK ) of small synthetic

anion. The higher is the basicity of the anion the stronger in

general is the binding, leading to the approximate order of

increasing binding strength, lactate<benzoate<acetateꢀ

trimethylacetate, which holds with all investigated receptors.

Nevertheless, there are a number of occasions when the

binding order changes with changing of the carboxylate

anion, sometimes quite substantially. Principal component

analysis (PCA) reveals that this is primarily connected to pref-

erential binding of trimethylacetate, supposedly caused by

an additional hydrophobic/solvophobic interaction. These

findings enable making better predictions, which receptor

framework or cavity is best suited for carboxylate anions in

receptor design.

ass

receptor molecules based on indolocarbazole, carbazole,

indole, urea and some others, as well as their combinations

were measured for small carboxylate anions of different ba-

sicity, hydrophilicity and steric demands, that is, trimethyla-

cetate, acetate, benzoate and lactate, in 0.5% H O/[D ]DMSO

2

6

by using the relative NMR-based measurement method. As

a result, four separate binding affinity scales (ladders) includ-

ing thirty-eight receptors were obtained with the scales

anchored to indolocarbazole. The results indicate that the

binding strength is largely, but not fully, determined by the

strength of the primary hydrogen-bonding interaction. The

latter in turn is largely determined by the basicity of the

[3]

[4]

Introduction

tions (e.g., sensors) or acting as anion transporters in mem-

branes is attracting intense current interest.

Carboxylates are among the most important anions in nature

Carboxylate anions have a distinct geometry with equal CO

[

1]

[5]

and in technology. Smaller carboxylates are important metab-

olites whereas carboxylic acids with long aliphatic chains are

crucial in the formation of fats. Amino acids are the key com-

ponents in the formation of peptides and proteins and many

widely used anti-inflammatory drugs such as aspirin and ibu-

bond lengths (1.26 ꢀ in acetate) and bond angles between

[5]

the CO bonds (close to 1208 in acetate) and a distance be-

[6]

tween the oxygen atoms around 2.2 ꢀ. The negative charge

of carboxylate ions is largely distributed between the two

oxygen atoms making these ions strongly solvated in hydro-

[

2]

[7]

profen are carboxylic acids. Between pH 7 and 8, that is,

under physiological conditions, carboxylic acids exist predomi-

nantly in their anionic form. For these reasons the synthesis of

receptors capable of binding carboxylates in analytical applica-

gen-bond-donating solvents, especially in water. Because car-

[8]

boxylic acids are quite strong acids in aqueous media they

are deprotonated quite readily, although the respective car-

boxylates are not protonated so easily. The geometry of car-

boxylates enables formation of hydrogen-bonded complexes

with chelating receptors of suitable geometry in 1:1 stoichiom-

etry. The alkyl or aryl moiety (often with substituents) of a car-

boxylate ion significantly modifies its properties (e.g., size, ba-

sicity and hydrophilicity) and forms the basis of differentiating

between different carboxylates.

[

a] S. A. Kadam, K. Martin, K. Haav, Dr. C. Mayeux, A. Pung, Prof. I. Leito

University of Tartu, Institute of Chemistry

Ravila 14a, 50411 Tartu (Estonia)

Phone: +372-51-84-176

E-mail: ivo.leito@ut.ee

[

b] Dr. L. Toom

Numerous synthetic receptor molecules have been pro-

posed for binding carboxylates. In 2005, Gale and co-workers

reported the anion-binding ability of acyclic receptors contain-

University of Tartu, Institute of Technology

Nooruse 1, 50411 Tartu (Estonia)

[

c] Prof. P. A. Gale, Dr. J. R. Hiscock, Dr. S. J. Brooks, Dr. I. L. Kirby,

Dr. N. Busschaert

[9,10]

ing ortho-phenylenediamine-based bis-urea units.

The four

Chemistry, University of Southampton

Southampton, SO17 1BJ (UK)

NH urea protons stabilise hydrogen-bond interactions with the

negatively charged oxygen atoms of the carboxylate, produc-

ing a complex through four hydrogen bonds with functional-

ised systems offering additional amide hydrogen-bond

Supporting information (containing the relative binding measurement spec-

1

tra ( H NMR and UV/Vis spectrophotometric), additional compound charac-

1

13

15

terisation data ( H, C and N NMR spectra, IR and HR MS data) of the

synthesised compounds) for this article is available on the WWW under

http://dx.doi.org/10.1002/chem.201405858.

[9,10]

donors.

Other similar structures have been reported, for ex-

[11]

ample, receptors based on 1,8-diaminocarbazole and 1,2-dia-

Chem. Eur. J. 2015, 21, 1 – 17

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[

12]

minoanthraquinone.

In 2005, Beer and co-workers intro-

duced indolo[2,3-a]carbazole as a useful binding fragment for

[

13]

anions, specifically for carboxylates.

The ultimate goal of synthetic carboxylate receptor research

would be developing receptor molecules that are strongly

binding and can discriminate between carboxylates with differ-

ent structures. Simple receptor molecules can be neither suffi-

ciently sensitive nor sufficiently selective to differentiate be-

tween different carboxylates as a simple receptor molecule will

interact first of all with the carboxylate centre and the binding

will be influenced by the rest of the ion through its influence

on the electron density of the carboxylate. Other interactions

will be limited by the small size of the receptor. Such small

molecules can, however, be regarded as building blocks of

more complex receptors. Understanding the relationship be-

tween molecular structures and the binding behaviour towards

different carboxylate anions is important for designing more

complex receptors.

Scheme 1. Structures of the investigated anions.

tors (number and positions of NH groups, locations of other

nearby groups, size of the binding cavity, etc).

ꢁ

The binding affinity of a receptor R towards an anion A to

ꢁ

form a receptor–anion complex RA according to a 1:1 stoichi-

ometry is quantified by the binding (association) constant K_a_s_s

according to the following equilibria [Eqs. (1) and (2)]; in Equa-

tion (2) a denotes the activities of the different species.

Kass

ꢁ

RþA !RA

ð1Þ

ð2Þ

In this work, four different small carboxylate anions of differ-

ent basicity, hydrophilicity and steric demand—acetate, trime-

thylacetate, benzoate and lactate (see Scheme 1)—were select-

ed for an experimental study of their binding to thirty-eight

different synthetic urea-, indole-, carbazole-, thiourea- and in-

dolocarbazole-based receptors (see Scheme 2) with the aim of

studying possible “embryonic” stereoselectivity of the recep-

tors towards selected anions and to discuss it in terms of

anion properties as well as structural parameters of the recep-

a

RAꢁ

K

¼

ass

^aR^a

A

ꢁ

The binding constant measurements are based on the rela-

tive measurement method recently introduced by our group

[14]

[15]

and applied both for UV/Vis

and NMR spectroscopy

as

techniques. The NMR version of this method enables the un-

precedented ability to differentiate between very close binding

constants, that is, logK_a_s_sdifferences of 0.05 are detectable. An

Scheme 2. Structures of the molecular receptors for which the logKass values were determined.

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additional advantage of the NMR measurement method is its

ability to simultaneously measure the binding of several differ-

ent receptors to the same anion. This relative NMR measure-

ment method is also used in this work and its abilities have

been better characterised than previously.

NMR spectra (see the Supporting Information). The binding af-

finities of all four anions towards thirty-eight receptors were

measured in [D ]DMSO/H O (99.5:0.5 m/m) by using the rela-

6

2

tive measurement method as previously reported for the ace-

[15]

tate anion. The binding constants of the receptors are pre-

sented in Table 1 and in the binding scales containing all rela-

tive measurement results in the Supporting Information.

Results

At low and moderate anion concentrations a 1:1 stoichiome-

^t^r^y^w^a^s^f^o^uⁿ^d^wⁱ^t^h^a^l^l^r^e^c^e^p^t^o^r^–^aⁿⁱ^oⁿ^p^aⁱ^r^s^.^T^h^e^l^o^g^Kass values

were calculated from the NMR titration data according to the

1:1 binding model [Eq. (1)] in the case of all receptors. In the

case of receptors 3–5 at higher anion concentration a 1:2 stoi-

chiometry (two anions bound to one receptor) was observed

as described in reference [10]. In the case of these receptors

only titration points with a low anion concentration were

taken into account where formation of the 1:2 complexes is

1

H NMR-based relative binding measurements

The compounds 1–47 were synthesised by methods that were

[

15]

used by our groups previously as described below. All the

relative NMR measurements were performed under the fast ex-

change conditions. On binding of the carboxylate anions to

form the receptor–anion complexes, complex formation is

easily identifiable through the shifts of the NH protons in the

[

a]

Table 1. Binding constants of the carboxylate anions in [D

6

]DMSO/H

2

O (99.5:0.5 m/m) at 258C.

Receptor

Lactate anion

Benzoate anion

Acetate anion

Trimethylacetate anion

[

b]

[c]

[b]

[c]

c

[b]

[c]

[b]

[c]

logKass

u

c

u

c

logKass

u

c

u

logKass

u

c

u

c

logKass

u

c

u

c

receptor 25

3.38

3.25

3.19

3.17

2.87

2.68

2.58

2.55

2.53

2.52

2.51

2.45

2.44

2.43

2.42

2.39

2.37

2.35

2.30

2.29

2.27

2.22

2.18

2.14

2.13

2.05

1.96

1.91

1.89

1.85

1.74

1.65

1.62

0.02

0.01

0.02

0.01

0.05

3.88

4.08

4.01

3.96

3.53

3.34

3.22

3.27

3.16

3.11

3.18

3.17

3.07

2.99

3.18

2.89

3.08

2.91

2.98

2.95

3.00

2.93

3.25

2.94

2.82

2.73

2.76

2.70

2.63

2.96

2.63

2.49

2.44

2.48

2.31

2.27

2.08

2.11

0.01

0.03

0.01

0.02

0.01

0.05

0.06

0.05

4.67

4.56

4.63

4.94

4.13

3.90

3.88

3.77

3.70

3.79

3.82

3.67

3.64

3.85

3.62

3.58

3.59

3.54

3.58

3.67

3.55

3.74

3.56

3.33

3.24

3.36

3.27

3.26

3.38

3.16

3.09

2.85

2.89

2.80

2.41

2.51

2.45

0.01

0.03

0.01

0.09

0.08

0.09

0.08

0.09

0.08

0.09

0.08

0.09

0.08

0.09

0.08

0.09

0.08

0.09

4.88

5.33

5.07

4.95

4.16

3.98

3.85

4.08

3.81

4.03

3.84

3.82

3.72

3.96

3.99

3.75

3.66

3.58

3.60

3.59

3.93

3.54

4.22

3.55

3.39

3.23

3.36

3.28

3.14

3.76

3.21

3.40

3.02

3.01

2.90

3.03

2.57

2.72

0.01

0.06

1

,3-dicarbazolylurea 29

,3-diindolylurea 30

receptor 26

receptor 45

1-(3-NO

2

-phenyl)-3-phenyl urea 8

4

-NO -indolocarbazole 35

2

receptor 5

,7-(BuOCO)

receptor 32

4

2

-indolocarbazole 42

2

,7-(BuOCO)

,9-(BuOCO)

,7-Cl -indolocarbazole 43

2

-indolocarbazole 41

-indolocarbazole 40

2

receptor 17

receptor 4

receptor 3

receptor 7

receptor 38

receptor 34

receptor 33

receptor 2

receptor 37

receptor 18

receptor 16

1,3-diphenylurea 46

receptor 10

receptor 14

indolocarbazole 39

2

2,9-(MeO) -indolocarbazole 44

receptor 24

receptor 13

receptor 31

1

-naphthalen-1-yl-3-phenyl-urea 47

-Cl-indolocarbazole 36

-benzyl-3-phenyl-thiourea 28

receptor 23

1-benzyl-3-phenyl-urea 27

1,3-di-naphthalen-1-yl-urea 19

[a] All logKass values correspond to Equation (1). The binding constant values of the acetate anion in the table are on an average by 0.13 log units higher

than the values previously published for the same receptors in reference [15], because a systematic mistake was found in the calculation of the anchor

point logKass values in reference [15] and those values were recalculated. [b] Standard uncertainties for comparing logKass values within the same scale.

[c] Standard uncertainties for comparing logKass values between different scales or with those from other research groups.

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negligible. In all cases the binding affinity was measured by

the chemical shift change induced by anion complexation

upon addition of anionic guests in the form of tetrabutylam-

the same anion) from the same set of solutions. In this work,

we were able to successfully measure simultaneously DlogK_a_s_s

values between up to six receptors in one solution (see the

[

15]

1

monium salts.

Supporting Information). Figure 1 shows the H NMR spectra of

The numbers of relative binding measurements carried out

were 77, 89, 47 and 86 with lactate, benzoate, acetate and tri-

methylacetate, respectively. The consistency parameters of the

resulting four binding scales are 0.01 log units, indicating ex-

cellent consistency. The logK_a_s_sranges of the receptors are the

following: lactate anion 1.76, benzoate anion 1.99, acetate

anion 2.53 and trimethylacetate anion 2.76 orders of magni-

tude. The scales are anchored to the absolute logK_a_s_svalues of

binding of the respective anions to indolocarbazole 39 (see

Table 2).

the measurement of DlogK_a_s_svalues between receptors 2, 29,

30 and 42 towards the benzoate anion. The differences of the

chemical shifts of the NH protons of the free receptor and the

receptor–anion complex are the following: receptor 2 (Dd=

1.49 and 1.06 ppm), receptor 29 (Dd=0.95 and 2.25 ppm), re-

ceptor 30 (Dd=0.99 and 2.14 ppm) and receptor 42 (Dd=

3.5 ppm). As expected from the structure, receptors 29 and 30

have significantly stronger binding affinities towards the ben-

zoate anion than the remaining receptors, due to the carba-

zole and indole rings. Overall, the binding affinity order for the

benzoate anion is 29>30>42>2.

The binding constant values of the acetate anion in Table 1

are on an average by 0.13 log units higher than the values pre-

viously published for the same receptors in reference [15], be-

cause a systematic mistake was found in the calculation of the

anchor point logK_a_s_svalues in reference [15] and those values

were recalculated. However, all relative binding affinities

remain the same. For compounds not included in this study

the logK_a_s_svalues from reference [15] can be corrected by

adding 0.13 log units.

Comparison with literature data

The binding affinities of receptors 29 and 30 towards the ace-

tate and benzoate anions in the same solvent have been pub-

[16,17]

4

lished

and were found to be “above 10 ”, which is in

agreement with our data. The logK_a_s_svalue in the same solvent

has also been published for receptor 3 with the acetate and

benzoate anions and values of 3.78 and 4.00, respectively,

With an NMR instrument of sufficient signal separation

[10]

(700 MHz in our case) it is possible to simultaneously measure

were obtained.

The logK_a_s_svalue for the acetate anion

the DlogK_a_s_svalues between a number of receptors (towards

agrees very well with our value, that is, 3.62. However, our

1

Figure 1. H NMR spectra of the relative binding affinity measurement between receptors 2, 29, 30 and 42 in [D

6

]DMSO/H

2

O (99.5:0.5 m/m) with the benzoate

anion. Titration proceeds from bottom to top. The bottom-most spectrum corresponds to a solution without titrant added.

&

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value of 2.89 for the benzoate anion is by an order of magni-

tude lower than that published in reference [10]. To some

extent, this discrepancy can be due to the different fitting

model used in reference [10], but this cannot explain the dif-

ference of one order of magnitude. The measurement of log

K_a_s_sbetween the benzoate anion and receptor 3 was carried

out separately by using the absolute UV/Vis method. The log

K_a_s_svalue obtained was 3.05, which agrees with the value ob-

tained from the relative measurement.

mations (i.e., syn–syn, syn–anti and anti–anti). In the absence of

anion, the receptor is in the anti–anti conformation and in the

presence of an anionic guest the complex adopts the syn–syn

conformation.

Receptor 29 enables naked-eye detection of carboxylates:

the colour of a solution in [D ]DMSO/H O (99.5:0.5 m/m)

6

2

changes from colourless to light pink with all carboxylate

anions. An especially strong colour is observed upon addition

of the trimethylacetate anion.

1

A separate H NMR titration of receptors 29 and 30 with the

In relative binding measurement experiments some minor

aromatic proton interactions in receptors 7, 8, 10, 18, 19 and

47 with all the carboxylate anions were observed (see the Sup-

porting Information), resulting in Dd values being mostly in

the range of 0.2–0.3 ppm.

trimethylacetate anion was carried out and found that in both

cases there is a hydrogen-bonding interaction in the receptor–

anion complex between the H-3 proton as demonstrated both

by NMR data and COSMO-RS calculations (see Figures 2 as well

as S271, S301 and S302 in the Supporting Information) and the

carbonyl oxygen atoms of the receptor. According to Figure 2,

the H-3 protons are deshielded during the addition of the tri-

methylacetate anion (almost Dd=0.80 ppm deshielding

effect). The effect is caused by 1) favourable orientation of the

H-3 proton near the carbonyl oxygen atoms in the complex

and 2) the increased negative partial charge on the carbonyl

oxygen atoms in the receptor–anion complex. Similar, but

weaker, effects were observed with other carboxylate anions.

According to COSMO-RS calculations both free receptors are

preferably in conformations where the indole/carbazole NH

bonds are turned towards the carbonyl oxygen atoms (anti–

anti conformation, see Figures S301 and S302 in the Support-

ing Information)

Absolute binding measurements

The absolute logK_a_s_svalues with all investigated anions were

measured with the unsubstituted indolocarbazole 39. For each

anion the logK_a_s_svalue was measured on at least two different

days. The logK_a_s_svalue for receptor 39 with the lactate anion

was obtained by using the UV/Vis method, the logK_a_s_svalue

with the benzoate anion was obtained by using NMR, UV/Vis

and fluorescence methods and the logK_a_s_svalues with the ace-

tate and trimethylacetate anions were obtained by using the

NMR and UV/Vis methods. Several independent datasets were

obtained on each day and for each of the data sets three cal-

culation procedures were applied (see Refs. [14] and [15] for

details). The results of the measurements are presented in

Table 2.

A similar hydrogen-bond interaction has been observed in

reference [18] for the acetate and benzoate anions, where it

was demonstrated that receptor 30 has three possible confor-

1

Figure 2. H NMR spectra of the titration of receptor 30 in [D

6

]DMSO/H

2

O (99.5:0.5 m/m) with the trimethylacetate anion. Titration proceeds from bottom to

top. The bottom-most spectrum corresponds to a solution without titrant added.

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weakest one of the four towards the acetate anion. Compound

Table 2. Results of absolute logKass value measurements with indolocar-

bazole 39 in [D ]DMSO/H O (99.5:0.5 m/m).

6 2

29 has a very high binding affinity difference between the tri-

methylacetate and acetate anions (DlogK_a_s_s0.77), whereas the

same difference in the case of receptor 26 is only 0.01. Recep-

tor 30 is similar to compound 29, but binds all anions except

acetate weaker than receptor 29.

[

b]

[b]

Anion

Method

UV/Vis

Absolute S

logKass

N

Assigned CI

[

a]

[c]

logKass

(95%)

lactate anion

2.14

0.07 5 2.14

0.09

0.08

Based on the binding data and the computational geome-

tries of the receptors and the complexes the reason for these

differences (especially those between receptors 29 and 26)

seems to be that compound 29 forms a suitable cavity for ac-

commodating the trimethylacetate anion and partial shielding

of its hydrophobic moiety from the polar solvent without in-

troducing significant steric strain (see Figure S301 in the Sup-

porting Information). The cavity formed by receptor 26 (Fig-

ure S300 in the Supporting Information) is smaller and is

crowded by substituents. This hinders binding of the trimethy-

lacetate anion and introduces a significant steric strain (Fig-

ure S300 in the Supporting Information), whereas the acetate

anion fits better with receptor 26 because of its small size (Fig-

ure S300 in the Supporting Information).

benzoate anion

UV/Vis

NMR

fluorescence 2.66

2.71

2.79

0.01 2 2.7

0.01 2

0.02 2

acetate anion

UV/Vis

NMR

3.33

3.17

0.02 5 3.27

0.25 4

0.13

trimethylacetate

anion

UV/Vis

NMR

3.35

3.16

0.02 3 3.28

0.06 2

[

a] Average logKass values from the different techniques. Acetate anion

values were taken from reference [15], the remaining values are from this

work. [b] Standard deviation of values from independent experiments

and numbers of independent experiments (on different days). [c] As-

signed logKass values and 95% confidence intervals of the assigned

values.

The preferential binding of trimethylacetate with respect to

acetate was also observed with receptors 18, 23, 24, 31 and

Discussion

32 and somewhat weaker with compound 3–5. The receptors

3 and 24 from the family of the 1,8-disubstituted carbazoles,

2

Selectivity toward carboxylate anions

but also receptors 18, 4 and 5 have bulky and hydrophobic

substituents, which can be oriented around the large hydro-

phobic moieties of the trimethylacetate anion and also the

benzoate anion in such a way that hydrophobic/solvophobic

interactions can take place (but at the same time no steric hin-

drance is introduced), differently from acetate and lactate,

which lack such hydrophobic moieties. The data of receptors

23 and 24 support this: they bind relatively stronger to the tri-

methylacetate (logK_a_s_s3.03 and 3.76, respectively) and ben-

zoate anions (logK_a_s_s2.27 and 2.96, respectively) and relatively

weaker to the acetate (logK_a_s_s2.41 and 3.38, respectively) and

lactate (log K_a_s_s1.65 and 2.05, respectively) anions (Figure 3).

The remaining receptors seem to bind preferentially the trime-

thylacetate anion but not to the benzoate anion.

Table 1 and Figure 3 indicate that the binding affinity in broad

terms follows the order of anion basicity, that is, trimethylace-

tateꢂacetate>benzoate>lactate. The aqueous pK values of

a

[19]

the respective acids are 5.01, 4.76, 4.20 and 3.86, respectively

(

the higher the pK value, the higher the basicity). Neverthe-

a

less, there are numerous smaller differences between the bind-

ing orders, which were revealed thanks to the high precision

of the NMR-based relative binding measurement method.

The most pronounced binding order changes are observed

between the acetate and trimethylacetate anions. With most

indolocarbazoles and receptor 26 the logK_a_s_svalues for the

acetate and trimethylacetate anions are similar. At the same

time, with most urea- or amidocarbazole-based receptors the

trimethylacetate anion binds more strongly than the other

anions. The strongest carboxylate binders out of the studied

receptors are receptors 25, 26, 29 and 30 (different anions

having different binding orders). Their strong binding is

caused by numerous suitably located hydrogen-bond donor

sites leading to tetradentate binding and a suitable size of the

pocket for fitting the anion, so that a nearly planar structure

with little steric strain is formed, as is indicated by the compu-

tational geometries (see Figures S299–S302 in the Supporting

Information). In Figure 3, receptor 25 has a relatively high

binding affinity towards the lactate anion and an intermediate

affinity towards the acetate anion but in the case of the ben-

zoate and trimethylacetate anions it has relatively the lowest

binding affinity of the other three receptors. Out of these four

receptors, compound 26 has the highest binding affinity to-

wards the acetate anion and the lowest affinity towards the

lactate anion and an intermediate affinity towards the ben-

zoate and trimethylacetate anions. Receptor 29 is the strongest

binder of the benzoate and trimethylacetate anions but is the

Figure 3 also implies that some indolocarbazole-based re-

ceptors (i.e., compounds 35 and 44) might bind the acetate

anion stronger than the trimethylacetate anion. However, the

uncertainties of the anchor compound logK_a_s_svalues are of the

same order of magnitude as the differences, so it is impossible

to claim this.

The phenyl- and/or naphthyl-substituted urea-based recep-

tors 46, 47 and 19 bind carboxylate ions distinctly weaker than

the related indole- or carbazole-substituted receptors 26, 29

and 30 and the more naphthyl groups are present the weaker

is the binding. Naphthyl rings are more electronegative than

phenyl rings and the positive polarisation of the NH hydrogen

atoms increases on sequential replacement of phenyl rings by

naphthyl rings. Nevertheless, the binding affinity towards all

four anions decreases on this replacement. With the addition

of each naphthyl ring the binding affinity decreases by around

0.2–0.5 log units. Examining the computational results sheds

light on these results. Binding of the anions to receptor 46

does not introduce significant steric strain (see Figure 305 in

&

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Figure 3. Trends of the binding constant changes with the trimethylacetate, acetate, benzoate and lactate anion and different families of receptors in

[D

6

]DMSO/H

2

O (99.5:0.5 m/m).

Chem. Eur. J. 2015, 21, 1 – 17

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7

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&

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the Supporting Information) but is only bidentate, thus it

forms a distinctly weaker complex than in the cases of com-

pounds 26, 29 and 30. Each of the naphthyl rings when intro-

duced to receptor 46, makes the binding less favourable. In

contradistinction to the indolyl or carbazolyl groups, the naph-

thyl groups are unable to contribute additional hydrogen

bonds (which would not be completely uncommon even for

the one found in bis-indolyl or bis-carbazolyl ureas, for ex-

ample, in receptors 26, 29 and 30.

3) The ortho-phenylenediamine-bis-urea receptors, although

also featuring four or six hydrogen-bond donor fragments

form weaker complexes, because of an unsuitable spatial

arrangement of the NH groups (see for example, Figur-

es S291–294 in the Supporting Information).

[

20,21]

CH groups)

but are pushed out of the urea plane by the

4) Carbazole-based tridentate receptors are inferior to the tet-

radentate systems and lead to asymmetrical binding of the

anions, which is not optimal from the point of view of

forming hydrogen bonds (see Figures S297–299 in the Sup-

porting Information).

anions, thus creating a significant steric strain (see Figur-

es S295 and S296 in the Supporting Information). The steric

effect is caused first of all by the oxygen atoms of the carboxyl

group. This explains the lack of sensitivity towards the anion

size.

5) Bidentate diphenylurea and indolocarbazole centres have

similar efficiency in binding carboxylate anions. This is

caused by a trade-off between two factors, firstly, dipheny-

lurea has a lower hydrogen-bond donicity because of

A different picture is observed for the receptor pair 32 and

18. Here, receptor 18, containing naphthyl rings, shows higher

binding affinity towards the benzoate, acetate and trimethyl-

acetate anions and lower binding affinity towards the lactate

anion. The computations (Figures S303 and S295 in the Sup-

porting Information) show that these receptors are significantly

strained before anion binding and that the anions are bound

in such a way as not to cause additional disturbance of the

naphthyl rings.

a lower acidity of the NH protons (pK values in DMSO for

a

indole, carbazole and urea are 20.95, 19.9, 26.95, respective-

[25]

ly, the acidity of indolocarbazole is expected to be in the

range of indole and carbazole), but the bond angle in hy-

drogen-bond formation is more suitable and the respective

urea is able to produce an eight-membered ring with two

almost parallel individual hydrogen bonds. Secondly, the

NH sites in the indolocarbazole are less suitably spatially

oriented but have higher hydrogen-bond donicity due to

higher acidity of the NH protons.

The above discussion of binding orders of the anions to the

receptors was done in terms of logK_a_s_svalues, molecular struc-

tures (of the receptors and receptor–anion complexes) as well

as solvation effects. The binding orders are defined in terms of

logK_a_s_svalues, relating them to free energy changes (DG ) on

ass

binding. This way of data analysis does not enable separating

the DG_a_s_svalues into enthalpy (DH ) and entropy (TDS ) com-

ass

Principal component analysis of the obtained data

ponents. Although in the majority of cases the enthalpy term

governs the binding processes, it is increasingly realised that

sometimes the entropy term can play a major (even decisive)

Principal component analysis (PCA) was performed on the

binding constant data to further assess the differences be-

tween the studied receptors in their selectivity patterns to-

wards the selected carboxylate anions, that is, the possibility of

finding receptors able to differentiate between the carboxylate

anions. This kind of multivariate analysis of data from

a number of receptors is the basis of achieving selectivity by

[

22–24]

role.

This is true first of all in structured solvents especially

in water. Our experimental protocol does not enable the deter-

mination of enthalpy and entropy contributions without a very

large additional experimental effort but for getting the infor-

mation about general trends between binding and molecular

structures of receptors and anions the DG_a_s_svalue (actually log

K_a_s_s) is sufficient and it is not inevitable to determine the DH_a_s_s

and TDS_a_s_sterms, especially considering that in our case the

content of water in the solvent is only 0.5%. The general con-

clusions on the binding ability of different receptors towards

carboxylate anions presented below are based only on the log

K_a_s_sdata:

[25]

receptor arrays, where none of the individual receptors by

themselves are selective enough.

The plot of scores of different receptors according to the

PC1 and PC2 is presented in Figure 4. PC1 describes 97% of

the variance. The axes of the binding constants of all four

anions are quite well aligned with PC1, so PC1 shows the gen-

eral binding affinity of the receptors towards the carboxylate

anions. The receptors having the highest binding affinities are

positioned to the left-hand side of the plot. PC2 describes 2%

of the variance. Looking at the axes of the binding constants

of the anions indicates that PC2 characterises the selectivity

between large hydrophobic and small hydrophilic ions. Recep-

tors that have a (relatively) lower affinity towards the acetate

and lactate anions and a relatively higher affinity towards the

trimethylacetate and benzoate anions are positioned in the

upper part of the plot. The plot also reveals that the selected

receptors are almost incapable of differentiating between the

acetate and lactate anions.

1

) The main factors determining the binding efficiency are the

number of hydrogen-bond donor sites, their donicity, their

mutual position and the possible steric crowding around

the binding sites. In many cases the hydrogen-bond donici-

ty and the steric crowding are mutually competitive. Not

only is it important to have multiple hydrogen-bond donor

sites but it is also crucial whether they are suitably posi-

tioned so that all of them can produce hydrogen bonds

with the anion of interest.

2

) A tetradentate system of four suitably located NH centres

seems (out of the studied systems) to be the most success-

ful combination for binding carboxylate anions, especially

Four groups of receptors emerge on the plot: 1) receptors

25, 26, 29 and 30, which are the strongest binders, 2) recep-

&

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Full Paper

ylate anions. The results of this work help in predicting, which

binding moieties are most suitable to be used for the con-

struction of synthetic receptors for carboxylate anions.

Experimental Section

Instruments and methods: NMR measurements were carried out

on a 200 MHz NMR Bruker Avance II 200 NMR spectrometer or

a 700 MHz NMR Bruker Avance II 700 NMR spectrometer. UV/Vis

spectrophotometric measurements were carried out by using

a Thermo Nicolet Evolution 300 spectrophotometer and fluores-

cence spectrofluorometric measurements were carried out by

using a Horiba FluoroMax-4 spectrofluorometer. All receptor mole-

cules were characterised on a 400 MHz Bruker Avance II 400 NMR

spectrometer of a 700 MHz NMR Bruker Avance II 700 NMR spec-

trometer. The water content of the DMSO solvent was checked

with a Mettler Toledo DL 32 titrator. Melting points were deter-

mined in open capillaries and are uncorrected. COSMO-RS calcula-

tions were done by using COSMOthermX version C30_1401 para-

[26]

Figure 4. PCA plot of the binding constant data. Scores of PC2 versus scores

metrisation BP_TZVP_C30_1401, solvent DMSO with 0.5% water.

of PC1.

We used only the geometries from the COSMO-RS calculations for

discussions because it has been demonstrated that the ability of

COSMO-RS to reproduce experimental energetics of hydrogen-

[26]

tors 18, 23, 24 and 31, which have relatively the strongest af-

finity towards the trimethylacetate anion, supposedly made

possible by hydrophobic/solvophobic interaction, 3) receptors

bond formation is insufficient. ATR-IR spectra were recorded on

a Thermo Electron Nicolet 6700 FTIR device by using a micro-ATR

[27]

accessory with a diamond crystal. The spectrometer had a DTGS

CsI detector and a CsI beamsplitter. About 128 scans were record-

2

, 4, 5, 17 and 32, which are all based on combining two urea

ꢁ1

ed over the range of n˜ =400–4000 cm . High-resolution mass

spectra were obtained on a Varian (now Agilent) 930 FT-ICR mass

spectrometer equipped with a 7 T superconducting magnet and an

IonSpec Omega data system, by using electrospray ionisation (ESI)

moieties through an 1,2-phenylene fragment and can also pos-

sibly have some solvophobic interaction and 4) all other recep-

tors, which seem to bind anions mostly by hydrogen bonding,

without significant involvement of other interactions. Examin-

ing the PCA plot together with the structural features can be

of help in picking molecular fragments for designing new re-

ceptors.

[

28]

or matrix-assisted laser desorption/ionisation (MALDI).

In the

case of the ESI source the ionisation chamber temperature was

408C, the spray needle voltage was set to ꢁ3000 V, the shield volt-

age was set to ꢁ300 V, the nebulising gas (N ) pressure was set to

2

1

5 psi, the drying gas (N ) pressure was set to 10 psi at 2008C. The

2

ion optic was optimised for every compound infused. In the case

of the MALDI source positive ions were generated from a target

obtained by evaporation under vacuum of a DMSO/iPrOH solution

of the studied compound/2,5-dihydroxybenzoic mixture deposited

as a thin layer on a MALDI target plate. The samples for the HR-MS

were dissolved in DMSO/iPrOH solution (10:90 mL) leading to

Conclusions

We have reported a series of anion receptors from different

compound families, including indolocarbazole, carbazole,

indole, urea, thiourea and amide moieties. The binding affini-

ties (expressed as logK_a_s_svalues) of receptors described in this

work were measured with the trimethylacetate, acetate, ben-

zoate and lactate anions.

ꢁ

1

a stock solution with a concentration of 20 mgmL . An aliquot

1 mL) was dissolved a) in iPrOH (1 mL) and infused (ESI) with

(

ꢁ1

a flow rate of 3 mLmin or b) in a 0.1 molL solution of 2,5-dihy-

droxybenzoic acid in iPrOH (for details see the Supporting Informa-

tion). Purification of the compounds was performed by column

chromatography on silica gel (pore size 60 ꢀ, 230–400 mesh). Ana-

lytical thin-layer chromatography (TLC) was conducted on TLC

plates (silica gel 60 with fluorescent UV₂₅₄marker on aluminium

sheets).

It is evident that binding of the carboxylate anions to the in-

vestigated receptors is primarily determined by the basicity of

the anion and the binding affinity follows the approximate

order: lactate<benzoate<acetateꢀtrimethylacetate. The

reason for this is that the binding is predominantly determined

by hydrogen-bonding interactions. Tetradentate receptors with

planar structures seem to be one of the most suitable. The car-

boxylate anions also have planar structures and can form two

bifurcated hydrogen bonds with tetradentate receptors. How-

ever, other important factors to consider are the size and the

geometry of the anion and the receptors as well as hydropho-

bic interactions and steric demands. The addition of functional

groups can introduce additional interactions between the re-

ceptor and the anion. PCA analysis indicates that the studied

receptors can only weakly differentiate between small carbox-

Solvents and chemicals: The solvent for the binding measure-

ments (DMSO with 0.5% of water) was prepared by using anhy-

drous DMSO 99.9% (for UV/Vis and fluorescence measurements) or

[

D ]DMSO 99.8% (for NMR measurements) and water from a MilliQ

6

Advantage A10 system. The final water content of the solvent was

checked with a Karl–Fischer titration and was mostly between 0.48

and 0.52% and always between 0.45 and 0.55%. Titrant solutions

were prepared from tetrabutylammonium acetate and tetrabuty-

lammonium benzoate (99% Sigma–Aldrich). The solvent for the

synthesis, THF (Romil, 99.9%, water content less than 5 ppm, ac-

cording to Karl–Fisher titration), was additionally dried by means of

Chem. Eur. J. 2015, 21, 1 – 17

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9

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&

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Full Paper

continuous circulation through

a column filled with alumina and

was delivered inside a glovebox.

Dichloromethane and DMF were

dried as described in refer-

ence [29].

Synthesis of the different recep-

tor families: The ortho-phenyle-

nediamine-urea-type receptors 1–

5

have been prepared from ortho-

phenylenediamine coupled with

-nitrophenylisocyanate to form

2

compound 1, which was reduced

with 10% Pd/C and hydrazine hy-

drate in ethanol to form com-

pound

2 (Schemes 3a–i). Com-

pound 2 was coupled with lauric

acid, benzoic acid or 3-phenylpro-

panoic acid by using N’-(3-dime-

thylaminopropyl)-N-ethylcarbo-

diimde (EDC·HCl), 4-dimethylami-

nopyridine (DMAP) and 1-hydrox-

ybenzotriazole (HOBt) in dry DMF

to form compounds 3–5. Com-

pound 7 was prepared from 3-

amino-benzoic acid by reacting

with phenyl isocyanate to get

compound 6, which in turn was

coupled with substituted pyridine

by using diethyl azodicarboxylate

(

DEAD)/PPh to get compound 7.

3

Compound 10 was prepared from

compound 8 (obtained as de-

scribed in reference [15]) reduced

with 10% Pd/C and the hydrazine

hydrate 9 and coupled with meth-

acrylic acid to form compound

1

0. The substituted indolocarba-

zole 13 was prepared from com-

pound 11 (obtained as described

in reference [14]), which was

transferred to compound 12 and

then demethylated in BBr (1m in

3

dry DCM). Compound 14 was pre-

pared by reacting compound 13

with tert-butoxycarbonyl (Boc) an-

hydride. Compound 16 was pre-

pared from compound 15 (pre-

pared as described in refer-

ence [15]) coupled with 3-bromo-

propan-1-ol by using K CO in dry

2

3

[15]

DMF.

prepared from 4-methylbenzene-

,2-diamine, ortho-phenylenedia-

Compounds 17–19 were

1

mine and 1-aminonaphthalene

with phenylisocyanate and 1-

naphthyl isocyanate in dichloro-

methane. Compounds 20–22

were prepared by following pub-

[30,31]

lished methods.

3 was prepared by Boc-protec-

tion of compound 22. Compound

4 was prepared from compound

Compound

2

Scheme 3. Synthesis of different substituted indolocarbazole-, urea- and carbazole-based receptors.

&

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2

2 coupled with 1-pyrenebutyric acid by using EDC·HCl, HOBt and

amide), 8.60 (brs, 2H; 1,2-(NH) -C H ), 8.43 (brs, 2H; 2’-NH-C H ),

2

6

4

6

4

3

4

DMAP and compound 25 was prepared from compound 22 cou-

pled with 1-naphthyl isocyanate in acetonitrile. The following re-

ceptors were synthesised as described in literature: 26, 27,

8.00 (m, 4H; CH-2,6_C₆_H₅), 7.79 (ddm, J(H,H)=8.2, J(H,H)=1.5 Hz,

2H; CH-3’_C₆_H₄), 7.58 (m, 2H; CH-4_C₆_H₅), 7.54 (AA’ of AA’XX’, 2H; CH-

[31]

[32]

3

4

3,6_C₆_H₄), 7.51 (m, 4H; CH-3,5_C₆_H₅), 7.41 (ddm, J(H,H)=7.9, J(H,H)=

[

33]

[16]

[17]

[12]

[14,15]

3

2

8, 29, 30, 31 and 32–47.

Preparation of compound 1: ortho-Phenylenediamine (0.20 g,

.85 mmol) was dissolved in dry dichloromethane (60 mL) then 2-

1.6 Hz, 2H; CH-6’_C₆_H₄), 7.20 (ddd, J(H,H)=8.2, J(H,H)=7.4,

4

3

J(H,H)=1.6 Hz, 2H; CH-4’_C₆_H₄), 7.09 (ddd, J(H,H)=7.9, J(H,H)=7.4,

J(H,H)=1.5 Hz, 2H; CH-5’_C₆_H₄), 7.04 ppm (XX’ of AA’XX’, 2H; CH-

4

1

13

4

,5_C₆_H₄); C NMR (176.0 MHz, [D ]DMSO, +208C): d=165.6 (CO-

6

nitrophenylisocyanate (0.67 g, 4.07 mmol) was added drop-wise

through a syringe. During the addition a precipitate was formed.

The reaction mixture was stirred at reflux temperature for 18 h.

The reaction was monitored by TLC. After completion of the reac-

tion the mixture was cooled to room temperature, filtered and the

obtained solid was washed with diethyl ether (50 mL) to get com-

amide), 153.8 (NH-CO-NH), 134.2 (C-1_C₆_H₅), 134.1 (C-2’_C₆_H₄), 131.8

CH-4_C₆_H₅), 131.1 (C-1,2_C₆_H₄), 128.48 (C-1’_C₆_H₄), 128.45 (CH-3,5_C₆_H₅),

(

1

27.8 (CH-2,6_C₆_H₅), 127.1 (CH-6’_C₆_H₄), 126.2 (CH-4’_C₆_H₄), 124.12 (CH-

,6_C₆_H₄), 124.06 (CH-4,5_C₆_H₄), 123.0 (CH-5’_C₆_H₄), 122.4 ppm (CH-3’_C₆_H₄);

3

15

N NMR (40.6 MHz, [D ]DMSO, +258C): d=120.95 (NH-amide),

6

1

02.86 (2’-NH-C H ), 100.71 ppm (1,2-(NH) -C H ); IR (ATR-FTIRS):

6

4

2

6

4

pound 1 (0.70 g, 1.60 mmol, 87.5%) as a light-yellow solid. M.p.

ꢁ1

1

n˜ =3276, 3250, 3060, 3026, 1650, 1595, 1507, 1291, 748, 696 cm

MALDI FTICR (solvent ꢃ0.01% DMSO/iPrOH): m/z calcd for

[C H N O +Na] : 607.20643 [M+Na] ; found: 607.20567.

;

2

20.78C; R =0.78 (10% methanol in dichloromethane); H NMR

f

(

700.1 MHz, [D ]DMSO, +208C): d=9.74 (brs, 2H), 9.17 (brs, 2H),

6

+

3

4

5

34

28

6

4

8

.24 (ddd, J(H,H)=8.5, J(H,H)=1.3, J(H,H)=0.4 Hz, 2H), 8.07

3

4

5

(

ddd, J(H,H)=8.4, J(H,H)=1.6, J(H,H)=0.4 Hz, 2H), 7.69 (ddd,

J(H,H)=8.5, J(H,H)=7.2, J(H,H)=1.6 Hz, 2H), 7.60 (AA’ of AA’XX’,

Preparation of compound 4: Compound 2 (0.14 g, 0.37 mmol),

EDC·HCl (0.21 g, 1.12 mmol), DMAP (0.14 g, 1.12 mmol), HOBt

3

4

3

4

2

7

H), 7.21 (ddd, J(H,H)=8.4, J(H,H)=7.2, J(H,H)=1.3 Hz, 2H),

(0.15 g, 1.12 mmol) and 3-phenylpropionic acid (0.17 g, 1.12 mmol)

13

.14 ppm (XX’ of AA’XX’, 2H); C NMR (176.0 MHz, [D ]DMSO,

6

were dissolved in dry DMF (5 mL). The reaction mixture was stirred

at room temperature for 60 h. The reaction was monitored by TLC.

After completion of the reaction (determined by disappearance of

the starting material and intermediate from TLC) the mixture was

quenched with water (100 mL). The formed precipitate was filtered,

washed with methanol (40 mL), dichloromethane (30 mL) and di-

ethyl ether (30 mL) to give compound 4 (0.15 g, 0.23 mmol, 63.2%)

+

208C): d=152.6, 138.1, 134.9, 134.7, 130.9, 125.4, 124.6, 124.5,

1

7

23.0, 122.5 ppm; IR (ATR-FTIRS): n˜ =3276, 1650, 1492, 1338, 1278,

32 cm ; MALDI FTICR: (solvent ꢃ0.01% DMSO/iPrOH): m/z calcd

ꢁ1

+

for [C H N O +Na] : 459.10235 [M+Na] ; found: 459.10268.

2

0

16

6

Preparation of compound 2: 10% Pd/C (0.04 g) and hydrazine

monohydrate (1.0 mL) were added to a stirring suspension of com-

pound 1 (0.55 g, 1.26 mmol) in ethanol (100 mL) and the reaction

mixture was heated to reflux for 24 h under nitrogen atmosphere.

The mixture was then allowed to cool to room temperature and

the resulting product (white precipitate) and Pd/C was removed by

using filtration. The product was re-dissolved in DMF (30 mL) and

as an off-white solid. M.p. 188.2–189.48C; R =0.47 (10% methanol

f

1

in dichloromethane); H NMR (700.1 MHz, [D ]DMSO, +208C): d=

6

9

2

3

7

.55 (brs, 2H; NH-amide), 8.55 (brs, 2H; 1,2-(NH) -C H ), 8.25 (brs,

2 6 4

3

4

H; 2’-NH-C H ), 7.73 (ddm, J(H,H)=8.2, J(H,H)=1.4 Hz, 2H; CH-

6

4

^’C6H4⁾^,⁷^.⁵⁷⁽^A^A^’^o^f^A^A^’^X^X^’^,²^H^;^C^H^-³^,⁶C6H4⁾^,⁷^.²⁷⁽^m^,⁴^H^;^C^H^-³^,⁵C6H5),

.23 (m, 2H; CH-6’ ), 7.23 (m, 4H; CH-2,6C6H5⁾^,⁷^.¹⁸⁽^m^,²^H^;^C^H^-

filtered to remove Pd/C. The DMF solution was quenched with H O

C6H4

2

3

4

⁴C6H5), 7.11 (ddd, J(H,H)=8.2, J(H,H)=7.4, J(H,H)=1.6 Hz, 2H; CH-

(

100 mL) to obtain the crude compound 2 as a white precipitate.

3

4

^’C6H4), 7.09 (XX’ of AA’XX’, 2H; CH-4,5 ), 7.01 (ddd, J(H,H)=7.9,

The product was removed by using filtration and washed with H O

C6H4

2

3

4

J(H,H)=7.4, J(H,H)=1.4 Hz, 2H; CH-5’ ), 2.90 (m, 4H; CH -3),

(

[

50 mL) followed by methanol (3ꢂ10 mL) to afford compound 2

0.40 g, 1.06 mmol, 84.4%) as a white solid. M.p. 317.28C; R =0.45

10% methanol in dichloromethane); H NMR (700.1 MHz,

D ]DMSO, +208C): d=8.15 (brs, 2H; 1,2-(NH) -C H ), 8.11 (brs,

C6H4

2

13

2

.64 ppm (m, 4H; CH -2); C NMR (176.0 MHz, [D ]DMSO, +208C):

2

6

f

1

d=171.3 (CO-CH ), 153.6 (NH-CO-NH), 141.1 (C-1C6H5⁾^,¹³³^.²⁽^C^-

2

^’C6H4⁾^,¹³¹^.³⁽^C^-¹^,²C6H4⁾^,¹²⁸^.⁹⁽^C^-¹^’C6H4⁾^,¹²⁸^.⁴⁽^C^H^-³^,⁵C6H5), 128.3

6

2

6

4

(^C^H^-²^,⁶C6H5⁾^,¹²⁶^.⁰⁽^C^H^-⁴C6H5⁾^,¹²⁵^.⁹⁽^C^H^-⁶^’C6H4⁾^,¹²⁵^.⁶⁽^C^H^-⁴^’C6H4),

2

H; 1’-NH-C H ), 7.56 (AA’ of AA’XX’, 2H; CH-3,6_C₆_H₄), 7.32 (ddm,

6 4

4

3

1

5

²⁴^.³⁽^C^H^-³^,⁶C6H4⁾^,¹²⁴^.²⁽^C^H^-⁴^,⁵C6H4), 123.2 (CH-3’C6H4⁾^,¹²³^.¹⁽^C^H^-

15

J(H,H)=7.9, J(H,H)=1.5 Hz, 2H; CH-6’ ), 7.05 (XX’ of AA’XX’,

C6H4

3

4

^’C6H4), 37.5 (CH -2), 31.0 ppm (CH -3);

N NMR (40.6 MHz,

2

H; CH-4,5_C₆_H₄), 6.84 (ddd, J(H,H)=7.9, J(H,H)=7.2, J(H,H)=

2

3

4

[

D ]DMSO, +258C): d=126.98 (NH-amide), 102.30 (2’-NH-C H ),

1

.5 Hz, 2H; CH-4’_C₆_H₄), 6.73 (ddd, J(H,H)=7.9, J(H,H)=1.5,

6

4

5

3

1

00.78 ppm (1,2-(NH) -C H ); IR (ATR-FTIRS): n˜ =3250, 3020, 1650,

2 6 4

J(H,H)=0.3 Hz, 2H; CH-3’_C₆_H₄), 6.56 (ddd, J(H,H)=7.9, J(H,H)=7.2,

ꢁ

1

4

13

522, 1507, 1291, 748, 696 cm ; MALDI FTICR (solvent ꢃ0.01%

J(H,H)=1.5 Hz, 2H; CH-5’_C₆_H₄), 4.81 ppm (brs, 4H; NH₂); C NMR

+

DMSO/iPrOH): m/z calcd for [C H N O +Na] : 663.26902 [M+Na]

(

176.0 MHz, [D ]DMSO, +208C): d=153.9 (NH-CO-NH), 141.1 (C-

38 36

6

4

6

;

found: 663.26961.

2

’_C₆_H₄), 131.5 (C-1,2_C₆_H₄), 124.58 (CH-4’_C₆_H₄), 124.57 (C-1’_C₆_H₄), 124.1

(

1

CH-6’_C₆_H₄), 123.9 (CH-3,6_C₆_H₄), 123.7 (CH-4,5_C₆_H₄), 116.7 (CH-5’_C₆_H₄),

Preparation of compound 5: Compound 2 (0.10 g, 0.26 mmol),

EDC·HCl (0.13 g, 0.66 mmol), triethylamine (TEA) (0.13 g,

15.8 ppm (CH-3’_C₆_H₄); IR (ATR-FTIRS): n˜ =3388, 3225, 1692, 1558,

ꢁ

1

504, 742 cm ; MALDI FTICR (solvent ꢃ0.01% DMSO/iPrOH): m/z

0

.66 mmol), HOBt (0.09 g, 0.66 mmol) and lauric acid (0.13 g,

.66 mmol) were dissolved in dry DMF (5 mL). The reaction mixture

+

calcd for [C H N O +Na] : 399.15399 [M+Na] ; found: 399.15375.

2

0

20

6

2

Preparation of compound 3: Compound 2 (0.10 g, 0.26 mmol),

EDC·HCl (0.15 g, 0.79 mmol), DMAP (0.09 g, 0.73 mmol), HOBt

was stirred at room temperature for 65 h. The reaction was moni-

tored by TLC. After completion of the reaction (determined by dis-

appearance of the starting material and intermediate from TLC)

the mixture was quenched with water (100 mL). The formed pre-

cipitate was filtered and washed with methanol (60 mL) and di-

chloromethane (50 mL) to give compound 5 (0.14 g, 0.19 mmol,

(

0.10 g, 0.74 mmol) and benzoic acid (0.10 g, 0.82 mmol) were dis-

solved in dry DMF (5 mL). The reaction mixture was stirred at room

temperature for 60 h. The reaction was monitored by TLC. After

completion of the reaction (determined by disappearance of the

starting material and intermediate from TLC) the mixture was

quenched with water (100 mL). The formed precipitate was filtered,

washed with methanol (50 mL) and dichloromethane (40 mL) to

give compound 3 (0.10 g, 0.17 mmol, 63.9%) as an off-white solid.

72.7%) as a white solid. M.p. 179.6–180.88C; R =0.53 (10% metha-

f

1

nol in dichloromethane); H NMR (700.1 MHz, [D ]DMSO, +208C):

6

d=9.48 (brs, 2H; NH-amide), 8.53 (brs, 2H; 1,2-(NH) -C H ), 8.23

2

6

4

3

4

(brs, 2H; 2’-NH-C H ), 7.70 (ddm, J(H,H)=8.2, J(H,H)=1.4 Hz, 2H;

6

4

3

M.p. 190.38C; R_f=0.46 (10% methanol in dichloromethane);

CH-3’ ), 7.56 (AA’ of AA’XX’, 2H; CH-3,6_C₆_H₄), 7.29 (ddm, J(H,H)=

C6H4

4 3

1

H NMR (700.1 MHz, [D ]DMSO, +208C): d=10.05 (brs, 2H; NH-

7.9, J(H,H)=1.6 Hz, 2H; CH-6’_C₆_H₄), 7.13 (ddd, J(H,H)=8.2,

6

Chem. Eur. J. 2015, 21, 1 – 17

www.chemeurj.org

11

ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

&

These are not the final page numbers! ÞÞ

Full Paper

3

4

13

J(H,H)=7.4, J(H,H)=1.6 Hz, 2H; CH-4’ ), 7.07 (XX’ of AA’XX’,

2H; CH -3), 2.05 ppm (m, 2H; CH -2); C NMR (176.0 MHz,

C6H4

2

3

4

2

1

4

H; CH-4,5_C₆_H₄), 7.03 (ddd, J(H,H)=7.9, J(H,H)=7.4, J(H,H)=

.4 Hz, 2H; CH-5’_C₆_H₄), 2.31 (t, J(H,H)=7.5 Hz, 4H; CH -2), 1.57 (m,

H; CH -3), 1.15–1.35 (m, 32H; CH -4-11), 0.84 ppm (vt, 6H; CH );

C NMR (176.0 MHz, [D ]DMSO, +208C): d=172.1 (CO-CH ), 153.7

[D ]DMSO, +208C): d=165.7 (COO), 152.5 (NH-CO-NH), 149.7 (CH-

6

3

2_P_y_r), 147.4 (CH-6_P_y_r), 140.2 (C-3 ), 139.5 (C-1 ), 136.6 (C-3_P_y_r), 135.9

2

Bn

Ph

(CH-4_P_y_r), 130.3 (C-1 ), 129.2 (CH-5 ), 128.8 (CH-3,5 ), 123.5 (CH-

Bn Bn Ph

5_P_y_r), 122.8 (CH-4 ), 122.5 (CH-6 ), 122.1 (CH-4 ), 118.6 (CH-2 ),

Bn Bn Ph Bn

2

3

1

3

6

2

(

NH-CO-NH), 133.0 (C-2’_C₆_H₄), 131.3 (C-1,2_C₆_H₄), 129.2 (C-1’_C₆_H₄), 125.8

CH-6’_C₆_H₄), 125.5 (CH-4’_C₆_H₄), 124.2 (CH-3,6_C₆_H₄), 124.1 (CH-4,5_C₆_H₄),

118.4 (CH-2,6 ), 63.9 (CH -1), 29.5 (CH -2), 28.7 ppm (CH -3);

Ph 2 2 2

15

N NMR (70.9 MHz, [D ]DMSO, +208C): d=317.3 (N-1_P_y_r), 108.86

6

1

23.4 (CH-3’_C₆_H₄), 123.2 (CH-5’_C₆_H₄), 36.0 (CH -2), 31.4 (CH -10), 25.2

(NH-Ph), 108.67 ppm (NH-Bn); IR (ATR-FTIRS): n˜ =3275, 1719, 1592,

2

ꢁ1

(

CH -3), 29.13, 29.10, 29.06, 28.9, 28.82, 28.79 (CH -4-CH -9), 22.2

CH -11), 14.0 ppm (CH ); N NMR (40.6 MHz, [D ]DMSO, +258C):

1562, 1462, 1294, 1082 cm ; MALDI FTICR (solvent ꢃ0.01%

2

15

+

DMSO/iPrOH): m/z calcd for [C H N O +Na] : 398.14751 [M+Na]

2

3

6

22 21

3

d=126.97 (NH-amide), 102.30 (2’-NH-C H ), 100.66 ppm (1,2-(NH) -

; found: 398.14810.

6

4

2

C H ); IR (ATR-FTIRS): n˜ =3281, 2919, 2851, 1646, 1519, 1452,

6

4

ꢁ1

[15]

7

48 cm ; MALDI FTICR (solvent ꢃ0.01% DMSO/iPrOH): m/z calcd

Preparation of compound 9: Compound 8 (0.18 g, 0.70 mmol),

and 10% Pd/C (0.030 g) were suspended in EtOH (40 mL) then hy-

drazine monohydrate (0.5 mL) was added drop-wise. The reaction

mixture was stirred at reflux temperature for 2 h under nitrogen at-

mosphere. After disappearance of the starting material (monitored

by TLC) the mixture was allowed to cool to room temperature and

Pd/C was removed by using filtration. The filtrate was concentrated

under reduced pressure to get compound 9 as (0.15 g, 0.66 mmol,

+

for [C H N O +Na] : 763.48812 [M+Na] ; found: 763.48786.

4

64

6

4

Preparation of compound 6: 3-Aminobenzoic acid (0.50 g,

.64 mmol) was dissolved in dry THF (60 mL) then phenyl isocya-

3

nate (0.43 g, 3.64 mmol) was added drop-wise. The reaction mix-

ture was stirred at room temperature for 60 h. The reaction was

monitored by TLC (disappearance of the starting material from

TLC). The formed white precipitate was filtered and washed with

dichloromethane (70 mL) and diethyl ether (60 mL) to obtain com-

9

4.4%) a white solid. M.p. 188.28C; R =0.51 (10% methanol in di-

f

1

chloromethane); H NMR (700.1 MHz, [D ]DMSO, +208C): d=8.55

6

pound 6 (0.80 g, 0.31 mmol, 85.6%) as a white solid. M.p. 153-

(

brs, 1H; NH), 8.37 (brs, 1H; NH), 7.43 (m, 2H; CH-2,6 ), 7.26 (m,

H; CH-3,5 ), 6.94 (m, 1H; CH-4 ), 6.88 (ddd, J(H,H)=8.0,

Ph Ph

J(H,H)=7.9, J(H,H)=0.3 Hz, 1H; CH-5 ), 6.77 (ddd, J(H,H)=2.2,

J(H,H)=2.1, J(H,H)=0.3 Hz, 1H; CH-2 ), 6.55 (ddd, J(H,H)=8.0,

J(H,H)=2.1, J(H,H)=1.0 Hz, 1H; CH-4^o^r^C^H^-⁶C6H4), 6.18 (ddd,

C6H4

J(H,H)=7.9, J(H,H)=2.2, J(H,H)=1.0 Hz, 1H; CH-4

⁶C6H4⁾^,⁵^.⁰⁴^p^p^m⁽^b^r^s^,²^H^;^N^H2⁾^; C NMR (176.0 MHz, [D ]DMSO,

208C): d=152.4, 149.2, 140.3, 139.9, 129.1, 128.8, 121.6, 118.0,

1

Ph

3

1

548C; R =0.25 (10% methanol in dichloromethane); H NMR

f

2

(

400.1 MHz, [D ]DMSO, +258C): d=12.90 (brs, 1H; COOH), 8.88

6

3

5

4

C6H4

(

brs, 1H; C H -NH), 8.68 (brs, 1H; C H -NH), 8.12 (ddd, J(H,H)=2.4,

6

4

5

6

5

4

3

5

3

4

3

C6H4

J(H,H)=1.6, J(H,H)=0.5 Hz, 1H; CH-2), 7.63 (ddd, J(H,H)=8.1,

J(H,H)=2.4, J(H,H)=1.1 Hz, 1H; CH-4), 7.55 (ddd, J(H,H)=7.7,

J(H,H)=1.6, J(H,H)=1.1 Hz, 1H; CH-6), 7.46 (m, 2H; CH-2’,6’), 7.40

4

3

4

or CH-

C6H4

4

13

3

5

6

(

ddd, J(H,H)=8.1, J(H,H)=7.7, J(H,H)=0.5 Hz, 1H; CH-5), 7.28 (m,

+

1

13

2

H; CH-3’,5’), 6.98 ppm (m, 1H; CH-4’); C NMR (100.6 MHz,

08.1, 106.1, 103.7 ppm; IR (ATR-FTIRS): n˜ =3322, 3288, 1650, 1545,

[

D ]DMSO, +258C): d=167.2 (COOH), 152.5 (NH-CO-NH), 140.0 (C-

6

ꢁ1

492, 1441, 1312, 1222 cm ; ESI FTICR (solvent ꢃ0.01% DMSO/

3

), 139.5 (C-1’), 131.3 (C-1), 128.9 (CH-5), 128.7 (CH-3’,5’), 122.6 (CH-

), 122.3 (CH-4), 121.9 (CH-4’), 118.8 (CH-2), 118.3 ppm (CH-2’,6’);

N NMR (40.6 MHz, [D ]DMSO, +258C): d=108.98 (C H -NH),

ꢁ

iPrOH): m/z calcd for [C H N O ꢁH] : 226.09859 [MꢁH] ; found:

13

3

1

6

2

26.09845.

1

5

6

5

1

08.74 ppm (C H -NH); IR (ATR-FTIRS): n˜ =3288, 2632, 2566, 1685,

6 4

Preparation of compound 10: Compound 9 (0.16 g, 0.70 mmol),

EDC·HCl (0.24 g, 1.25 mmol) and DMAP (0.17 g, 1.39 mmol) were

dissolved in dry DMF (5 mL) then 2-methylacrylic acid (0.08 g,

ꢁ

1

592, 1564, 1305 cm ; ESI FTICR (solvent ꢃ0.01% DMSO/iPrOH):

ꢁ

m/z calcd for [C H N O ꢁH] : 255.07752 [MꢁH] ; found:

1

4

12

2

3

2

55.07735.

0

.93 mmol) was added drop-wise. The reaction mixture was stirred

Preparation of compound 7: Compound 6 (0.31 g, 1.21 mmol)

and 3-(pyridin-3-yl)propan-1-ol (0.22 g, 1.60 mmol) were dissolved

at room temperature for 24 h. After disappearance of the starting

material (monitored by TLC) the reaction mixture was quenched

with water (100 mL). The formed precipitate was extracted in ethyl

acetate (50 mL). The organic layer was washed with water (50 mL)

in dry THF (100 mL). Then PPh (0.60 g, 2.29 mmol) was added. The

3

reaction mixture was stirred at 08C for 15 min. The catalyst DEAD

(

40% assay in toluene) (0.32 g, 1.83 mmol) was added drop-wise.

and dried over MgSO , filtered and concentrated under reduced

4

The reaction mixture was stirred at 08C for 1 h then stirred for 15 h

pressure. The obtained product was washed with diethyl ether

at room temperature. After disappearance of the starting material

(50 mL) to get compound 10 (0.15 g, 0.51 mmol, 72.6%) as an off-

(

monitored by TLC) the reaction mixture was concentrated under

white solid. M.p. 210.48C; R =0.58 (10% methanol in dichlorome-

f

1

reduced pressure. The formed oily gel was diluted with ethyl ace-

tate (50 mL) and washed with water (100 mL). The organic layer

was concentrated under reduced pressure. The product was puri-

fied by column (230–400 mesh silica) chromatography eluting with

thane); H NMR (700.1 MHz, [D ]DMSO, +208C): d=9.78 (brs, 1H;

6

amide-NH), 8.70 (brs, 1H; NH-C H ), 8.62 (brs, 1H; Ph-NH), 7.85

6

4

5

(ddd, J(H,H)=2.0, J(H,H)=1.5, J(H,H)=1.0 Hz, 1H; CH-2_C₆_H₄), 7.44

(m, 2H; CH-2,6 ), 7.27 (m, 2H; CH-3,5 ), 7.26 (m, 1H; CH-6_C₆_H₄),

Ph

1

0

% methanol in dichloromethane to give compound 7 (0.33 g,

7.19 (m, 2H; CH-4

and CH-5_C₆_H₄), 6.96 (m, 1H; CH-4 ), 5.79 (dq,

C6H4

Ph

4

2

4

.88 mmol, 72.7%) as a white solid. M.p. 140.58C; R =0.45 (10%

J(H,H)=0.9, J(H,H)=0.9 Hz, 1H;=CH ), 5.50 (dq, J(H,H)=1.6,

J(H,H)=0.9 Hz, 1H; =CH ), 1.94 ppm (dd, J(H,H)=1.6, J(H,H)=

E

f

Z

1

2

4

methanol in dichloromethane); H NMR (700.1 MHz, [D ]DMSO,

6

13

+

208C): d=8.94 (brs, 1H; NH-Bn), 8.71 (brs, 1H; Ph-NH), 8.49 (dm,

0.9 Hz, 3H; CH₃); C NMR (176.0 MHz, [D ]DMSO, +208C): d=

167.0 (amide-CO), 152.5 (NH-CO-NH), 140.5 (C=CH ), 139.9 (C-3_C₆_H₄),

6

4

3

4

J(H,H)=2.3 Hz, 1H; CH-2_P_y_r), 8.41 (ddm, J(H,H)=4.7, J(H,H)=

2

4

5

1

0

1

.7 Hz, 1H; CH-6_P_y_r), 8.17 (ddd, J(H,H)=2.3, J(H,H)=1.6, J(H,H)=

.4 Hz, 1H; CH-2 ), 7.70 (ddd, J(H,H)=7.8, J(H,H)=2.3, J(H,H)=

.7 Hz, 1H; CH-4_P_y_r), 7.67 (ddd, J(H,H)=8.1, J(H,H)=2.3, J(H,H)=

.1 Hz, 1H; CH-4 ), 7.55 (ddd, J(H,H)=7.6, J(H,H)=1.6, J(H,H)=

139.8 (C-1 ), 139.5 (C-1 ), 128.91 (CH-3,5 ), 128.86 (CH-5_C₆_H₄),

Ph

C6H4

Ph

3

4

121.9 (CH-4 ), 120.0 (=CH ), 118.2 (CH-2,6 ), 114.0 (CH-6_C₆_H₄), 113.5

Ph 2 Ph

(CH-4_C₆_H₄), 110.2 (CH-2_C₆_H₄), 18.9 ppm (CH₃); N NMR (40.6 MHz,

Bn

3

4

15

3

4

[D ]DMSO, +258C): d=128.27 (amide-NH), 109.02 (NH-C H ),

Bn

6

4

3

1

.1 Hz, 1H; CH-6 ), 7.47 (m, 2H; CH-2,6 ), 7.43 (ddd, J(H,H)=8.1,

108.71 ppm (NH-Ph); IR (ATR-FTIRS): n˜ =3301, 1643, 1597, 1535,

Bn

Ph

3

5

3

ꢁ1

J(H,H)=7.6, J(H,H)=0.4 Hz, 1H; CH-5 ), 7.32 (ddd, J(H,H)=7.8,

1487, 1314, 1296, 693, 632 cm ; ESI FTICR (solvent ꢃ0.01%

Bn

3

5

ꢁ

J(H,H)=4.7, J(H,H)=0.9 Hz, 1H; CH-5_P_y_r), 7.29 (m, 2H; CH-3,5_P_h),

DMSO/iPrOH): m/z calcd for [C H N O ꢁH] : 294.12480 [MꢁH] ;

17

3

2

3

6

.98 (m, 1H; CH-4 ), 4.27 (t, J(H,H)=6.4 Hz, 2H; CH -1), 2.77 (m,

found: 294.12516.

Ph

2

&

Chem. Eur. J. 2015, 21, 1 – 17

www.chemeurj.org

12

ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!

Full Paper

[14]

[15]

Preparation of compound 13: Compound 12

.08 mmol) was dissolved in dry dichloromethane (20 mL) and the

solution was cooled for 30 min at 08C. Then a 1m solution of BBr₃

4 mL) was added drop-wise. The reaction mixture was stirred at

8C for 15 min and then 24 h at room temperature. After disap-

(0.31 g,

Preparation of compound 16: Compound 15

(0.10 g,

1

0.33 mmol) and K CO₃(0.09 g, 0.66 mmol) were dissolved in dry

DMF (3 mL) then 3-bromopropan-1-ol (0.055 g, 0.40 mmol) was

added drop-wise. The reaction mixture was stirred for 3 h at 808C

2

(

0

under N atmosphere. After disappearance of the starting material

2

pearance of the starting material (monitored by TLC) the reaction

mixture was cooled to 08C, quenched by adding methanol (5 mL)

drop-wise and concentrated under reduced pressure. Thereafter

the following treatment was carried out two times (for removing

boric acid in the form of its volatile trimethyl ester): 5% solution of

methanol in dichloromethane (150 mL) was added to the concen-

trated mixture and the mixture was concentrated again under re-

duced pressure. A solid product was obtained and washed with di-

ethyl ether (30 mL) to give compound 13 (0.21 g, 0.77 mmol,

(monitored by TLC) the reaction mixture was cooled to room tem-

perature and quenched with water (75 mL). The product was ex-

tracted with ethyl acetate (3ꢂ20 mL). The ethyl acetate solution

was washed with water (50 mL) and a saturated aqueous solution

of NaCl (25 mL) and thereafter concentrated under reduced pres-

sure. The obtained yellow solid was washed with ethyl acetate

(10 mL) and diethyl ether (25 mL) to get the pure compound 16

(0.08 g, 0.22 mmol, 67.1%) as yellow solid. M.p. decomposed

1

above 3508C; R =0.53 (30% ethyl acetate in hexane); H NMR

f

7

0

+

1.4%) as an off-white solid. M.p. decomposed above 3508C; R =

(400.1 MHz, [D ]DMSO, +258C): d=11.33 (brs, 1H; NH-11), 11.31

(brs, 1H; NH-12), 8.37 (dd, J(H,H)=1.5, J(H,H)=0.7 Hz, 1H; CH-1),

f

6

1

4

5

.12 (30% ethyl acetate in hexane); H NMR (400.1 MHz, [D ]DMSO,

6

3

5

258C): d=10.89 (brs, 1H; NH-11), 10.73 (brs, 1H; NH-12), 9.33

8.26 (ddd, J(H,H)=8.2, J(H,H)=0.7, J(H,H)=0.6 Hz, 1H; CH-4),

3

4

5

3

4

5

(

brs, 1H; OH), 8.10 (dddd, J(H,H)=7.8, J(H,H)=1.2, J(H,H)=0.8,

J(H,H)=0.6 Hz, 1H; CH-7), 7.89 (ddd, J(H,H)=8.5, J(H,H)=0.6,

J(H,H)=0.5 Hz, 1H; CH-4), 7.82 (dd, J(H,H)=8.2, J(H,H)=0.4 Hz,

8.18 (dddd, J(H,H)=7.8, J(H,H)=1.2, J(H,H)=0.8, J(H,H)=0.6 Hz,

5

3

5

3

1H; CH-7), 7.97 (brs, 2H; CH-5 and CH-6), 7.83 (dd, J(H,H)=8.2,

J(H,H)=1.5 Hz, 1H; CH-3), 7.70 (ddd, J(H,H)=8.1, J(H,H)=1.0,

J(H,H)=0.8 Hz, 1H; CH-10), 7.42 (ddd, J(H,H)=8.1, J(H,H)=7.1,

J(H,H)=1.2 Hz, 1H; CH-9), 7.22 (ddd, J(H,H)=7.8, J(H,H)=7.1,

J(H,H)=1.0 Hz, 1H; CH-8), 4.40 (t, J(H,H)=6.5 Hz, 2H; OCH ), 3.63

(t, J(H,H)=6.2 Hz, 2H; CH OH), 1.95 ppm (tt, J(H,H)=6.5, J(H,H)=

6.2 Hz, 2H; CH CH CH ); C NMR (100.6 MHz, [D ]DMSO, +258C):

5

3

5

4

5

4

3

4

3

5

3

1

H; CH-6), 7.75 (dd, J(H,H)=8.2, J(H,H)=0.4 Hz, 1H; CH-5), 7.64

3

4

5

3

(

ddd, J(H,H)=8.1, J(H,H)=1.0, J(H,H)=0.8 Hz, 1H; CH-10), 7.35

ddd, J(H,H)=8.1, J(H,H)=7.0, J(H,H)=1.2 Hz, 1H; CH-9), 7.17

ddd, J(H,H)=7.8, J(H,H)=7.0, J(H,H)=1.0 Hz, 1H; CH-8), 7.01

dd, J(H,H)=2.2, J(H,H)=0.5 Hz, 1H; CH-1), 6.69 ppm (dd,

3

4

3

2

3

4

3

2

13

4

5

2

6

3

4

13

J(H,H)=8.5, J(H,H)=2.2 Hz, 1H; CH-3); C NMR (100.6 MHz,

D ]DMSO, +258C): d=155.7 (C-2), 140.6 (C-12’), 138.9 (C-10’),

d=166.6 (COO), 139.2 (C-10’), 138.3 (C-12’), 127.5 (C-4’), 127.5 (C-

11“), 125.5 (C-2), 125.4 (C-11’), 124.9 (CH-9), 123.6 (C-7’), 121.0 (C-

6’), 119.9 (CH-7), 119.7 (CH-3), 119.5 (CH-4), 119.4 (C-5’), 119.1 (CH-

8), 113.2 (CH-1), 112.4 (CH-5 or CH-6), 112.1 (CH-5 or CH-6), 111.7

[

6

1

25.7 (C-11’), 124.9 (C-11“), 124.1 (CH-9), 123.9 (C-7’), 120.7 (C-5’),

20.2 (CH-4), 119.4 (CH-7), 119.0 (C-6’), 118.7 (CH-8), 116.7 (C-4’),

1

5

111.34 (CH-10), 111.25 (CH-6), 110.8 (CH-5), 108.7 (CH-3), 97.1 ppm

(CH-10), 61.9 (OCH ), 57.4 (CH OH), 31.8 ppm (CH CH CH ); N NMR

2 2 2 2 2

1

5

(

CH-1); N NMR (40.6 MHz, [D ]DMSO, +258C): d=112.27 (NH-12),

(40.6 MHz, [D ]DMSO, +258C): d=114.99 (NH-12), 114.32 ppm (NH-

6

1

12.21 ppm (NH-11); IR (ATR-FTIRS): n˜ =3402, 3050, 1625, 1324,

11); IR (ATR-FTIRS): n˜ =3351, 2960, 2888, 1672, 1613, 1240, 1045,

ꢁ1

1151, 740 cm ; ESI FTICR (solvent ꢃ0.01% DMSO/iPrOH): m/z

754 cm ; ESI FTICR (solvent ꢃ0.01% DMSO)iPrOH): m/z calcd for

ꢁ

calcd for [C H N O ꢁH] : 271.08769 [MꢁH] ; found: 271.08761.

[C H N O ꢁH] : 357.12446 [MꢁH] ; found: 357.12514.

1

8

12

2

1

22 18

2

3

Preparation of compound 17: 4-Methylbenzene-1,2-diamine

0.09 g, 0.75 mmol) was dissolved in dry dichloromethane (25 mL)

then phenylisocyanate (0.21 g, 1.71 mmol) was added drop-wise.

(

Preparation of compound 14: Compound 13 (0.10 g, 0.36 mmol)

was dissolved in THF (5 mL) then DMAP (0.022 g, 0.18 mmol) was

added, the reaction mixture was stirred at 08C, then di-tert-butyl

dicarbonate (0.16 g, 0.74 mmol) was added drop-wise. The reaction

mixture was stirred for 2 h and then concentrated under reduced

pressure. The crude product was purified by column chromatogra-

phy (230–400 mesh silica) eluting with 3% ethyl acetate in hexane

The reaction mixture was heated to reflux under N atmosphere

2

for 24 h. After disappearance of the starting material (monitored

by TLC) the formed white precipitate was filtered and washed with

diethyl ether (30 mL) to obtain the pure compound 17 (0.25 g,

0

.69 mmol, 93.2%) as a white solid. M.p. 241.38C; R =0.60 (10%

f

1

methanol in dichloromethane); H NMR (700.1 MHz, [D ]DMSO,

6

to get compound 14 (0.07 g, 0.18 mmol, 50.5%) as a brown solid.

+

208C): d=9.09 (brs, 1H; 2-NHCONH), 8.98 (brs, 1H; 1-NHCONH),

4

1

M.p. 340.68C; R =0.40 (30% ethyl acetate in hexane); H NMR

f

8

2

3

.01 (brs, 1H; 2-NH), 7.94 (brs, 1H; 1-NH), 7.48 (dm, J(H,H)=

.1 Hz, 1H; CH-3_C₆_H₃⁾^,⁷^.⁴⁷⁽^m^,²^H^;^C^H^-²^,⁶Ph-2), 7.46 (m, 2H; CH-

^,⁶Ph-1), 7.40 (dm, J(H,H)=8.1 Hz, 1H; CH-6C6H3⁾^,⁷^.²⁷⁽^m^,²^H^;^C^H^-

^,⁵Ph-2), 7.26 (m, 2H; CH-3,5 ), 6.96 (m, 1H; CH-4Ph-2⁾^,⁶^.⁹⁵⁽^m^,¹^H^;

(

400.1 MHz, [D ]DMSO, +258C): d=11.12 (brs, 1H; NH-11), 11.10

6

3 4 5

brs, 1H; NH-12), 8.15 (dddd, J(H,H)=7.8, J(H,H)=1.2, J(H,H)=

3

5

3

5

0

.8, J(H,H)=0.6 Hz, 1H; CH-7), 8.14 (ddd, J(H,H)=8.4, J(H,H)=0.6,

5

3

5

Ph-1

J(H,H)=0.5 Hz, 1H; CH-4), 7.93 (dd, J(H,H)=8.3, J(H,H)=0.5 Hz,

H; CH-6), 7.90 (dd, J(H,H)=8.3, J(H,H)=0.5 Hz, 1H; CH-5), 7.68

3

4

CH-4_P_h_-₁), 6.89 (ddq, J(H,H)=8.1, J(H,H)=2.1, J(H,H)=0.8 Hz, 1H;

^C^H^-⁵C6H3), 2.27 ppm (dm, J(H,H)=0.8 Hz, 3H;^C^H3⁾^;

3

5

1

4

13

C NMR

3

4

5

(

ddd, J(H,H)=8.1, J(H,H)=1.0, J(H,H)=0.8 Hz, 1H; CH-10), 7.55

(

176.0 MHz, [D ]DMSO, +208C): d=153.4 (1-NH-CO), 153.1 (2-NH-

4

5

3

6

(

dd, J(H,H)=2.2, J(H,H)=0.5 Hz, 1H; CH-1), 7.39 (ddd, J(H,H)=

^C^O⁾^,¹⁴⁰^.⁰⁽^C^-¹Ph-1⁾^,¹³⁹^.⁹⁽^C^-¹Ph-2⁾^,¹³³^.⁴⁽^C^-²C6H3⁾^,¹³¹^.⁷⁽^C^-¹C6H3),

3

4

3

8

.1, J(H,H)=7.1, J(H,H)=1.2 Hz, 1H; CH-9), 7.20 (ddd, J(H,H)=7.8,

J(H,H)=7.1, J(H,H)=1.0 Hz, 1H; CH-8), 7.01 (dd, J(H,H)=8.4,

J(H,H)=2.2 Hz, 1H; CH-3), 1.54 ppm (s, 9H; CMe₃); C NMR

1

²⁸^.⁸³⁽^C^H^-³^,⁵Ph-2⁾^,¹²⁸^.⁸¹⁽^C^H^-³^,⁵Ph-1⁾^,¹²⁸^.²⁽^C^-⁴C6H3), 124.5 (CH-

3

4

3

⁶C6H3⁾^,¹²⁴^.⁴⁽^C^H^-⁵C6H3⁾^,¹²⁴^.⁰⁽^C^H^-³C6H3⁾^,¹²¹^.⁸⁽^C^H^-⁴Ph-2), 121.7 (CH-

4

13

4

_P_h_-₁), 108.13 (CH-2,6_P_h_-₂), 108.11 (CH-2,6_P_h_-₁), 20.7 ppm (CH₃);

(

100.6 MHz, [D ]DMSO, +258C): d=151.8 (C=O), 148.2 (C-2), 139.0

6

15

N NMR (40.6 MHz, [D ]DMSO, +208C): d=108.64 (2-NHCONH),

6

C-12’), 138.9 (C-10’), 126.1 (C-11’’), 125.5 (C-11’), 124.5 (CH-9), 123.6

C-7’), 121.6 (C-4’), 120.04 (C-6’), 119.97 (CH-4), 119.68 (CH-7), 119.65

C-5’), 118.9 (CH-8), 112.8 (CH-3), 111.9 (CH-6), 111.5 (CH-5), 111.4

1

08.24 (1-NHCONH), 100.06 (2-NH), 98.22 ppm (1-NH); IR (ATR-

FTIRS): n˜ =3275, 3055, 1629, 1599, 1565, 1540, 1310, 1211,

ꢁ

1

6

89 cm ; MALDI FTICR (solvent ꢃ0.01% DMSO/iPrOH): m/z calcd

15

CH-10), 104.5 (CH-1), 82.9 (CMe ), 27.3 ppm (CMe ); N NMR

3

+

for [C H N O +Na] : 383.14785 [M+Na] ; found: 383.14772.

21

20

4

2

40.6 MHz, [D ]DMSO, +258C): d=113.29 (NH-11), 114.22 ppm (NH-

6

1

7

2); IR (ATR-FTIRS): n˜ =3403, 2925, 1762, 1274, 1250, 1137,

Preparation of compound 18: ortho-Phenylenediamine (0.10 g,

0.92 mmol) was dissolved in dry dichloromethane (50 mL) then 1-

naphthyl isocyanate (0.37 g, 2.22 mmol) was added drop-wise. The

ꢁ1

44 cm ; ESI FTICR (solvent ꢃ0.01% DMSO/iPrOH): m/z calcd for

ꢁ

[

C H N O ꢁH] : 371.14012 [MꢁH] ; found: 371.13983.

2

3

20

2

3

Chem. Eur. J. 2015, 21, 1 – 17

www.chemeurj.org

13

ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

&

These are not the final page numbers! ÞÞ

Full Paper

1

5

reaction mixture was heated to reflux under N₂atmosphere for

4 h. After disappearance of the starting material (monitored by

TLC) the formed white precipitate was filtered and washed with di-

28.2 ppm (OC(CH₃)₃); N NMR (40.6 MHz, [D ]DMSO, +258C): d=

6

2

109.77 (NH-9), 99.61 ppm (NH-CO); IR (ATR-FTIRS): n˜ =3362, 3327,

2959, 1728, 1687, 1597, 1489, 1364, 1225, 1156 cm ; MALDI FTICR

ꢁ1

+

chloromethane to obtain the pure compound 18 (0.35 g,

(solvent ꢃ0.01% DMSO/iPrOH): m/z calcd for [C H N O +Na] :

30

43

3

4

+

0

.78 mmol, 78.3%) as a white solid. M.p. 273.58C; R =0.58 (10%

532.31458 [M+Na] ; found: 532.31419.

f

1

methanol in dichloromethane); H NMR (700.1 MHz, [D ]DMSO,

6

Preparation of compound 24: Compound 22 (0.10 g, 0.32 mmol)

was dissolved in dry DMF (3 mL). The reaction mixture was stirred

at room temperature, then EDC·HCl (0.15 g, 0.80 mmol), DMAP

+

208C): d=9.13 (brs, 2H; NH-Naph), 8.58 (brs, 2H; NH-Ph), 8.21

3 3 4

(

dm, J(H,H)=8.5 Hz, 2H; CH-8 ), 8.04 (dd, J(H,H)=7.6, J(H,H)=

Naph

3

1

.1 Hz, 2H; CH-2_N_a_p_h), 7.93 (dm, J(H,H)=8.1 Hz, 2H; CH-5_N_a_p_h), 7.69

(

0.04 g, 0.32 mmol), HOBt (0.09 g, 0.70 mmol) and 1-pyrenebutyric

(

AA’ of AA’XX’, 2H; CH-3,6 ), 7.64 (m, 2H; CH-4_N_a_p_h), 7.59 (ddd,

Ph

acid (0.20 g, 0.70 mmol) were added. The reaction mixture was

stirred for 17 h at room temperature. After disappearance of the

starting material (monitored by TLC) the reaction mixture was

quenched with water (50 mL). The formed white precipitate was fil-

tered, washed with water (50 mL), methanol (70 mL) and diethyl

ether (30 mL) to give the pure compound 24 (0.17 g, 0.20 mmol,

1.9%) as a white solid. M.p. 311.38C; R =0.88 (10% methanol in

dichloromethane); H NMR (700.1 MHz, [D ]DMSO, +208C): d=

0.07 (brs, 2H; NH-amide), 9.87 (brs, 1H; NH-9 ), 8.28 (d,

carb

J(H,H)=9.3 Hz, 2H; CH-10_p_y_r), 8.23 (dd, J(H,H)=7.7, J(H,H)=

.2 Hz, 2H; CH-6 ), 8.20 (dd, J(H,H)=7.9, J(H,H)=1.2 Hz, 2H; CH-

pyr

⁸pyr), 8.09 (d, J(H,H)=7.8 Hz, 2H; CH-3 ), 8.08 (d, J(H,H)=9.0 Hz,

H; CH-5_p_y_r), 8.06 (d, J(H,H)=9.3 Hz, 2H; CH-9 ), 8.05 (d, J(H,H)=

pyr

9.0 Hz, 2H; CH-4 ), 8.02 (dd, J(H,H)=7.9, J(H,H)=7.7 Hz, 2H; CH-

pyr

7_p_y_r), 7.99 (d, J(H,H)=1.8 Hz, 2H; CH-4,5_c_a_r_b), 7.81 (d, J(H,H)=

7.8 Hz, 2H; CH-2_p_y_r), 7.45 (d, J(H,H)=1.8 Hz, 2H; CH-2,7_c_a_r_b), 3.28

(m, 4H; CH -4), 2.50 (m, 4H; CH -2), 2.08 (m, 4H; CH -3), 1.39 ppm

(s, 18H; CH₃); C NMR (176.0 MHz, [D ]DMSO, +208C): d=171.1

3

4

J(H,H)=8.5, J(H,H)=6.8, J(H,H)=1.4 Hz, 2H; CH-7_N_a_p_h), 7.54 (ddd,

3

4

J(H,H)=8.1, J(H,H)=6.8, J(H,H)=1.2 Hz, 2H; CH-6_N_a_p_h), 7.48 (dd,

3

J(H,H)=8.2, J(H,H)=7.6 Hz, 2H; CH-3_N_a_p_h), 7.12 ppm (XX’ of

13

AA’XX’, 2H; CH-4,5_P_h); C NMR (176.0 MHz, [D ]DMSO, +208C): d=

6

1

31.3 (C-1,2 ), 153.7 (CO), 134.5 (C-1_N_a_p_h), 133.8 (C-4a_N_a_p_h), 128.5

Ph

(

1

CH-5_N_a_p_h), 125.983 (CH-6_N_a_p_h), 125.976 (CH-3_N_a_p_h), 125.9 (C-8a_N_a_p_h),

²⁵^.⁷⁽^C^H^-⁷Naph), 124.00 (CH-3,6 ), 123.97 (CH-4,5 ), 123.0 (CH-

6

f

Ph

1

15

6

4_N_a_p_h), 121.6 (CH-8_N_a_p_h), 117.5 ppm (CH-2_N_a_p_h); N NMR (40.6 MHz,

1

[

D ]DMSO, +258C): d=101.94 (NH-Naph), 100.25 ppm (NH-Ph); IR

6

3

4

(

7

ATR-FTIRS): n˜ =3261, 3046, 1644, 1555, 1499, 1398, 1274, 1245,

3

4

1

ꢁ1

84 cm ; MALDI FTICR (solvent ꢃ0.01% DMSO/iPrOH): m/z calcd

3

+

pyr

for [C H N O +Na] : 469.16350 [M+Na] ; found: 469.16354.

2

8

22

4

2

3

2

3

Preparation of compound 19: 1-Aminonaphthalene (0.15 g,

.05 mmol) was dissolved in dry dichloromethane (20 mL) then

4

3

1

4

TEA (0.1 mL) was added drop-wise and thereafter 1-naphthyl isocy-

anate (0.23 g, 1.36 mmol) was added drop-wise. The reaction mix-

2

13

ture was stirred under N atmosphere for 24 h at room tempera-

2

6

ture. After disappearance of the starting material (monitored by

TLC) the formed precipitate was filtered and washed with diethyl

ether (20 mL) to obtain the pure compound 19 (0.25 g, 0.80 mmol,

(CO), 141.7 (C-3,6_c_a_r_b), 136.5 (C-1_p_y_r), 131.3 (C-8a,9a_c_a_r_b), 130.9 (C-

5a_p_y_r), 130.4 (C-8a_p_y_r), 129.3 (C-3a_p_y_r), 128.2 (C-10a_p_y_r), 127.51 (CH-

2_p_y_r), 127.46 (CH-4_p_y_r), 127.2 (CH-9_p_y_r), 126.5 (CH-5_p_y_r), 126.2 (CH-7_p_y_r),

125.0 (CH-6_p_y_r), 124.9 (CH-3_p_y_r), 124.8 (CH-8_p_y_r), 124.7 (C-4a,4b_c_a_r_b),

124.25 (C-10b_p_y_r), 124.17 (C-10c_p_y_r), 123.5 (CH-10_p_y_r), 122.5 (C-1,8_c_a_r_b),

117.0 (CH-2,7_c_a_r_b), 113.0 (CH-4,5_c_a_r_b), 35.4 (CH -2), 34.5 (CMe ), 32.1

7

6.2%) as a white solid. M.p. 287.68C; R =0.83 (10% methanol in

f

1

dichloromethane); H NMR (400.1 MHz, [D ]DMSO, +258C): d=9.17

6

3

(

brs, 2H; NH), 8.25 (dm, J(H,H)=8.5 Hz, 2H; CH-8), 8.08 (dd,

2

3

4

3

4

3

15

J(H,H)=7.6, J(H,H)=1.2 Hz, 2H; CH-2), 7.96 (dddd, J(H,H)=8.1,

J(H,H)=1.3, J(H,H)=0.7, J(H,H)=0.6 Hz, 2H; CH-5), 7.66 (dm,

J(H,H)=8.1 Hz, 2H; CH-4), 7.64 (ddd, J(H,H)=8.5, J(H,H)=6.8,

J(H,H)=1.3 Hz, 2H; CH-7), 7.57 (ddd, J(H,H)=8.1, J(H,H)=6.8,

(CH -4), 31.9 (CH₃), 27.3 ppm (CH -3);

N NMR (40.6 MHz,

2

4

5

[D ]DMSO, +258C): d=129.45 (NH-CO), 114.05 ppm (NH-9); IR

6

3

ꢁ1

(ATR-FTIRS): n˜ =3273, 2955, 2865, 1652, 1548, 1235, 839 cm

;

3

MALDI FTICR (solvent ꢃ0.01% DMSO/iPrOH): m/z calcd for

3

+

J(H,H)=1.2 Hz, 2H; CH-6), 7.50 ppm (dd, J(H,H)=8.1, J(H,H)=

[C H N O +Na] : 872.41865; [M+Na] ; found: 872.41702.

60

55

3

2

1

3

7

1

8

1

.6 Hz, 2H; CH-3); C NMR (100.6 MHz, [D ]DMSO, +258C): d=

6

Preparation of compound 25: Compound 22 (0.10 g, 0.32 mmol)

was dissolved in acetonitrile (25 mL) then 1-naphthyl isocyanate

53.3 (CO), 134.4 (C-1), 133.7 (C-4a), 128.4 (CH-5), 125.92 (C-8a),

25.90 (CH-6), 125.87 (CH-3), 125.7 (CH-7), 122.9 (CH-4), 121.4 (CH-

(0.14 g, 0.81 mmol) was added drop-wise. The reaction mixture

15

), 117.5 ppm (CH-2); N NMR (40.6 MHz, [D ]DMSO, +258C): d=

6

was stirred at room temperature under N₂atmosphere for 17 h.

After disappearance of the starting material (monitored by TLC)

the formed white precipitate was filtered and washed with diethyl

ether (30 mL) to obtain the pure compound 25 (0.15 g, 0.23 mmol,

02.17 ppm (NH); IR (ATR-FTIRS): n˜ =3272, 3051, 1637, 1549, 1501,

ꢁ1

245, 1212, 1211, 783 cm ; MALDI FTICR (solvent ꢃ0.01% DMSO/

+

iPrOH): m/z calcd for [C H N O +Na] : 335.11548 [M+Na] ;

21

16

2

1

found: 335.11572.

7

1.8%) as a white solid. M.p. 246.4-247.28C; R =0.64 (10% metha-

f

1

Preparation of compound 23: Di-tert-butyl dicarbonate (0.30 g,

nol in dichloromethane); H NMR (700.1 MHz, [D ]DMSO, +208C):

6

1

.37 mmol) was added drop-wise to a solution of compound 22

d=10.10 (brs, 1H; NH-9), 9.21 (brs, 2H; NH-C-1_c_a_r_b), 8.96 (brs, 2H;

3

(

0.21 g, 0.68 mmol) in dichloromethane (70 mL) at 08C. The mix-

NH-C-1 ), 8.21 (dm, J(H,H)=8.5 Hz, 2H; CH-8 ), 8.13 (dd,

Naph

4

3

4

ture was stirred 17 h at room temperature. After disappearance of

the starting material (monitored by TLC) water (35 mL) was added,

the mixture was extracted with dichloromethane (2ꢂ30 mL), dried

with anhydrous Na SO , filtered, and evaporated to give a light-

J(H,H)=7.6, J(H,H)=1.1 Hz, 2H; CH-2 ), 7.96 (d, J(H,H)=1.8 Hz,

Naph

2H; CH-4,5 ), 7.95 (dm, J(H,H)=8.1 Hz, 2H; CH-5 ), 7.65 (dm,

J(H,H)=8.2 Hz, 2H; CH-4_N_a_p_h), 7.59 (ddd, J(H,H)=8.5, J(H,H)=6.7,

J(H,H)=1.4 Hz, 2H; CH-7_N_a_p_h), 7.54 (ddd, J(H,H)=8.1, J(H,H)=6.7,

J(H,H)=1.2 Hz, 2H; CH-6 ), 7.48 (d, J(H,H)=1.8 Hz, 2H; CH-

2,7_c_a_r_b), 7.42 (dd, J(H,H)=8.2, J(H,H)=7.6 Hz, 2H; CH-3_N_a_p_h),

1.43 ppm (s, 18H; CH₃); C NMR (176.0 MHz, [D ]DMSO, +208C):

3

carb

Naph

3

4

3

2

4

pink solid. This solid was purified by column chromatography

silica 230-400 mesh) eluting with 5% ethyl acetate in hexane to

Naph

3

(

13

get compound 23 (0.22 g, 0.43 mmol, 63.0%) as a light-brown

6

solid. M.p. 222.78C; R =0.78 (30% ethyl acetate in hexane);

d=153.5 (CO), 142.1 (C-3,6_c_a_r_b), 134.4 (C-1_N_a_p_h), 133.8 (C-4a_N_a_p_h),

131.1 (C-8a,9a_c_a_r_b), 128.5 (CH-5_N_a_p_h), 126.03 (C-8a_N_a_p_h), 125.97 (CH-

6_N_a_p_h), 125.93 (CH-3_N_a_p_h), 125.8 (CH-7_N_a_p_h), 124.9 (C-4a,4b_c_a_r_b), 123.2

(C-1,8_c_a_r_b), 123.0 (CH-4_N_a_p_h), 121.4 (CH-8_N_a_p_h), 117.7 (CH-2_N_a_p_h), 115.8

f

1

H NMR (400.1 MHz, [D ]DMSO, +258C): d=10.32 (brs, 1H; NH-9),

6

4

9

.11 (brs, 2H; NH-CO), 7.85 (d, J(H,H)=1.8 Hz, 2H; CH-4,5), 7.60

(

brs, 2H; CH-2,7), 1.52 (s, 18H; OC(CH ) ), 1.38 ppm (s, 18H;

3 3

1

3

15

CC(CH ) ); C NMR (100.6 MHz, [D ]DMSO, +258C): d=153.4 (CO),

(CH-2,7_c_a_r_b), 112.0 (CH-4,5_c_a_r_b), 34.5 (CMe ), 31.9 ppm (CH ); N NMR

3

6

3

1

41.5 (C-3,6), 130.4 (C-8a,9a), 123.9 (C-4a,4b), 122.5 (C-1,8), 116.0

(40.6 MHz, [D ]DMSO, +258C): d=111.76 (NH-9), 103.14 (NH-C-

6

(

CH-2,7), 111.7 (CH-4,5), 79.1 (OCMe ), 34.4 (CCMe ), 31.9 (CC(CH ) ),

1_c_a_r_b), 101.14 ppm (NH-C-1_N_a_p_h); IR (ATR-FTIRS): n˜ =3317, 3260, 2951,

3

3 3

&

Chem. Eur. J. 2015, 21, 1 – 17

www.chemeurj.org

14

ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!

Full Paper

ꢁ

1

(

6

645, 1562, 1542, 1495, 1273, 1234, 782, 764 cm ; MALDI FTICR

Technology Materials for Sustainable Development” HIGHTECH-

MAT and by the Estonian National Research. P.A.G. thanks the

Royal Society and the Wolfson Foundation for a Royal Society

Wolfson Research Merit Award. P.A.G. also thanks the EPSRC for

funding (EP/J009687/1).

+

solvent ꢃ0.01% DMSO/iPrOH): m/z calcd for [C H N O +Na] :

4

2

41

5

2

+

70.31524 [M+Na] ; found: 670.31553.

Tetrabutylammonium carboxylate salt preparation: Tetrabuty-

lammonium trimethylacetate and tetrabutylammonium lactate

salts were prepared by adding one equivalent of tetrabutylammo-

nium hydroxide in methanol to a solution of the corresponding

acid (1 equiv) in methanol. The mixture was stirred at room tem-

perature for 24 h, evaporated to dryness under reduced pressure

and then dried under high vacuum at room temperature over-

night. The salts are stored in a glovebox under argon atmosphere.

Keywords: carboxylate anions

·

hydrophobic effects

·

molecular recognition · NMR spectroscopy · receptors

Measurement of the relative and absolute binding constants:

The relative and absolute binding constant measurements were

carried out by using the above-described two NMR instruments

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1] a) J. I. Kroschwitz, A. Seidel, Kirk-Othmer, Encyclopedia of Chemical Tech-

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(

200 or 700 MHz), UV/Vis and fluorescence instrument. All solutions

were prepared in [D ]DMSO or in DMSO with 0.5% water (m/m).

6

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The measurement and data treatment procedures of the NMR and

UV/Vis measurements have been described previously.

[14,15]

Fluorescence titration measurements were carried out in 1 cm

quartz cells by using an excitation wavelength of l=350 nm and

recording the emission spectra between l=365 and 500 nm. Titra-

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UV/Vis measurements of the absolute binding constants. For indo-

locarbazole 39 the logK_a_s_svalue measurements the concentrations

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2

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0

.00016–0.0016m. The working concentration of indolocarbazole

during the measurements (in the spectrofluorometer cell) was ap-

ꢁ

6

proximately 4ꢂ10 m. The concentration of TBA benzoate in the

concentrated titrant solution was approximately 0.14m and in di-

luted titrant solutions approximately 0.01m. During titration the

spectrofluorometric cell was weighed before and after each addi-

tion of titrant (in order to take volume correction into account).

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spectrum of the free receptor was obtained before the first addi-

tion of titrant. The spectrum of the indolocarbazole–benzoate

complex was obtained by adding a large amount of titrant. From

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calculations of the logK_a_s_svalues were carried out the same way as

in the case of UV/Vis measurements.

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(Regulation No. 34) funded by the Enterprise Estonia founda-

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Estonian Ministry of Education and Science. S.K. was supported

by the European Social Fund’s Doctoral Studies and Interna-

tionalisation Programme DoRa, which is carried out by the

Foundation Archimedes. L.T. was supported from Mobilitas top

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These are not the final page numbers! ÞÞ

Full Paper

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Received: October 28, 2014

Published online on && &&, 0000

5592–5593.

&

Chem. Eur. J. 2015, 21, 1 – 17

www.chemeurj.org

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ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!

Full Paper

FULL PAPER

&

Carboxylate Receptors

S. A. Kadam, K. Martin, K. Haav, L. Toom,

C. Mayeux, A. Pung, P. A. Gale,

J. R. Hiscock, S. J. Brooks, I. L. Kirby,

N. Busschaert, I. Leito*

&& – &&

Towards the Discrimination of

Carboxylates by Hydrogen-Bond

Donor Anion Receptors

Can we discriminate? Comprehensive

binding studies of four carboxylate

anions with a number of anion recep-

tors (see figure) reveals that the binding

strength is largely determined by the

basicity of the anion (leading to the

general binding order lactate <benzoa-

te<acetateꢀtrimethylacetate) and

modulated by additional effects, such as

the steric fit between the anion and the

receptor as well as the hydrophilicity/

hydrophobicity of the anion.

Chem. Eur. J. 2015, 21, 1 – 17

www.chemeurj.org

17

ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

&

These are not the final page numbers! ÞÞ

Article Doi

Towards the Discrimination of Carboxylates by Hydrogen-Bond Donor Anion Receptors

DOI: 10.1002/chem.201405858

Source and publish data:

Authors:

Article abstract of DOI:10.1002/chem.201405858

Full text of DOI:10.1002/chem.201405858

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