BETA-CYCLODEXTRIN MODIFICATION AND HOST-GUEST … · Duc-Truc Pham Chapter 4 - 143 - It is seen...

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BETA-CYCLODEXTRIN MODIFICATION AND HOST-GUEST COMPLEXATION Duc-Truc Pham (Phm Đức Trc) Thesis submitted for the degree of Doctor of Philosophy in The University of Adelaide School of Chemistry and Physics October, 2007

Transcript of BETA-CYCLODEXTRIN MODIFICATION AND HOST-GUEST … · Duc-Truc Pham Chapter 4 - 143 - It is seen...

Page 1: BETA-CYCLODEXTRIN MODIFICATION AND HOST-GUEST … · Duc-Truc Pham Chapter 4 - 143 - It is seen from their structures that 3βCDida2-and 6CDidaβ 2-have same number of coordinating

BETA-CYCLODEXTRIN MODIFICATION AND

HOST-GUEST COMPLEXATION

Duc-Truc Pham

(Phạm Đức Trực)

Thesis submitted for the degree of

Doctor of Philosophy

in

The University of Adelaide

School of Chemistry and Physics

October, 2007

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4 Chapter

CHAPTER 4

METALLO-β-CYCLODEXTRINS:

THEIR FORMATION,

ENANTIOSELECTIVITY

AND POTENTIAL ENVIRONMENTAL USE

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4.1. Europium(III)-β-Cyclodextrins: NMR Enantioselective Agents.

4.1.1. Introduction

Enantioselectivity is of particular importance to the pharmaceutical industry as the two

enantiomers of a chiral drug usually possess different physiological properties and those of

one enantiomer may cause harmful effects.1 Cyclodextrins, CDs, are homochiral and

exhibit chiral recognition by forming diastereomeric complexes. Consequently there have

been many studies on enantioselectivity using substituted CDs.

A range of methods has been utilised to study enantioselectivity including

electrophoresis,2 chromatographic techniques,3 calorimetry,4 mass spectrometry,5 X-ray

analysis,6 spectroscopic,7 potentiometry8 and molecular mechanics and molecular dynamics

calculations.9 NMR spectroscopy is one of the most sensitive methods for studying

enantioselectivities by CDs.1 It not only allows the determination of complex

stoichiometries and their stability constants but also the spatial relationships between

hydrogen atoms of the host and guest molecules and the dynamics of the complex and its

constituent parts.

Although CDs can be effective enantioselective agents, the extent of enantiomeric

distinction in the NMR spectrum is often small. It has been demonstrated that the addition

of either Eu3+, Y3+ or Dy3+ to the solution of sulfonated and carboxymethylated βCD,10,11

or 6βCDen and 2βCDen12 can enhance the spectroscopic enantiomeric resolution of guests

as observed by NMR spectroscopy. The addition of one equivalent of Eu3+ to a solution of

6A-(1,4,7-tri(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl)-6A-deoxy-β-cyclo-

dextrin (6βCD-DO3A) (4.1, Appendix 1) results in the appearance of doubled resonances

of aromatic protons of D- and L-histidinate (H1(D) 8.52, H1(L) 8.48, H2(D) 7.37 and H2(L)

7.34 ppm) compared with the singlet resonances of racemate histidinate (H1(D/L) 7.59,

H2(D/L) 6.89 ppm) alone. However, the resonances of (D/L)-tyrosinate, (D/L)-

phenylalaninate and (D/L)-tryptophanate are broadened in the presence of Eu3+ and 6βCD-

DO3A.13

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The aim of this research is the preparation of (2AS,3AS)-3A-[bis(carboxylatomethyl)-

amino]-3A-deoxy-β-cyclodextrin (3βCDidaH2), 6A-[bis(carboxylatomethyl)amino]-6A-

deoxy-β-cyclodextrin (6βCDidaH2) and 6A-[tri(carboxylatomethyl)(2-aminoethyl)amino]-

6A-deoxy-β-cyclodextrin (6βCDedtaH3) and an examination of their enantioselectivities

and those of their metallo-β-cyclodextrins formed with Eu3+.

4.1.2. Substituted β-Cyclodextrins

The substituted β-cyclodextrins were prepared through small modification of previous

procedures.8,13 Aqueous solutions containing chloroacetic acid and NaOH were combined

and added to an aqueous solution of either (2AS,3AS)-3A-amino-3A-deoxy-β-cyclodextrin,

3βCDNH2, 6A-amino-6A-deoxy-β-cyclodextrin, 6βCDNH2, (Chapter 2) or 6A-(2-

aminoethyl)amino-6A-deoxy-β-cyclodextrin,14 6βCDen. After adjusting the pH to 10-11

with aqueous NaOH, the reaction solution was heated at 80 oC for 24h with very slow

addition of NaOH solution. After purification by ion exchange, the residue was freeze-

dried (Scheme 4.1).

NH2

NH2

6βCDNH2

3βCDNH2

HN

NH2

6βCDen

N O-

O-

OO

N O-

O-

OO

6βCDida2-

3βCDida2-

N

O-

O

N

O-O

-OO

6βCDedta3-

OOHCl

OH-, 80 oC, 24 h

Scheme 4.1. Preparation of 3βCDida2-, 6βCDida2- and 6βCDedta3-.

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It is seen from their structures that 3βCDida2- and 6βCDida2- have same number of

coordinating atoms (three), however the structure of βCD of 3βCDida2- differs from that of

6βCDida2- due to the inversion of the C2A and C3A carbons of the A ring (glucopyranose) to

give the altropyranose conformation during the synthesis of 3βCDNH2 (Section 2.2,

Chapter 2), which may affect complexation behaviour. The 6βCDedta3- has five

coordinating atoms, and consequently forms metal complexes of higher stability.

Therefore, these three substituted βCD should show different behaviour in ternary

complexation with metal ions and guests.

Molecular models of the substituted βCDs were constructed and energy-minimised

(MM2) using the Cambridge Chem3D Ultra 8.0 protocol,15 and are displayed in the space-

filling and cylindrical-bond representation in Figs. 4.1-4.3. The hydrogens and lone pairs

are not shown to obtain a clearer view. It is seen that whilst the acetate arms of 6βCDida2-

and 6βCDedta3- are located far from the centre of the primary rim of βCD, those of

3βCDida2- are closer to the centre of the secondary rim of βCD. This structure difference

may affect the complexation of guests.

Figure 4.1. Molecular models (no H and lone pairs show) of 3βCDida2-, constructed

and energy-minimised (MM2) using Chem3D15 (C – grey, O – red, N – dark blue).

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Figure 4.2. Molecular models (no H and lone pairs show) of 6βCDida2-, constructed

and energy-minimised (MM2) using Chem3D15 (C – grey, O – red, N – dark blue).

Figure 4.3. Molecular models (no H and lone pairs show) of 6βCDedta3-, constructed

and energy-minimised (MM2) using Chem3D15 (C – grey, O – red, N – dark blue).

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4.1.3. The Acid Dissociation Constants

The acid dissociation constants of 3βCDidaH2, 6βCDidaH2 and 6βCDedtaH3 were

determined in aqueous NaClO4 by potentiometric titration. The titration curves are shown

in Fig. 4.4. The results obtained from the best fit of these data using Hyperquad 200316

(Protonic Software)17 are given in Table 4.1 in addition to the literature results from similar

titrations of 6βCDidaH28 and free IDAH2 (iminodiacetic acid)18 and EDTAH4

(ethylenedinitrilotetraacetic acid).18 The pKw obtained from calibration is 13.77. Speciation

plots calculated using Hyss 200619 (Protonic Software)17 from the data in Table 4.1 for the

species produced are shown in Figs. 4.5-4.7.

0

2

4

6

8

10

12

0.15 0.20 0.25 0.30 0.35

V NaOH (cm3)

pH

a

b

c

Figure 4.4. The pH profiles of a) 3βCDidaH2 0.001 (mol dm3), b) 6βCDidaH2 0.001

(mol dm3) and c) 6βCDedtaH3 0.001 (mol dm3) in aqueous 0.010 (mol dm3) HClO4 at I =

0.10 mol dm-3 (NaClO4) and 298.2 K.

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Table 4.1. The pKas of 3βCDidaH2, 6βCDidaH2 and 6βCDedtaH3 in aqueous solution

(I = 0.10 mol dm-3 NaClO4) at 298.2 K.

3βCDidaH2a 6βCDidaH2

a 6βCDidaH2

8 IDAH218 6βCDedtaH3

a EDTAH418

pKa1 8.03 ± 0.04 8.75 ± 0.07 8.38 ± 0.03 9.34 9.48 ± 0.03 10.17

pKa2 4.55 ± 0.05 4.08 ± 0.09 3.65 ± 0.07 2.61 4.28 ± 0.05 6.11

pKa3 - - - - 2.89 ± 0.08 2.68

pKa4 - - - - - 2.00 a Potentiometric titration data were fitted over the pH range 3-10. pKa1 for equilibrium [H][L]/[HL], pKa2 for equilibrium [HL][H]/[H2L], pKa3 for equilibrium [H2L][H]/[H3L]and pKa4 for equilibrium [H3L][H]/[H4L]. The errors shown are the fitting errors, but when experimental error is taken into account the overall error is ± 3%.

2 4 6 8 10pH

0

20

40

60

80

100

% s

peci

atio

n to

[3βC

Did

a2+] to

tal a c

b

Figure 4.5. Speciation with [3βCDida2-]total = 100%, curve a = 3βCDidaH2, curve b =

3βCDidaH-, curve c = 3βCDida2-.

2 4 6 8 10pH

0

20

40

60

80

100

% s

peci

atio

n to

[6βC

Did

a2+] to

tal

acb

Figure 4.6. Speciation with [6βCDida2-]total = 100%, curve a = 6βCDidaH2, curve b =

6βCDidaH-, curve c = 6βCDida2-.

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CDedtaH3

2 4 6 8 10pH

0

20

40

60

80

100

% s

peci

atio

n to

[6βC

Ded

ta3+

] tota

l

a

db

c

Figure 4.7. Speciation with [6βCDedta3+]total = 100%, curve a = 6βCDedtaH3; curve b

= 6βCDedtaH2-; curve c = 6βCDedtaH2-; curve d = 6βCDedta3-.

It is seen from Table 4.1 that the pKa of 6βCDidaH2 is quite close to a previous study.

The differences between the pKas of 3βCDidaH2 and 6βCDidaH2 may due to the inversion

of the A ring of 3βCDidaH2 so that the acetate arms much closer to the hydroxyl groups of

βCD that those of 6βCDidaH2. The differences between the pKas of the substituted βCDs

and those of IDAH2 and EDTAH4 are attributable to changes induced in the electronic

character of the substituents of the substituted βCDs and changes in their hydration

because of their proximity to the hydroxyl groups of βCD.14 The pKas of the protonated

amine groups of IDAH3+ (pKa = 1.82)18 and EDTAH6

2+ (pKas = 1.5 and -0.1)18 have been

reported but we were unable to determine the corresponding values for the substituted βCDs.

The speciation plots (Figs. 4.5-4.7) show that at near neutral pH values, 3βCDidaH-,

6βCDidaH- and 6βCDedtaH2- are the predominate forms of the respective compounds. At

pH 10, the predominated species are unprotonated.

4.1.4. NMR Enantioselective Studies

The NMR enantioselective abilities of 3βCDida2-, 6βCDida2- and 6βCDedta3- and their

Eu3+ complexes ([Eu(3βCDida)]+, [Eu(6βCDida)]+ and [Eu(6βCDedta)]0) with D/L-

tryptophanate (Trp-), 4-hydroxyl-D/L-phenylglycinate (4OHPhg-), D/L-histidinate (His-),

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D/L-pheniramine {is ca. equimolar PhmH+ (pKa = 9.9 in D2O) and Phm under the

experimental conditions and is indicated as Phm from this point on}, D/L-phenylglycinate

(Phg-) and (D/L)-β-phenylserinate (βPhs-) (Fig. 4.8) in solution were investigated.

CO2-

NH2

HO

CO2-

NH2

CO2-

NH2

HO

N

NH

NH2

CO2-N

HNNH2

CO2-N

HN

-O2CNH2

OH

N

NH+

1

22

1

12

12

12

12

1

2

34

1

2

34

* *

*

**

(D)(L)

(D) (L)

NH2

CO2-

NH

NH2

CO2-

NH

1

23

4

5

1

23

4

5

(D) (L)

a)

b)

c)

and

e)

f)

d)

Figure 4.8. The structures of the aromatic guests studied showing the labelling of

protons: a) D/L-tryptophanate (Trp-), b) 4-hydroxyl-D/L-phenylglycinate (4OHPhg-), c)

D/L-histidinate (His-), d) D/L-pheniramine (Phm), e) D/L-phenylglycinate (Phg-) and f)

(D/L)-β-phenylserinate (βPhs-).

The guests are chosen because of their different structures, the different distances from

the chiral carbon to the aromatic rings, and the numbers of chiral carbons (Fig. 4.8) in the

anticipation that insight would be gained into enantioselectivity. All of the guests chosen

contain aromatic groups, which may be complexed in βCD annuli and whose resonances

are not overlapped by those of βCD. The guests used have previously been shown to form

complexes with βCD and Eu3+/βCD.10,12,20,21

The [Eu(EDTA)]- complex has a high stability (log(K/dm3 mol-1) = 17.32)18 hence

strong complexation of Eu3+ by 6βCDedta3- was anticipated. The stability constants of Eu3+

by 3βCDida2- and 6βCDida2- are lower as their ida2- substituents possess only three

coordinating groups. (Determination of K for [Eu(3βCDida)]+, [Eu(6βCDida)]+ and

[Eu(6βCDedta)] was prevented by precipitation of the Eu3+ complexes at the

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concentrations required for potentiometric studies at pH 2-8). Other coordination sites on

Eu3+ in the complexes may be occupied by the secondary hydroxyl groups of the βCD

(3βCDida2-), primary hydroxyl groups of the βCD (6βCDida2- and 6βCDedta3-) or aqua

ligands to give a coordination number of either 8 or 9.

4.1.4.1. 1D 1H NMR Studies

1H NMR spectra were recorded using a Varian Inova 600 Spectrometer operating at

599.957 MHz at 298.2 K and resonances were referenced against an external standard,

trimethylsilylpropiosulfonic acid, in D2O. Only those resonances of the guest not

overlapped by βCD resonances were examined for enantioselective resolution upon the

complexation of substituted βCDs and their Eu3+ complexes. The D- and L- enantiomers of

tryptophanate, 4-hydroxyl-phenylglycinate and histidinate are commercially available and

consequently samples with different ratios of D- and L- guests were prepared to assign the

resonances of the protons of the enantiomers.

Stock solutions of 0.05 mol dm-3 of each the guests and each of βCD, 3βCDida2-,

6βCDida2-, 6βCDedta3- were prepared in D2O (pD = 10, NaOH). The solution samples of

free guests was prepared by adding 0.1 cm3 of the stock solution and 0.9 cm3 D2O (pD =

10). The solution samples of (1:1) host:guest complexation was prepared by adding 0.1

cm3 of the stock solution of free guests and either βCD, 3βCDida2-, 6βCDida2- or

6βCDedta3- and 0.8 cm3 D2O (pD = 10, NaOH). The solution samples with Eu3+ present

were prepared by adding 0.1 cm3 of the stock solutions of free guests and either βCD,

3βCDida2-, 6βCDida2- or 6βCDedta3- and Eu3+, and 0.7 cm3 D2O (pD = 10, NaOH).

The NMR spectra of the solution samples 0.005 mol dm-3 in the chosen guest and

equimolar in either βCD, 3βCDida2-, 6βCDida2- or 6βCDedta3-, and each of 3βCDida2-,

6βCDida2- or 6βCDedta3- and Eu3+ are shown in Figs. 4.9-4.20. A downfield or upfield

shift of a resonance was attributed to either complexation either in a βCD annulus, or by

Eu3+, or both. A summary of the results obtained are given in Tables 4.2-4.5.

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7.107.207.307.407.507.607.707.80 ppm

H2 H5 H1 H4 H3a

b

c

d

e

f

H2 L

H2 L

NH2

CO2-

NH

NH2

CO2-

NH

1

23

4

5

1

23

4

5

(D) (L)

H2 D

H2 D

H3 L

H3 L

Figure 4.9. The observed 1H NMR (600 MHz, D2O, pD 10) resonances of a) D/L-Trp-

0.005 mol dm-3, then in the presence of either one equivalent of βCD, 3βCDida2-, or

[Eu(3βCDida)]+: b) βCD.(D/L-Trp-), c) (3βCDida2-).(D/L(1:1)-Trp-), d) (3βCDida2-).(D/L

(4:1)-Trp-), e) [Eu(3βCDida)(D/L(1:1)-Trp)] and f) [Eu(3βCDida)(D/L(4:1)-Trp)] where

the binary and ternary complexes formed (in equilibrium with their components) are

shown in the captions b)-f).

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7.107.207.307.407.507.607.707.80 ppm

H2 H5 H1 H4 H3

H2 L

H2 L

a

b

c

d

e

f

NH2

CO2-

NH

NH2

CO2-

NH

1

23

4

5

1

23

4

5

(D) (L)

H2 D

H2 D

H3 L

H3 L

Figure 4.10. The observed 1H NMR (600 MHz, D2O, pD 10) resonances of a) D/L-Trp-

0.005 mol dm-3, then in the presence of either one equivalent of βCD, 6βCDida2-, or

[Eu(6βCDida)]+: b) βCD.(D/L-Trp-), c) (6βCDida2-).(D/L(1:1)-Trp-), d) (6βCDida2-).(D/L

(4:1)-Trp-), e) [Eu(6βCDida)(D/L(1:1)-Trp)] and f) [Eu(6βCDida)(D/L(4:1)-Trp)] where

the binary and ternary complexes formed (in equilibrium with their components) are

shown in the captions b)-f).

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7.107.207.307.407.507.607.707.807.90 ppm

H2 H5 H1 H4 H3

a

b

c

d

e

f

H2 L

H2 L

NH2

CO2-

NH

NH2

CO2-

NH

1

23

4

5

1

23

4

5

(D) (L)

H2 D

H2 D

H3 L

H3 L

Figure 4.11. The observed 1H NMR (600 MHz, D2O, pD 10) resonances of a) D/L-Trp-

0.005 mol dm-3, then in the presence of either one equivalent of βCD, 6βCDedta3-, or

[Eu(6βCDedta)]: b) βCD.(D/L-Trp-), c) (6βCDedta3-).(D/L(1:1)-Trp-), d) (6βCDedta3-).

(D/L(4:1)-Trp-), e) [Eu(6βCDedta)(D/L(1:1)-Trp)]- and f) [Eu(6βCDedta)(D/L(4:1)-Trp)]-

where the binary and ternary complexes formed (in equilibrium with their components) are

shown in the captions b)-f).

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6.76.86.97.07.17.27.37.4 ppm

a

b

c

d

e

f

CO2-

NH2

HOCO2

-

NH2

HO

12

12

12

12

(D) (L)

H2 H1

H2 L

H2 D

Figure 4.12. The observed 1H NMR (600 MHz, D2O, pD 10) resonances of a) D/L-

4OHPhg- 0.005 mol dm-3, then in the presence of either one equivalent of βCD,

3βCDida2-, or [Eu(3βCDida)]+: b) βCD.(D/L-4OHPhg-), c) (3βCDida2-).(D/L(1:1)-

4OHPhg-), d) (3βCDida2-).(D/L(4:1)-4OHPhg-), e) [Eu(3βCDida)(D/L(1:1)-4OHPhg)]

and f) [Eu(3βCDida)(D/L(4:1)-4OHPhg)] where the binary and ternary complexes formed

(in equilibrium with their components) are shown in the captions b)-f).

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6.76.86.97.07.17.27.37.4 ppm

H2 H1

a

b

c

d

e

f

CO2-

NH2

HOCO2

-

NH2

HO

12

12

12

12

(D) (L)

H1 L

H1 D

Figure 4.13. The observed 1H NMR (600 MHz, D2O, pD 10) resonances of a) D/L-

4OHPhg- 0.005 mol dm-3, then in the presence of either one equivalent of βCD,

6βCDida2-, or [Eu(6βCDida)]+: b) βCD.(D/L-4OHPhg-), c) (6βCDida2-).(D/L(1:1)-

4OHPhg-), d) (6βCDida2-).(D/L(4:1)-4OHPhg-), e) [Eu(6βCDida)(D/L(1:1)-4OHPhg)]

and f) [Eu(6βCDida)(D/L(4:1)-4OHPhg)] where the binary and ternary complexes formed

(in equilibrium with their components) are shown in the captions b)-f).

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6.76.86.97.07.17.27.37.4 ppm

a

b

c

d

e

f

CO2-

NH2

HOCO2

-

NH2

HO

12

12

12

12

(D) (L)

H2 H1

Figure 4.14. The observed 1H NMR (600 MHz, D2O, pD 10) resonances of a) D/L-

4OHPhg- 0.005 mol dm-3, then in the presence of either one equivalent of βCD,

6βCDedta3-, or [Eu(6βCDedta)]: b) βCD.(D/L-4OHPhg-), c) (6βCDedta3-).(D/L

(1:1)-4OHPhg-), d) (6βCDedta3-).(D/L(4:1)-4OHPhg-), e) [Eu(6βCDedta)(D/L(1:1)-

4OHPhg)]- and f) [Eu(6βCDedta)(D/L(4:1)-4OHPhg)]- where the binary and ternary

complexes formed (in equilibrium with their components) are shown in the captions b)-f).

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Duc-Truc Pham Chapter 4

- 156 -

6.807.307.808.308.80 ppm

a

b

c

d

e

f

H2 H1

NH2

CO2-N

HNNH2

CO2-N

HN 1

22

1

(D) (L)

Figure 4.15. The observed 1H NMR (600 MHz, D2O, pD 10) resonances of a) D/L-His-

0.005 mol dm-3, then in the presence of either one equivalent of βCD, 3βCDida2-, or

[Eu(3βCDida)]+: b) βCD.(D/L-His-), c) (3βCDida2-).(D/L (1:1)-His-), d) (3βCDida2-).(D/L

(4:1)-His-), e) [Eu(3βCDida)(D/L(1:1)-His)] and f) [Eu(3βCDida)(D/L(4:1)-His)] where

the binary and ternary complexes formed (in equilibrium with their components) are

shown in the captions b)-f).

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Duc-Truc Pham Chapter 4

- 157 -

6.807.307.808.308.80 ppm

H2 H1

a

b

c

d

e

f

NH2

CO2-N

HNNH2

CO2-N

HN 1

22

1

(D) (L)

Figure 4.16. The observed 1H NMR (600 MHz, D2O, pD 10) resonances of a) D/L-His-

0.005 mol dm-3, then in the presence of either one equivalent of βCD, 6βCDida2-, or

[Eu(6βCDida)]+: b) βCD.(D/L-His-), c) (6βCDida2-).(D/L(1:1)-His-), d) (6βCDida2-).(D/L

(4:1)-His-), e) [Eu(6βCDida)(D/L(1:1)-His)] and f) [Eu(6βCDida)(D/L(4:1)-His)] where

the binary and ternary complexes formed (in equilibrium with their components) are

shown in the captions b)-f).

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Duc-Truc Pham Chapter 4

- 158 -

6.807.007.207.407.607.80 ppm

a

b

c

d

e

f

H2 H1

NH2

CO2-N

HNNH2

CO2-N

HN 1

22

1

(D) (L)

Figure 4.17. The observed 1H NMR (600 MHz, D2O, pD 10) resonances of a) D/L-His-

0.005 mol dm-3, then in the presence of either one equivalent of βCD, 6βCDedta3-, or

[Eu(6βCDedta)]: b) βCD.(D/L-His-), c) (6βCDedta3-).(D/L(1:1)-His-), d) (6βCDedta3-).

(D/L (4:1)-His-), e) [Eu(6βCDedta)(D/L(1:1)-His)]- and f) [Eu(6βCDedta)(D/L(4:1)-His)]-

where the binary and ternary complexes formed (in equilibrium with their components) are

shown in the captions b)-f).

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Duc-Truc Pham Chapter 4

- 159 -

7.27.47.67.88.08.28.48.68.8 ppm

H4 H2 H1 H3, H Phea

b

c

d

e

f

g

h

H4

H4

H4

H4

H4

H4

H4

H2

H2

H2

H2

H2

H2

H2

H1

H1

H1

H1

H1

H1

H1

H3

H3

H3

H3

H3

H3

N

NHN

NH1

2

34

1

2

34

(D) (L)

Figure 4.18. The observed 1H NMR (600 MHz, D2O, pD 10) resonances of a) D/L-Phm

0.005 mol dm-3, then in the presence of either one equivalent of b) βCD, c) 3βCDida2-, d)

6βCDida2-, e) 6βCDedta3-, f) [Eu(3βCDida)]+, g) [Eu(6βCDida)]+ and h)

[Eu(6βCDedta)], where for f)-h) the complexes shown are those formed by equimolar Eu3+

and the substituted βCD.

N

NHN

NH+

1

2

34

1

2

34

* *

and

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Duc-Truc Pham Chapter 4

- 160 -

7.207.257.307.357.407.457.507.557.60 ppm

a

b

c

d

e

f

g

h

CO2-

NH2

CO2-

NH2

(D) (L)

Figure 4.19. The observed 1H NMR (600 MHz, D2O, pD 10) resonances of a) D/L-Phg-

0.005 mol dm-3, then in the presence of either one equivalent of b) βCD, c) 3βCDida2-, d)

6βCDida2-, e) 6βCDedta3-, f) [Eu(3βCDida)]+, g) [Eu(6βCDida)]+ and h)

[Eu(6βCDedta)], where for f)-h) the complexes shown are those formed by equimolar Eu3+

and the substituted βCD.

CO2-

NH2

*

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Duc-Truc Pham Chapter 4

- 161 -

7.207.257.307.357.407.457.507.557.60 ppm

a

b

c

d

e

f

g

h

-O2CNH2

OH

-O2CNH2

OH

(D)(D)

(L)(L)

Figure 4.20. The observed 1H NMR (600 MHz, D2O, pD 10) resonances of a) D/L-

βPhs- 0.005 mol dm-3, then in the presence of either one equivalent of b) βCD, c)

3βCDida2-, d) 6βCDida2-, e) 6βCDedta3-, f) [Eu(3βCDida)]+, g) [Eu(6βCDida)]+ and h)

[Eu(6βCDedta)], where for f)-h) the complexes shown are those formed by equimolar Eu3+

and the substituted βCD.

-O2CNH2

OH

**

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Duc-Truc Pham Chapter 4

- 162 -

Table 4.2. Chemical shift changes in the 1H NMR (600 MHz, D2O, pD 10) spectra for

the guests by complexation with βCD, 3βCDida2-, 6βCDida2- and 6βCDedta3-.

Appearance, δ ppmb (Δδ ppm)

Free Addition of one equivalent of

Guest protona

guest βCD 3βCDida2- 6βCDida2- 6βCDedta3-

Trp- H2 d., 7.72 d., 7.72 d., 7.72 d., 7.72 d., 7.72

H5 d., 7.51 d., 7.50 (-0.01) d., 7.52 (+0.01) d., 7.51 d., 7.51

H1 s., 7.26 s., 7.26 s., 7.30 (+0.04) (L) d., 7.28 (+0.02)

(D) d., 7.27 (+0.01)

s., 7.28 (+0.02)

H4 t., 7.25 t., 7.24 (-0.01) t., 7.26 (+0.01) t., 7.26 (+0.01) t., 7.25

H3 t., 7.17 t., 7.16 (-0.01) t., 7.18 (+0.01) t., 7.17 t., 7.17

4OHPhg- H1 d., 7.19 d., 7.20 (+0.01) d., 7.31 (+0.12) d., 7.31 (+0.12) d., 7.28 (+0.09) H2 d., 6.76 d., 6.77 (+0.01) d., 6.93 (+0.17) d., 6.93 (+0.17) d., 6.89 (+0.13)

His- H1 s., 7.65 s., 7.66 (+0.01) s., 8.63 (+0.98) s., 8.44 (+0.79) s., 7.71 (+0.06) H2 s., 6.91 s., 6.92 (+0.01) s., 7.37 (+0.46) s., 7.30 (+0.39) s., 7.01 (+0.10)

Phm H4 d., 8.45 m., 8.57 (+0.12) d., 8.62 (+0.17)

d., 8.60 (+0.15)

t., 8.58 (+0.13) d., 8.64 (+0.19)

d., 8.61 (+0.16) H2 t., 7.85 m., 7.88 (+0.03) t., 8.33 (+0.48)

t., 8.29 (+0.44)

q., 8.07 (+0.22) t., 8.28 (+0.43)

t., 8.23 (+0.38) H1 d., 7.48 d., 7.38 (-0.10) d., 7.85 (+0.37)

d., 7.84 (+0.36)

d., 7.59 (+0.11) d., 7.77 (+0.29)

d., 7.75 (+0.27) H3 t., 7.39 t., 7.40 (+0.01) p., 7.72 (+0.33) t., 7.55 (+0.16)

t., 7.54 (+0.15)

t., 7.70 (+0.31)

t., 7.67 (+0.28)

Phg- Ar. protons

m., 7.37 m., 7.39 (+0.02) m., 7.46 (+0.09) m., 7.40 (+0.03) m., 7.48 (+0.11)

m., 7.44 (+0.07)

βPhs- Ar. protons

m., 7.38 m., 7.39 (+0.01)

m., 7.35 (-0.03)

m., 7.47 (+0.09)

m., 7.40 (+0.02)

m., 7.43 (+0.05)

m., 7.35 (-0.03)

m., 7.47 (+0.09)

m., 7.40 (+0.02)(s - singlet, d - doublet, t - triplet, q - quartet, p - pentuplet, m - multiple, br - broad, Ar. aromatic). a Protons labelled as shown in Fig. 4.8. b Values taken from central peak or centre of resonances.

The values in bold indicate enantioselectivity. The values in brackets indicate chemical shift

change of a particular resonance of a complexed guest compared with that of the free guest.

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Duc-Truc Pham Chapter 4

- 163 -

Table 4.3. Observed changes in the 1H NMR (600 MHz, D2O, pD 10) spectra for the

guests by complexation with 3βCDida2- and [Eu(3βCDida)]+.

Appearance, δ ppmb (Δδ)

Guest Free Addition of one equivalent of Protona guest 3βCDida2- [Eu(3βCDida)]+

Trp- H2 d., 7.72 d., 7.72 (L) br. d., 7.75 (+0.03)

(D) d., 7.72

H5 d., 7.51 d., 7.52 (+0.01) d., 7.53 (+0.02)

H1 s., 7.26 s., 7.30 (+0.04) s., 7.27 (+0.01)

H4 t., 7.25 t., 7.26 (+0.01) br. t., 7.28 (+0.03)

H3 t., 7.17 t., 7.18 (+0.01) (L) t., 7.21 (+0.04)

(D) t., 7.19 (+0.02)

4OHPhg- H1 d., 7.19 d., 7.31 (+0.12) d., 7.29 (+0.10) H2 d., 6.76 d., 6.93 (+0.17) (L) d., 6.95 (+0.19)

(D) d., 6.94 (+0.18)

His- H1 s., 7.65 s., 8.63 (+0.98) s., 8.65 (+1.00) H2 s., 6.91 s., 7.37 (+0.46) s., 7.37 (+0.46)

Phm H4 d., 8.45 d., 8.62 (+0.17)

d., 8.60 (+0.15)

t., 8.57 (+0.12)

H2 t., 7.85 t., 8.33 (+0.48)

t., 8.29 (+0.44)

q., 8.46 (+0.61)

H1 d., 7.48 d., 7.85 (+0.37)

d., 7.84 (+0.36)

t., 8.02 (+0.54)

H3 t., 7.39 p., 7.72 (+0.33) t., 7.83 (+1.44)

Phg- Ar. protons

m., 7.37 m., 7.46 (+0.09) m., 7.49 (+0.12) br., 7.41 (+0.04)

βPhs- Ar. protons

m., 7.38 m., 7.47 (+0.09) m., 7.40 (+0.02)

m. 7.45 (+0.07)

(s - singlet, d - doublet, t - triplet, q - quartet, p - pentuplet, m - multiple, br - broad, Ar. aromatic). a Protons labelled as shown in Fig. 4.8. b Values taken from central peak or centre of resonances.

The values in bold indicate enantioselectivity. The values in brackets indicate chemical shift

change of a particular resonance of a complexed guest compared with that of the free guest.

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Duc-Truc Pham Chapter 4

- 164 -

Table 4.4. Observed changes in the 1H NMR (600 MHz, D2O, pD 10) spectra for the

guests by complexation with 6βCDida2- and [Eu(6βCDida)]+.

Appearance, δ ppmb (Δδ)

Guest Free Addition of one equivalent of protona guest 6βCDida2- [Eu(6βCDida)]+

Trp- H2 d., 7.72 d., 7.72 (L) d., 7.75 (+0.03)

(D) d., 7.72

H5 d., 7.51 d., 7.51 d., 7.52 (+0.01)

H1 s., 7.26 (L) d., 7.28 (+0.02)

(D) d., 7.27 (+0.01)

s., 7.29 (+0.03)

H4 t., 7.25 t., 7.26 (+0.01) m., 7.28 (+0.03)

H3 t., 7.17 t., 7.17 (L) t., 7.20 (+0.03)

(D) t., 7.19 (+0.02)

4OHPhg- H1 d., 7.19 d., 7.31 (+0.12) (D) d., 7.29 (+0.10)

(L) d., 7.28 (+0.09) H2 d., 6.76 d., 6.93 (+0.17) d., 6.93 (+0.17)

His- H1 s., 7.65 s., 8.44 (+0.79) s., 8.52 (+0.87) H2 s., 6.91 s., 7.30 (+0.39) s., 7.32 (+0.41)

Phm H4 d., 8.45 t., 8.58 (+0.13) t., 8.58 (+0.13) H2 t., 7.85 q., 8.07 (+0.22) t., 8.28 (+0.43) H1 d., 7.48 d., 7.59 (+0.11) d., 7.84 (+0.36) H3 t., 7.39 t., 7.55 (+0.16)

t., 7.54 (+0.15)

t., 7.70 (+0.31)

Phg- Ar. protons

m., 7.37 m., 7.40 (+0.03) m., 7.47 (+0.10) m., 7.42 (+0.05)

βPhs- Ar. protons

m., 7.38 m., 7.43 (+0.05) m., 7.35 (-0.03)

m., 7.46 (+0.08) m., 7.40 (+0.02)

(s - singlet, d - doublet, t - triplet, q - quartet, p - pentuplet, m - multiple, br - broad, Ar. aromatic). a Protons labelled as shown in Fig. 4.8. b Values taken from central peak or centre of resonances.

The values in bold indicate enantioselectivity. The values in brackets indicate chemical shift

change of a particular resonance of a complexed guest compared with that of the free guest.

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Duc-Truc Pham Chapter 4

- 165 -

Table 4.5. Observed changes in the 1H NMR (600 MHz, D2O, pD 10) spectra for the

guests by complexation with 6βCDedta3- and [Eu(6βCDedta)].

Appearance, δ ppmb (Δδ)

Guest Free Addition of one equivalent of protonsa guest 6βCDedta3- [Eu(6βCDedta)]

Trp- H2 d., 7.72 d., 7.72 (L) br. s., 7.78 (+0.06)

(D) d., 7.75 (+0.03)

H5 d., 7.51 d., 7.51 d., 7.54 (+0.03)

H1 s., 7.26 s., 7.28 (+0.02) s., 7.31 (+0.05)

H4 t., 7.25 t., 7.25 t., 7.28 (+0.03)

H3 t., 7.17 t., 7.17 (L) t., 7.22 (+0.05)

(D) t., 7.20 (+0.03)

4OHPhg- H1 d., 7.19 d., 7.28 (+0.09) br. d., 7.30 (+0.11) H2 d., 6.76 d., 6.89 (+0.13) d., 6.94 (+0.18)

His- H1 s., 7.65 s., 7.71 (+0.06) br. s., 7.71 (+0.06) H2 s., 6.91 s., 7.01 (+0.10) br. s., 6.98 (+0.07)

Phm H4 d., 8.45 d., 8.64 (+0.19)

d., 8.61 (+0.16)

t., 8.60 (+0.15)

H2 t., 7.85 t., 8.28 (+0.43)

t., 8.23 (+0.38)

q., 8.47 (+0.62)

H1 d., 7.48 d., 7.77 (+0.29)

d., 7.75 (+0.27)

d., 8.02 (+0.54)

H3 t., 7.39 t., 7.70 (+0.31)

t., 7.67 (+0.28)

p., 7.84 (+0.45)

Phg- Ar. protons

m., 7.37 m., 7.48 (+0.11) m., 7.44 (+0.07)

m., 7.48 (+0.11) m., 7.42 (+0.05)

βPhs- Ar. protons

m., 7.38 m., 7.47 (+0.09) m., 7.40 (+0.02)

m., 7.48 (+0.10) m., 7.42 (+0.04)

(s - singlet, d - doublet, t - triplet, q - quartet, p - pentuplet, m - multiple, br - broad, Ar. - aromatic). a Protons labelled as shown in Fig. 4.8. b Values taken from central peak or centre of resonances.

The values in bold indicate enantioselectivity. The values in brackets indicate chemical shift

change of a particular resonance of a complexed guest compared with that of the free guest.

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Duc-Truc Pham Chapter 4

- 166 -

4.1.4.2. 2D 1H ROESY NMR Studies

To gain further understanding of the effects of the substituted βCDs and their Eu3+

complexes on the D- and L- enantiomers of the guests it was decided to undertake 2D 1H

ROESY NMR studies. In ROESY experiments a NOE cross-peak between a proton of the

βCD annulus and a proton of the guest is observed if these protons are closer than 4 Å

through space.22 Such cross-peak are expected to show the different interaction of D- and

L- protons of the guests with the H3, H5 and H6 annular protons of βCD. Solutions for

ROESY studies were prepared in D2O under the same conditions as those for 1D 1H NMR

studies except that the either D- or L- enantiomer was studied separately in the cases of

Trp- and 4OHPhg-. The ROESY spectra are shown in Figs. 4.21-4.24.

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Duc-Truc Pham Chapter 4

- 167 -

H3,5

Trp- CH2

βCD H2,4,6

Trp- CH

H3,5

Trp- CH2

βCD H2,4,6

Trp- CH

H2 H5 H4 H3H1

H2 H5 H4 H3H1

a)

b)

7.73

7.71 7.53

7.51

7.29

7.27

7.26

7.21

7.20

7.19

7.76

7.74

7.53

7.52

7.29

7.28 7.

277.

227.

217.

20

Figure 4.21. Contour plots of ROESY spectra (D2O, pD 10, 600 MHz, 0.3 s mixing

time) of samples containing 0.005 mol dm-3 of a) [Eu(6βCDida)(D-Trp)] and b)

[Eu(6βCDida)(L-Trp)].

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Duc-Truc Pham Chapter 4

- 168 -

H3,5

βCD H2,4,6

H3,5

βCD H2,4,6

H2 H1

a)

b)

7.30

7.28

6.95

6.93

H2 H1

7.30

7.28

6.96

6.94

N-CH2

N-CH2

Figure 4.22. Contour plots of ROESY spectra (D2O, pD 10, 600 MHz, 0.3 s mixing

time) of samples containing 0.005 mol dm-3 of a) [Eu(3βCDida)(D-4OHPhg)] and b)

[Eu(3βCDida)(L-4OHPhg)].

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Duc-Truc Pham Chapter 4

- 169 -

H3,5

βCD H2,4,6

H3,5

βCD H2,4,6

H2 H1

a)

b)

7.28

7.26

6.92

6.90

H2 H1

7.27

7.25

6.92

6.90

Figure 4.23. Contour plots of ROESY spectra (D2O, pD 10, 600 MHz, 0.3 s mixing

time) of samples containing 0.005 mol dm-3 of a) [Eu(6βCDida)(D-4OHPhg)] and b)

[Eu(6βCDida)(L-4OHPhg)].

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Duc-Truc Pham Chapter 4

- 170 -

βCD H2-6

H4 H2 H1 H3 H Phe

H4 H2 H1 H3 H Phe

H4 H2 H1 H3 H Phe

a)

βCD H2-6

βCD H2-6

b)

c)

N-CH2

N-CH2

N-CH2

Figure 4.24. Contour plots of ROESY spectra (D2O, pD 10, 600 MHz, 0.3 s mixing

time) of samples containing 0.005 mol dm-3 of a) (3βCDida2-)(D/L-Phm), b) (6βCDida2-)

(D/L-Phm) and c) (6βCDedta3-)(D/L-Phm).

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Duc-Truc Pham Chapter 4

- 171 -

4.1.5. Discussion and Summary

NMR spectra of enantiomers are identical as enantiomeric groups are isochronous.

Enantio-differentiation in NMR spectra requires a enantioselective host that converts the

mixture of enantiomers into a mixture of diastereomeric complexes of which lifetimes

range from very short in the fast exchange limit of the NMR time scale to very long in the

slow exchange limit where exchange between the complexed and free states is slow (Fig.

4.25a). In the case of fast exchange (Fig. 4.25b) two averaged resonances are seen whose

observed chemical shift: δobs = χfδf + χcδc,1 where χf and χc are the mole fractions of the

enantiomers in the free and complexed states and δf and δc are the corresponding chemical

shifts. Broadening of the resonances are indicative of the intermediate exchange rate

regime in which the averaged resonances show varying degrees of broadening (Fig. 4.25c).

a)

b)

c)

complexed D enantiomer

complexed L enantiomer

free D/L racemate

D enantiomeraverage

L enantiomeraverage

Figure 4.25. Dependences of the chemical shifts and widths of NMR resonances on the

rate of exchange between the free and complexed enantiomers: a) slow exchange rate, b)

fast exchange rate and c) intermediate exchange rate.

The complexes of βCD and its substituted forms with enantiomeric guests may exist in

two diastereomeric pairs as shown in Scheme 4.2. Depending on the structures of the

enantiomeric guests and charge effects, one of these complexes may be dominant.

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Duc-Truc Pham Chapter 4

- 172 -

D D L L

D L

Scheme 4.2. The equilibria for the complexation of the D/L-guests by βCD. A similar

situation applies for a substituted βCD and its Eu3+ complexes.

The equilibria typifying host-guest complexation are shown in Scheme 4.3 for the

6βCDida2-/D/L-Trp-/Eu3+ system and similar equilibria apply to the other systems. In

principle there are two isomers, (a) and (b), of the host-guest complex [(6βCDida)(D/L-

Trp)]3- in which the orientations of D/L-Trp are reversed. Their relative proportions depend

on the balance of complexing forces. While the orientation of D/L-Trp- in isomer (a)

appears likely to experience the most inter-component electrostatic repulsion, it also

appears the most likely to lead to the formation of [Eu(6βCDida)(D/L-Trp)]. However,

there is an alternative path to [Eu(6βCDida)(D/L-Trp] through [Eu(6βCDida)]+ which may

be electrostatically more favourable.

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Duc-Truc Pham Chapter 4

- 173 -

N

CO2-

CO2-

NHH2N

O

-O

(b) [(6βCDida2-)(D/L-Trp-)]

+D/L-Trp-

-D/L-Trp-

N

CO2-

CO2-

6βCDida2-

N

CO2-

CO2-

HNNH2

OO-

+Eu3+

[Eu(6βCDida)]+

[Eu(6βCDida)(D/L-Trp)](a) [(6βCDida2-)(D/L-Trp-)]

+D/L-Trp- -D/L-Trp-

HNH2N

O

N OEu(OH2)3

O

O

OO 0

N OEu(OH2)5

O

OO

+D/L-Trp- -D/L-Trp-

-Eu3+

+Eu3+

-Eu3+

+

Scheme 4.3. The formation of a metallo-β-cylodextrin exemplified by

[Eu(6βCDida)]+, and host-guest complexes exemplified by [(6βCDida)(D/L-Trp)]3- and

[Eu(6βCDida)(D/L-Trp)]. One or more of the coordination sites on Eu3+ in its complex

may be occupied by a primary hydroxyl group of the βCD entity instead of an aqua ligand

as shown.

4.1.5.1. Complexation and Enantioselectivity in the D/L-Tryptophanate (Trp-)

System.

It is seen from Fig. 4.9a that the D/L-Trp- H2 resonance is a doublet because of coupling

with H3 with fine structure superimposed as consequence of weak coupling with more

distance H4 and H5. The H5 resonance is a doublet because of coupling with H4 with fine

structure superimposed from coupling with H3. The H4 resonance is a triplet because of

coupling with H3 and H5 with fine structure superimposed from coupling with H2. The H3

resonance is a triplet because of coupling with H2 and H4 with fine structure superimposed

from coupling with H5, and the H1 resonance is singlet. This simplified analysis of the

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Duc-Truc Pham Chapter 4

- 174 -

proton spectrum of the aromatic group is sufficient for the purpose of discussing

enantioselective complexation.

While βCD and the substituted βCDs induced small changes in the D/L-Trp- spectrum

they were insufficient to attribute them to enantioselective host-guest complexation (Figs.

4.9-4.11, a-d). However, in the presence of equimolar 6βCDida2- and Eu3+ the narrow fast

exchange D/L H2 Trp- doublet resolves into two doublets with that downfield arising from

L-Trp- (Fig. 4.10e) as shown when the D/L-Trp- ratio is 4/1 (Fig. 4.10f). There is also a

partial resolution of the H3 triplet and some lesser changes in the H1 and H4 multiplets.

This is consistent with the formation of [Eu(6βCDida)]+ and the subsequent

enantioselective formation of the [Eu(6βCDida)(D/L-Trp)] host-guest complexes. Under

similar conditions similar but smaller enantioselective changes are seen in Figs. 4.9e and

4.9f consistent with the formation of the [Eu(3βCDida)(D/L-Trp)]. Enantioselective

formation of [Eu(6βCDedta)(D/L-Trp)]- is evidenced by the changes induced in the D/L-

Trp- spectrum seen in Figs. 4.11e and 4.11f. However, the resonances are broadened

consistent with exchange between the guest in the free state and the host-guest complex

environments being in the intermediate exchange regime of the NMR timescale. This is

either a consequence of the chemical shift difference between the free D/L-Trp- and the

[Eu(6βCDedta)(D/L-Trp)]- environments being greater, or the exchange process being

slower than those in the two preceding systems. Differentiation between these two

possibilities cannot be made on the basis of the current data as is also the case for the other

systems studied.

A 2D 1H ROESY NMR plot (Fig. 4.21a) shows a cross-peak arising from dipolar

through-space interaction between H3 and H5 of [Eu(6βCDida)]+ and H2 of D-Trp- while

this cross-peak is replaced by one arising from interaction between H3 and H5 of

[Eu(6βCDida)]+ and H4 of L-Trp- in Fig. 4.21b. These data indicate a significant difference

of orientation of Trp- within [Eu(6βCDida)(D-Trp)] by comparison with that in

[Eu(6βCDida)(L-Trp)] as the observation of a significant ROESY cross-peak requires the

interacting protons to be within 400 pm proximity. This difference is probably induced by

the combined effects of the bidentate coordination of Eu3+ through the amino acid

carboxylate and amine groups and the differing interaction of the homochirality of the

βCD of [Eu(6βCDida)(D/L-Trp)] with the opposite chiralities of the D-Trp- and L-Trp-

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Duc-Truc Pham Chapter 4

- 175 -

guests. This evidently corresponds to the three point contact required for enantioselectivity

suggested by Dodziuk et al.1

4.1.5.2. Complexation and Enantioselectivity in the 4-Hydroxyl-D/L-phenylglycinate

(4OHPhg-) System.

It is seen from the Fig. 4.12.a that the H1 and H2 resonances are doublets because of

coupling with each other with fine structure superimposed as consequence of weak

coupling with the more distance H on the chiral carbon. This simplified analysis of the

proton spectrum of the phenyl ring is sufficient for the purpose of the discussing

enantioselective complexation.

The 1D 1H NMR spectrum of D/L-4HOPhg– shows no evidence of enantioselectivity

occurring in the presence of either equimolar βCD or any of the three substituted βCDs

although substantial downfield chemical shift changes occur indicating host-guest

complexation (Figs. 4.12-14, a-d). In the presence of equimolar 3βCDida2- and Eu3+ the H2

doublet almost resolves into two broadened doublets with that downfield characterizing the

[Eu(3βCDida)(L-4HOPhg)] host-guest complex, but the H1 doublet only shows broadening

(Figs. 4.12e and 4.12f). In contrast the H1 doublet resolves into two sharp doublets with

that of [Eu(6βCDida)(L-4HOPhg)] being upfield and the H2 doublet showing no evidence

of enantioselectivity (Fig. 4.13e and 4.13f). These contrasting data are consistent with

either D/L-4HOPhg- entering opposite ends of the 3βCDida- and 6βCDida- to minimize

electrostatic repulsion, or with the C2A and C3A carbon inversions inducing significantly

different 4HOPhg- orientations within the 3βCDida- and 6βCDida- annuli or a combination

of these effects. Both the H1 and H2 doublets of [Eu(6βCDedta)(D/L-4HOPhg)]- are

broadened consistent with exchange of D/L-4HOPhg- between the free and host-guest

complex environments being in the intermediate exchange regime of the NMR timescale

(Figs. 4.14e and 4.14f).

The 2D 1H ROESY NMR plots of [Eu(3βCDida)(D-4HOPhg)] and [Eu(3βCDida)(L-

4HOPhg)] both show strong cross-peaks formed between either D-4HOPhg- or L-4HOPhg-

H2 and the 3βCDida2- H3, H5 and NCH2 protons (Fig. 4.22). However, no cross-peaks are

formed by either D-4HOPhg- or L-4HOPhg- H1. This suggests that D/L-4HOPhg- is bound

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Duc-Truc Pham Chapter 4

- 176 -

to Eu3+ through the amino acid carboxylate and amine groups such that its H2 proton is

deeper in the βCD annulus than is H1. Whereas, the 2D 1H ROESY NMR plots of

[Eu(6βCDida)(D-4HOPhg)] and [Eu(6βCDida)(L-4HOPhg)] both show strong cross-peaks

formed between either D-4HOPhg- or L-4HOPhg- H1 and H2, and the 6βCDida2- H3 and H5

protons (Fig. 4.23). This suggests that D/L-4HOPhg- is also bound to Eu3+ through the

amino acid carboxylate and amine groups, but now the aromatic ring fully complexed in

the βCD annulus.

4.1.5.3. Complexation and Enantioselectivity in the D/L-Pheniramine (Phm) System.

It is seen from the Fig. 4.18a that the H4 resonance is a doublet because of coupling with

H3 with fine structure superimposed as consequence of weak coupling with more distance

H2 and H1. The H2 resonance is a triplet because of coupling with H1 and H3 with fine

structure superimposed. The H1 resonance is a doublet with fine structure superimposed

from coupling with H3 and H on the chiral carbon. The H3 multiplet structure is uncertain

because of resonance overlapped. This simplified analysis of the proton spectrum of the

pyridine ring is sufficient for the purpose of discussing enantioselective complexation.

The series of 1D 1H NMR spectra of D/L-Phm alone and in the presence of equimolar

βCD, equimolar substituted βCDs, and equimolar substituted βCDs and Eu3+ (Fig. 4.18)

shows interesting contrasts with those of D/L-Trp- and D/L-4HOPhg- discussed above.

These probably arises from the quite different structure and the positive as opposed

negative charge of D/L-Phm. While βCD induces some significant chemical shift changes

and overlapping doubling of the H1, H2 and H4 resonances (Fig. 4.18b), 3βCDida2- induces

a well-resolved doubling of the H1-H4 resonances consistent with D/L-Phm being in fast

exchange between the free state and the [(3βCDida-2-)(D-Phm)] and [(3βCDida2-)(L-Phm)]

enantioselective host-guest complexes (Fig. 4.18c). This is echoed by the [(6βCDedta3-

)(D/L-Phm)] host guest complexes (Fig. 4.18e) and together these systems show the

greater enantioselectivity. However, the enantioselectivity of the [(6βCDida2-)

(D/L-Phm)] host-guest complexes (Fig. 4.18d) is decreased by comparison with both the

[(3βCDida2-)(D/L-Phm)] and [(6βCDedta3-)(D/L-Phm)] host-guest complexes. This is

attributable to the structural differences between similarly charged 6βCDida2- and

3βCDida2- on the one hand while the higher charge of 6βCDedta3- coincides with a greater

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Duc-Truc Pham Chapter 4

- 177 -

electrostatic attraction for D/L-Phm and a coincident greater enantioselectivity on the

other.

The 2D 1H ROESY NMR spectra of the three substituted βCDs and D/L-Phm only

show cross-peaks for the phenyl ring consistent with it being complexed inside the βCD

annulus with the pyridine ring residing adjacent to the annulus hydroxy groups to which it

might hydrogen bond through its nitrogen (Fig. 4.24). This may coincide with the phenyl

group entering from the wide secondary hydroxy group annular end of the 3βCDida2- and

the narrower primary hydroxy group annular end of 6βCDida2- and 6βCDedta3-.

In contrast to the negatively charged D/L-Trp- and D/L-4HOPhg- systems, the Eu3+

complexes of D/L-Phm show a similar or lesser degree of enantioselectivity than their

parent substituted βCDs as evidenced by the extent of doubling of the H1-H4 resonances. It

is probable that the positive charges of [Eu(3βCDida)]+ and [Eu(6βCDida)]+ and the zero

charge of [Eu(6βCDedta)] decrease electrostatic host-guest interactions by comparison

with the parent substituted βCDs (and thereby complexation) which is not compensated for

by direct complexation by Eu3+ as D/L-Phm has no metal ion chelating group.

4.1.5.4. Complexation and Enantioselectivity in the D/L-Histidinate (His-), D/L-

Phenylglycinate (Phg-) and (+/-)-β-Phenylserinate (βPhs-) System.

The aromatic resonances of D/L-Phg- and D/L-βPhs- are complex and the spectral

changes induced by equimolar amounts of βCD, substituted βCDs, and substituted βCDs

and Eu3+ were consistent with the formation of host-guest complexes their complexity

precluded a reliable analysis in terms of enantioselectivity (Figs. 4.19 and 4.20). In contrast

the equimolar 6βCDida2-, 3βCDida2- and 6βCDedta3- induced large downfield shifts for the

sharp singlet H1 and H2 resonances of D/L-His- as did equimolar 6βCDida2- and Eu3+,

3βCDida2- and Eu3+, and 6βCDedta3- and Eu3+ (Figs. 4.15-4.17). In the latter case the

resonances were substantially broadened consistent with exchange of D/L-His- between the

free and host-guest complex environments being in the intermediate exchange regime of

the NMR timescale (Fig. 4.17e and 4.17f). It appears that D/L-His- may be too small by

comparison with the βCD annulus for enantioselective host-guest complexation to occur.

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Duc-Truc Pham Chapter 4

- 178 -

4.2. Iron(II)-β-cyclodextrins: Formation and Potential Environmental

Use.

4.2.1. Introduction

The coordinated metal ion in a binary metallocyclodextrin held in close proximity to the

annulus and the subsequent complexation of a guest for the formation of a ternary

metallocyclodextrin are of considerable interest as metalloenzyme mimics and particularly

as chiral discriminators (Section 1.2.2). In collaboration with the research group of Prof.

Matthew A. Tarr (University of New Orleans, USA), the iron(II)-βCDs has been used to

enhance Fenton reactions for pollutant degradation.

The Fenton reaction23,24 involves the formation of a hydroxyl radical through reaction of

Fe2+ with H2O2 (Eqn. 4.1) and has been utilized for the degradation of hydrophobic

pollutants.25,26

H2O2 + Fe2+ Fe3+ + HO- + HO· (4.1)

The ferrous ion is regenerated through additional reactions and therefore acts as a catalyst.

The hydroxyl radical reacts with a wide variety of compounds. Reaction with alkenes and

aromatics is very fast, with second-order rate constants in the range of 109- 1010 dm3 mol-1

s-1.27 Since the hydroxyl radical is nonselective, it may be useful for degrading a broad

range of pollutants.28 However, major limitations of this approach include: 1) scavenging

of the hydroxyl radical by non-pollutant species and 2) isolation of pollutants through

binding in hydrophobic sites.29

Recent improvements in Fenton degradations of polycyclic aromatic hydrocarbons

(PAHs) and polychlorinated biphenyls (PCBs) showed that the efficiency of degradation

was enhanced by addition of βCD or carboxymethyl-β-cyclodextrin (βCDcm), which is a

mixture with substitution at multiple hydroxyl positions and is commercial available. It

was proposed in the presence of βCD and βCDcm a pollutant/cyclodextrin binary complex

is often formed due their complexing abilities. At the same time, the hydroxyl groups in

βCD and the carboxyl groups in βCDcm are able to bind Fe2+. In such a ternary complex,

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Duc-Truc Pham Chapter 4

- 179 -

pollutant molecules are brought closer to the catalyst and become an easier target for

degradation by the hydroxyl radical (Fig. 4.26).29-31

HO OH

Fe

HO

Cl

H O2 2

HO .

Cl

Cl Cl

Figure 4.26. Ternary Fe(II)-cyclodextrin-pollutant complex.29

The research described herein, in collaboration with the research group of Prof.

Matthew A. Tarr, (University of New Orleans, USA), has utilized 6βCDidaH2 and

6βCDedtaH3 to improve Fenton degradation to some extent, and comparisons with the

βCD and βCDcm systems are made. Both 6βCDidaH2 and 6βCDedtaH3 have been

characterized in terms of their speciation with respect to deprotonation (Section 4.1.3). To

further enhance this research, it was decided to study binary complexations of Fe2+ by

6βCDida2- by potentiometric titrations. For βCDedtaH3, the Fe2+ complexation is too

strong to be quantified by potentiometric titration.

4.2.2. Binary Iron(II) Complexation by 6A-Bis(carboxylmethyl)amino-6A-

deoxy-β-cyclodextrin (6βCDida2-) and its Protonated Forms

The titrations curves for the complexation of Fe2+:6βCDida2- (1:1) and (1:2) at the ratios

shown in brackets and associated protonation are shown on Fig. 4.27. The results obtained

from the best fit of these data using Hyperquad 200316 (Protonic Software)17 are given in

Table 4.6. The pKw obtained from electrode calibration is 13.77. The hydrolysis constant

for this formation of Fe(OH)+ used for fitting is 7.10.32 Speciation plots calculated using

Hyss 200619 (Protonic Software)17 from the data in Table 4.6 for the species produced are

shown in Figs. 4.28-4.29.

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Duc-Truc Pham Chapter 4

- 180 -

0

2

4

6

8

10

12

0.10 0.15 0.20 0.25 0.30 0.35

V NaOH (cm3)

pHa

b

c

Figure 4.27. The pH profiles of a) 6βCDidaH2 0.001 (mol dm3), b) Fe2+ 0.001 (mol

dm3)/6βCDidaH2 0.001 (mol dm3) (1:1) and c) Fe2+ 0.0005 (mol dm3)/6βCDidaH2 0.001

(mol dm3) (1:2) in aqueous 0.010 (mol dm3) HClO4 at I = 0.10 mol dm-3 (HClO4/NaClO4)

and 298.2 K.

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Duc-Truc Pham Chapter 4

- 181 -

Table 4.6. The stability constants for the complexation of Fe2+ by 6βCDida2- and their

acid dissociation constants (pKas) at I = 0.10 (HClO4/NaClO4) and 298.2 K.

Equilibrium reaction log(K)a log(K)b Eqn. No.

Fe2+ + 6βCDidaH- [Fe(6βCDidaH)]+ 3.15±0.08 3.10±0.07 (4.2)

Fe2+ + 6βCDida2- [Fe(6βCDida)] (K1) 5.44±0.06 5.41±0.05 (4.3)

[Fe(6βCDida)] + OH- [Fe(6βCDida)(OH)]- 5.96±0.05 5.88±0.05 (4.4)

Fe2+ + 6βCDida2- + OH- [Fe(6βCDida)(OH)]- 11.40±0.05 11.29±0.02 (4.5)

[Fe(6βCDida)(OH)]- + OH-

[Fe(6βCDida)(OH)2]2- 4.82±0.06 4.98±0.06 (4.6)

Fe2+ + 6βCDida2-+ 2OH-

[Fe(6βCDida)(OH)2]2- 16.22±0.04 16.26±0.06 (4.7)

Fe2+ + 2 6βCDida2- [Fe(6βCDida)2]2- 9.25±0.02 9.33±0.07 (4.8)

pKaa pKa

b

[Fe(6βCDidaH)]+ [Fe(6βCDida)] + H+ 6.46±0.08 6.45±0.07 (4.9)

[Fe(6βCDida)(H2O)]

[Fe(6βCDida)(OH)]- + H+ 7.74±0.05 7.81±0.05 (4.10)

[Fe(6βCDida)(OH)(H2O)]-

[Fe(6βCDida)(OH)2]- + H+ 8.88±0.06 8.73±0.06 (4.11)

a Data fitted over the pH range 3-10 for the systems Fe2+:6βCDida2- (1:1). b Data fitted over the pH range 3-10 for the systems Fe2+:6βCDida2- (1:2). The errors shown are the fitting errors, but when experimental error is taken into account the overall error is ± 3%.

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Duc-Truc Pham Chapter 4

- 182 -

CDida-Fe 1:1

3 5 7 9 11pH

0

20

40

60

80

100

% s

peci

atio

n to

[Fe2+

] tota

l a

bc d

e

f

g

Figure 4.28. Speciation with [Fe2+]total = 100%, curve a = Free Fe2+, curve b =

Fe(OH)+, curve c = [Fe(6βCDidaH)]+, curve d = [Fe(βCDida)], curve e =

[Fe(βCDida)(OH)]-, curve f = [Fe(βCDida)(OH)2]2- and curve g = [Fe(βCDida)2]2- for

the complexation of systems Fe2+:6βCDida2- (1:1) at I = 0.10 mol dm-3 (NaClO4) and

298.2 K.

Fe-CD 1:2

3 5 7 9 11pH

0

20

40

60

80

100

% s

peci

atio

n to

[Fe2+

] tota

l

a

bc d

e

f

g

Figure 4.29. Speciation with [Fe2+]total = 100%, curve a = Free Fe2+, curve b =

Fe(OH)+, curve c = [Fe(6βCDidaH)]+, curve d = [Fe(βCDida)], curve e =

[Fe(βCDida)(OH)]-, curve f = [Fe(βCDida)(OH)2]2- and curve g = [Fe(βCDida)2]2- for

the complexation of systems Fe2+:6βCDida2- (1:2) at I = 0.10 mol dm-3 (NaClO4) and

298.2 K.

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Duc-Truc Pham Chapter 4

- 183 -

The stability constants (K1) obtained for [Fe(6βCDida)] (Scheme 4.4 and Table 4.6) are

in good agreement between the titrations for the (1:1) and (1:2) Fe2+:6βCDida2- systems. It

is seen that K1 for [Fe(6βCDida)] fit in the sequence [Fe(6βCDida)] < [Co(6βCDida)]

(log(K1/dm3mol-1) = 7.29)33 < [Ni(6βCDida)] (log(K1/dm3mol-1) = 9.74).33 This is in

agreement with the Irving-Williams sequence34 for K1 increasing in the sequence Mn2+ <

Fe2+ < Co2+ < Ni2+ for the complexation of bidentate ligands with N and O donor atoms.

The K1 for the [Fe(6βCDida)] and [Fe(IDA)] (log(K1/dm3 mol-1) = 5.5418 at I = 0.0 mol

dm-3 and 298.2 K) are identical within experimental error.

The stability of [Fe(6βCDidaH)]+ is less than that of [Fe(6βCDida)]. This is to be

anticipated from the charge attraction between Fe2+ and 6βCDidaH- being less than that

between Fe2+ and 6βCDida2- and/or restriction of the denticity of the protonated

substituents of 6βCDidaH-. This is in accord with ligand protonation usually decreasing the

stability of metal complexes.35

The coordination of Fe2+ by two 6βCDida2- to give [Fe(6βCDida)2]2- is characterised by

log(β/dm6 mol-2) = 9.29 (Table 4.6) which is slightly less than log(β/dm6 mol-2) = 9.8118

for [Fe(IDA)2]2-. This suggests that steric hindrance from the βCD entities in the formation

of [Fe(6βCDida)2]2- is small.

The pKa of [Fe(6βCDidaH)]+ (pKa = 6.46) (Eqn. 4.10) is lower than that of 6βCDidaH-

(pKa = 8.75) consistent with the positive charge of the [Fe(6βCDidaH)]+ enhancing

deprotonation. The formation of [Fe(6βCDida)(OH)]- and [Fe(6βCDida)(OH)2]2- (Table

4.6) may be viewed as either the deprotonation of aqua ligands coordinated to the Fe2+

centre or as OH- acting as incoming ligands.

4.2.3. Iron(II)-β-cyclodextrins for Targeted Fenton Oxidation

The degradation of 2,4,6-trinitrotoluene (TNT) in aqueous solution in the presence of

Fenton reagent was studied (M. A. Tarr, University of New Orleans) in the presence of

6βCDidaH2 and βCDcm at pH 3 and pH 7. These substituted βCDs accelerated the

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Duc-Truc Pham Chapter 4

- 184 -

degradation of TNT in aqueous solution. The degradation products differed for each

substituted βCD which in turn differed from those produced in the absence of substituted

βCD (Fig. 4.30).29 At pH 3 where [Fe(6βCDidaH)]+ is the only complex present the

degradation of TNT was marginally more rapid than at pH 7 where a higher proportion of

Fe2+ is complexed as a mixture of [Fe(6βCDidaH)]+, [Fe(6βCDida)] and

[Fe(6βCDida(OH)]-. However, βCDcm (at pH 3) was the more effective accelerator of

TNT degradation. Evidently, the mode of complexation of Fe2+ has a significant effect on

the rate of the degradation process.

-14.0-13.5-13.0-12.5-12.0-11.5-11.0-10.5-10.0

-9.5-9.0

0 2 4 6 8 10

Reaction Time (min)

ln[T

NT]

Water, pH 3

1 mM βCDcm, pH 3

1 mM βCDida2-, pH 3

1 mM βCDida2-, pH 7

Figure 4.30. TNT degradation kinetics with βCDs.29

The mechanisms for enhanced degradation are not fully understood, but could involve

either formation of a ternary complex that brings TNT closer to the Fe2+ catalytic site or

reactions between oxidized βCD and TNT.36 Further identification of the degradation

products is needed in order to better understand the degradation mechanism. Future work

utilised 6βCDedtaH3 may cast more light on this.36

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