1. 1
Binding of Inorganic Anions by New Polyaza-Macrocycles and
Macrobicycles
A thesis submitted for the
Degree of
Doctor of Philosophy
In the faculty of Science of the
University of London
By
Christos A. Ilioudis
Department of Chemistry
King’s College London
2003
3. 3
ABSTRACT
The synthesis of six monocyclic polyamines (60, 61, 62, 115, 116 and 117)
was achieved by the dipod-dipod cyclization reaction between 1,3-bis-bromomethyl-
benzene and aliphatic tosylated polyamines, followed by reduction of the resulting
monocyclic tosylamides. The crystal structures of five monocyclic tosylamides, two
monocyclic polyamines and fifteen monocyclic polyammonium salts are reported. It
was found that the largest of the monocyclic polyammonium species synthesized in
this project behave as ditopic receptors towards halide species. A supramolecular
‘Russian doll’ of the type positively charged species-anionic species-neutral species-
anionic species-positively charged species-etc was also crystallized from compound
62 and hydriodic acid.
The basicity behaviour of the monocyclic polyamines was studied by means
of pH titrations. pH titrations in the presence of sodium halides were also conducted
but no significant binding of halide species was found.
The synthesis of three bicyclic (126, 127 and 128) polyamines was achieved
by the tripod-tripod cyclization reaction between 1,3,5-tris-bromomethyl-benzene
and aliphatic tripodal tosylated polyamines, followed by the reduction of the
resulting bicyclic tosylamides. The crystal structures of two bicyclic tosylamides,
two bicyclic polyamines and six bicyclic polyammonium salts are reported. An
unusual intramolecular NH··· interaction, the first of its kind for an artificial
supramolecular system is observed for compound 126 and it is studied by means of
X-ray crystallography, potentiometry, NMR studies and theoretical studies.
X-ray studies revealed the formation of inclusive 1:1 complexes of 127
with fluoride, chloride, bromide and iodide. Many similarities between the anion
binding coordination modes of 127 and Dietrich’s octaazacryptand were found.
Potentiometric titrations showed very high binding constants for fluoride and
chloride with a F-
/Cl-
selectivity of more than five logarithmic units. No binding was
observed for either bromide or nitrate, something which is attributed to the higher pH
under which potentiometric studies were performed, in comparison with the pH
under which crystallizations were performed.
4. 4
Acknowledgements
I would like first of all to thank my supervisor Dr. Jon Steed, for giving me
the opportunity to do this Ph.D. I hope he has not regretted it, no matter how
stubborn or single minded I have been! I believe we have done some good research
in the past few years.
I am also very grateful to all the persons I have worked with. Many thanks to
Warwick for his valuable guidance and expertise in practical chemistry; to Karl who
has been a very good friend and colleague since I started the Ph.D.; to Asif, rightly
described as the ‘soul of the group’ by Warwick; to Dave for his contribution in
running things smoothly in our group; to all final year, Erasmus, and M. Sc. students
who made our lab an excellent working place. Special thanks also to Swamy and
Hasim from Professor Susan Gibson’s group for their help in the lab.
Thanks also to John Cobb and Jane Hawks for their help and for running my
NMR samples, to Roger Tye and Andy Cakebread for mass spectra, and to S. Boyer
(London Metropolitan University) for elemental analysis. Special thanks to Professor
Peter Gans (University of Leeds) for his guidance over the use of the program
‘Hyperquad’ and his extensive comments on the steps needed to be taken in order to
conduct pH titrations and analyze the results. Many thanks to Dr. C. Dennis Hall for
leaving a 736 GP Titrino along with a very old PC in lab 611 (still does its job!) after
his retirement. It was proved an immensely useful instrument during the last stages
of my Ph.D. I would also like to thank Dr. Michael Bearpark for carrying out
theoretical calculations on compound 126 as well as Dr. Derek Tocher from
University College London (although I could not understand much of what he said
because of his strong scottish accent!) for running the crystal structure of the iodide
salt of the cryptand 127 whilst our X-ray machine was down.
I am also very grateful to the Department of Chemistry at King’s College
London for my studentship.
Last but by no means least, I would like to thank my parents for financing my
studies and supporting me in any possible way during my life as a student.
5. 5
Table of Contents
Abstract
Acknowledgements
Table of contents
List of figures
List of schemes
List of tables
Abbreviations
Chapter One: Introduction
1.1 General introduction
1.1.1 Why anion binding is important but challenging
1.1.2 The choice of polyamine-based macrocycles as hosts for anionic
guests
1.2 Synthesis of macrocyclic polyamines
1.2.1 Introduction
1.2.2 High dilution
1.2.3 The choice of protecting and leaving groups
1.2.4 The use of templates
1.2.5 The choice of a solvent
1.3 Positively charged hosts operating by hydrogen bonding
1.3.1 Early advances in the field
1.3.2 Corands
1.3.3 Cryptands
1.3.4 Guanidinium based macrocyclic receptors
1.3.5 Cyclophanes
1.3.5.1 Two dimensional cyclophanes
1.3.5.2 Three dimensional cyclophanes
1.4 Other hosts
1.4.1 Non-protonated polyaza hosts
1.4.1.1 Zwitterions
6. 6
1.4.1.2 Positively charged systems
1.4.2 Neutral hosts operating by hydrogen bonding
1.5 Concluding remarks
Chapter Two: Synthesis and binding of inorganic anions by macrocyclic
azaphanes
2.1 Previous work and conclusions on polyammonium coordination
environments for anionic species
2.2 Aims of the project
2.3 The choice of macrocyclic azaphanes as complexones for inorganic species
2.4 The choice and synthesis of starting materials for meta-azacyclophanes
2.5 Synthesis of precursor macrocycles (cyclization)
2.6 Synthesis of target compounds (detosylation)
2.7 Crystal structures of tosylated polyaza-metacyclophanes
2.8 Crystal structures of polyaza-metacyclophanes
2.8.1 Crystal structures of two polyaza-metacyclophanes: 2,5,8
triaza[9]metacyclophane (115) and 2,6,9,13-
pentaaza[14]metacyclophane (60)
2.8.2 Crystal structures of polyaza-metacyclophane polyammonium salts in
which the host displays a good complementarity for halides
2.8.3 Other crystal structures of polyaza-metacyclophane polyammonium
salts with halides
2.8.4 Crystal structures of polyaza-metacyclophane polyammonium
salts including oxoanions
2.9 Solution studies
2.10 Crystallographic parameters for new macrocyclic systems
2.11 Hydrogen bond parameters for new macrocyclic systems
Chapter Three: Synthesis and properties of macrobicyclic azaphanes
3.1 Synthesis
3.2 Crystallographic evidence for an attractive intramolecular NH··· interaction
7. 7
3.3 Crystal structures of 128 and 128·3HCl
3.4 Crystal structure of 125
3.5 Crystal structures of polyammonium salts of 127
3.6 Potentiometric studies
3.6.1 Protonation studies of macrobicyclic azaphanes
3.6.2 Anion binding studies of 127
3.7 NMR studies
3.8 Computational studies
3.9 Crystallographic parameters for new macrobicyclic systems
3.10 Hydrogen bond parameters for new macrobicyclic systems
Chapter Four: Experimental Section
4.1 General
4.2 Synthesis
4.2.1 Synthesis of polyaza-metacyclophanes
N,N’,N’’-Tritosyl-1,4,7-triazaheptane (103)
N,N’,N’’-Tritosyl-1,5,9-triazanonane (104)
N,N’,N’’-Tritosyl-1,8,15-triazadecapentane (105)
N,N’,N’’,N’’’-Tetratosyl-1,4,7,10-tetraazadecane (106)
N,N’,N’’,N’’’-Tetratosyl-1,5,8,12-tetraazadodecane (107)
N,N’,N’’,N’’’,N’’’’-Pentatosyl-1,4,7,10,13-pentaazadecatriane (108)
N,N’,N’’-Tritosyl-2,5,8-triaza[9]metacyclophane (109)
N,N’,N’’-Tritosyl-2,6,10-triaza[11]metacyclophane (110)
N,N’,N’’-Tritosyl-2,9,16-triaza[17]metacyclophane (111)
N,N’,N’’,N’’’-Tetratosyl-2,5,8,11-tetraaza[12]metacyclophane (112)
N,N’,N’’,N’’’-Tetratosyl-2,6,9,13-tetraaza[14]metacyclophane (113)
N,N’,N’’,N’’’N’’’’-Pentatosyl-2,5,8,11,14-tetraaza[15]metacyclophane (114)
2,6,9,13-tetraaza[14]metacyclophane (60)
2,5,8,11,14-tetraaza[15]metacyclophane (61)
2,9,16-triaza[17]metacyclophane (62)
2,5,8-triaza[9]metacyclophane (115)
2,6,10-triaza[11]metacyclophane (116)
2,5,8,11-tetraaza[12]metacyclophane (117)
9. 9
List of Figures
Chapter 1
Figure 1.1. A list of commonly used protecting/ activating and leaving groups
used in macrocyclic polyamine synthesis.
Figure 1.2. Some of the most common azacorands for anion binding.
Figure 1.3. Some of the most common azaoxacorands for anion binding.
Figure 1.4. AMP, ADP, ATP, NAD and NADP are a few examples of
biological molecules that have been in the center of attention for supramolecular
chemists for many years.
Figure 1.5. Boat conformation and hydrogen bonding interactions between
the fully protonated [21]N5O2 and bromide.
Figure 1.6. Ligand conformation and hydrogen bonding for [22]N6- 6H+
,
6Cl-
. The ligand is planar with one chloride above and one below the plane.
Figure 1.7. The lariat macrocycles 29 and 30, bearing acridine moieties.
Figure 1.8.
Figure 1.9. Two optically active hexa-azamacrocycles with C2 and D2
symmetry respectively, synthesized from an enzymatically prepared material.
Figure 1.10. Bridged bis(macrocyclic pentaamines).
Figure 1.11. Inclusion of nitrate into the macrocyclic pocket of the
polyprotonated form of 27.
Figure 1.12. X-ray crystal structure of the salt [30]N10-10H+
·3[Pd(Cl)4]-2
·4Cl-
.
One [Pd(Cl)4]-2
anion is held inside the cavity by two bifurcated hydrogen bonds
(one crystallographically unique), H···Cl1: 2.413 Å, H···Cl2: 2.308 Å.
Figure 1.13. Commonly used cryptands for anion complexation.
Figure 1.14. The ‘soccer ball’ ligand possesses a tetrahedral recognition site
and great versatility depending on the pH of the medium.
Figure 1.15. Schematic representation of the binding versatility of the soccer
ball ligand. This ligand binds NH4
+
when unprotonated (a), water when neutral (b)
and a chloride when protonated (c).
Figure 1.16. Linear recognition of the hexaprotonated bis-tren ligand towards
the N3
-
anion which lies on the bridgehead N-N axis.
10. 10
Figure 1.17. Spherical recognition of the hexaprotonated bis-tren ligand
towards chloride. The chloride is located almost exactly on the N-N axis joining the
two bridgehead N-atoms and at equal distances from them. It is also coordinated in
an octahedral fashion to the six protonated secondary N-atoms. The structure of the
bromide complex of bis-tren is identical to the chloride.
Figure 1.18. A suitable cavity for F-
is provided by the hexaprotonated form
of 6. Strangely, in a recent crystallographic analysis of the chloride salt of the same
ligand, chloride fits inside the cavity despite the low affinity of the ligand for Cl-
in
comparison with F-
(selectivity F-
/Cl-
ratio: 108
).
Figure 1.19. The hexaprotonated forms of the macrocycles 39 and 40 have
displayed complete encapsulation of ClO4
-
and SiF6
-
respectively.
Figure 1.20. Complete encapsulation of ClO4
-
by the hexaprotonated ligand
39.
Figure 1.21. Encapsulation of SiF6
-
by the polyprotonated ligand 40. Notably,
each of the fluorines is attached via hydrogen bonding to each amine moiety.
Figure 1.22. Macrobicyclic carriers used for membrane transport of anions.
Figure 1.23. Binding pattern for guanidinium moiety with oxoanions.
Figure 1.24. The first examples of guanidinium-based macrocyclic hosts.
Figure 1.25. The guanidinium moiety embedded in a bicyclic framework.
Figure 1.26. Macrocyclic guanidinium-based systems for the synthesis of
aminoacids in their zwitterionic form.
Figure 1.27. The structure of dioctanoyl-L- -phosphatidylcholine (DOPC)
and the derivatized calixarene that was synthesized for its binding.
Figure 1.28. Calixarene 49 can form stable monolayers with 5’-AMP-
and 5’-
GMP-
by complementary hydrogen bonding in 1:1 and 2:1 molar ratios respectively.
Figure 1.29. Bis-amidinium calix[4]arene receptors for the binding of bis-
carboxylate anions.
Figure 1.30. A preorganized macrocycle containing a bicyclic guanidinium
subunit with six convergent hydrogen bonds for anion recognition.
Figure 1.31. Polyazacyclophanes used for the complexation of anionic
species.
Figure 1.32. A cyclophane host built upon the diphenylmethane moiety for
the binding of ANS.
11. 11
Figure 1.33. Complexation of the fluoride anion by the protonated ligand 60.
Figure 1.34. Complexation of chloride anion by the protonated ligand 61.
Figure 1.35. Encapsulation of the iodide anion by the protonated ligand 62.
Figure 1.36. Three-dimensional cyclophanes for the recognition of anionic
species.
Figure 1.37. Inclusion of the terephthalate anion by the protonated ligand 69.
Figure 1.38. Dome-shaped cyclophanes exhibit three-fold symmetry, suited
for the binding of the nitrate anion.
Figure 1.39. A cubic cyclophane suitable for the binding of ANS (8-
anilinonaphthalene-1-sulfonate).
Figure 1.40. Zwitterionic receptors for anion binding.
Figure 1.41. Quaternary ammonium salts as hosts for anionic species.
Figure 1.42. Iodide encapsulation inside the cavity of 76.
Figure 1.43. A quaternary ammonium cyclophane with catalytic activity.
Figure 1.44. Calixarenes have been proved successful candidates as neutral
receptors for a variety of anionic species.
Figure 1.45. An amide-linked bicyclophane and its crystal structure with
2Bu4NOAc in which encapsulation of the AcO-
anion is observed.
Figure 1.46. A cyclic peptide showing very strong affinity for p-nitrophenyl
phosphate.
Figure 1.47. Neutral macrocyclic systems for anion binding based on amide,
urea or thiourea units.
Figure 1.48. Polylactam-type neutral systems as receptors for anionic species.
Figure 1.49. Fluoride binding by the polylactam-type receptor 101.
Figure 1.50. Encapsulation of the (H2O-Cl-
)2 assembly in the cavity of the
macrocyclic polylactam 102.
Chapter 2
Figure 2.1. Ligand conformation and Cl(1) coordination environment for
triprotonated 2,2’,2’’-triaminoethylamine trichloride.
Figure 2.2. Ligand conformation and chloride anion coordination
environments for diprotonated diethylenetriamine dichloride.
12. 12
Figure 2.3. Bromide anion coordination environment and ligand
conformation for diprotonated diethylenetriamine dibromide.
Figure 2.4. V-shape coordination mode for one of the oxygen atoms of a
phosphate anion in the crystal structure of tetraprotonated triethylenetetramine
diphosphate dihydrate.
Figure 2.5. Three-coordination environment for one the oxygen atoms of a
phosphate anion in the crystal structure of tetraprotonated triethylenetetramine
diphosphte dihydrate.
Figure 2.6. Array of binding -NH sites of the proposed macrocyclic products
and possible binding mode of halides or oxygen atoms that belong to oxoanions.
Figure 2.7. The starting materials synthesized and used in this project.
Figure 2.8. The precursor tosylamides synthesized in this project.
Figure 2.9. The target compounds used as anion complexones in this project.
Figure 2.10. Up and down conformation of the tosyl groups in the crystal
structures of 109 and 110.
Figure 2.11. Crystal structure of 112. Note the ‘up’ conformation of two tosyl
groups in succesion, in contrast with 109 and 110.
Figure 2.12. Crystal structures of 113 and 114. Note the random positions of
the tosyl groups in both compounds as well as the ‘disarray’ of the atoms of the
aliphatic ring in 114.
Figure 2.13. Hydrogen bond network for the macrocyclic amine 115.
Figure 2.14. Crystal structure of 60. Note the all-anti, preorganized form of
this amine, as compared with the non-preorganized form of 115.
Figure 2.15. Space filling model of the fully protonated ligand 61 with two
chloride anions nesting on each side of the macrocycle.
Figure 2.15. Hydrogen bonding environments for the chloride anions on each
side of the hexaprotonated ligand 61. Note the ‘boat’ conformation of the
macrocyclic framework.
Figure 2.16. Hydrogen bonding environments for the chloride anions on each
side of the ligand for the crystal structure of 61·5HCl·H2O. Note the ‘boat’
conformation of the macrocyclic framework.
Figure 2.17. C-H···Cl-
short contacts for the anions positioned at the top and
bottom side of the macrocyclic cavity.
13. 13
Figure 2.18. Anion binding environments in the vicinity of the two
crystallographically unique macrocycles for 61·5HCl·2.5H2O. Note the ditopic nature
of the fully protonated macrocycle.
Figure 2.19. ‘Flat’ versus ‘boat’ conformation for the same hexaprotonated
ligand in the cases of: a) 61·5HCl·2.5H2O and b) 61·5HCl·H2O.
Figure 2.20. Anion binding environments in the vicinity of the fully
protonated ligand 60 in the crystal structure of 60·3HF·F-H-F·5H2O.
Figure 2.21. Ditopic binding mode of the pentaprotonated receptor 61
towards iodide anions.
Figure 2.22. Triprotonated ligand 61 has a good structural match for an iodide
anion.
Figure 2.23. Complexation of the species I-
···I2···I-
between two triprotonated
ligands 62.
Figure 2.24. Anion coordination environment in the vicinity of the protonated
ligand for 116·3HF·3H2O.
Figure 2.25. Hydrogen bond network in the proximity of the ligand for the
crystal structure of 116·3HCl.
Figure 2.26. Hydrogen bond network in the proximity of the ligand for the
crystal structure of 116·3HBr.
Figure 2.27. Hydrogen bond network in the vicinity of the macrocycle for the
crystal structure of 60·4HBr.
Figure 2.28. Oxygen atom of a perchlorate anion in the proximity of the
triprotonated ligand 114. Note the the short C-H···O contacts formed in the absence
of NH···O hydrogen bonds.
Figure 2.29. Hydrogen bond network between the pentaprotonated ligand 60,
a perchlorate anion at the ‘top’ and a bromide anion at the ‘bottom’ of the
macrocyclic ring.
Figure 2.30. The ‘parent’ aliphatic amines used for the synthesis of
metacyclophanes.
Figure 2.31. Distribution diagram for species present in solution for the
system 115. In each of the following diagrams in this section, LHn(n+) denotes the
state of protonation of the macrocyclic ligand.
14. 14
Figure 2.32. Distribution diagram for species present in solution for the
system 115.
Figure 2.33. Distribution diagram for species present in solution for the
system 117.
Figure 2.34. Distribution diagram for species present in solution for the
system 60.
Figure 2.35. Distribution diagram for species present in solution for the
system 61.
Chapter 3
Figure 3.1. Cryptand precursor macrocycles (124, 125) and target compounds
(126, 127, 128) synthesized in this project.
Figure 3.2. NH··· interaction in the aza-cryptand salt 126·4HCl·2H2O and the
crystal structure of the precursor macrobicycle 124. All other protons have been
omitted for clarity from both structures as well as the chloride anions and water
molecules from 126·4HCl·2H2O.
Figure 3.3. Schematic representation of the distances between each of the
carbons next to the aromatic ring and the plane defined by the aromatic ring.
Figure 3.4. Hydrogen bonding between the NH2
+
protons and the chloride
anions surrounding the protonated ligand 126.
Figure 3.5. Crystal structure of 128. Unexpectedly, the N···Centroid distance
is shorter than that for 126·4HCl·2H2O.
Figure 3.6. Crystal structure of 125. All atoms belonging to the tosyl moieties
have been removed for the sake of clarity with the exception of sulfur atoms.
Figure 3.7. Encapsulation of a fluoride anion in the crystal structure of
127·2HF·2H2SiF6·7H2O and in the crystal structure of 6·3HF·HCl·2PF6·5H2O (b) The
similarities between the ligand conformations and the coordination geometries of the
included anions are evident.
Figure 3.8. Encapsulation of a chloride anion in the crystal structure of
127·6HCl·4.5H2O (a) and in the crystal structure of 6·6HCl·2.75H2O (b). Very
similar coordination environments are observed again.
15. 15
Figure 3.9. Parameter dav which is the average of all the intramolecular
distances d1, d2, and d3 (see text) provides a useful insight into the conformational
change imposed to the ligand as a result of inclusive anion binding.
Figure 3.10. Encapsulation of a bromide anion in the crystal structure of
127·7HBr·3H2O. An additional NH···Br-
hydrogen bond is formed as a result of the
larger size of the bromide ion.
Figure 3.11. Inclusion of an iodide anion in the crystal structure of
127·2HI·4HI3. Smaller ‘bite’ angles are observed as a result of the positioning of the
encapsulated iodide further away from the apical nitrogen.
Figure 3.12. Several I3
-
anions are aligned across the hexaprotonated ligand
127 contributing in its ellipsoidal shape.
Figure 3.13. Distribution diagram for species present in solution for the
system 126 in 0.01 M HNO3/ 0.1M NaNO3.
Figure 3.14. Distribution diagram for species present in solution for the
system 128 in 0.01 M HNO3/ 0.1M NaNO3.
Figure 3.15. Distribution diagram for species present in aqueous solution for
the system 127 in 0.01 M HNO3/ 0.1M NaNO3.
Figure 3.16. Distribution diagram for species present in aqueous solution for
the system 127 in 0.01 M TsOH/ 0.1M TsONa.
Figure 3.17. Distribution diagram for species present in aqueous solution for
the titration of 127 with excess of NaF.
Figure 3.18. Distribution diagram for species present in aqueous solution for
the titration of 127 with excess of NaCl.
Figure 3.19. NMR spectra of 126 as a function of pH.
Figure 3.20. VT-NMR of compound 126 in CDCl3.
Figure 3.21. VT-NMR of compound 128 in CDCl3.
16. 16
List of Schemes
Chapter 1
Scheme 1.1. From Supramolecular Chemistry to Polyamine-Based Organic
Macrocyclic Hosts for Anion Recognition.
Scheme 1.2. Generalized procedure for the synthesis (dipode coupling) of
macrocyclic polyamines based on the formation of C-N bonds. X can be a strong
nucleophile group such as -NH2, -NH-Bn or -NH-Ts. L can be a good leaving group
such as a halide or -O-Ts. Reduction or deprotection follows which affords the
desired product.
Scheme 1.3. The Richman-Atkins cyclization,27
a typical example of a dipode
coupling cyclization.
Scheme 1.4. Schematic representation of synthetic alternatives to dipode
coupling affording macrocyclic polyamines.
Scheme 1.5. In the single capping version of the ‘crab-like’ cyclization,
reaction of a bis- -chloroacetamide takes place with a primary amine.
Scheme 1.6. The formation of tetraoxo[24]aneN8 as a byproduct of the dipode
coupling reaction that leads to dioxo[12]aneN4.
Scheme 1.7. Schematic representation of synthetic strategies for the
preparation of macrobicyclic species.
Scheme 1.8. Synthesis of an octaaza-cryptand by one-step
macrobicyclization.
Scheme 1.9. Double capping synthesis of NaBr cryptands.
Scheme 1.10. The high dilution principle. Low concentrations favor the
formation of the macrocyclic product.
Scheme 1.11. Synthesis of [18]N2O4. Catalytic hydrogenation of the
precursor macrocycle leads to the final product.
Scheme 1.12. An example of the use of diethoxyphosphoryl as a protecting-
activating group in the synthesis of polyazacyclophanes.
Scheme 1.13. An external template is a center or group which after
facilitating the cyclization reaction, is then eliminated.
Scheme 1.14. Synthesis of [12]N3 from a tricyclic orthoamide by virtue of an
endo-template effect.
17. 17
Scheme 1.15. Metal-templated synthesis of [14]N4.
Scheme 1.16. Template effect in the synthesis of a cryptand.
Scheme 1.17. Encapsulation of halide anions by diammonium catapinands,
the first artificial organic hosts for anionic species.
Chapter 2
Scheme 2.1. Formation of the starting materials (B). For S, see figure 2.7.
Scheme 2.2. The reaction that leads to the formation of the precursor
macrocycles. For precursor macrocycles, see figure 2.8.
Scheme 2.3. Detosylation leads to the formation of the target compounds.
Chapter 3
Scheme 3.1. Synthesis of starting material (A).
Scheme 3.2. Synthesis of starting materials (B).
Scheme 3.3. The reaction that leads to the formation of the precursor
macrocycles. The precursor macrocycles can be seen in figure 3.1.
18. 18
List of Tables
Chapter 2
Table 2.1. Logarithms of the stepwise protonation constants (logK) for the
meta-cyclophanes synthesized. Conditions: 0.001 M ligand, 0.01 M HCl, 0.1 M
NaNO3. a) Precipitation occurs at pH 9.3, thus making the determination of logK
values impossible, b) Conditions: 0.001 M ligand, 0.01 M TsOH, 0.1 M TsONa, c)
Cumulative constant (logK4 + logK5).
Table 2.2. Logarithms of the stepwise protonation constants for the ‘parent’
amines. Conditions: I = 0.1 mol dm-3
, T = 298 K; a: Not studied.
Chapter 3
Table 3.1 Comparison of structural data for 124 and 126·4HCl·2H2O.
Table 3.2. Structural data regarding the cryptates crystallized in the present
work. Napex refers to the apical nitrogen of the ligand, X-
refers to the corresponding
halide anion inside the cavity of the cryptand, and Centr (centroid) refers to the point
that corresponds to the centre of the aromatic ring of the cryptand. For definition of
parameter dav see figure 3.9. The values of the second crystallographically unique
cryptates for the chloride and the bromide salts are also given.
Table 3.3. Logarithms of the stepwise protonation constants for the
synthesized meta-cyclophanes. Conditions: a) 0.001 M ligand, 0.01 M HCl, 0.1 M
NaNO3, b) 0.001 M ligand, 0.01 M HCl, 0.1 M Et4NCl, c) 0.001 M ligand, 0.01 M
TsOH, 0.1 M TsONa.
Table 3.4. First anion binding constants observed for ligand 127 at different
states of protonation.
19. 19
Abbreviations
Ar (NMR) aromatic
b (NMR) broad
CDCl3 deuterated chloroform
CD3CN deuterated acetonitrile
d (NMR) doublet
DFT density functional theory
DMSO-d6 deuterated dimethyl sulfoxide
D2O deuterated water
FAB fast atom bombardment
HRMS high resolution mass spectrometry
wavelength
J coupling constant
m (NMR) multiplet
MHz megahertz
mL millilitre
MP2 Møller-Plesset 2
MS mass spectroscopy
NMR nuclear magnetic resonance
K protonation constant
Ks binding constant
pt (NMR) pseudo-triplet
s (NMR) singlet
t (NMR) triplet
VT (NMR) variable temperature
Dep diethoxyphosphoryl
Bus tert-butylsulfonyl
AMP adenosine monophosphate
ADP adenosine diphosphate
ATP adenosine triphosphate
pH -log[H]
DNNS dinonyl naphthalene sulfonate
21. 21
CHAPTER ONE:
INTRODUCTION
1.1 General introduction
1.1.1 Why anion binding is important but challenging
Anion complexation1-6
has been one of the most rapidly growing research
fields within supramolecular chemistry.7, 8
Many areas of chemistry and biochemistry
are directly affected by the advances in anion recognition.9
A few examples include
the binding and transport of nucleotides10
and amino acids,11
applications in
catalysis,12
analytical chemistry,13, 14
as well as in anion-templated reactions.15-17
However, anion recognition was relatively slow to develop until rather recently and
this is because of a number of difficulties associated with anion binding.18
In general,
anions are larger than cations and therefore require receptors of greater size than
cations. For example, F-
which is one of the smallest anions has an ionic radius
comparable to that of K+
(1.36 Å vs. 1.33 Å). In addition, anions have higher free
energies of solvation than cations of similar size ( GF- = -434.3 kJ mol-1
vs. GK+ =
-337.2 kJ mol-1
) which means that anion hosts must compete more effectively with
the surrounding medium. The shape of many anionic species is another challenge as
even simple inorganic anions occur in a range of geometries. Apart from the
spherical halides, PO4
3-
and SO4
2-
are tetrahedral, NO3
-
is trigonal planar, SCN-
and
N3
-
are linear and many other inorganic, organic and biologically important anions
exist in a variety of shapes. Moreover, many anions only exist in a narrow pH
window which can cause problems especially in polyamine-based receptors
operating by hydrogen bonding, where the host may not be fully protonated in the pH
region in which the anion is present in the desired form. Finally, anions are usually
coordinatively saturated and therefore bind only via weak forces such as hydrogen
bonding and van der Waals interactions.
22. 22
1.1.2 The choice of polyamine-based macrocycles as hosts for anionic guests
Many imaginative approaches have been taken in order to tackle the inherent
difficulties in anion binding and an impressive amount of work has been put into the
synthesis and study of various types of systems. Irrespective of their formal charge or
their binding site, these systems can be categorized in two major classes depending
on their structure: acyclic (podands) and cyclic (or macrocyclic) receptors (scheme
1.1).
Scheme 1.1. From Supramolecular Chemistry to Polyamine-Based Organic
Macrocyclic Hosts for Anion Recognition
Podands are chain-like hosts with a number of binding units situated at
intervals along their length whereas in cyclic receptors the binding units are arranged
around a closed ring. The cyclic receptors offer the advantage of being more
preorganized and therefore potentially more efficient as anion hosts due to the
thermodynamic stability of their complexes (chelate and macrocyclic or
macrobicyclic effect).19
In the development of macrocyclic systems as receptors for
anionic (and cationic) species the amine moiety has played a key role.20
It has been
SUPRAMOLECULAR CHEMISTRY
ANION RECOGNITION
MACROCYCLIC HOSTSACYCLIC HOSTS
ORGANOMETALLIC HOSTS ORGANIC HOSTS
POLYAMINE-BASED HOSTS
23. 23
an obvious choice for many researchers because it can act as a hydrogen donor, a
positively charged binding site, or both. Moreover, amine moieties have triggered
researchers’ interest as they are present in the recognition processes of many anionic
species by biological substrates. For example, the arginine residue, which contains a
guanidine group, is present in very important biological systems such as superoxide
dismutase, carboxypeptidase A and citric synthase.21
The crystallographic
characterization of two periplasmic anion transport proteins termed phosphate
binding protein (PBP)22, 23
and sulphate binding protein (SBP)24, 25
revealed the
complementarity of the arrangement of hydrogen bonding residues which gives rise
to their almost complete selectivity despite their remarkable similarity. N-H···O
hydrogen bonds play a crucial role in the tight binding of either phosphate or
sulphate within the cleft of PBP and SBP respectively. But apart from its
ubiquitousness in biological systems, the amine moiety is synthetically very diverse
and can be readily incorporated into a large variety of molecular scaffolds. Many
effective synthetic techniques are available for the formation of C-N bonds upon
which such macrocycles can be constructed. These techniques are briefly surveyed in
the following paragraphs.
1.2 Synthesis of macrocyclic polyamines
1.2.1 Introduction
The synthesis of macrocyclic polyamines has been largely based on the
formation of the C-N bond by reaction of amines or sulfone amides with strong
electrophiles such as halogeno compounds, acid chlorides and tosylates.26
The
cyclization step is usually followed by a reduction (of a C=O bond if, for example, an
acid chloride has been used as a starting material or of a N-S bond if a sulfone amide
has been used as such, scheme 1.2). A classic example of this type of cyclization was
reported by Richman and Atkins in the preparation of cyclic amines of medium to
large size, such as 1 (scheme 1.3).27
Apart from this dipode coupling, other synthetic
strategies such as single capping28, 29
or dipode capping30, 31
are also applicable to the
synthesis of polyamine macrocyclic products (scheme 1.4).
24. 24
Scheme 1.2. Generalized procedure for the synthesis (dipode coupling) of
macrocyclic polyamines based on the formation of C-N bonds. X can be a strong
nucleophile group such as -NH2, -NH-Bn or -NH-Ts. L can be a good leaving group
such as a halide or -O-Ts. Reduction or deprotection follows which affords the
desired product
Scheme 1.3. The Richman-Atkins cyclization,27
a typical example of a dipode
coupling cyclization
X
L
X
L
N NY Y
N NH H
Cyclization
Reduction/
Deprotection
N
N N
N
N
N N
N
N
H
NH NH
N
H
Ts
Ts
Ts
Ts
X X
+ Ts
Ts
Ts
Ts
a. X = OTs
b. X = OMs
c. X = Cl
d. X = Br
e. X = I
_
+
_
Na Na+
DMF
100 oC, 1-2 hr
H2SO4
100 oC, 48 hr
1
25. 25
Scheme 1.4. Schematic representation of synthetic alternatives to dipode coupling
affording macrocyclic polyamines
A
Scheme 1.5. In the single capping version of the ‘crab-like’ cyclization, reaction of a
bis- -chloroacetamide takes place with a primary amine
An interesting method for the synthesis of monofunctionalized polyaza-
crown ethers and cyclams, which is a typical example of a single capping reaction,
was developed by Bradshaw et al. for the synthesis of lariat azamacrocycles such as
2 and 3. This method consists of the ring closure reaction of a crab-like bis-a-
chloroamide with a primary amine, followed by a reduction (scheme 1.5).28, 29
Dipode capping reactions are often reported as byproducts of dipode coupling
reactions. Kimura et al. reported the formation of tetraoxo[24]aneN8 (5) along with
the formation of the monomer dioxo[12]aneN4 (4, scheme 1.6). Of course, these
general synthetic strategies can also be applied to the formation of macrobicyclic
species (scheme 1.7).32
The preparation of a well studied octaazacryptand (6) has
been reported by a tripode capping bicyclization (scheme 1.8),33
a much quicker
procedure than the stepwise syntheses of the same product.34
Two elegant synthesis
of NaBr cryptand complexes (7 and 8) in one step by double capping were reported
single capping dipode capping
a) b)
O
N N
Cl Cl
O O
NH2
N
H
Me
O
N
N
N
O
NHEt
N
N
N O
OHN N ClCl
O O
Me Me
OH O NH2
EtEt
+ Et Et
1) CH3CN, 0 to 80 oC, Na2CO3
2) BH3
.THF, THF
Me
Me
+
1) CH3CN, LiBr
2) LiAlH4
2
3
26. 26
in 1984 (scheme 1.9).35
It must be noted, however, that one-pot macrobicyclizations
usually lead to considerably lower yields than macrocyclizations. The reason is
simply because the formation of three bonds instead of two in a single condensation
step is required and thus, more polycondensation side reactions occur at the same
time.
Scheme 1.6. The formation of tetraoxo[24]aneN8 as a byproduct of the dipode
coupling reaction that leads to dioxo[12]aneN4
Scheme 1.7. Schematic representation of synthetic strategies for the preparation of
macrobicyclic species
N
H
NH
N
H
NH
NH
N
H
NH
N
H
O O
O O
N
H
OEt OEt
O O
N
H
NH2
NH2
NH
N
H
NH
N
H
O O
+
(monomer)
Dioxo[12]aneN4
(dimer)
Tetraoxo[24]aneN8
4
5
tripode coupling
single capping double capping
tripode capping
a) b)
c) d)
27. 27
Scheme 1.8. Synthesis of an octaaza-cryptand by one-step macrobicyclization
Scheme 1.9. Double capping synthesis of NaBr cryptands
N
H
N
H
N
N
H
N
H
N
N
H
N
H
NH2
NH2
N
NH2
1) 3 (CHO)2
2) NaBH4
6
NH3
NN
Br Br
NN
Br Br
NH3
N
N
NN
NN
NN
NN
N N
NN
N
N
+
+
MeCN, 100 oC, 18h
medium pressure
MeCN, 100 oC, 18h
medium pressure
7
8
28. 28
Macrocyclic synthesis is usually more difficult than it appears on paper.
However, chemists are armed with a number of techniques such as high dilution, the
use of efficient protecting and leaving groups, the use of compounds that can act as
templates and the use of suitable solvents (or their absence)36
as the reaction media.
The essential elements of these cyclization techniques are outlined in this overview.
For the reader who is interested in obtaining more detailed information in cyclization
procedures involving the formation of C-N bond or in synthesis of aza-crowns in
general, many other detailed reviews are available.26, 37-39
1.2.2 High dilution
High dilution is possibly the oldest of the techniques used for the synthesis of
macrocyclic polyamines.40
It was first applied by Ruggli41-43
in the formation of
cyclic amides in 1912. The concept of high dilution is depicted in scheme 1.10. The
intramolecular ring closure reaction is a first order reaction and therefore its rate is
proportional to the concentration. On the other hand, the intermolecular condensation
reaction is second order and therefore its rate is proportional to the square of the
concentration. As a result, high dilution favors the intramolecular reaction.
Scheme 1.10. The high dilution principle. Low concentrations favor the formation of
the macrocyclic product
A B
AB
A
B
i
ii
R inter.= aii[CAB]2
R intra.= ai[CAB]
29. 29
In practice, the high dilution principle is implemented by dissolving the
starting materials in large amounts of solvents and introducing the resulting solutions
into the reaction flask over a long period of time. The addition rate of the solutions is
a critical parameter and must be adjusted such as to make cyclization dominant over
polymerization. For that reason, specially adapted apparatus is frequently used in
cyclizations.44
The crucial features are precision addition funnels or syringe pump
apparatus which deliver the solutions into the reaction flask at a low and constant
rate, as well as the vigorous stirring of the reaction mixture achieved by a magnetic
stirrer bar or by a high-speed motor. All these experimental conditions are not
necessarily a prerequisite however as cyclizations may occur at relatively high
concentrations (depending on the intrinsic rate of each reaction step and the
preorganization of the precursors) or without the simultaneous slow addition of the
starting materials. For example, Tabushi et al. reported the synthesis of a series of
cyclic amides45
and C-alkylated macrocyclic polyamines46
by a procedure that
requires neither high dilution nor nitrogen protection. The Richman-Atkins
cyclization does not require high dilution conditions and neither does the single
capping method for the preparation of monofunctionalized azacrowns, developed by
Bradshaw et al.29
Interestingly, in the latter case the reactants were first mixed in a
small amount of acetonitrile at low temperature for a few hours. The authors
suggested that mixing at the initial low temperature provides an ordered association
of the reactants through hydrogen bonding that could lead to higher yields. The
existence of the template effect, which is discussed separately, also plays an essential
role in reactions that may proceed under more usual concentration conditions.
1.2.3 The choice of protecting and leaving groups
A list of the more commonly used protecting and leaving groups in
polyamine macrocycle synthesis is given in figure 1.1.
As early as 1954, Stetter and Roos reported that the condensation of terminal
halide derivatives with bis-sulfonamide sodium salts proceeded under high dilution
conditions to give moderate yields of macrocyclic sulfonamides.47
Twenty years
later, Richman and Atkins found that, by using either tosylate, mesylate or halides as
30. 30
leaving groups and performing the reaction in a dipolar aprotic solvent such as DMF,
the need for high dilution conditions is obviated.27
It seems that other factors such as
template effects48, 49
as well as ordered association of the reactants through hydrogen
bonding29
play a crucial role in successful cyclizations although there are references
to high-yield cyclizations which can not be explained by any known effect.50, 51
Since
the Richman-Atkins paper, toluenesulfonamide has become the most popular group
for the protection of polyamine starting materials. Its purpose in the cyclization
reactions is dual. It enhances the acidity of the secondary NH moiety making it easier
to deprotonate under basic conditions and it also acts as a nitrogen-protecting group,
allowing monoalkylation at the nitrogen atom. Another not very obvious advantage
of the tosylamides is that, due to their relatively high polarity and molecular weight
they are often solid materials that can be easily purified by recrystallization. Worth
mentioning is also the low price of tosyl chloride as well as the ease at which an NH
moiety can be tosylated.52, 53
Problems may arise at the last step of the synthetic procedure which is the
removal of the tosyl group and the isolation of the target macrocyclic amine.
31. 31
Figure 1.1. A list of commonly used protecting/ activating and leaving groups used in
macrocyclic polyamine synthesis
Techniques for the deprotection of toluenesulfonamides have been briefly
surveyed.54
For the deprotection of macrocyclic toluenesulfonamides, the most
popular method is by far the use of a concentrated acid, frequently HBr/AcOH in the
presence of phenol.55
Reductive methods including the use of NH3/THF-EtOH,56
LiAlH4 in THF or in Et2O,57
and sodium amalgam are also effective.52
The drastic
conditions under which these reactions are performed (refluxing for a prolonged
time) highlight the robust nature of the tosylated macrocycles. Other protecting
groups such as benzoyl,58
diethoxyphosphoryl,59, 60
benzyl,61
2,4-
dinitrobenzenesulfonamide,62
naphthalene-2 sulfonamide,63
and the tert-
butylsulfonamide (Bus) unit64
have been proposed for the protection of amines.
S
O
O
O S
O
O
O S
O
O
O
Y
Cl
O
S
O
O
NO2
O2N
S
O
O
S
O
O
S
O
O
P
O
OEt
OEt
O
Protecting and / or activating groups
Leaving groups
Y in where Y= O-Cl, O-Me, O-Et -Cl in
Toluenesulfonyl-
(Tosyl-)
acid derivative
halides: -Cl, -Br, -I
2,4 Dinitrobenzenesulfonyl- Benzenesulfonyl-
2-Naphthalenesulfonyl- Tert-butylsulfonyl
(Bus)
Diethoxyphosphoryl
(DEP)
Benzoyl-
mesyl- tosyl-
acetyl chloride
32. 32
However, all these protecting groups suffer from disadvantages such as difficult
reaction conditions, low yields or contamination of the target product with impurities
that are difficult to separate. For example, removal of the benzyl group in the
synthesis of the [18]N2O4 macrocycle (9) is achieved in a Parr hydrogenation
apparatus after three days (scheme 1.11).65
The exception is possibly the
diethoxyphosphoryl (DEP) unit which has been recently used in the synthesis of
polyazacyclophanes such as 10 (scheme 1.12).60
This group can be removed easily
by stirring the protected macrocycles in 1,4-dioxane saturated with gaseous HCl at
room temperature for 12-24 h.
33. 33
Scheme 1.11. Synthesis of [18]N2O4. Catalytic hydrogenation of the precursor
macrocycle leads to the final product
Selecting a leaving group is somewhat easier than selecting a protecting
group as there is a greater variety of choices. Chlorides and bromides are widely used
as they are inexpensive and easily obtainable. However, the most popular choice has
been the tosylates as they are very reactive (more than iodide) and also very easy to
make.66
Mesylates have been also used, especially in macrobicycle synthesis32, 53
but
generally tosylates are more stable (being less reactive than mesylates). Moreover,
when it comes to alkyl compounds, tosylates are often solid materials that can be
easily recrystallized, in contrast with alkyl halides which are liquid and therefore
have to be distilled. For example, diethylene glycol ditosylate is a crystalline solid
with melting point 87-89 o
C.67
In contrast, diethylene glycol diiodide is a liquid with
a boiling point 78-84 o
C at 0.8-0.9 Torr.68
O O II
OON N
N
OO
N
O O
NH
OO
NH
O O
+ BnBn
Bn Bn
MeCN, Na2CO3
NaI, 75%
H2 , EtOH
Pd(OH)2
92%
H H
9
34. 34
Scheme 1.12. An example of the use of diethoxyphosphoryl as a protecting-activating
group in the synthesis of polyazacyclophanes
1.2.4 The use of templates
A template is defined as any species that can bring about the organization of a
number of reacting components in order to direct the geometry of a specific
product.69
In polyamine-based macrocyclic systems, the use of temporary, external
templates (exo-templates), especially metals, has been very common. An external
template is a temporary center or group which may be used in cyclization reactions
and then eliminated (scheme 1.13).
N
N
N
N
O
Br
Dep
Dep
Dep
N
H
NH2
NH2
N
O
Br
Cl Cl
N
NH NH
Dep Dep
Dep
NH
N
NH
N
H
O
Br
(Et2O)P(O)H, CCl4
NaHCO3, Bu4NBr, r.t.
50% NaOH/PhMe, Bu4N(HSO4)
HCl(g) in dioxane, r.t.,
then NaOH
10
35. 35
Scheme 1.13. An external template is a center or group which after facilitating the
cyclization reaction, is then eliminated
This contrasts to an internal template (endo-template) by which a smaller ring is ring-
enlarged to include all the pre-existing parts of the molecule. Such an example is the
synthesis of [12]N3 (11) from a tricyclic orthoamide (scheme 1.14). The subsequent
cleavage of C=N and C-N bonds affords the target compound.70
A classic example of
an external metal-templated synthesis is that of 12 in which Ni2+
is used (scheme
1.15).71
Subsequent demetallation may be achieved either by adding acid, by a ligand
exchange process or following reduction of the metal if it has a suitable redox
couple.
36. 36
Scheme 1.14. Synthesis of [12]N3 from a tricyclic orthoamide by virtue of an endo-
template effect
Scheme 1.15. Metal-templated synthesis of [14]N4
An impressive template effect was observed in the synthesis of [2.2.2] cryptand (13)
by Kulstad and Malmsten (scheme 1.16).48, 49
Reaction of 1,8-diamino-3,6-
dioxaoctane and 1-iodo-8-chloro-3,6-dioxaoctane yielded the cryptand whereas
reaction of the same amine with 1,8-diiodo-3,6-dioxaoctane afforded the diaza-18-
crown-6. In the former reaction the iodide reacted much faster than the chloride
affording an intermediate amine with three branches. This intermediate was then
cyclized into the cryptand. On the other hand, the diiodo starting material reacts
N
NN Br
Br
N
N N
N
H
NH NH
1. NaH, THF
2.
+ BF4
1. LiAlH4
2. H3O+
3. BF4
11
_
_
3. OH
_
N
N
N
N
H H
H H
NH2
N
NH2
N
H H
N
N
NH2
N
H H
Ni
Ni2+, H2O
2+
1. OHC-CHO
2. BH4
-
3. CN-
+ [Ni(CN)4]2-
12
H2
37. 37
simultaneously with both amine moieties in the presence of the template cation
affording the diaza-crown.
Scheme 1.16. Template effect in the synthesis of a cryptand
1.2.5 The choice of a solvent
The choice of a suitable solvent as a medium for the synthesis of a polyamine
macrocycle is rather straightforward. A good solubility of the starting materials and
the base (of which the cation often serves the role of template) is desired. Thus, polar
solvents are usually chosen. For example, sodium hydride when combined with
DMSO produces dimsyl sodium which is a very powerful base. However, this
system has found little use in macrocyclic polyamine synthesis because of the high
boiling point of DMSO. In fact, DMF and acetonitrile are the most popular solvents
for polyamine cyclization followed by alcohols and benzene. DMF and acetonitrile
have both relatively high polarities and reasonable boiling points. In the case that an
unprotected aliphatic diamine is used as a starting material, then nonpolar, lipophilic
O O ClI
OONH2
NH2
O O
OO
N
O O
Cl
NH2
Cl
O O
N
OO
N
O O
+
Na2CO3
MeCN
13
38. 38
solvents like benzene44, 72
or toluene73
may be chosen. Usually these reactions
succeed in good yields as they are undertaken under high dilution.74
To the best of
our knowledge, solventless conditions have never been used for the synthesis of
macrocyclic polyamines.
1.3 Positively charged hosts operating by hydrogen bonding
All of the hosts that will be examined in sections 3.1-3.5 bind anionic species
through hydrogen bonding interactions which are both strong and directional. These
hosts, when protonated, possess a formal positive charge which assists further in
their anion complexing ability.
1.3.1 Early advances in the field
Seven months after the submission of Pedersen’s landmark paper on the
cation-binding behavior of dibenzo[18]crown-6,75
Simmonds and Park submitted a
manuscript in which the complexation of halides by synthetic organic hosts was
reported for the first time.76
The organic ligands used were the katapinands (scheme
1.17- in Greek: swallow up, engulf). The authors postulated that the
stability of the katapinate anion complexes must arise in part from the high positive
potential of the hole with respect to the anions and from hydrogen bonding within the
cavity and that it is not unlikely that a structure with two hydrogen bonds is involved.
This hypothesis was confirmed eight years later by an X-ray crystal structure
determination of the structure of chloridekatapinato-in, in-1,11-
diazabicyclo[9,9,9]nonacosane-bis(ammonium)chloride.77
39. 39
Scheme 1.17. Encapsulation of halide anions by diammonium catapinands, the first
artificial organic hosts for anionic species
1.3.2 Corands
Azacorands (the nitrogen analogues of crown ethers)78
and azaoxacorands are
possibly the most well studied class of macrocyclic polyamine receptors for anionic
species. They have attracted the interest of researchers since the early 1980’s as these
substances are cyclic analogues of biological polyamines such as histamine,
spermidine and putrescine and could therefore interact with biomolecules. Some of
these macrocycles can be seen in figure 1.2 (azacorands) and figure 1.3
(azaoxacorands).
N N N H NH
(CH2)n
(CH2)n
(CH2)n
n=7-10
(CH2)n
(CH2)n
(CH2)n
n=7-10
X-+ +
40. 40
Figure 1.2. Some of the most common azacorands for anion binding
NH
N
H
NH
NH
N
H
NH
n
NHNH
N
H
NHNH
N
H
N
H
NH
N
H
NH
NH
N
H
NH
N
H
NH
N
H
N
N
N
NH
N
H
NH NH
N
H
NHNH
H H
H
NH
N
NH
NH
N
NH
Me
Me
NH
N
NH
N
N
N
Me Me
Me
Me
[24]N6
[32]N8
[24]N6C6
14: n=1
15: n=2
16: n=3
17: n=5
[22]N6
[3n]Nn
18 19
20
21
22 23
41. 41
Figure 1.3. Some of the most common azaoxacorands for anion binding
One of the first applications involving azacorands was the supramolecular
catalysis of phosphoryl anion transfer processes. Nucleotide polyphosphates are
biologically very important anions. For example adenosine mono-, di-, and
triphosphate (figure 1.4) are basic components in bioenergetics.11
Their
oligophosphate chains are the center for chemical energy storage and transfer in all
living organisms. Naturally, the molecular recognition of nucleotides and other
phosphates has been the theme for much of the work regarding positively charged
azamacrocycles operating by hydrogen bonding, especially azacorands.79
Indeed, in
these species the arrangement of -NH2
+
moieties around the macrocyclic ring is
complementary to that of phosphate oxygen atoms along a polyphosphate chain. The
rings 19, 21 and 28 are amongst the first azacorands that were synthesized with the
purpose of binding biologically important phosphate derivatives. The binding
constants (log Ks) for 19-6H+
with AMP2-
, ADP3-
, ATP4-
in aqueous solution were
O
N NH
NH NH
NH N
O
NH
N
O
O
N
H
N
N
H
NH
O
NH
NH
N
H
N
H
N
H
O
N O
NH
O N
H
N
H
NH
N
H
NH
O
NH
NH
O
NH
H H
H
H
H
[21]N6O [21]N5O2
[24]N6O2
[27]N6O3
[18]N4O2
24 25 26
27
28
42. 42
found to be 3.4, 6.5 and 8.9 respectively.80
This clearly shows the importance of
electrostatic interactions in anion recognition. The ditopic macrocyclic hexaamine 27
was found to bind nucleotide polyphosphates strongly and selectively via
electrostatic interactions and charge assisted hydrogen bonding between the cationic
binding sites of the host and the phosphate groups of the guest.81
The same system
was also found to catalyze the hydrolysis of acetyl phosphate to orthophosphate as
well as the synthesis of pyrophosphate. This synthesis represents a process of
covalent bond formation taking place via supramolecular species and provides
evidence that these systems are able to catalyze not only bond-breaking but also
bond-making reactions.82
Figure 1.4. AMP, ADP, ATP, NAD and NADP are a few examples of biological
molecules that have been in the center of attention for supramolecular chemists for
many years
In the case of catalytic dephosphorylation of adenosine triphosphate, it was found
that the ring size plays a crucial role. The 21-membered polyamine ring was found to
be superior to larger macrocycles. Moreover, rates of dephosphorylation were found
to increase with increasing number of nitrogen atoms in the ring. In an effort to
obtain further insight into the mechanism of the dephosphorylation reaction, the
crystal structure of the pentahydrobromide salt of 26 was determined (figure 1.5)55
.
N
NN
N
NH2
OH OH
X O
N
NN
N
NH2
OH Y
OPO
O
O
N O
OH OH
PO
O
O
NH2
O
OP
O
O
O
OPOPO
O O
O O
PO
O
O
PO
O
O
O P
O
O
O
OP
O
O
O
OH
(AMP)
-
-
-
- -
-
-
- -
X:
X: (ADP)
X: (ATP)
-
-Y:
(NAD)Y:
(NADP)
- -
+
43. 43
In contrast with 18-6H+
, 6Cl-
(figure 1.6),83
the macrocycle ring crystallizes in a boat
form (which is also the case for the tetrachloride salt of 1584
as well as 2785
),
maintaining an ellipsoidal shape.55
However, no bromide is incorporated in the
macrocyclic cavity. The interaction of 15 with NAD+
and NADP+
was studied in
aqueous solution by using pH-metric titration, cyclic voltammetry and NMR
spectroscopy. NADP+
is selectively bound by the receptor over NAD+
due to its extra
phosphate moiety which interacts strongly with two adjacent ammonium groups
present in the tetraprotonated receptor.86
Figure 1.5. Boat conformation and hydrogen bonding interactions between the fully
protonated [21]N5O2 and bromide
Figure 1.6. Ligand conformation and hydrogen bonding for [22]N6- 6H+
, 6Cl-
. The
ligand is planar with one chloride above and one below the plane
44. 44
The interactions of phosphate and pyrophosphate anions with many polyammonium
cations deriving from several polyamines such as 14, 15, 22, and 23 were studied by
potentiometric, microcalorimetric and NMR measurements in solution. This work
showed that very stable 1:1 receptor-to-anion complexes are formed.87
A 1:1
receptor-to-anion complexation is also observed in the case of the sulfate anion
interacting with the same or similar polyprotonated azacorands.88
In another study of
phosphate binding with the polyammonium macrocycle deriving from 20, an unusual
crystallographic result in which both H2PO4
-
and H3PO4 coexist, was reported. The
potentiometric data support the crystallographic findings and suggest that these types
of ligands, based on two triamine units, can provide ditopic binding sites for two
discrete species.89
The synthesis of polyamine macrocycles with pendant chains has attracted
considerable interest since the late 1980’s.26, 90-92
New and facile synthetic
procedures have been developed but lariat azamacrocycles have only found limited
application as receptors for anionic species. An elegant example of increased
nucleotide binding ability in the order bibracchial azacorand > monobracchial
azacorand > azacorand was provided by Lehn et al.93
It was found that the receptor
30 (figure 1.7) bearing two acridine unities makes use of combined electrostatic and
stacking interactions. Thus it can interact simultaneously with both the adenine and
the nicotinamide moieties of NADP(H) whereas 29, bearing only one acridine group,
interacts less effectively with NADP(H). Also, a high selectivity for NADP(H) over
NADP (ca. 103
) and NAD(H) (>106
) was observed for 30.
45. 45
Figure 1.7. The lariat macrocycles 29 and 30, bearing acridine moieties
The synthesis and binding behavior towards ATP of the first optically active
macrocyclic polyamine was reported in 1986 (figure 1.8). Compound 31 was
prepared in high yield from L-ornithine via the Richman-Atkins cyclization
procedure. 31
P-NMR studies indicated the formation of a 1:1 complex of the
protonated macrocycle with ATP.94
In a more recent work, Alfonso et al. have
achieved the synthesis of two optically active hexa-azamacrocycles with C2 and D2
symmetry from an enzymatically prepared starting material (figure 1.9).95
Both
azamacrocycles 32 and 33 can be used in their protonated forms as receptors for
chiral anions, leading to stable complexes in aqueous solution.96
Macrocycle 32
shows moderate D-preference, while 33-6H+
binds to N-Ac-D-aspartate more
strongly than to the corresponding L-isomer. Moreover, the N-Ac derivative of
glutamate anion forms very stable complexes with both compounds. The
stoichiometry of these complexes can be either 1:1 or 1:2 depending on the
protonation state and the enantiomer of the anion.
Figure 1.8
N
O
N NH
N NH
NH N
ONH
N
N
O
N NH
N N
NH N
ONH
NH
O
N NH
NH NH
NH N
O
H
H
H
H
H
H
[24]N6O2
27
29 30
NHN
NNH
CH2OH
H
H
31
46. 46
Figure 1.9. Two optically active hexa-azamacrocycles with C2 and D2 symmetry
respectively, synthesized from an enzymatically prepared material
Apart from the organic and inorganic phosphates that have been a major point
of interest in anion binding, other anionic species have also been studied as targets
for aza(oxa)corands. The binding affinity of 19 (hexacyclen) towards anionic species
has been studied in aqueous solution by conductometry and pH potentiometry. It was
found that the hexacyclen chloride complex was about 4 times less stable at 25 o
C
than the nitrate complex despite the strong and direct NH2
+
···Cl-
hydrogen bonding
observed in the solid phase by X-ray crystallography for the species
19-H6·(NO3)2·Cl2·2H2O. The nitrate anions are indirectly bonded to the macrocycle
via enclathrated water molecules.97
Bridged bis-macrocyclic pentaamines such as 34
and 35 have also been synthesized and studied as hosts for inorganic and organic
anionic guests (figure 1.10). The workers found that the attachment of the second
polyamine moiety always enhances anion encapsulating abilities suggesting the
formation of sandwich-type complexes.30
In 1996, the crystal structure of the nitrate
complex of 27 in its tetraprotonated form was reported.98
One of the nitrate anions
was located within the macrocyclic cavity (figure 1.11). In the case of the smaller 18-
membered analogue 24, the four nitrates fall above and below the cavity of the planar
macrocycle.98
For these two nitrate salts in particular, molecular-dynamics
simulations have shown that solvation effects play an important role in
conformational changes in solution.
NH
NH
N
H
NH
NH
N
H
NHNH
NH
N
H
NH
N
H
32 33
47. 47
Figure 1.10. Bridged bis(macrocyclic pentaamines)
Figure 1.11. Inclusion of nitrate into the macrocyclic pocket of the polyprotonated
form of 27
Several protonated macrocycles have been found to form a number of
“supercomplexes” with coordination complex anions such as [Co(CN)6]3-
,
[Fe(CN)6]4-
and [PtCl6]2-
. X-ray crystallographic analysis has shown that in most
cases, the anions bridge between the macrocycles, and little anion selectivity is
observed. This indicates that binding takes place primarily by coulombic attractions.
The expression “supercomplex” 99, 100
is used to describe the second-sphere
coordination between the above anions and polyammonium macrocyclic receptors.
These supercomplexes may be considered as complexes of complexes. The central
NH
N
H
N
NH
NH
NH
N
H
N
NH
NH
O O
H H
R
R =
R = (CH2)3
34:
35:
48. 48
cation forms a complex with the respective anionic ligands and the resulting anionic
species is complexed by the polyammonium macrocycles. In fact, the second
complexation process is the organization of the second coordination sphere around
the central transition metal cation. The formation of the supercomplexes results in the
modification of the electrochemical as well as the photochemical properties of the
complexed anion. These properties are dependent upon the structure of the
polyammonium receptor. The binding of the square planar complexes [Pt(CN)4]2-
and
[PdCl4]2-
by the protonated polyazamacrocycle 17 was reported by Bencini et al.101,
102
For [PdCl4]2-
, solution studies revealed that the anion is inclusively bound by
macrocycles of the type [3 k]Nk with k 9. The macrocycle 17 exhibits a cavity size
more complementary to the dimensions of the complexed anion. The included anion
is exchanged only slowly with other complex anions in solution and the binding is
exothermic with o
= -16.3(4) kJ·mol-1
.101, 102
The inclusive character of this salt
was demonstrated by X-ray analysis (figure 1.12).102
In more detail, the macrocyclic
receptor adopts an “S-shaped” conformation in order to enfold the guest anion and
maximize N-H···Cl hydrogen-bonding interactions. However, in 17-
10H+
·5[Pt(CN)4]2-
·2H2O, two independent [Pt(CN)4]2-
anions are located outside the
macrocycle cavity, forming very short hydrogen bonds with the protonated nitrogen
atoms of the ligand.103
49. 49
Figure 1.12. X-ray crystal structure of the salt [30]N10-10H+
·3[Pd(Cl)4]-2
·4Cl-
. One
[Pd(Cl)4]-2
anion is held inside the cavity by two bifurcated hydrogen bonds (one
crystallographically unique), H···Cl1: 2.413 Å, H···Cl2: 2.308 Å
The acid-base properties as well as the photochemical reactivity of the
complexes formed between [Co(CN)5(SO3)]4-
and the polyammonium macrocyclic
receptors 16-8H+
, 17-10H+
and 21-8H+
were also studied. This particular anion
([Co(CN)5(SO3)]4-
) has attracted interest because it contains two different ligands
both having basic properties and being able to form hydrogen bonds with the
macrocycle. The results showed that in the case of the 21-8H+
, the cyanides are
involved in hydrogen bonding but the sulfites are not. Both ligands are involved in
hydrogen bonding with the other two macrocycles.104
.
1.3.3 Cryptands
The development of strategies for the synthesis of cryptands32, 44, 105
began
with the work of Lehn’s group published shortly after the discovery of the
katapinands by Park and Simmons.76
These molecules were used as hosts for cations
in the first place44, 105-107
but their potential as hosts for anionic species and especially
50. 50
halides, soon became apparent. Some of the most commonly used cryptands for
anion complexation can be seen in figure 1.13.
Figure 1.13. Commonly used cryptands for anion complexation
In 1975, the synthesis of the tetraprotonated macrotricyclic ligand 36, known
as ‘soccer ball’ was reported by Graf and Lehn.108
This ligand possesses a tetrahedral
recognition geometry which is achieved by placing four binding sites at the corners
of a tetrahedron and linking them with six bridges. Thus, the halides are bound by
four N+
-H···X-
hydrogen bonds (figure 1.14). The inclusive character of the chloride
anion complex was confirmed by X-ray analysis109
and inclusion of F-
, Cl-
and Br-
was observed in acidic solutions by 13
C NMR spectroscopy. In contrast, I-
does not
form a complex nor do any of the anions NO3
-
, CF3COO-
, or ClO4
-
. Notably, this
particular ligand was also found to bind a tetrahedral cation NH4
+
when unprotonated
(36a)109
and a water molecule (36b) when neutral,110
thus displaying a great
flexibility depending on the pH of the medium (figure 1.15).
Figure 1.14. The ‘soccer ball’ ligand possesses a tetrahedral recognition site and
great versatility depending on the pH of the medium
N
H
N
H
N
N
H
N
H
N
N
H
N
H
N
N
H
N
H
N
H
N
H
N
H N
N
H
N
H
N
N
O
N
N
H
N
H
N
O
N
O
H
H
H
6 37
38
O
N
N
O
O
N
N
O
O
O
36
51. 51
Figure 1.15. Schematic representation of the binding versatility of the soccer ball
ligand. This ligand binds NH4
+
when unprotonated (a), water when neutral (b) and a
chloride when protonated (c)
The ligand 37, also called ‘bis-tren’ is possibly one of the most extensively
studied cryptands as an anion complexon. The binding of chloride by bis-tren in
aqueous solutions was measured by several techniques, including 35
Cl NMR and
suggested that a chloride anion is located inside the cavity.111
The same conclusion
(formulation of a 1:1 complex) was derived for the azide cryptate by NMR data.112
These findings were confirmed by the crystal structures of the anion cryptates
formed by the fully protonated bis-tren ligand with F-
, Cl-
, Br-
and N3
-
.113
In the case
of the N3
-
complex (figure 1.16), linear recognition is observed resulting from the
high degree of size and shape complementarity between the cavity of the protonated
ligand and the linear triatomic N3
-
.
H
N
+
H
H
H
N
N
N
N
H
O
H
H
H
N
+
N
N
N
+
H
Cl
H
H
H
N
+
N
+
N
+
N
+
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
36a 36b 36c
52. 52
Figure 1.16. Linear recognition of the hexaprotonated bis-tren ligand towards the
N3
-
anion which lies on the bridgehead N-N axis
The structures of the bromide and the chloride complexes (figure 1.17) are very
similar to each other.
Figure 1.17. Spherical recognition of the hexaprotonated bis-tren ligand towards
chloride. The chloride is located almost exactly on the N-N axis joining the two
bridgehead N-atoms and at equal distances from them. It is also coordinated in an
octahedral fashion to the six protonated secondary N-atoms. The structure of the
bromide complex of bis-tren is identical to the chloride
53. 53
On the other hand, in the case of the fluoride complex, a mismatch of the included F-
anion with the ligand cavity was revealed.113
However, the macrobicyclic ligand 6
possesses a more suitable cavity for F-
. A remarkable stability constant (logKs= 11.2)
and a high F-
/Cl-
selectivity (ca. 108
) were observed for this ligand.34
X-ray analysis
of the hexafluoride salt of this compound confirmed the inclusive character of the
cryptate (figure 1.18).114
Nevertheless, a recent insight to the selectivity of this
octaazacryptand showed a dramatic increase in its affinity for chloride at pH 2.5.115
This evidence is supported by 1
H NMR titrations as well as by X-ray analysis of the
hexachloride salt revealing a chloride anion inside the bicyclic cavity. Complexation
of the sulfate and other polyanions (especially phosphates like HPO4
2-
, AMP2-
,
ADP3-
, ATP4-
) by the polyprotonated bis-tren was also studied and revealed high
binding constants. In the case of the phosphates the binding constants are somewhat
lower than those expected and this is possibly due to the fact that these large
substrates can be only partially included in the ligand cavity.
Figure 1.18. A suitable cavity for F-
is provided by the hexaprotonated form of 6.
Strangely, in a recent crystallographic analysis of the chloride salt of the same
ligand, chloride fits inside the cavity despite the low affinity of the ligand for Cl-
in
comparison with F-
(selectivity F-
/Cl-
ratio> 108
)
54. 54
The receptors 39 and 40, closely related to bis-tren, (figure 1.19) have been shown to
form inclusive complexes with the ClO4
-
(figure 1.20) and the SiF6
-
(figure 1.21)
anions respectively.116
In the later case, the cryptate was formed from the reaction of
the cryptand with HBF4. Unexpectedly, the encryptated anion turned out to be SiF6
-
which derived from action of HBF4 on the glass reaction vessel. Encapsulation of
perchlorate and nitrate within the hexaprotonated host 39 was later confirmed by
potentiometric and NMR titration methods.117
A 1:1 complexation stoichiometry for
both anions proved to be dominant with high complexation constants (log K = 3.4
and 3.7 for perchlorate and nitrate respectively).
Comparison of the stability constants for anion binding between 19 and the
bicyclic analogue 38 demonstrates a definite macrobicyclic effect.118
More
specifically, the protonated cryptand forms stable and selective complexes with
halides and the stability sequence was found to be I-
>Br-
>Cl-
. This trend is opposite
to that observed for bis-tren and can be explained by the structural features of the
ligands. Indeed, the structure of 38 is based on two wider N[(CH2)3NH2] tripod units
linked together by -(CH2)3- chains resulting in a higher and more spherical cavity.
Moreover, 38 forms stronger complexes with oxalate2-
and malonate2-
showing a
high selectivity between them.
Figure 1.19. The hexaprotonated forms of the macrocycles 39 and 40 have displayed
complete encapsulation of ClO4
-
and SiF6
-
respectively
O
N
N
H
O
O
N
H
N
N
H
N
H
NN
H H H H
N
N
H
N
N
H
N
N
N
N
H
N
H
N
N
39 40
55. 55
Figure 1.20. Complete encapsulation of ClO4
-
by the hexaprotonated ligand 39
Figure 1.21. Encapsulation of SiF6
-
by the polyprotonated ligand 40. Notably, each
of the fluorines is attached via hydrogen bonding to each amine moiety
56. 56
Two tosylated macrobicycles (41 and 42) as well as a katapinand (43, figure
1.22) have been used as lipophilic carriers for anions such as Cl-
, Br-
and NO3
-
across
an artificial liquid membrane.119
The workers used a large lipophilic counterion,
dinonyl naphthalene sulfonate (DNNS-
) that was expected to remain outside the
cavity of the carrier but stays within the organic membrane phase. A clear ability of
the 41·DNNS-
system to discriminate between Br-
and NO3
-
was observed. Other
selectivities exhibited by this system were rather modest and this could be due to
competition with exclusive complexes or due to the low inherent ability of these
amines to act as anion receptors.
1.3.4 Guanidinium based macrocyclic receptors
The guanidinium moiety has been a popular choice as an anion binding unit
due to its distinct oxoanion binding mode featuring two parallel hydrogen bonds in
addition to an electrostatic interaction (figure 1.23). The native guanidinium ion has
a logK of 13.5, meaning that it is protonated and therefore positively charged and an
effective hydrogen bond donor, over a wide pH range.8
Interest in the guanidinium
unit was sparked by its occurrence as part of arginine residues in naturally occurring
anion binding hosts.21
The majority of the artificial guanidinium-based systems are
acyclic and analogous to podand hosts for cations.
57. 57
Figure 1.22. Macrobicyclic carriers used for membrane transport of anions
Figure 1.23. Binding pattern for guanidinium moiety with oxoanions
The first examples of macrocyclic guanidinium-based anionic receptors 44 and 45
were reported by Lehn et al. in 1978 (figure 1.24).120
Both of these systems showed
only weak complexation of PO4
3-
(logKs = 1.7 and 2.4 in methanol/water), governed
by electrostatic interactions.
NN
N
O
N
N
N
N
O
N
O
N
N
N
N
N
N
N
N
N
N
Ts
Ts Ts
Ts
Ts
Ts
Ts Ts
Ts
Ts
Ts
Ts
(CH2)10
(CH2)10
(CH2)10
41 42
43
NH
N N
R
H H
R
R
NH
N N
R
H H
R
R
OO
R
P
O O
O ROH
¦
¦
¦
¦
¦
¦
¦
¦
¦
¦
¦
¦
_
+ +
_
58. 58
Figure 1.24. The first examples of guanidinium-based macrocyclic hosts
The binding characteristics of the guanidinium group can be improved by embedding
it in a bicyclic framework (figure 1.25). Thus, the hydration of the charged moiety is
reduced by the accumulation of hydrocarbon residues and the predictability of the
host-guest orientation can be improved.2
Figure 1.25. The guanidinium moiety embedded in a bicyclic framework
Following this principle, de Mendoza and his group synthesized the host 46 (figure
1.26) with the purpose of amino acid recognition in the zwitterionic form.121
Single-
point liquid-liquid extraction experiments showed that selectivity for aromatic amino
acids such as tryptophan and phenylalanine suggested that chiral recognition
occurred by simultaneous noncovalent interactions of the substrate with the receptor.
This model was further supported by molecular modelling.122
A similar receptor (47,
figure 1.26) was reported by Gloe and Schmidtchen in a study on the extraction of
14
C-labeled amino acids.123
It was observed that even quite hydrophilic amino acids
such as serine and glycine could be transferred to the organic phase with 1:1 host-
guest stoichiometry. Maximum extractability was reached at pH 9, suggesting that
the amino acids were indeed extracted in their zwitterionic forms.
O O
NH NH
OO
NHNH
NH2
NH2
NHNH
N N
N
H
N
H
NH2
NH2
NH2
H H
++
++
+
44
45
N
N
H
N
HR R
R R
+
59. 59
Figure 1.26. Macrocyclic guanidinium-based systems for the synthesis of aminoacids
in their zwitterionic form
Apart from azaoxacrown ethers, calixarenes have also been used in
combination with guanidinium moieties with the purpose of anion binding.
Calixarenes have a reputation as one of the most extensively used class of molecules
for cation binding.124
A review of the chemistry of the calixarenes bearing
azaaromatic moieties, including their synthetic approaches along with complexing
properties and catalytic activities has appeared recently.125
For the binding of a rather
complicated zwitterionic substrate, dioctanoyl-L- -phosphatidylcholine (DOPC) the
receptor 48 (figure 1.27) was synthesized with the intention to make use of the key
interactions found in the crystal structure between the McPC603 antibody with
phosphorylcholine.126, 127
The calix[6]arene introduced for the binding of the
tetraalkylammonium function was linked to a chiral guanidinium unit. Strong
binding was observed in chloroform (Ks = 7.3 x 104
) and NMR data as well as
molecular modeling supported the anticipated binding mode with the calixarene
encapsulating the ammonium group by adopting a cone conformation.128
Molecular
recognition of nucleotides by a simple calix[4]arene derivative with two alkyl
guanidinium groups at the air-water interface has been recently reported by Liu et al
(figure 1.28).129
Film balance measurements and relaxation experiments showed the
formation of stable monolayers of 49 with 5’-AMP-
and 5’-GMP2-
. The anionic
subspecies can then be easily transferred onto solid substrates along with the
monolayers of 49 because of the strong intermolecular interactions (XPS analysis of
the LB films revealed that the binding constants of 49 with 5’-AMP-
and 5’-GMP2-
N
N
H
N
H
O
O
OO
O
O N
O
O
N
N
H
N
H
O
Si
O
NO
N
O N
S
CH3
CH3
+ +
46 47
60. 60
are (1 0.5) x 106
and (6 1) x 106
respectively. It was concluded that that recognition
takes place through multiple hydrogen bonding and electrostatic interactions with a
molar ratio of 1:1 for the 49·5’-AMP complex and 1:2 for the 49·5’-GMP complex.
The amidinium moiety (closely related to guanidinium) has also been recently
utilized in a calixarene framework especially aimed at the recognition of bis-
carboxylate anions.
Figure 1.27. The structure of dioctanoyl-L- -phosphatidylcholine (DOPC) and the
derivatized calixarene that was synthesized for its binding
N
N
H
N
H
OH
N
H
OMe
MeO
OMe
MeOOMe
OH
O
O
(CH3
)3
N O
P
O O
C(CH2)6CH3
OO O
tBu
tBu
tBu
tBu
tBu
+
+
DOPC
48
61. 61
Figure 1.28. Calixarene 49 can form stable monolayers with 5’-AMP-
and 5’-GMP-
by complementary hydrogen bonding in 1:1 and 2:1 molar ratios respectively
Two simple calix[4]arene receptors containing amidinium moieties were synthesized
and tested for this purpose (figure 1.29).130
Solution studies have shown that these
receptors coordinate bis-carboxylate anions with multiple equilibriums in solution.
Moreover, X-ray crystallographic analysis of the picrate salt of 50 and the malonate
salt of 51 revealed the propensity of these species to form complex hydrogen
bonding networks.
Figure 1.29. Bis-amidinium calix[4]arene receptors for the binding of bis-
carboxylate anions
N
N
O
OH
OH
O
NH2
H2N
NH2
NH2
H H
Cl
Cl
49
+
+
_
_
O
OH
OH
O
NH2 NH2 NH2 NH2
O
OH
OH
O
NH2 NH2
NH2
NH2
+ +
+ +
50 51
62. 62
An interesting example of a preorganized macrocyclic host based on a bicyclic
guanidinium subunit with the purpose of binding tetrahedral oxoanions such as
phosphates, is 52 (figure 1.30). This receptor was obtained in a one-pot synthesis and
contains the chiral bicyclic guanidinium subunit (figure 1.24) in a macrocyclic
framework. Overall, six binding units are arranged in such a way as to wrap around
the anion by means of six hydrogen bonds tightly orientated in towards the center of
the cavity.131
However, NMR evidence showed that despite the fact that phosphates
are bound tightly, they do not enter the cavity. In contrast, the chloride complex was
found to have a perfect C2 symmetry at any temperature indicating encapsulation of
the anion.
Figure 1.30. A preorganized macrocycle containing a bicyclic guanidinium subunit
with six convergent hydrogen bonds for anion recognition
1.3.5 Cyclophanes
Cyclophanes represent the central class of receptor molecules for any kind of
guest species.132
The rigidity and electromagnetic properties of the systems based on
the arene units have made cyclophanes a very popular choice for anion binding
purposes.
O
N
N
H
N
H
O O
NH NH
NH NH
MeMe
O O
O O
+
52
63. 63
1.3.5.1 Two-dimensional cyclophanes
As with corands, the recognition of nucleotides and phosphate moieties in
general has been the theme of much of the work done on anion azacyclophanes.
Some two dimensional azacyclophanes used in their protonated form for anion
complexation can be seen in figure 1.31. Cyclophanes provide an advantage in
nucleotide binding because of the possibility of -stacking interactions. For example,
the cyclophane receptor 53 was found to have the right topology and size to bind
ATP, ADP and AMP in aqueous solution through electrostatic, hydrogen bonding
and -stacking interactions.133, 134
Electrostatic interactions occur between the
polyammonium sites of 53 and the phosphate chain of the nucleotides, and 1
H NMR
evidence suggests that -stacking interactions take place between the m-phenylene
subunit and the adenine ring of the nucleotides. The closely related hexaaza meta-
cyclophane ligand 54 was found to form binary complexes with the nucleotides
AMP, ADP and ATP as a result of coulombic and hydrogen bonding interactions.135
The strength of binding, established by potentiometric titration methods, was in the
order ATP>ADP>AMP but the hydrolytic effectiveness of the macrocycle is reduced
because of its rigid nature.
64. 64
Figure 1.31. Polyazacyclophanes used for the complexation of anionic species
A detailed study of the interaction between phosphates and nucleotides with the
hexaazamacrocyclic ligands 54 - 55 containing m-xylylic spacers136
vs. ligands
containing diethyl ether spacers137
highlighted the importance of ligand basicity,
rigidity and -stacking capability in the binding affinity of these systems for
inorganic phosphate anions as well as nucleotides. It was found that in ligands
containing aromatic spacers, - interactions have a key effect that can reverse
selectivity compared to competitive systems with similar basicity, not containing aryl
rings. The binding properties of the ligand 54 towards nitrate and sulphate were also
examined.138
Significant binding was observed for sulfate but little affinity was
N
H
N
H
N
H
N
H
N
N
H
NHN
NH NH
NH N
H
H
H
NH
N
H
N
H
NH
NH
N
H
N
H
NH
N
H NH
NH
N
H
N
N
N
N
N
N
Me Me
Me
Me
Me
Me
N
H NH
N
H NH
N
H
N
H
N
H
NH
N
H
H
N NH
NH NH
NH N
NH
NH
N
H
H
53
54
55
56
57 58 59
60 61
62
65. 65
revealed for monoanions by potentiometric studies. X-ray crystallography showed an
extensive network of hydrogen bonds in the crystalline state for both the nitrate and
the sulfate salt. Another extensive study by means of potentiometric,
microcalorimetric and NMR measurements on the thermodynamics of phosphate and
pyrophosphate binding by several cyclophanes (56 - 59) has been reported by
Bazzicalupi et al.87
It was concluded that very stable 1:1 receptor-to-anion complexes
are formed and that the stability trends of these complexes were not solely
determined by electrostatic forces but also by hydrogen bond interactions which play
a considerable role.
The diphenylmethane moiety has been a common choice as a spacer in the
synthesis of cyclophanes as hosts for both anions and neutral molecules. It imparts
curvature and increases the size of the host walls while retaining rigidity. For
example, early work by Koga et al. demonstrated that the macrocycle 63 forms
inclusion complexes with a number of aromatic guests in aqueous solution such as 1-
anilino-8-naphthalenesulphonate (ANS, figure 1.32).139
The binding of this substrate
relies on hydrophobic and - stacking as well as electrostatic interactions and
hydrogen bonds, since neutral molecules are also bound.
Figure 1.32. A cyclophane host built upon the diphenylmethane moiety for the
binding of ANS
One of the questions concerning anion recognition via hydrogen bonding is
that of the existence of any preferred coordination environment for anionic species.
The subject has been recently approached by an X-ray study of a series of acyclic
polyammonium salts of halides140
and oxoanions.141
Three and four-coordinate
pyramidal-type anion geometries commonly observed in these studies have been
N
H
N
H
N
H
(CH2)4
N
H
(CH2
)4
SO3
NH
ANS63
66. 66
used as a design template in the construction of azacyclophanes, capable of
mimicking these coordination environments. X-ray studies revealed binding of F-
,
Cl-
and I-
by the polyprotonated hosts 60, 61 and 62 respectively (figures 1.33-
1.35).142
For the first two salts, a mismatch between the halides and the protonated
hosts is evident. However, for the latter compound X-ray studies revealed a good
match between the macrocyclic cavity and the iodide anion.
Figure 1.33. Complexation of the fluoride anion by the protonated ligand 60
Figure 1.34. Complexation of chloride anion by the protonated ligand 61
67. 67
Figure 1.35. Encapsulation of the iodide anion by the protonated ligand 62
1.3.5.2 Three-dimensional cyclophanes
The design of three-dimensional cyclophanes (figure 1.36) has been very
much based on the structures of the early katapinands. For example, extension of the
katapinand ligands by addition of rigid aromatic spacer groups gives the compound
64. As suggested by NMR-spectroscopic investigations, this host in its diprotonated
form is capable of including one or even two bromide or iodide anions within its
large, macrobicyclic cavity.143
In 1986, the synthesis of more elaborate receptors for
anionic species was reported.144
Their binding properties were examined by 1
H-NMR
spectroscopy. Only small chemical shift changes were observed on titrating 66-6H+
and 67-6H+
with various anions but 65-6H+
showed high affinities for NO3
-
, SO4
2-
and Cl-
. NMR titration experiments indicated the formation of 1:1 complexes by 65-
6H+
with NO3
-
, Cl-
and oxalate. However, X-ray analysis of the nitrate salt revealed
that the anion was not located within the cavity of the host.
An efficient, two-step synthesis of the ligand 68 along with the crystal
structure of its octabromide salt was reported in 1991 by Menif et al.145
The cryptand
is associated with three of the bromide anions, each one being situated on the
cryptand periphery. The octaprotonated cryptand has a ‘Y’ shape with the three legs
being the planes of the phenyl rings. However, the molecular cavity is empty and
does not contain a bromide anion or a solvent (water) molecule. The closely related
ligand 69146
represents an elongated, cyclophane analogue of the bis-tren
68. 68
macrobicycle. It forms stable complexes with dicarboxylates in aqueous solution at
weakly acidic pH.147
In the , -dicarboxylate series -
O2C-(CH2)n-CO2
-
, adipate (n =
4) is bound more strongly than either the shorter or the longer species, thus 69
performs linear recognition of the substrate of which the length probably corresponds
best to the size of the intramolecular cavity.
Figure 1.36. Three-dimensional cyclophanes for the recognition of anionic species
Very strong binding of the more rigid terephthalate anion has also been observed
indicating significant structural complementarity between the receptor and the
substrate. This results from both electrostatic and hydrophobic effects. The inclusive
nature of this complex is supported by its X-ray structure which shows that one
terephthalate anion is located inside the molecular cavity while the other two are
outside (figure 1.37). NMR titration data in aqueous solution showed that the
N
O
O
O
N
O
O
O
HN
NH
NH
NHN
N
NH
HN
NH
NH
NH
HN
HN
H H
N
H
N
N
H
N
N
N
H
N
H
N H H
N
H
N
N
H
N
N
N
H
N
H
N
H
(CH2)6
(CH2)6
(CH2)6
R
RR
R
R
R
64
65 R= -(CH2)3
66 R= -(CH2)2O(CH2)2
67 R= -(CH2)2O(CH2)2
68
69
69. 69
complexes had 1:1 stoichiometry with stability constants (Ks) 2600 and 25000 for
adipate and terephthalate respectively.147
Figure 1.37. Inclusion of the terephthalate anion by the protonated ligand 69
The synthesis and binding properties of dome-shaped macrotricyclic
cyclophanes 70 and 71 that may function as anion receptor molecules when
protonated were reported in 1988 (figure 1.38).148
The three-fold symmetry of these
molecules is suited for the recognition of trigonal anions of compatible size such as
nitrate. Indeed, proton NMR spectra studies showed that these macrocycles have
three-fold symmetry in their protonated form. Moreover, 70-6H+
forms a 1:1
inclusive complex of three-fold symmetry with NO3
-
.
70. 70
Figure 1.38. Dome-shaped cyclophanes exhibit three-fold symmetry, suited for the
binding of the nitrate anion
The binding properties of the cubic cyclophane 72 towards an anionic guest,
ANS (8-anilinonaphthalene-1-sulfonate) were examined by fluorescence studies
(figure 1.39).149
This cyclophane is made of six faces, each being constructed with
the [3.3.3]azaparacyclophane ring. It was found to be soluble in acidic aqueous
media at pH = 4 (in which its tetracationic form is dominant) while all the amino
nitrogens are protonated in a pH region below 2.5. A 1:1 host-guest interaction was
established with a drastic change of the binding constant in the pH region 2.5-4.0,
showing a maximum value at 3.7 (logKs 5.7).
NH
N
HN
H
R
R
N
N
N
70: R = -(CH2)3-
71: R = -(CH2)4-
R
71. 71
Figure 1.39. A cubic cyclophane suitable for the binding of ANS (8-
anilinonaphthalene-1-sulfonate)
1.4 Other hosts.
1.4.1 Non-protonated polyaza hosts
1.4.1.1 Zwitterions
A zwitterion is a neutral molecule containing both positive and negative
charge. The majority of biological anion binding proteins and enzymes are
zwitterionic, having positively charged regions in which the anion binding occurs.
The positively charged regions are coupled to negatively charged carboxylates,
which impart overall electrical neutrality, thus facilitating the proteins’ membrane
solubility.8
These species arouse interest because anion binding using protonated
polyaza hosts is handicapped by the restriction to acidic pH regions. Moreover,
hydrogen bonding is sensitive to the accumulation of any negative charge density, for
example, to lone electron pairs in the anionic guest. In an effort to tackle these
problems, Schmidtchen’s group synthesized and studied zwitterionic molecules with
high connectivity and corresponding rigidity in which their positive charge pointed
towards the binding center (figure 1.40). Solution studies in chloroform showed that
a large number of inorganic anions were successfully complexed by the host 73
N
N N
N
N N
N N
72
72. 72
giving evidence for discrimination according to size.150
Similar hosts were
synthesized (74-75), this time with their distinct positive and negative domains being
held apart and prevented from mutual contact. These ligands showed extraordinary
solubility in water and good complexation with halides and cyanides as revealed by
1
H and 35
Cl NMR titration data.151
Figure 1.40. Zwitterionic receptors for anion binding
1.4.1.2 Positively charged systems
Another approach to tackling the problems associated with anion binding by
protonated hosts is the construction of quaternary ammonium salts such as
compounds 76-81 (figure 1.41). As in zwitterionic hosts, anion recognition in these
species takes place solely by electrostatic forces. Schmidtchen’s group has prepared
quaternary ammonium analogues of the soccer ball molecule 36 bearing
polyethylene fragments that connect the ammonium center.152
NN
N
N
B
B B
B
H
H
H
H
H
H H
H
H
H
H H
NN
N
N
O
O
O
O
O
O
O
O
X
X
X X
X
X
+
+
+
+
X
X
X X
X
X
+
+
+
+
_
_
_
_
_
__
_
73: X = (CH2 )6 74: X = (CH2 )6
75: X = (CH2 )8
73. 73
Figure 1.41. Quaternary ammonium salts as hosts for anionic species
These organic ligands have very good solubility in water and exhibit a purely
electrostatic ion-ion interaction forming 1:1 complexes with guests in aqueous
solution but with relatively low affinities. The highest stability constants were
measured for bromide and iodide, apparently due to better steric fit and the lower
solvation energies of these anions. The receptor 76 was prepared as the tetraiodide
salt and its crystal structure was reported.153
One of the four crystallographically
unique iodides was bound at the center of the electron deficient cavity, equidistant
from the four positively charged nitrogen atoms (figure 1.42).
NN
N
N
CH3
CH3
CH3
CH3
O
N
O
N
O
N
NN
N
N
CH3
CH3
CH3
CH3
CH3
NN
N
N
CH3
CH3
CH3
NN
N
N
CH3
CH3
CH3
X
X
X X
X
X
+
+
+
+ X
X
X X
X
X
+
+
+
+
X
X
X X
X
X
+
+
+
+
X
X
X X
X
X
+
+
+
+
76: -(CH2)6-
77: -(CH2)8-
78: -(CH2)6-
79: -(CH2)8-
81: -(CH2)8-
80: -(CH2)6-
:
74. 74
Figure 1.42. Iodide encapsulation inside the cavity of 76
The potential enzyme-like catalytic behavior of positively charged systems
has also been explored. Tabushi et al. discovered the catalytic effect of the
quaternary ammonium cyclophane 82 (figure 1.43) on the hydrolysis of suitable ester
substrates. The accelerations of the hydrolysis rates of the substrates are attributed to
inclusion-electrostatic catalysis. It is concluded that this catalysis takes place by the
spatial arrangement of the carbonyl group of the organic substrates which is directed
to the quaternary ammonium residue of the host. Thus, the transition state of the
substrate is stabilized.
Figure 1.43. A quaternary ammonium cyclophane with catalytic activity
NN
N N
Me
Me Me
Me
Me
Me Me
Me
+ +
+ +
82
75. 75
1.4.2 Neutral hosts operating by hydrogen bonding
Probably the most effective type of neutral hosts for anion binding is based
on hydrogen bonding interactions which are both strong and directional. Indeed,
these hosts have potentially greater anion selectivity than cations, since they do not
rely upon nondirectional electrostatic forces to achieve anion coordination.
Calixarenes have been widely used as a framework for the design of many
neutral hosts for anions (figure 1.44). For example, calixarene 83 was found to be
selective for HSO4
-
(Ks=103400) over chloride or nitrate but unfortunately, no Ks
value for 1:1 complexation of H2PO4
-
could be determined.154
Compounds 84 - 85
bind halide and tricarboxylate anions exclusively through hydrogen bonding in a 1:1
fashion in CDCl3. Receptor 84 containing thiourea moieties exhibits selectivity
towards bromide, 1,2,4- and 1,2,3- benzenetricarboxylate anions whereas urea
receptor 85 has a preference for 1,3,5-benzenetricarboxylate anions.155
It was
suggested that topological complementarity in this case as well as breaking of the
hydrogen bond association in thiourea host were responsible for the selectivities
observed. The synthesis of a bis-calix[4]arene receptor in which the upper rim of one
calix[4]arene moiety is covalently linked via amide bonds to the lower rim of another
(86) was reported by Beer et al in 1995.156 1
H NMR titration studies in CD2Cl2
showed that only fluoride was complexed with significant affinity, suggesting that
oxoanions may be too large to enter into the cavity.
Another interesting approach in the binding of carboxylates by calixarene
derivatives has been recently taken by Sansone et al. Two efficient receptors for
carboxylate anion recognition were obtained by bridging the C-linked 1,3-
dialanylcalix[4]arenes in the cone conformation with 2,6-diacylpyridine (87) or
isophthaloyl (88) moieties.157
Thus, the receptors gain preorganization and display
enhanced efficiency. Selectivity towards aromatic carboxylates was observed
(especially benzoate) which is attributed to - stacking interactions with the
pyridine moiety and/or a calix[4]arene aromatic nucleus which act in addition to
hydrogen bonding with amide NH groups.
76. 76
Figure 1.44. Calixarenes have been proved successful candidates as neutral
receptors for a variety of anionic species
Recognition of sulfate and phosphate by proteins that contain amide moieties
has been well studied21
and inspired synthetic chemists for the construction of amide-
O
O
O
O
SO2
SO2 SO2
O O
O
O
N N
SO2
N N
NH NH NH NH
O
O
O
O
O
OH
OH
O
TOS TOS
NH
NH
O
OH
OH
O
O O
O O
OO
O
O
NH
NH
NH
NH
NH
NH
X
X
X
HH H H
X
O
O
O
O
N NH
NH N
O O
O
O
H
H
83
85: X=O
86
87: X=CH
84: X=S
88: X=N
77. 77
linked neutral receptors. The bicyclic cyclophane 89 has been successfully used as a
receptor for anionic species and exhibits particular affinity for acetate and nitrate
over cyanide.158
X-ray crystallographic studies showed that AcO-
is encapsulated in
the cavity (figure 1.45). The workers implied that this is the case for nitrate anion as
well. Complete encapsulation is suggested by 1
H NMR titration experiments with the
involvement of six hydrogen bonds.
Figure 1.45. An amide-linked bicyclophane and its crystal structure with 2Bu4NOAc
in which encapsulation of the AcO-
anion is observed
The efficiency of amide-type receptors was also demonstrated by the macrocycle 90
(figure 1.46), synthesized by Ishida et al. UV spectroscopic analysis revealed very
strong binding of p-nitrophenyl phosphate (Ks = 1.2 x 106
) consistent with 1:1 host-
guest stoichiometry.159
The binding mode of this peptide was explored by 1
H NMR
experiments in DMSO-d6 which suggested that the peptide has a C3-symmetry and
binds the phosphomonoester via hydrogen bonds between every amide proton of the
backbone and phosphate oxygen atoms. The high affinities observed for this type of
receptors towards p-nitrophenyl phosphate show clearly their potential as
phosphoester receptors.
N
N
N
N
N
N
N
NH
N
O
O
O
O
O
O
H
H
H
H
H
89
78. 78
Figure 1.46. A cyclic peptide showing very strong affinity for p-nitrophenyl
phosphate
Apart from their use in calixarene frameworks, urea and thiourea groups have
also attracted considerable interest in cyclophane-based systems (figure 1.47).
N
H
N
H
O
O
H R
n
n=3
90
79. 79
Figure 1.47. Neutral macrocyclic systems for anion binding based on amide, urea or
thiourea units
In general, thiourea derivatives display stronger anion-binding ability than
that of the corresponding ureas because of their higher acidity. Neutral anion
receptors based on the C3 -symmetric metacyclophane structure with three thiourea
groups as linkers between aromatic groups have been synthesized and studied as
receptors for anionic species.160
Compounds 91 and 92 can be envisioned as
hexahomooxacalix[3]arene analogues in which the six oxygen atoms are replaced
with three thiourea groups as hydrogen bond donors for anion binding. The
NH
N
H
N
H
NH NH
NH
R
R R
S
S
S
R R
R
R
R
R
O
NH
O
N
H
ONH
R
RR
N
H
N
H
N
N
S
S
OBu
OBu
OBu
OBu
OBu
BuO
N N
H
N
H
S
N
H
N
H
N
H
N
H
S
S
Bu
Bu
H
H
91: R=H
92: R=Et
93: R=CO2Et
94: R=NHBoc
R
95: R=
96: R=
98: R=
But
But
But
But
99: R=
97: R=
But
But
100
80. 80
conformationally more rigid compound 92 with three convergent thiourea groups
pointing towards the molecular cavity, showed increased binding affinities to several
anions with a selectivity order AcO-
>H2PO4
-
>Cl-
>N3
-
>Br-
. The more
conformationally flexible 91 exhibited the selectivity order H2PO4
-
>AcO-
>Cl-
in
DMSO-d6. On the same idea, Hamilton et al. prepared the receptors 93 and 94 with
convergent binding groups and C3 symmetry.161
This receptor binds tetrahedral
anions such as sulfate and phosphate with high affinity as this was demonstrated by
NMR titration experiments in DMSO-d6 /CDCl3. A linear analogue in this case
showed much weaker binding to all anions tested, indicating that preorganization is a
key feature in this successful host. The synthesis and anion-binding properties of a
series of cyclophane-based receptors 95-99 including thiourea units in their
framework have been recently reported by Sasaki et al.162, 163
These receptors were
found to bind H2PO4
-
most strongly, followed by CH3COO-
, Cl-
, HSO4
-
, and Br-
. As
expected, cyclic thioureas bind anions more strongly than acyclic compound 100
does.
New macrocyclic polylactam-type neutral receptors with interesting behavior
have been recently reported by Szumna et al (figure 1.48).31, 164
For ligand 101, X-
ray crystal structure determination showed that Cl-
is too bulky to be included but F-
fits well (figure 1.49). NMR studies in deuterated DMSO demonstrated selectivity of
the receptor towards AcO-
which is attributed to a very favorable binding geometry,
as revealed by X-ray structures.164
Ligand 102 resulted as a byproduct of the
macrocyclization reaction that afforded ligand 101 as a major product. Surprisingly,
X-ray structure analysis showed that the 36-membered ring is suitable for
complexation of the planar (H2O-Cl-
)2 assembly by forming hydrogen bonds to every
corner of the dimer (figure 1.50).31
The authors assume that the presence of the
pyridine lone pairs forces amide protons to be arranged in a convergent manner and
that this is the reason why the bigger macrocycle 102 does not adopt a collapsed
conformation.
81. 81
Figure 1.48. Polylactam-type neutral systems as receptors for anionic species
Figure 1.49. Fluoride binding by the polylactam-type receptor 101
NH
N
NH
NH
N
NH
O O
O O
N
NHNH
NN
OO
NN
N
NH NH
N N
O O
O
O O
O
H
H
H
H
101
102
82. 82
Figure 1.50. Encapsulation of the (H2O-Cl-
)2 assembly in the cavity of the
macrocyclic polylactam 102
1.5 Concluding remarks
Developments in the synthesis of polyamine-based macrocycles for anionic
species have provided a great deal of exciting results in the past thirty years. The
potential of the field has been realized by many research groups and exploited by the
construction of highly effective receptors. Apart from the ‘classic’ corands and
cryptands, new macrocyclic frameworks such as cyclophanes and calixarenes have
been used in combination with various binding units such as thioureas and
guanidium moieties with considerable success. It is believed that polyamine-based
macrocyclic receptors for anion recognition will continue to be at the center of the
attention for supramolecular chemists for many years to come.
83. 83
CHAPTER 2:
SYNTHESIS AND BINDING OF INORGANIC ANIONS BY
MACROCYCLIC AZAPHANES
2.1 Previous work and conclusions on polyammonium coordination
environments for anionic species
One of the open questions in anion binding is whether there is any
preferential coordination geometry for bound anionic species. In our previous
crystallographic work,140, 141
we approached this problem by reacting several
aliphatic polyamines with various acids resulting in the formation of the
corresponding salts. X-ray analysis of these salts provided information on the
hydrogen bonding network and consequently, on the coordination environment of the
complexed anions. Usually, halides were found to be at the apex of a trigonal or
tetragonal pyramid as shown in figures 2.1 and 2.2 for N[(CH2)2NH2]3·3HCl and
H2N(CH2)2NH(CH2)2NH2·2HCl respectively.140
Figure 2.1. Ligand conformation and Cl(1) coordination environment for
triprotonated 2,2’,2’’-triaminoethylamine trichloride
