PhD Thesis

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
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
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
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
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
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’’,N’’’-Tetratosyl-2,5,8,11-tetraaza[12]metacyclophane (112)
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)

8
4.2.2 Synthesis of polyaza-macrobicycles
Trimethyl 1,3,5-Benzenetricarboxylate (118)
1,3,5-Tribromo-trimethylbenzene (119)
Tris-[2-(tosyl)-ethyl]-amine (120)
3,3’,3’’-Tritosyl-6,6’,6’-nitrilotri(3-azahexanenitrile) (121)
3,3’,3’’-Tritosyl-6,6’,6’-nitrilotri(3-azahexylamine) (122)
N,N’,N’’,3,3’,3’’-Hexatosyl-6,6’,6’-nitrilotri(3-azahexylamine) (123)
5,11,16-Tritosylyl)-5,8,11,16-tetraaza-tricyclo[6.6.4.13,13
]nonadeca-
1(14),2,13(19)-triene (124)
5,9,15,19,24,28-Hexakis-(toluene-4-sulfonyl)-5,9,12,15,19,24,28-heptaaza-
tricyclo[10.10.8.13,21
]hentriaconta-1(22),2,21(31)-triene (125)
5,8,11,16-Tetraaza-tricyclo[6.6.4.13,13
]nonadeca-1(14),2,13(19)-triene (126)
5,9,12,15,19,24,28-Heptaaza-tricyclo[10.10.8.13,21
]hentriaconta-
1(22),2,21(31)-triene (127)
5,11,16-Trimethyl-5,8,11,16-tetraaza-tricyclo[6.6.4.1*3,13*] nonadecane
(128)
Chapter Five: Conclusion
References

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
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
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
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
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
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
system 115.
system 117.
system 60.
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
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.
system 126 in 0.01 M HNO3/ 0.1M NaNO3.
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.
the system 127 in 0.01 M TsOH/ 0.1M TsONa.
the titration of 127 with excess of NaF.
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
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
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
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
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

20
h hour
DMF dimethyl formamide
THF tetrahydrofurane
Ts p-toluenesulfonyl (tosyl)

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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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

84
Figure 2.2. Chloride anion coordination environment and ligand conformation for
diprotonated diethylenetriamine dichloride
Figure 2.3. Bromide anion coordination environment and ligand conformation for
diprotonated diethylenetriamine dibromide
In other cases, the halide was found to be in the middle of the base of a
square pyramid (figure 2.3). For the oxoanions, more complex coordination patterns
were revealed but, in general, two (in a V-shape, figure 2.4) or three-coordination
environments around the oxygen atoms (similar to those for halides, figure 2.5) were
observed.141

85
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 of the oxygen atoms of a
diphosphate dihydrate

86
2.2 Aims of the project
Given the results of our previous crystallographic studies, our aim has been to
synthesize new macrocyclic hosts capable of displaying specific coordination
environments such as those described above. In order to bind, a host must have
binding sites that are of correct electronic character to complement those of the
guest. Furthermore, those binding sites must be spaced out on the host in such a way
as to make it possible for them to interact with the guest in the binding conformation
of the host molecule. Indeed, preorganization is a key issue in designing a successful
host for any binding species. For this purpose, macrocyclic hosts were chosen
because they have a higher affinity for the target species than acyclic products, as a
result of their preorganized structure.165
Halide anions, as well as oxoanions, are well
known hydrogen bond acceptors and thus, a molecular scaffold with hydrogen bond
donor moieties attached to it would be a very reasonable design for a halide receptor.
Based on our crystallographic results,140, 141
we envisaged as potential candidates,
macrocyclic polyamines possessing their amine moieties in an array such as that
shown in figure 2.6.
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
2.3 The choice of macrocyclic azaphanes as complexones for inorganic
species
Moving from the question of arrangement of binding units, there is also the
question of the nature of the target host molecules. It seemed advantageous to use a
macrocyclic host with a rigid framework and cyclophanes are probably the best
H H
H H
H
H
H
N N
N N
A
_
N
N
N
A
_

87
candidates for providing such a potentially preorganized arrangement.132
As stated in
section 1.3.5 cyclophanes represent the central class of receptor molecules for any
kind of guest species, including anions. Indeed, cyclophanes have been used
extensively in anion binding applications.2, 165, 166
Moreover, they possess the
advantage of rigidity by virtue of their aromatic unit. The aromatic unit allows also
the assessment of binding constants in solution by other methods than potentiometry
and NMR spectroscopic studies, such as UV-Vis spectroscopy and fluorescence
spectroscopy. Another, rather understated advantage of cyclophanes is their
relatively high melting point which means that can be easily handled at room
temparature. Meta-cyclophanes were chosen as target products instead of ortho- or
para-cyclophanes for topological reasons. In the case of para-cyclophanes it was
thought that small anion binding would be hampered by the large distance between
the binding functionalities represented by the termini of the polyamine macrocyclic
framework. On the other hand, only two carbon atoms connect the termini of the
macrocyclic framework in the case of the ortho-compounds but this contributes into
bringing the amine moieties too close together, potentially making the host
inappropriate for anion binding. Indeed, for the ortho-derivative of 117, solution and
X-ray studies indicated the formation of an intramolecular hydrogen bond network
between protonated and non-protonated amino groups.167
2.4 The choice and synthesis of starting materials for meta-azacyclophanes
The starting materials chosen for the synthesis of azacyclophane (azaphane)
macrocyclic products should fulfil two criteria. First, they should be easy to make in
good yields and high purities and second, they should be inexpensive. A logical step
to the synthesis of a target compound bearing the characteristics shown in figure 2.6
would be the choice of two starting materials, one bearing the aromatic unit (A), the
other bearing the polyamine macrocyclic framework (B). Starting material A should
bear two good leaving groups such as those listed in figure 1.1 (section 1.2.3) and
starting material B (the amine) would bear two nucleophilic groups.
1,3-Bis(bromomethyl)benzene is a commmercially available starting material in the
form of a solid with very good solubility in all solvents in which cyclizations are
performed. Numerous cyclizations have been successfully performed with bromide

88
as a leaving group. Thus, 1,3-bis(bromomethyl)benzene was chosen as starting
material A. On the other hand, starting materials B can be very easily prepared from
the acyclic aliphatic amines used in our previous studies140, 141
and tosyl chloride
(scheme 2.1). Apart from the convenient synthetic procedure, these materials are
solid and easy to handle. Typical conditions include the mixing of 40 mmol of
polyamine with Nx40 mmol of tosyl chloride (where N the number of amino groups
of the polyamine) and large excess of K2CO3 in 600 mL of water. This mixture is
vigorously stirred and heated to 80-90 o
C overnight. The precipitate is filtered,
washed with copious amounts of water and ethanol and then dried. Usually, no
further purification is needed, as after drying, analytically pure tosylamides can be
obtained in good yields (around 70%). Five out of six tosylamides were synthesized
by following this method. The only exception to this rule was 108 which could not
be prepared in this way. This tosylamide was synthesized using a different
methodology (see experimental part) in satisfactory yield (41%). According to this
method,82
tosyl chloride, water, and diethyl ether were stirred and cooled to 0 o
C in
an ice bath. To this mixture, a solution of tetraethylenepentamine and sodium
hydroxide in water was added dropwise over a period of 1 h. The reaction mixture
was stirred for further 3 h at room temperature. The precipitate was filtered and then
washed with diethyl ether and water. Recrystallization from hot CHCl3/ MeOH
afforded 108 as white powder. A full list of starting materials synthesized is given in
figure 2.7.
Scheme 2.1. Synthesis of the starting materials (B). For S, see figure 2.7
H2N NH2
S
HN NH
S
TsTs
TsCl, K2CO3
H2O, 80 oC
B

89
Figure 2.7. The starting materials synthesized and used in this project
2.5 Synthesis of precursor macrocycles (cyclization)
Crucial parameters for the successful synthesis of macrocyclic products are
the solvent and the salt, of which the anion plays the role of the base and the cation
serves as a template. Among the solvents used for the synthesis of macrocyclic
polyamides, DMF has been the most popular choice.78
It is a polar, aprotic solvent in
which both the starting materials and salts such as K2CO3 and Cs2CO3 display a
satisfactory solubility. However, DMF has a relatively high boiling point and is
rather toxic, thus making acetonitrile (CH3CN) a good alternative choice.
N
H
N
N
H
NH N NH
N
NH NH
NH
N
N
NH
NH
N
N
N
NH
N
H
N
N N
H
Ts
TsTs
Ts
Ts
Ts
Ts Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
TsTs
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-triazaheptane (105)
N,N',N'',N'''-Tetratosyl-1,4,7,10-tetraazadecane (106)
N,N',N'',N''',N''''-Pentatosyl-1,4,7,10,13-pentaazadecatriane (108)
Ts
Ts
Ts
Ts
N,N',N'',N'''-Tetratosyl-1,5,8,12-tetraazadodecane (107)

90
Acetonitrile is also a polar aprotic solvent, having a lower boiling point (81-82 o
C)
than DMF (153 o
C).
The cyclization reaction was aimed to be a [1+1] as shown in scheme 2.2.
Thus, the choice of a suitable template for this reaction is very important. A very
large cation could lead to the synthesis of a substantial amount of [2+2] by-product
whereas a small cation could result in the reaction not taking place at all. K2CO3 was
proved a successful choice and all cyclizations proceeded in satisfactory yields (68-
76%). It was observed during the course of the experiments that a large excess of salt
(20-fold) is needed. A small excess of salt (2- or 3-fold) leads to very low yields. It is
suspected that the reason for this is the increased basicity of the tosylamide in
solution as well as the abundance of potassium cations that serve as templates. A
larger than 20-fold excess of K2CO3 was not used for practical reasons. Typical
conditions for cyclization reactions involved the dropwise addition of 700 mL
solution of 1,3-bis-bromomethyl-benzene (18.9 mmol) in acetonitrile into a refluxing
and vigorously stirred solution of the tosylamide (18.9 mmol) and K2CO3 (378
mmol) in acetonitrile. The mixture was left to react for 36 h, then filtered and after
the solvent was evaporated, the crude material was purified either by column
chromatography or by recrystallization from THF.
A general schematic representation of the cyclisation procedure is given in
scheme 2.2 and a full list of the precursor macrocycles synthesized is given in figure
2.8.
Scheme 2.2. The reaction that leads to the formation of the precursor macrocycles.
For precursor macrocycles, see figure 2.8
Br
Br
S
HN
HN
Ts
Ts
+
N
N
Ts
Ts
S
K2CO3
CH3CN
A B PRECURSOR
MACROCYCLE

91
Figure 2.8. The precursor tosylamides synthesized in this project
N
N
N
N
N
N
N
N
N
N
N N
N
N
N
N
N
NN
N N
N
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts Ts
Ts
Ts Ts
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-pentaaza[15]metacyclophane (114)

92
2.5 Synthesis of target compounds (detosylation)
The last step of the synthetic procedure is the removal of the tosyl group to
yield the target product (detosylation). The accomplishment of this step was proved
to be very troublesome and it took a considerable amount of time until a suitable
method was found. A typical reductive method that includes the use of lithium
aluminum hydride in refluxing THF was unsuccessful even when performed for a
prolonged time. A problem that has to be addressed here is the rather low solubility
of these tosylamides in THF. Other newly developed techniques such as the use of
iodotrimethylsilane in acetonitrile at reflux temperature61
and the use of KF-Al2O3
under microwave irradiation168
were also unsuccesful. The use of a strongly acidic
solution has been succesful only under very extreme conditions. Typical conditions
include refluxing and vigorous stirring of 1 mmol of the macrocyclic tosylamide in
27 mL of 48% aqueous hydrobromic acid in excess of phenol (20 mmol) for three
days. The very dark solution was then washed with copious amounts of chloroform
and the target was isolated by acid-base extraction. This method, although succesful,
takes a substantial amount of time and requires very extreme and potentially
dangerous conditions. Another method succesfully used was a slight modification of
the use of metallic sodium. It involves the addition of 10 mL ethanol into a mixture
of 3 g of a 30% suspension of sodium in toluene and 1 mmol of macrocyclic
tosylamide in 50 mL THF. Ethanol is to be added slowly, in a vigorously stirred
solution and in such a way as to maintain a gentle reflux. After two hours, the
solution is left to reach room temperature, the solvents are evaporated and the
product is isolated by acid-base extraction. This is a much quicker and equally
effective method to acidic hydrolysis.
A full list of the target compounds synthesized is given in figure 2.9.

93
Scheme 2.3. Detosylation leads to the formation of the target compounds
N
N
Ts
Ts
S
PRECURSOR
MACROCYCLE
N
N
S
TARGET
COMPOUND
H
H
48% aq. HBr, PhOH, 3d reflux
or:
Na/Toluene/THF, EtOH

94
Figure 2.9. The target compounds used as anion complexons in this project
2.6 Crystal structures of tosylated polyaza-metacyclophanes
Suitable crystals for X-ray analysis were grown for five out of a total of six
tosylated polyaza-metacyclophanes synthesized in this project. Crystals were grown
by the slow liquid-liquid diffusion or the vapour diffusion method. The crystal
structures are not of good quality in some cases, but we can safely come to
conclusions on gross structural features and make comparisons with the structural
features of the polyammonium salts derived from these tosylated starting materials.
The crystal structures of 109 and 110 reveal the aromatic moieties of the
products in a succession of up and down positions (figure 2.10). This is expected
because of the relatively small size of the macrocycles and the bulky size of the
tosylated groups. A similar situation is encountered in 112 although the odd number
of aromatic moieties results in two tosyl groups pointing ‘upwards’ (figure 2.11). In
113 however, the tosyl groups are splayed more or less in the same level with the
macrocyclic ring, not showing any preference for ‘up’ or ‘down’ position (figure
N
H
NH
NH
NH
N
H
N
H
N
H
N
H
NH
N
H
N
H
NH
N
H
NH
N
H
N
H
N
H
NH
N
H
N
H N
H
NH
2,6,9,13-tetraaza[14]metacyclophane (60) 2,5,8,11,14-pentaaza[15]metacyclophane (61)
2,9,16-triaza[17]metacyclophane (62) 2,5,8-pentaaza[9]metacyclophane (115)
2,6,10-triaza[11]metacyclophane (116) 2,5,8,11-tetraaza[12]metacyclophane (117)

95
2.12). The larger size of the macrocycle eases the repulsion between the tosyl groups,
making crystal packing effects the dominant factor here. The same applies for the
crystal structure of 114 where the arrangement of carbon and nitrogen atoms of the
aliphatic part of the ring do not follow any obvious pattern, far from the zig-zag
position, familiar to these systems (figure 2.12). Also, the tosyl groups seem to be
placed in random positions compared to each other. Overall, these molecular cavities
are clearly not preorganized for the binding of spherical species but it was anticipated
that they would become more organized upon protonation due to the mutual
repulsive forces between ammonium sites.
A full list of crystallographic parameters of tosylated polyaza-
metacyclophanes as well as of all structures of metacyclophane species analyzed by
X-ray crystallography is given in table 1.
109 110
Figure 2.10. Up and down conformation of the tosyl groups in the crystal structures
of 109 and 110

96
Figure 2.11. Crystal structure of 112. Note the ‘up’ conformation of two tosyl groups
in succesion, in contrast with 109 and 110
113 114
Figure 2.12. Crystal structures of 113 and 114. Note the splayed placement of the
tosyl groups in both compounds as well as the ‘disarray’ of the atoms of the aliphatic
ring in 114

97
2.7 Crystal structures of polyaza-metacyclophanes
2.7.1 Crystal structures of two polyaza-metacyclophane: 2,5,8
triaza[9]metacyclophane (115) and 2,6,9,13-pentaaza[14]metacyclophane
(60)
It was possible to grow crystals for X-ray analysis of two free macrocyclic
amines, 115 and 60. All other amines were isolated as oils or waxy materials rather
than crystalline solids. It is useful, however, to examine the crystal structure of these
amines as they provide an insight to the structure of unprotonated ligands, free from
any interactions with anionic species. In the structure of 115, there are two
crystallographically unique macrocycles. The ‘bottom’ parts of the macrocyclic rings
interact with each other forming a dimer held together by five hydrogen bonds with
N···N distances ranging from 3.121(9) to 3.293(10) Å. A bifurcated hydrogen bond,
shown in figure 2.13 is also formed (N(4)···N(2): 3.121(9) Å). A rather unexpected
consequence of the strained nature of this molecule is an intramolecular C-H···
interaction observed for one of the crystallographically unique macrocycles
(centroid···C(4): 3.608(12) Å), shown in figure 2.13.
Figure 2.13. Hydrogen bond network for the macrocyclic amine 115

98
Compound 60 was also crystallized revealing a different picture from that
seen for compound 115. A dimer similar to that seen for compound 60 is formed as
well but this time, as it can be seen in figure 2.14, the ligand is preorganized for the
binding of a spherical species inside its cavity. Importantly, the aromatic ring is at an
almost parallel position with the cavity formed by the polyamine chain. Therefore,
the non-preorganized nature of compound 115, discussed above, has to be attributed
to the small size of the macrocyclic ring. The aromatic moiety seems to pose a steric
hindrance to the nine atoms of the polyamine chain for compound 115. This is not a
problem for compound 60 where the polyamine chain consists of fourteen atoms.
Another question that remains to be answered is why 60 is preorganized even in its
unprotonated form whereas its tosylated precursor 113 is not. Indeed, the differences
observed in the torsion angles between analogous atoms in the polyamine chains of
these species are striking. For example, the torsion angle observed for C(16)-N(4)-
C(15)-C(14) was –80.0(5)o
and –178.9(3)o
(almost linear) for the tosylated precursor
113 and the free amine 60 respectively (figure 2.14). Again, the torsion angle
observed for C(13)-N(3)-C(12)-C(11) was –62.8(4)o
and –167.7(4)o
for 113 and 60
respectively. Presumably, the preorganized conformation of the free amine is a result
of the repulsive forces between the N-H protons of the amine moieties.
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

99
2.7.2 Crystal structures of polyaza-metacyclophane polyammonium salts in
which the host displays a good complementarity for halides
2,5,8,11,14-pentaaza[15]metacyclophane (61) is one of the largest
macrocyclic products synthesized in this project. The crystal structures of two
pseudopolymorphic chloride salts were analyzed and in both cases 61 shows a good
structural match with chloride anion. The first of these chloride salts,
pentaprotonated 2,5,8,11,14-pentaaza[15]metacyclophane pentachloride
monohydrate reveals a key characteristic of these macrocycles, their ditopic
character. As shown in the space-filling diagram (figure 2.15), one chloride anion is
on the ‘top’ of the macrocyclic ring whereas another nests at the ‘bottom’. The
chloride at the top, ‘facing’ the aromatic ring forms two hydrogen bonds with the
amine moieties of the macrocyclic ring and one hydrogen bond with an amine moiety
from another macrocycle at the top (figure 2.16). On the other hand, the chloride at
the ‘bottom’ forms three strong hydrogen bonds with three amine moieties of the
macrocycle plus one weak hydrogen bond with an adjacent amine moiety from
another macrocycle. The fact that Cl(1) does not face the aromatic ring, allows a
closer approach and the formation of more and shorter hydrogen bonds than Cl(2). It
is interesting to note that an Ar-H···Cl short contact takes place between the aromatic
ring and Cl(1) (H(9)···Cl(1): 2.65 Å). In structural terms, the macrocycle adopts a
boat conformation, wrapping around Cl(1). This phenomenon has also been observed
in other macrocyclic systems, for example in the chloride complexes of 1584
and 2785
(see section 1.3.2), as well as in the bromide salt of 2683
(figure 1.5, section 1.3.2)
and the nitrate salt of 27 (figure 1.11, section 1.3.2).98
Comparing the structures of
the macrocyclic frameworks between 61·5HCl·H2O and 114, the structural difference
imposed by the presence of the chloride anions and the ammonium protons is
evident. Indeed, the torsion angles observed for the same groups of atoms belonging
to the macrocyclic chain are very different between the polyprotonated ligand and its
tosylated precursor. For instance, the torsion angle for C(7)-N(1)-C(8)-C(9) is
–159.0(4) and 81.8(12) for the polyprotonated ligand and its tosylated precursor,
respectively. For C(16)-N(5)-C(15)-C(14) the torsion angles are –170.3(5) and
–98.5(11) for the protonated ligand and the tosylated precursor, respectively (figure
2.16).

100
Figure 2.15. Space filling model of the fully protonated ligand 61 with chloride
anions nesting on each side of the macrocycle
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
A common feature revealed in these structures is the existence of several C-
H···X-
interactions, depending on the size of the complexed anion and its proximity to

101
the macrocyclic cavity. For the crystal structure of 61·5HCl·H2O they are shown in
figure 2.17. These interactions vary between 3.457(10) and 3.549(10) Å, typical
C···Cl-
distances for short C-H···Cl-
contacts. Interestingly, in all the structures of
polyammonium macrocyclic salts studied there is an Ar-H···X-
short contact between
the hydrogen of the 2 position of the aromatic ring and the anion nesting at the
bottom side of the macrocycle (figure 2.17; C(1)···Cl(1)-
: 3.457(10) Å for
61·5HCl·H2O).
Figure 2.17. C-H···Cl-
short contacts for the anions positioned at the top and bottom
side of the macrocyclic cavity
Under different crystallization conditions (slow evaporation) the macrocyclic
ligand 61 yielded another pseudopolymorphic crystal structure with hydrochloric
acid, that is 61·5HCl·2.5H2O. The basic features of this compound are not very
different from 61·5HCl·H2O. In this case the unit cell consists of two macrocycles
and five water molecules. The aromatic moiety is in a position that is more ‘parallel’
to the macrocyclic ring in comparison with 61·5HCl·H2O. This conformation favours
an even closer contact between the chloride anions and the macrocyclic ring.

102
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
Each of the two crystallographically unique hosts has two chloride anions in
close proximity (figure 2.18), one at its ‘top’ and one at its ‘bottom’ as seen for
61·5HCl·H2O. Also, each of these chloride anions forms three strong hydrogen bonds
with the amine moieties of its host macrocycle. It seems that the chloride anions,
despite being surrounded by the protonated amine moieties of their host macrocycle,
do form an extra hydrogen bond on the top of their coordination sphere in a similar
mode with that seen for 61·5HCl·H2O (figure 2.16). Another interesting point is the
‘flat’ conformation of the macrocyclic hosts compared to the slightly boat-shaped
conformation of the ligand in 61·5HCl·H2O (figure 2.19). However, it is not clear if
this is the result of the simultaneous closer approach of two chlorides or the result of
the existence of more water molecules in the crystal lattice or both. Also, the closer
approach of the chloride anions to the amino groups of the macrocyclic rings leads to
longer Ar-H···Cl interactions (C···Cl-
: 3.740(6) and 3.763(6) Å compared with
3.457(10) Å for 61·5HCl·H2O).

103
A B
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
Another example of a good match between a host and a guest is the crystal
structure of 60-4H+
·3F-
·HF2
-
·5H2O. In this case however, it is the ‘top’ side of the
macrocyclic ring that donates a larger number of hydrogen bonds to the ‘complexed’
fluoride anion rather than the ‘bottom’ side. In fact F(2) at the ‘bottom’ of the
macrocycle is a part of an F-H-F-
system which is sandwiched between the ‘bottom’
parts of two macrocyclic hosts as shown in figure 2.20. Interestingly there is only
one, rather weak hydrogen bond between the NH moiety of each macrocycle and the
fluoride of each F-H-F-
array. There are also several C-H···F-
short contacts between
the macrocyclic framework and the F-H-F-
array. On the other hand, F(1) at the ‘top’
of the macrocyclic ring comes very close to the host cavity by forming three short
hydrogen bonds with three out of four NH2 moieties of the ligand. Two of these
hydrogen bonds are very short (H(2B)···F(1): 1.70(7) Å, N(2)···F(1): 2.639(6) Å;
H(3B)···F(1): 1.68(7) Å, N(3)···F(1): 2.589(6) Å). There is also a fourth, longer
hydrogen bond between F(1) and an amine moiety from the top side of the anion
(H(2B)···F(1): 2.50(7) Å, N(2)···F(1): 2.946(6) Å).

104
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
Moving to the crystal structures of iodide salts, a common feature is the
existence of polyiodide chains. Despite their occurrence, it should be noted that in
our previous crystallographic studies, no crystals with polyiodide chains were formed
although the conditions of crystal growth were essentially the same. This could be
attributed to lattice energy and crystal growth kinetic effects. Some of the polyiodide
structures analyzed in the present work possess some very interesting characteristics.
Other kinds of species cocrystallized with polyiodide anions have been the subject of
study by many research groups.169
Those include oxa-crown ethers170
and aza-thia
ethers.171
For instance, template assembly of polyiodide networks by metal cations
complexed by macrocycles was reported by Schröder et al.171
In the present work,
the crystal structures of polyammonium macrocycles with iodide and polyiodide
anions in the absence of metals or other species are reported for the first time.
In the crystal structure of [61-5H+
]·4I-
·I3
-
, 61 behaves as a ditopic receptor in
a similar manner as seen before for chloride. However, the smaller space available
for the iodide anions that approach the macrocyclic cavity results in the almost

105
perpendicular orientation of the aromatic ring in relation with the macrocyclic
aliphatic ring. Still, the existence of two anionic species on the ‘top’ and the ‘bottom’
of the aromatic ring imposes a more ‘preorganized’ array on the aliphatic ring in
comparison with the tosylated precursor macrocycle, similar to that seen for
61·5HCl·2.5H2O (figure 2.18). The ‘top’ iodide I(1), forms three hydrogen bonds
with an equivalent number of adjacent amine moieties. The ‘bottom’ iodide I(2)
forms two hydrogen bonds with the two amine moieties close to the aromatic ring
(figure 2.21).
Figure 2.21. Ditopic binding mode of the pentaprotonated receptor 61 towards
iodide anions
Surprisingly, and despite their expected large coordination sphere, I(1) and
I(2) do not form any hydrogen bonds with other amine moieties apart from those
belonging to the host macrocyclic ring. A short Ar-H···I-
contact, similar to those
encountered before, is also observed (C(1)···I(2)-
3.820(13) Å). The I3
-
anion
participates in a single NH2
+
···I-
hydrogen bond. However, there are several short
contacts between I3
-
and the -CH2- moieties of the aliphatic chains.
The crystal structure of [62-3H+
]·2I-
·I3
-
·2I2, although of relatively low
quality, shows a near perfect match between the guest species (iodide) and the host
(triprotonated ligand 62, figure 2.22). The NH2
+
···I(1)-
distances suggest the
formation of three hydrogen bonds between I(1) and each of the ammmonium
moieties of the macrocycle. By comparison of [61-5H+
]·4I-
·I3
-
with

106
[62,3H+
]·2I-
·I3
-
·2I2 it seems that it’s easier for a macrocyclic aliphatic chain
comprising of ···-NH2
+
-(CH2)k-NH2
+
-··· units, where k is a relatively large number
(for example 6) to wrap around a halide species rather than a macrocyclic aliphatic
chain comprising of ···-NH2
+
-(CH2)l-NH2
+
-(CH2)m-NH2
+
-(CH2)n-NH2
+
-··· units where
l,m,n are relatively small numbers (for example 2 or 3). A possible reason for this
phenomenon could be that small distances between the ammonium moieties give rise
to repulsive forces that do not favour their aligning towards the target anionic
species. Although the ‘bottom’ part of the ligand is occupied by I1, the ‘top’ part is
occupied by the polyiodide species I3
-
that forms only one hydrogen bond with a
polyammonium moiety of the host macrocycle. There are ten hydrogen bonds overall
in this system despite the fact there are only six amine protons. This reflects the
existence of many bifurcated hydrogen bonds due to the large size of the iodide
anion. A similar trend has been observed in linear polyammonium salts, although no
polyiodide anions were formed in those cases.140
Figure 2.22. Triprotonated ligand 61 has a good structural match for an iodide
anion
The rather poor quality of the crystal structure of [62,3H+
]·2I-
·I3
-
·2I2 led to
efforts directed towards obtaining better crystals of the ligand 62 from a dilute
solution of hydriodic acid. Instead, another species with unexpected features
emerged, [62,3H+
]·3I-
·I2, despite the fact that the same crystallization conditions

107
were employed. The asymmetric unit (table 2.1, 62·3HI·I2(a)) consists of two ligands
and as seen with previous crystal structures, the ‘top’ and the ‘bottom’ of each ligand
is occupied with an iodide anion. Importantly, a neutral iodine species lies between
two iodide anions which, themselves, lie between the ‘bottom’ or the ‘top’ parts of
their macrocyclic hosts. Thus, an infinite chain of the type: protonated ligand-iodide-
iodine-iodide-protonated ligand-etc is formed. In other words we have a
supramolecular ‘russian doll’172
of the type positively charged species-anionic
species-neutral species-anionic species-positively charged species-etc (figure 2.23).
Also, the species I-
···I2···I-
is rather rare, although other polyiodide structures such as
I3
-
, I5
-
and I7
-
complexed with crown ethers have been reported.169
However,
cocrystallization of I-
···I2···I-
along with non-macrocyclic organic and organometallic
systems has been found in many structures.169
To the best of our knowledge, this is
the first time that the complexation of an I-
···I2···I-
species is observed in a
macrocyclic system. The iodide guest species nest at the ‘top’ and the ‘bottom’ of
each macrocyclic ring but they do not always form hydrogen bonds with all of the -
NH2
+
- moieties as not all of the ammonium protons point towards the anionic species
(figure 2.23).
Figure 2.23. Complexation of the species I-
···I2···I-
between two triprotonated ligands
62

108
Another supramolecular ‘Russian doll’ was synthesized in the same way,
[62,3H+
]·3I-
·I2 but yielded a different crystal structure (table 2.1, 62·3HI·I2(b)). The
conditions under which the crystal were grown were the same as those for
62·3HI·I2(a) but the reason for polymorphism is not known. Although many of the
atoms in this polymorph structure are disordered, we can safely conclude that the
motif protonated ligand-iodide-iodine-iodide-protonated ligand-etc takes place in
exactly the same manner as seen before in the crystal structure described in the
previous paragraph.
2.7.3 Other crystal structures of polyaza-metacyclophane polyammonium salts
with halides
X-ray quality crystals of the polyammonium ligand 116 with hydrofluoric,
hydrochloric and hydrobromic acid were successfully grown. Despite the small size
of this ligand’s cavity, the crystal structure of 116·3HF·3H2O shows that two
crystallographically equivalent fluoride anions approach the ring from the ‘top’ and
the ‘bottom’ side. There is only one hydrogen bond between an -NH2
+
moiety and
the fluoride anion at the ‘top’ side of the ring (N(2)···F(1)-
:2.569(5) Å) as well as one
hydrogen bond between an -NH2
+
moiety and the fluoride anion at the ‘bottom’ side
of the ring (N(1)···F(1)-
:2.624(5) Å, figure 2.24). It’s interesting that numerous C-
H···F-
contacts, possibly because of the large negative charge density on the surface
of the fluoride as well as a CAr-H···F-
contact complete the coordination sphere of the
‘bottom’ fluoride anion (figure 2.24). C-H···F-
contacts range from 3.174(5)-3.214(6)
for the corresponding C···F-
distances with the CAr···F-
distance at 3.231(6) .

109
Figure 2.24. Anion coordination environment in the vicinity of the protonated ligand
for 116·3HF·3H2O
In the case of 116·3HCl, the large size of chloride in comparison with the
small size of the cavity result in no anion being at the ‘top’ side of the macrocyclic
ring. Oddly, however, the aromatic group of another ring approaches the
macrocyclic ring, thus giving rise to a C-H··· interaction shown in figure 2.25
(C(11)··· : 3.890 Å). Moreover, probably to the lack of any anion at the ‘top’ side of
the macrocyclic ring, there is an intramolecular C-H··· interaction such as that seen
for compound 115 (C(11)-H(11B)··· : 3.027 Å, C(11)··· : 3.949 Å). Still, there is a
chloride at the ‘bottom’ side of the ring accepting only one hydrogen bond from an -
NH2
+
moiety (N(2)-H(2B)···Cl(2)-
: 2.339 Å, N(2)···Cl(2)-
: 3.183 Å). This chloride is
involved in three weak C-H···Cl-
interactions shown in figure 2.25 with distances
typical for this type of binding (3.645(2)-3.794(2) for the corresponding C···Cl(2)
distances).

110
Figure 2.25. Hydrogen bond network in the proximity of the ligand for the crystal
structure of 116·3HCl
For 116·3HBr there is a bromide anion at the bottom of the macrocyclic
cavity forming an NH···Br-
hydrogen bond as well as four C-H···Br-
weak
interactions, more than those seen for the fluoride and the chloride complexes. This
is apparently due to the larger size of the bromide anion. A very short NH···Br-
hydrogen bond is also formed between an amine moiety and the bromide anion at the
‘top’ of the macrocyclic ring (N(2)-H(2A)···Br(2): 2.01(7) Å, N(2)···Br(2): 3.216(4)
Å). The small size of the cavity as well as the fact that the aromatic ring ‘faces’ the
bromide anion (centroid-Br: 4.200(5) Å) disfavour any further interactions between
the bromide and the macrocycle. An intramolecular C-H··· interaction is again
observed, as seen in the case of the chloride anion (C(12)··· : 3.819(7) Å, figure
2.26).

111
Figure 2.26. Hydrogen bond network in the proximity of the ligand for the crystal
structure of 116·3HBr
Moving to the crystal structure of 60·4HBr, it is apparent that the cavity of
the ligand is not adequate to accommodate a bromide anion. It is interesting however,
that despite the size mismatch there is still one bromide anion at the top and one at
the bottom of the ring, as shown in figure 2.27. Hydrogen bond distances between
the ammonium moieties and the anions in the proximity of the macrocycle are typical
for N-H···Br-
systems: N···Br-
distances range between 3.279(16) and 3.437(17) Å.
Figure 2.27. Hydrogen bond network in the vicinity of the macrocycle for the crystal
structure of 60·4HBr

112
2.7.4 Crystal structures of polyaza-metacyclophane polyammonium salts
including oxoanions
Analysis of binding properties of polyammonium azaphanes towards halides
was the principal aim of this project. However, several polyammonium oxoanions
salts were synthesized as well for comparison. The complex 116·3HClO4·H2O was
prepared for analytical purposes as a means of purification of the macrocyclic amine
116. A few interesting features emerge from this crystal structure. The macrocycle is
surrounded by three perchlorate anions of which none comes close to the cavity,
obviously due to its small size. An important feature here is the large number of
partially negatively charged oxygen atoms that belong to perchlorate anions in
comparison with the number of protonated amino groups. As a result, there are many
oxygen atoms that do not form any hydrogen bonds. However, they do participate in
short C-H···O contacts with distances similar to those reported in the literature.173
For
example O(12) comes in close contact with three C-H protons that belong to the
macrocyclic system. One of the interactions is rather short (C(11)···O(12): 3.304(9)
Å) the other two are longer (C(1)···O(12): 3.481(10) Å, C(9)···O(12): 3.654(10) Å),
figure 2.28. Three-coordinate anion environments, although involving N-H···O
hydrogen bonds instead of C-H···O weak contacts, were also found for oxoanions
such as sulfates and phosphates in the case of aliphatic polyammonium species.140

113
Figure 2.28. Oxygen atom of a perchlorate anion in the proximity of the
triprotonated ligand 116. Note the short C-H···O contacts formed in the absence of
NH···O hydrogen bonds
Complex 60·3HClO4·HBr·H2O was accidentally synthesized from a solution
of 60 in perchloric acid treated with hydrobromic acid fumes in a fume cupboard
where a detosylation in boiling hydrobromic acid was performed. The crystal
structure revealed a perchlorate anion on the ‘top’ of the macrocyclic ring and a
bromide anion at the ‘bottom’. The perchlorate is aligned so that an oxygen atom
points towards the macrocyclic cavity (figure 2.29). Moreover, it participates in two
hydrogen bonds with the ammonium moieties of the macrocycle giving rise to a V-
shaped anion coordination environment, commonly encountered in the crystal
structures of aliphatic polyammonium oxoanion salts.140
In contrast, the other three
oxygen atoms of this perchlorate anion form just one or no hydrogen bonds with
ammonium moieties. It seems that the binding of the perchlorate anion to the cavity
has induced a rather long Cl-O distance (Cl(1)-O(3): 1.446(8) Å, in comparison with
the following distances: Cl(1)-O(1): 1.425(9) Å, Cl(1)-O(2): 1.450(8) Å, Cl(1)-O(4):
1.425(9) Å). A similar effect was observed in our previous studies of structures of
polyammonium salts with oxoanions, where generally the more distant oxygen atoms
were involved in a larger number of hydrogen bonds.140
Structurally, this system is
not much different from the chloride and the bromide salts where no good match
exists between the macrocyclic cavity and the complexed anion. The bromide anion
is placed at the ‘bottom’ side of the ring where it does not face the aromatic ring.
Apparently, the fact that the bromide anion is more electronegative than the

114
perchlorate anion is the reason driving the bromide at the ‘bottom’ side of the cavity.
This bromide forms two hydrogen bonds with two amine moieties, although this time
these amine moieties are next to each other instead of being at the opposite ends of
the macrocycle, as in the crystal structure of 60·4HBr (figure 2.29). Distances are
typical for NH···Br-
hydrogen bonds (N(1)···Br(1): 3.335(9), N(2)···Br(1): 3.173(9)).
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
2.8 Solution studies
2.8.1 Protonation of polyaza-metacyclophanes
The reaction involving the transfer of a proton from one atom to another has
been described as ‘the most general and important reaction in chemistry’.174
With
regard to this project, the macrocyclic polyamines synthesized are bases in aqueous
solution. Their complexation properties towards anionic and cationic species depend
largely on their basicity behaviour. Hydrogen bonding in anion coordination,
although not clearly understood, seems to be crucial in water.175, 176
Also, the positive
charge imparted to protonated macrocyclic polyamines in aqueous solutions is
obviously an important factor in stabilizing a host-anionic guest complex. Therefore,

115
the acid-base properties of these compounds have to be investigated prior to any
complexation studies.177
Acid-base properties of the monocyclic metacyclophanes were studied in
aqueous solutions, in the presence of 0.1 M NaNO3 as supporting electrolyte. The
study of 62 has not been possible, as precipitation occurs at pH 9.3. Solvent mixtures
of water and polar solvents such as DMSO, DMF and acetonitrile have also been
tried for the titration of 62 without success.
The metacyclophanes studied herein follow trends similar to those observed
for 1:1 and 2:2 polyazacyclophanes.177
As observed for paracyclophanes, the overall
basicity of these compounds increases in an almost linear fashion as a function of the
number of atoms in the polyamine chain bridging the arene unit.178
The stepwise
basicity constants depend on the number of amine moieties present in the macrocycle
as well as on the aliphatic spacers between the amine moieties. In general, minimum
electrostatic repulsion between charges of the same sign explains the protonation
trends observed.
log K1 log K2 log K3 log K4 log K5 log Ki
115 9.58(14) 7.69(11) 3.51(13) 20.78(38)
116 10.09(4) 8.74(3) 6.55(4) 23.92(10)
62a
--- --- --- ---
117 9.33(5) 8.65(4) 5.76(3) 2.71(4) 26.45(16)
60 9.80(5) 9.02(4) 7.13(3) 3.49(4) 29.44(16)
61 10.97(3) 9.18(6) 8.81(4) 7.35(4) 4.10(5) 40.41(22)
61b
9.63(7) 8.19(5) 4.65(6) 4.91(42)c
Table 2.1. Logarithms of the stepwise protonation constants 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)
Also, of interest are the marked differences in the stepwise protonation
constants between the metacyclophanes studied and the ‘parent’ aliphatic amines
(compare tables 2.1 and 2.2). These differences imply a greater conformational

116
freedom of the ‘parent’ amines in comparison with the macrocyclic compounds.
Indeed, with the exception of the pair 61-TEP, the overall basicities as well as each
stepwise basicity constant for the macrocycles studied are lower than the
corresponding basicity of the ‘parent’ aliphatic amine. Similar trends have been also
observed for the paracyclophane analogues.178
For example, the para-analogue of 61
displays larger basicity constants (10.68, 9.29, 8.66, 7.23, 3.83, log Ki = 39.7) than
its parent amine, TEP, not much different to those observed for 61. It is also of
practical interest to inspect the protonation state of these molecules at neutral pH. For
the first three macrocycles, the diprotonated form is the predominant species (figures
2.4, 2.5 and 2.7 for the species 115, 116, and 117 respectively) with relative
concentrations at around 90% or even more. For the larger and more basic species 60
and 61 (figures 2.7 and 2.8 respectively), at neutral pH, the triprotonated ligands are
the predominant species with relative concentrations 60-70%. This is indicative of
that fact that, despite the strong basicity of these species, it is rather difficult to
protonate a nitrogen next to an already protonated nitrogen.177, 179
This trend will be
discussed in the following paragraphs.

117
Figure 2.30. The ‘parent’ aliphatic amines used for the synthesis of metacyclophanes
Table 2.1. Logarithms of the stepwise protonation constants for the ‘parent’ amines.
Conditions: I = 0.1 mol dm-3
, T = 298 K; a: Not studied
log K1 log K2 log K3 log K4 log K5 log K6 log Ki
DET 9.84 9.02 4.23 23.09
DPT 10.65 9.57 7.69 27.91
DHTa
--- --- --- ---
TTT 9.74 9.07 6.59 3.27 28.67
BAP 10.53 9.77 8.30 5.59 34.19
TEP 9.70 9.14 8.05 4.70 2.92 34.51
NH2
N
H
NH2
NH2
N
H
NH2
N
H
NH2
NH2
NH2
N
H
N
H
NH2
NH2
N
H
N
H
N
H
NH2
NH2 N
H
N
H
NH2
Diethylenetriamine (DET) Dipropylenetriamine (DPT)
Dihexylenetriamine (DHT)
Triethylenetetramine (TTT)
Tetraethylenepentamine (TEP)
1,2-bis(3-aminopropylamino)ethane (BAP)

118
Starting with 115, two large stepwise protonation constants are observed and one
much lower. The reason for this is simple. The two NH moieties next to the aromatic
ring are protonated first. The last protonation steps is a lot more difficult involves the
entry of a proton on a nitrogen between two amine moieties already protonated.
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
The situation is different in 116, however, where the first two logK values are
larger than the corresponding logK values of 115. This is due to the presence of two
propylenic chains. The difference in basicity between 115 and 116 is even more
pronounced in the case of the third logK value. The larger propylenic spacers,
keeping the other two amine moieties apart, make it easier for the nitrogen in the
middle of the aliphatic part of the macrocycle to be protonated. The impact of the
larger propylene spacer can also be seen in the difference between the first and the
second as well as in the difference between the second and the third protonation
constant for 115 and 116. It can be observed that logK1- logK2 = 1.89 for 115
whereas logK1- logK2 = 1.35 for 116. Also, logK2- logK3 = 4.18 and 2.19 for 115 and
116 respectively. These simple trends are also reflected in the marked difference
between the overall basicity of 115 (20.78(38)) and 116 (23.92(10)).

119
Figure 2.32. Distribution diagram for species present in solution for the system 115
The same considerations explain the basicity constants of 117 (figure 2.33).
Again, the first two protonation constants are attributed to the nitrogen atoms close to
the arene ring. This time the first protonation constant is particularly low compared
to the other macrocycles. A similar trend was found for the para-analogue of this
compound and it was attributed to the effects of a particular solvation promoted by
the arene ring.178
The third protonation constant is considerably higher than the
corresponding logK value of 115 that also has ethylene units in its spacer. This is
because the third proton does not enter the macrocycle between two nitrogen atoms
already protonated but between one nitrogen that is protonated and one nitrogen that
is not. The last protonation constant of 117 is very low, as protonation takes place
between amine moieties already protonated.

120
Moving to 60, the trend is very similar to that observed for 117. This time
however, the existence of two propylene units increases the basicity constants in
comparison with 117. The impact of the propylene units is particularly shown in the
third protonation constant which is larger by 1.37 logarithmic units as compared with
that of 117. It is clear that the introduction of the propylene units makes it much
easier for the ‘middle’ nitrogen atoms to get protonated.

121
Even larger basicity constants were found for 61, obviously because of the
large size of the macrocycle. It is interesting, however, that the basicity constants of
this macrocycle are bigger than the basicity constants of its ‘parent’ amine, TEP. It is
also remarkable that the fourth protonation constant is quite large despite that the
protonation takes place next to at least one nitrogen atom that is already protonated.
Exactly the same trend was found in the para-analogue of 61 and implies that the
fourth protonation step for this species involves a reorganization of the protonation
sites within the molecule such that the middle nitrogen remains unprotonated and
each protonated nitrogen has only one adjacent protonated site.179
The basicity constants of 61 were redetermined in the presence of
TsOH/ TsONa (table 2.1). There is a remarkable difference between the logK values
observed in this medium and HNO3/ NaNO3, apparently because the basicity of 61 is
enhanced as a result of stronger anion binding in the presence of NO3
-
. Then pH
titrations were conducted in the presence of NaF and NaCl but no difference was
observed with the results of the pH titration in the presence of TsOH/ TsONa only. A
possible explanation for this result could be the fact that pH titrations is the least
sensitive method for the determination of binding constants, thus making the
measurement of low logK values difficult. It is also likely that the affinity of these
macrocycles for halides is insignificant for pH> 2.5. It has to be stressed that what is
observed in the solid state by means of X-ray crystallography does not necessarily
reflect what happens in solution. This is simply because all polyammonium halide
crystals of which their structures were discussed above, were grown from a very
acidic solution whereas pH titrations can be accurate only for 2.5<pH<11. A similar
effect is observed in the crystal structures of polyammonium salts of the cryptand
127 and it is discussed in detail in section 3.3.2.
In conclusion, macrocyclic meta-azaphanes studied by pH potentiometry
possess a protonation behaviour not different from that observed for macrocyclic
para-azaphanes and related compounds.177
Unfortunately, we have not been able to
detect the binding constants of any halide species probably due to the low affinity of
these species for halides at pH> 2.5.

122
2.9 Tables for chapter 2
Table 2.1: Crystallographic parameters for new macrocyclic systems
109 110 112
Formula C34H38Cl3N3O6S3 C35H41N3O6S3 C44H50Cl4N4O8S4
M 787.25 695.89 1032.92
System Triclinic Monoclinic Monoclinic
Space group P-1 P2(1)/c P2(1)/n
a/ 10.0306(11) 16.6393(8) 10.0881(10)
b/ 13.5130(13) 12.0999(7) 30.6387(28)
c/ 14.3379(15) 18.0854(11) 15.8038(16)
/deg 108.8166(52)
/deg 104.1185(74) 115.5684(3) 94.2915(27)
/deg 103.1323(61)
V/ 3
1682.0(6) 3284.6(11) 4870.9(17)
Z 2 4 4
No. msd. rflns. 8530 26070 17287

123
No. un. Rflns 4608 7513 8547
R1 (on F, I>2 (I)) 0.0620 0.0549 0.0526
wR2 (on F2
, all data) 0.1597 0.1234 0.1294
113 114 115
Formula C44H52N4O8S4 C51H59N5O10S5 C12H19N3
M 893.14 1062.39 205.30
System Triclinic Triclinic Orthorhombic
Space group P-1 P-1 P212121
a/ 11.8732(12) 13.9253(17) 10.8052(12)
b/ 13.1219(10) 16.0116(21) 10.8631(15)
c/ 15.1537(11) 22.8804(21) 19.5021(17)
/deg 88.4512(67) 90.0972(78)
/deg 86.6823(59) 98.6506(79)
/deg 68.4241(61) 90.2264(65)
V/ 3
1682.0(6) 5043.5(18) 2289.1(8)
Z 2 2 8
No. msd. rflns. 8530 26070 13345
No. un. Rflns 4608 7513 5132
R1 (on F, I>2 (I)) 0.0988 0.2614 0.1132
wR2 (on F2
, all data) 0.1583 0.4059 0.1759
60 61·5HCl·H2O 61·5HCl·2.5H2O
Formula C16H28N4 C16H36Cl5N5O C16H39Cl5N5O2.5
M 276.42 491.76 518.79
System Orthorhombic Triclinic Triclinic
Space group C2/c P-1 P-1
a/ 12.5482(8) 9.8619(7) 10.5378(8)
b/ 14.9721(11) 10.5250(7) 11.8423(6)
c/ 17.2980(14) 12.1130(10) 20.8415(12)
/deg 97.6535(19) 81.0248(41)
/deg 91.7346(29) 100.9902(21) 78.1161(36)
/deg 103.9682(28) 87.7689(35)

124
V/ 3
3248.3(11) 1176.3(4) 2513.9(9)
Z 8 2 2
No. msd. rflns. 5174 3946 22586
No. un. Rflns 2494 2333 10628
R1 (on F, I>2 (I)) 0.0572 0.0942 0.1078
wR2 (on F2
, all data) 0.1485 0.2683 0.2058
60·3HF·H[FHF]-
·3H2O 61·4HI·HI3 62·2HI·HI3·2I2
Formula C16H39N4F6O3 C16H34I7N5 C20H38I9N3
M 448.49 1184.78 1462.63
System Monoclinic Monoclinic Monoclinic
Space group C2/c C2/c P2(1)/c
a/ 21.1356(8) 33.7945(18) 18.0861(35)
b/ 11.3701(5) 11.5702(8) 14.9946(32)
c/ 19.3306(7) 15.8028(9) 14.1649(31)
/deg
/deg 111.3924(40) 103.8594(50) 108.0812(131)
/deg
V/ 3
4324.9(15) 5999(2) 3651.4(13)
Z 4 8 4
No. msd. rflns. 8370 12929 15720
No. un. Rflns 3449 5536 6242
R1 (on F, I>2 (I)) 0.0765 0.0555 0.2467
wR2 (on F2
, all data) 0.2239 0.1306 0.4381
62·3HI·I2(a) 62·3HI·I2(b) 116·3HF·3H2O
Formula C20H38I5N3 C20H38I5N3 C14H32F3N3O3
M 955.03 955.03 347.42
System Triclinic Triclinic Monoclinic
Space group P-1 P-1 P2(1)/c
a/ 11.0613(2) 11.0664(5) 5.4382(3)
b/ 16.6969(4) 11.5692(6) 16.5549(9)
c/ 17.4580(5) 12.5455(8) 19.6525(13)

125
/deg 94.6540(9) 92.5212(21)
/deg 102.9640(9) 91.3134(24) 91.5811(22)
/deg 105.4950(10) 111.2362(33)
V/ 3
2993.56(12) 1494.4(5) 1768.6(6)
Z 4 2 4
No. msd. rflns. 17304 7096 14435
No. un. Rflns 10512 4808 3628
R1 (on F, I>2 (I)) 0.0571 0.0795 0.0776
wR2 (on F2
, all data) 0.1260 0.2119 0.1460
116·3HCl 116·3HBr 117·4HCl·1.5H2O
Formula C14H26Cl3N3 C14H26Br3N3 C14H31Cl4N4O1.5
M 342.73 476.11 421.24
System Monoclinic Monoclinic Monoclinic
Space group P2(1)/n P2(1)/n C2/c
a/ 9.5996(3) 11.0558(5) 29.7246(30)
b/ 10.1003(4) 11.6209(5) 6.3480(7)
c/ 17.1572(6) 15.1984(7) 22.0537(28)
/deg
/deg 93.8496(20) 107.8422(26) 93.9990(44)
/deg
V/ 3
1659.7(6) 1858.6(6) 4151.2(14)
Z 4 4 8
No. msd. rflns. 10814 10798 2138
No. un. Rflns 3784 4242 1586
R1 (on F, I>2 (I)) 0.0313 0.0555 0.0440
wR2 (on F2
, all data) 0.0681 0.1371 0.1008
60·4HBr 61·5HBr·2H2O 116·3HClO4·H2O
Formula C16H32Br4N4 C16H38Br5N5O2 C14H28Cl3N3O13
M 600.10 732.03 552.74
System Triclinic Triclinic Triclinic
Space group P-1 P-1 P-1

126
a/ 9.4815(8) 8.4897(9) 8.7647(4)
b/ 11.0386(10) 11.1914(11) 11.2725(6)
c/ 11.4504(10) 14.9026(10) 12.7812(8)
/deg 88.5738(23) 82.7077(64) 82.1469(24)
/deg 68.2659(19) 81.8566(54) 71.7511(23)
/deg 86.0713(22) 69.5010(58) 69.0389(32)
V/ 3
1110.6(4) 1308.3(5) 1119.5(4)
Z 2 2 2
No. msd. rflns. 7106 9218 3311
No. un. Rflns 4839 5930 2214
R1 (on F, I>2 (I)) 0.1621 0.0707 0.0662
wR2 (on F2
, all data) 0.3011 0.1597 0.1571
60·3HClO4·HBr·H2O
Formula C16H32BrCl3N4O13
M 662.72
System Orthorhombic
Space group Pna2(1)
a/ 14.9001(6)
b/ 18.0530(7)
c/ 10.0562(3)
/deg
/deg
/deg
V/ 3
2704.2(3)
Z 4
No. msd. rflns. 15138
No. un. Rflns 5068
R1 (on F, I>2 (I)) 0.0924
wR2 (on F2
, all data) 0.2051

127
2.8.2 Hydrogen bond parameters for new macrocyclic systems
115
D-H...A d(D-H) d(H...A) d(D...A) <(DHA)
__________________________________________________________________
N(1)-H(10)...N(3)#1 0.98 2.37 3.254(5) 150.8
N(2)-H(20)...N(1)#1 1.05 2.23 3.144(5) 143.5
N(6)-H(60)...N(2)#2 1.09 2.09 3.141(5) 162.7
N(5)-H(50)...N(4)#3 1.03 2.24 3.147(5) 145.8
N(3)-H(30)...N(5)#1 0.97 2.18 3.141(5) 167.3
N(4)-H(40)...N(6)#3 1.02 2.31 3.256(5) 153.5
____________________________________________________________________
Symmetry transformations used to generate equivalent atoms:
#1 -x,-y,-z #2 -x+1,-y,-z #3 -x+1,-y+1,-z
60
____________________________________________________________________
N(1)-H(11)...N(2)#1 0.66(4) 2.60(4) 3.241(5) 169(5)
N(2)-H(21)...N(1) 0.74(3) 2.60(3) 3.033(4) 119(3)
N(4)-H(41A)...N(3) 0.81(5) 2.67(5) 3.096(5) 115(4)
N(4)-H(41B)...N(3)#2 0.88(7) 2.41(7) 3.287(6) 173(5)
N(3)-H(31A)...N(4) 0.77(4) 2.46(4) 3.096(5) 141(4)
N(3)-H(31B)...N(4)#2 0.75(6) 2.56(6) 3.287(6) 164(5)
____________________________________________________________________
#1 -x+1/2,-y+1/2,-z+1 #2 -x+1,-y+1,-z+1
61·6HCl·H2O
____________________________________________________________________
N(2)-H(2A)...Cl(3)#1 0.92 2.13 3.012(8) 161.0
N(2)-H(2B)...Cl(1) 0.92 2.20 3.099(8) 166.1
N(1)-H(1A)...Cl(1) 0.92 2.34 3.170(8) 149.9
N(1)-H(1A)...Cl(2)#2 0.92 2.71 3.156(8) 110.5
N(1)-H(1B)...Cl(2) 0.92 2.23 3.083(9) 153.2
N(5)-H(5A)...Cl(5) 0.92 2.21 3.100(9) 161.4

128
N(5)-H(5B)...Cl(4)#3 0.92 2.10 3.006(11) 169.7
N(3)-H(3A)...Cl(5)#4 0.92 2.25 3.080(8) 149.9
N(3)-H(3B)...Cl(1) 0.92 2.33 3.205(8) 159.1
N(3)-H(3B)...Cl(1)#1 0.92 2.78 3.267(8) 114.2
N(4)-H(4A)...Cl(3)#4 0.92 2.82 3.441(14) 126.1
N(4)-H(4B)...Cl(2)#2 0.92 2.17 3.087(10) 175.9
O(1)-H(101)*
...Cl(4) 2.435(10)
N(4)-H(4B) *
...Cl(2)#5 3.087(10)
____________________________________________________________________
#1 -x,-y,-z+1 #2 -x,-y,-z #3 x,y,z-1 #4 -x,-y+1,-z+1 #5 -x,-y+1,-z+2
61·6HCl·2.5H2O
____________________________________________________________________
N(9)-H(92)...Cl(6) 0.84 2.22 3.046(5) 165.5
N(7)-H(71)...Cl(4)#1 0.83 2.28 3.108(5) 176.3
N(8)-H(82)...Cl(9)#2 0.80 2.26 3.037(5) 165.2
N(2)-H(21)...Cl(1) 0.85 2.25 3.095(5) 171.5
N(10)-H(102)...Cl(3) 0.81 2.44 3.244(5) 168.3
N(1)-H(11)...Cl(1) 0.83 2.51 3.283(5) 155.7
N(1)-H(11)...Cl(9)#2 0.83 2.94 3.352(5) 112.4
N(10)-H(101)...Cl(4)#1 0.85 2.53 3.299(5) 150.4
N(10)-H(101)...Cl(2)#3 0.85 2.62 3.118(5) 118.5
N(6)-H(61)...Cl(7) 1.04 1.99 3.024(5) 177.3
N(4)-H(42)...Cl(6) 0.90 2.26 3.084(5) 153.1
N(4)-H(42)...Cl(1) 0.90 2.77 3.229(5) 113.2
N(8)-H(81)...Cl(3) 0.85 2.44 3.273(5) 170.5
N(5)-H(52)...Cl(10) 0.90 2.17 3.052(5) 167.4
N(4)-H(41)...Cl(2) 1.07 2.04 3.107(5) 170.5
N(5)-H(51)...Cl(2) 0.84 2.51 3.311(5) 160.7
N(9)-H(91)...Cl(3) 0.93 2.17 3.089(5) 173.2
N(2)-H(22)...Cl(5) 1.08 2.00 3.059(5) 165.8
N(6)-H(62)...Cl(4)#1 0.87 2.43 3.266(5) 159.6
N(3)-H(32)...Cl(8)#4 0.86 2.27 3.067(5) 153.9
N(3)-H(31)...Cl(1) 0.93 2.34 3.235(5) 160.7
N(7)-H(72)...Cl(5) 0.90 2.26 3.109(5) 156.5

129
N(1)-H(12)...Cl(2) 0.89 2.53 3.283(5) 142.4
N(1)-H(12)...Cl(4)#2 0.89 2.56 3.162(5) 125.1
O(5)-H(502)...O(1)#5 1.03 2.05 2.845(7) 132.1
O(3)-H(301)...O(4) 0.98 1.83 2.782(9) 164.4
O(2)-H(201)...O(3)#6 0.98 1.92 2.713(9) 136.2
O(2)-H(202)...Cl(10)#7 3.441(9)
O(4)-H(401) *
...Cl(10)#8 3.043(9)
O(4)-H(402) *
...Cl(9) 3.193(9)
O(3)-H(302) *
...Cl(6) 3.154(9)
O(1)-H(101) *
...Cl(7) 3.085(9)
O(1)-H(102) *
...Cl(8) 3.226(9)
____________________________________________________________________
#1 x+1,y+1,z #2 x+1,y,z #3 x,y+1,z #4 -x+2,-y+2,-z+1
#5 x,y-1,z #6 2-x,2-y,-z #7 2-x,1-y,-z #8 1-x,1-y,-z
60·2HF·2FHF·3H2O
____________________________________________________________________
N(1)-H(1A)...F(3)#1 0.92 1.69 2.599(5) 168.8
N(1)-H(1B)...F(1)#1 0.92 1.99 2.734(5) 136.5
N(1)-H(1B)...F(2)#1 0.92 2.25 2.913(5) 128.7
F(5)-H(5F)...F(5)#2 1.078(6) 1.078(6) 2.152(10) 173(7)
N(3)-H(3B)...F(1)#1 0.94(7) 1.68(7) 2.589(5) 162(6)
N(4)-H(4A)...F(4)#3 0.91(6) 1.85(6) 2.728(6) 162(5)
O(3)-H(301)...F(4)#4 0.92(10) 1.78(10) 2.688(5) 170(9)
N(2)-H(2A)...F(4) 0.83(6) 1.91(6) 2.689(7) 157(5)
N(4)-H(4B)...F(4)#5 0.94(7) 1.70(7) 2.629(6) 169(5)
N(2)-H(2B)...F(1)#1 0.96(7) 1.70(8) 2.639(6) 164(6)
N(3)-H(3A)...F(3)#6 0.95(6) 1.71(7) 2.638(6) 165(5)
O(1)-H(101)...F(3) 0.88(7) 1.82(8) 2.686(6) 165(6)
O(2)-H(202)...O(1)#7 0.92(8) 1.91(8) 2.828(7) 173(6)
O(2)-H(201)...F(3) 0.87(10) 1.87(10) 2.728(6) 166(7)
O(1)-H(102)...O(3)#8 0.80(9) 2.03(9) 2.802(7) 161(8)
O(3)-H(2)...F(5) 0.91(8) 1.74(8) 2.645(7) 177(6)
F(5)-H(5F)...F(5)#9 1.131(6) 1.131(6) 2.261(10) 176(7)
____________________________________________________________________

130
#1 -x+1/2,-y+3/2,-z #2 -x+1,y,-z-1/2 #3 x,y-1,z
#4 -x+1,y-1,-z-1/2 #5 -x+1,-y+2,-z #6 x+1/2,y+1/2,z
#7 -x+1/2,-y+1/2,-z #8 x,-y+1,z+1/2
61·4HI·HI3
____________________________________________________________________
N(5)-H(5A)...I(6)#1 0.92 2.67 3.557(11) 160.8
N(5)-H(5B)...I(2) 0.92 2.90 3.741(12) 153.1
N(2)-H(2A)...I(1) 0.92 2.66 3.559(10) 167.1
N(2)-H(2B)...I(3)#2 0.92 2.94 3.769(11) 150.0
N(2)-H(2B)...I(6) 0.92 3.08 3.598(10) 117.1
N(1)-H(1A)...I(2) 0.92 2.60 3.512(12) 170.0
N(1)-H(1B)...I(6)#3 0.92 2.57 3.480(10) 169.5
N(3)-H(3A)...I(7) 0.92 2.49 3.370(13) 159.7
N(3)-H(3B)...I(1) 0.92 2.50 3.422(13) 175.8
N(4)-H(4A)...I(1) 0.92 2.62 3.529(12) 169.7
N(4)-H(4B)...I(7)#4 0.92 2.72 3.438(11) 135.4
N(4)-H(4B)...I(3)#5 0.92 3.07 3.651(12) 122.6
N(5)-H(5B)...I(1)#1 0.92 3.24 3.650(12) 109.5
____________________________________________________________________
#1 x,-y,z+1/2 #2 -x,-y+1,-z+1 #3 x,-y+1,z+1/2
#4 -x-1/2,y-1/2,-z+1/2 #5 -x,-y,-z+1
62·2HI·HI3·2I2
____________________________________________________________________
N(1)-H(1A)...I(9)#1 0.92 2.61 3.39(4) 143.6
N(1)-H(1A)...I(5)#2 0.92 3.26 4.06(4) 146.5
N(1)-H(1B)...I(1) 0.92 3.02 3.81(4) 144.5
N(1)-H(1B)...I(6)#1 0.92 3.08 3.68(4) 125.0
N(2)-H(2A)...I(1) 0.92 2.78 3.63(4) 154.2
N(2)-H(2B)...I(2) 0.92 2.85 3.58(3) 137.0
N(2)-H(2B)...I(4)#3 0.92 3.29 3.97(4) 132.5
N(3)-H(3A)...I(2)#4 0.92 3.10 3.88(4) 143.8

131
N(3)-H(3B)...I(1) 0.92 2.76 3.67(4) 170.0
N(3)-H(3A)...I(1)#4 0.92 3.37 3.86(4) 115.7
____________________________________________________________________
#1 x,-y+1/2,z-1/2 #2 -x,-y+1,-z+1 #3 -x+1,y+1/2,-z+1/2
#4 x,-y+1/2,z+1/2
62·3HI·I2
____________________________________________________________________
N(1)-H(1C)...I(1) 0.92 2.84 3.730(9) 164.5
N(1)-H(1D)...I(9)#1 0.92 2.58 3.434(8) 155.1
N(2)-H(2C)...I(1) 0.92 3.00 3.706(8) 134.7
N(2)-H(2C)...I(9) 0.92 3.07 3.556(8) 114.7
N(2)-H(2D)...I(9)#2 0.92 2.79 3.568(8) 142.4
N(3)-H(3C)...I(1) 0.92 2.78 3.683(9) 168.3
N(3)-H(3D)...I(8)#3 0.92 2.93 3.709(9) 143.1
N(4)-H(4D)...I(10)#4 0.92 2.64 3.506(8) 158.1
N(4)-H(4C)...I(4) 0.92 2.69 3.579(9) 162.7
N(5)-H(5C)...I(10)#5 0.92 2.63 3.535(8) 169.0
N(5)-H(5D)...I(10) 0.92 2.57 3.490(9) 176.7
N(6)-H(6C)...I(5) 0.92 3.13 3.607(9) 114.6
N(6)-H(6D)...I(5)#6 0.92 2.75 3.542(9) 144.8
N(6)-H(6D)...I(5) 0.92 3.18 3.607(9) 110.4
____________________________________________________________________
#1 -x+3,-y+2,-z+1 #2 -x+4,-y+2,-z+1 #3 x+2,y,z+1
#4 -x+1,-y+1,-z #5 -x,-y+1,-z #6 -x+1,-y+2,-z
62·3HI·I2
____________________________________________________________________
N(1B)-H(1B1)...I(4A)#3 0.92 2.21 3.07(3) 156.1
N(1B)-H(1B2)...I(2) 0.92 2.59 3.49(3) 166.6
N(3B)-H(3B1)...I(1) 0.92 3.12 3.65(2) 118.5
N(3B)-H(3B2)...I(1)#4 0.92 2.66 3.48(3) 148.2
N(2A)-H(2A1)...I(4B)#5 0.92 3.01 3.54(3) 118.0

132
N(2A)-H(2A2)...I(4B) 0.92 2.69 3.49(3) 146.0
N(2B)-H(2B1)...I(4A) 0.92 2.65 3.55(2) 168.2
N(2B)-H(2B2)...I(4A)#5 0.92 2.55 3.47(2) 178.4
N(1A)-H(1A2)...I(4B)#3 0.92 3.02 3.85(3) 150.6
N(3A)-H(3A1)...I(1) 0.92 2.87 3.65(3) 142.5
____________________________________________________________________
#1 -x,-y,-z #2 -x-2,-y-1,-z+1 #3 x-1,y,z
#4 -x-1,-y-1,-z #5 -x,-y,-z+1
116·3HF
____________________________________________________________________
N(2)-H(2A)...O(3)#1 0.92 1.93 2.813(5) 160.3
N(2)-H(2B)...F(1) 0.92 1.69 2.569(5) 159.2
N(1)-H(1A)...F(1)#2 0.92 1.72 2.624(5) 166.5
N(1)-H(1B)...O(1) 0.92 1.76 2.657(5) 162.8
N(3)-H(3A)...F(3)#3 0.92 1.70 2.606(5) 169.2
N(3)-H(3B)...O(3)#4 0.92 2.04 2.848(6) 145.2
N(3)-H(3B)...O(2) 0.92 2.35 2.939(5) 122.0
O(1)-H(101)*
...O(2)#5 2.318(5)
O(1)-H(102) *
...O(3) 2.607(5)
O(3)-H(301) *
...F(3) 2.636(5)
O(2)-H(201) *
...O(3)#4 3.130(5)
____________________________________________________________________
#1 -x+1,-y+1,-z #2 x+1,y,z #3 x-1,-y+3/2,z+1/2
#4 x,-y+3/2,z+1/2 #5 x+1,-y+3/2,z-1/2
116·3HCl
____________________________________________________________________
N(2)-H(2A)...Cl(3)#1 0.86(2) 2.27(2) 3.0777(15) 155.0(17)
N(2)-H(2B)...Cl(2) 0.92(2) 2.34(2) 3.1832(16) 153.1(15)
N(3)-H(3A)...Cl(1)#2 0.929(19) 2.192(19) 3.0889(14) 161.9(16)
N(3)-H(3B)...Cl(2)#3 0.89(2) 2.27(2) 3.1163(15) 158.1(16)
N(1)-H(1B)...Cl(3) 0.935(19) 2.155(19) 3.0793(14) 169.4(16)

133
N(1)-H(1A)...Cl(1)#4 0.902(19) 2.268(19) 3.1194(14) 157.4(15)
____________________________________________________________________
#1 -x+1/2,y-1/2,-z+1/2 #2 x+1,y,z #3 -x+1,-y+1,-z
#4 x+1/2,-y+1/2,z+1/2
116·3HBr
____________________________________________________________________
N(3)-H(3B)...Br(2) 0.84(6) 2.39(6) 3.159(5) 151(5)
N(2)-H(2B)...Br(1) 0.85(6) 2.39(6) 3.234(4) 171(5)
N(1)-H(1A)...Br(1)#1 1.06(10) 2.25(10) 3.245(5) 155(8)
N(3)-H(3A)...Br(3)#2 0.98(6) 2.36(6) 3.283(5) 155(5)
N(1)-H(1B)...Br(3) 0.75(9) 2.56(9) 3.299(5) 173(8)
N(2)-H(2A)...Br(2)#2 1.25(7) 2.01(7) 3.216(4) 160(5)
____________________________________________________________________
#1 -x+1/2,y+1/2,-z+1/2 #2 -x+3/2,y-1/2,-z+1/2
117·4HCl·1.5H2O
____________________________________________________________________
N(4)-H(4A)...Cl(2)#1 0.92 2.22 3.107(5) 162.5
N(4)-H(4B)...Cl(4)#2 0.92 2.21 3.092(6) 160.7
N(2)-H(2A)...Cl(2)#3 0.92 2.27 3.081(5) 147.1
N(2)-H(2B)...Cl(1)#4 0.92 2.24 3.148(5) 170.4
N(1)-H(1A)...O(1) 0.92 1.89 2.783(6) 164.5
N(1)-H(1B)...Cl(1)#4 0.92 2.20 3.123(5) 177.2
N(3)-H(3A)...Cl(1)#4 0.92 2.32 3.167(5) 152.9
N(3)-H(3B)...Cl(4)#3 0.92 2.32 3.117(5) 144.4
N(3)-H(3B)...Cl(2)#4 0.92 2.65 3.139(6) 113.7
O(2)-H(201)...Cl(3) 0.65(5) 2.60(5) 3.241(7) 175(7)
O(1)-H(101)...Cl(3)#5 0.95(5) 2.07(6) 3.014(6) 171(6)
N(2)-H(2A)...O(2) 0.92 2.58 2.989(5) 107.5
O(2)-H(202) *
...Cl(4)#4 3.192(7)
____________________________________________________________________

134
#1 -x+1/2,-y+1/2,-z #2 x,-y+1,z-1/2 #3 -x+1/2,y-1/2,-z+1/2
#4 x,y-1,z #5 -x,y,-z+1/2
60·4HBr
____________________________________________________________________
N(2)-H(21)...Br(2)#1 0.92 2.48 3.352(14) 158.2
N(2)-H(22)...Br(2)#2 0.92 2.47 3.311(15) 151.6
N(1)-H(11)...Br(1) 0.92 2.58 3.437(17) 154.9
N(1)-H(12)...Br(4) 0.92 2.35 3.208(17) 156.0
N(4)-H(41)...Br(3)#3 0.92 2.39 3.250(14) 155.5
N(4)-H(42)...Br(1) 0.92 2.42 3.337(13) 175.6
N(3)-H(31)...Br(2)#2 0.92 2.37 3.279(16) 167.9
N(3)-H(32)...Br(3) 0.92 2.79 3.547(16) 140.1
N(3)-H(32)...Br(4)#4 0.92 2.94 3.579(16) 128.0
N(1)-H(11)...Br(3)#5 0.92 3.05 3.425(17) 106.5
N(1)-H(12)...Br(3)#5 0.92 3.08 3.425(17) 104.3
____________________________________________________________________
#1 x,y+1,z #2 -x+2,-y+1,-z #3 -x+1,-y+1,-z
#4 x,y,z-1
61·5HBr·2H2O
____________________________________________________________________
N(5)-H(5A)...Br(5) 0.92 2.32 3.226(6) 169.6
N(5)-H(5B)...Br(1) 0.92 2.38 3.252(7) 157.5
N(2)-H(2A)...Br(3)#1 0.92 2.54 3.249(7) 133.7
N(2)-H(2A)...Br(4)#1 0.92 3.13 3.647(6) 117.5
N(2)-H(2B)...Br(2) 0.92 2.50 3.357(7) 155.9
N(4)-H(4A)...Br(4)#2 0.92 2.36 3.233(7) 158.5
N(4)-H(4B)...Br(1)#2 0.92 2.68 3.486(6) 146.7
N(4)-H(4B)...Br(3)#2 0.92 2.77 3.338(6) 121.2
N(3)-H(3A)...Br(3)#3 0.92 2.33 3.199(6) 156.5
N(3)-H(3B)...Br(2) 0.92 2.37 3.225(6) 155.2
N(1)-H(1A)...Br(5)#4 0.92 2.42 3.294(6) 159.4
N(1)-H(1B)...O(1) 0.92 1.94 2.832(8) 164.1

135
O(2)-H(201)*
...O(2) 2.790(8)
O(2)-H(202) *
...O(1) 2.746(8)
____________________________________________________________________
#1 -x+1,-y+2,-z+1 #2 -x+2,-y+1,-z+1 #3 x+1,y,z
#4 x-1,y+1,z #5 2-x,2-y,2-z #6 1-x,2-y,2-z
116·3HClO4·H2O
____________________________________________________________________
N(3)-H(3A)...O(13) 0.92 1.98 2.900(8) 176.5
N(3)-H(3B)...O(10) 0.92 2.21 2.940(7) 135.8
N(3)-H(3B)...O(1)#1 0.92 2.28 2.922(7) 126.9
N(1)-H(1A)...O(4)#2 0.92 2.09 2.999(8) 172.0
N(1)-H(1A)...O(1)#2 0.92 2.46 3.065(8) 123.8
N(1)-H(1A)...Cl(1)#2 0.92 2.78 3.634(6) 155.0
N(1)-H(1B)...O(11)#3 0.92 2.21 3.029(8) 147.9
N(1)-H(1B)...O(10)#3 0.92 2.24 2.887(7) 127.1
N(1)-H(1B)...Cl(3)#3 0.92 2.72 3.515(6) 145.7
N(2)-H(2A)...O(13)#1 0.92 2.08 2.927(8) 153.4
N(2)-H(2B)...O(2)#4 0.92 2.21 3.008(7) 144.2
N(2)-H(2B)...O(4)#4 0.92 2.64 3.386(8) 138.9
N(2)-H(2B)...Cl(1)#4 0.92 2.97 3.809(6) 153.1
O(13)-H(131)...O(8)#5 0.70(7) 2.15(7) 2.841(9) 173(8)
O(13)-H(132)...O(7)#1 0.83(7) 2.07(8) 2.861(8) 159(7)
N(2)-H(2A)...O(2) 0.92 2.51 2.947(8) 109.2
____________________________________________________________________
#1 -x+2,-y,-z #2 -x+2,-y+1,-z #3 x,y+1,z
#4 -x+1,-y+1,-z #5 x+1,y,z
60·3HClO4 ·HBr·H2O
____________________________________________________________________
N(1)-H(1D)...O(10) 0.92 2.09 2.997(12) 168.7
N(1)-H(1D)...O(9) 0.92 2.61 3.230(13) 125.0
N(1)-H(1D)...Cl(3) 0.92 2.86 3.689(9) 150.0

136
N(1)-H(1C)...Br(1) 0.92 2.46 3.335(9) 158.0
N(2)-H(2D)...O(1)#1 0.92 2.05 2.870(16) 147.4
N(2)-H(2D)...Cl(1)#1 0.92 2.87 3.725(13) 154.7
N(2)-H(2C)...Br(1) 0.92 2.46 3.173(9) 134.0
N(2)-H(2C)...O(3) 0.92 2.58 3.174(15) 122.4
N(3)-H(3C)...O(3) 0.92 2.07 2.932(13) 154.8
N(3)-H(3C)...Cl(1) 0.92 2.92 3.558(10) 127.5
N(3)-H(3D)...O(13) 0.92 1.88 2.728(14) 151.6
N(3)-H(3D)...O(1) 0.92 2.54 3.096(13) 119.0
N(4)-H(4A)...O(7)#2 0.92 1.82 2.69(2) 156.6
N(4)-H(4A)...Cl(2)#2 0.92 2.71 3.523(14) 147.2
N(4)-H(4B)...Br(1)#2 0.92 2.56 3.473(16) 172.5
N(4A)-H(4A1)...Br(1) 0.92 2.60 3.51(2) 170.7
N(4A)-H(4A2)...O(11)#3 0.92 2.06 2.81(2) 137.2
N(4A)-H(4A2)...Cl(3)#3 0.92 2.91 3.65(2) 138.4
O(13)-H(131)*
...O(1)#2 3.14(2)
O(13)-H(132) *
...O(12) 3.01(2)
____________________________________________________________________
#1 x-1/2,-y+3/2,z #2 x+1/2,-y+3/2,z #3 -x+1/2,y-1/2,z-1/2
*
Note: Protons denoted with (*
) have not been refined experimentally.

137
CHAPTER 3:
MACROBICYCLIC AZAPHANES
3.1 Synthesis
The main aim of this project is the construction of macrocyclic polyamines
possessing specific coordination geometries for the binding of anionic species. A
common observation in our previous crystallographic studies was that halides form
the apex of a distorted or undistorted trigonal pyramid, especially when
cocrystallized with 2,2’,2’’-triaminotriethylamine (tren).140
Anion binding behaviour
of acyclic ligands based on the 1,3,5-trimethyl-benzene unit confirms the efficiency
of the trigonal pyramidal coordination mode for the binding of halides.180, 181
The
tren unit was chosen as the key structural feature for the new ligands. It is well
known that the tren unit has been incorporated in polyamine cryptands that display
very strong binding for halides.34, 114, 118, 144, 182
The choice of macrobicyclic
azaphanes (and therefore the incorporation of an aromatic unit) as candidates for the
purpose of anion binding is also important. These species possess a markedly more
rigid framework than their macrocyclic analogues.2, 165, 166, 183
Indeed, as seen in
sections 1.3.3 and 1.3.5.2 cryptands (and bicyclic cyclophanes that fall into this
general category) have been extensively used as complexones for anions since the
very beginning of modern supramolecular chemistry.76
In general, however, their
synthesis is more challenging than that of monocyclic hosts.184
This is because of the
usually greater number of steps required for the synthesis of cryptands as well as
because of the lower yields of multiple cyclization reactions. As seen in section
1.2.1, various strategies have been developed for the synthesis of macrobicyclic
species. The synthetic strategy chosen in this project was based on the tripod-tripod
bicyclization,32
very similar to the dipod-dipod cyclization strategy upon which the
synthesis of monocyclic cyclophanes was based, as described in section 2.4. Two
starting materials were synthesized, one bearing the aromatic unit (A), the other
bearing the polyamine framework (B). Starting material A would bear three good
leaving groups such as those listed in figure 1.1 and starting material B would bear
three nucleophilic groups. Having used 1,3-bis-(bromomethyl)-benzene succesfully
for the synthesis of monocyclic azaphanes, the tripodal analogue 1,3,5-tris-

138
(bromomethyl)-benzene (119) seemed a natural choice as the starting material A for
bicyclic azaphanes. This compound can be easily made in high yields from
inexpensive starting materials (scheme 3.1). Compound B is a tripodal triamine.
Such a compound can be made by using tris-(2-aminoethyl)-amine as a starting
material and then following a multistep synthetic procedure in order to ‘elongate’ it
(scheme 3.2). Either B1 or B2 can be used for the cyclization step (scheme 3.3) and
both have been used in this project. An advantage of using these starting materials,
for instance B1 or B2, is that they can in principle be elongated still further by
repetition of the procedure depicted at scheme 3.2.
Scheme 3.1. Synthesis of starting material (A)
O O
OOH
OHOH
MeO OMe
OMe
O O
O
Br Br
Br
CH3OH, H2SO4
1) LiAlH4, THF
2) 48% aq. HBr, toluene
A

139
Scheme 3.2. Synthesis of starting materials (B)
The cyclization reaction was aimed to be a [1+1] as shown in scheme 3.3. It
is well established that bicyclization reactions give lower yields than
monocyclization reactions. The reason is the formation of three rings instead of two
in a single condensation step (section 1.2.1). Thus, more polycondensation side
reactions occur at the same time. Indeed, the yields of the bicyclization reactions
reported in literature are generally lower than those of monocyclizations.26
A general representation of the cyclization reaction is given in scheme 3.3. A
full list of the precursor macrocycles along with the target compounds synthesized is
given in figure 3.1.
N
NH2
NH2
NH2
N
NHNH
NH
N
NN
N
N
N
N
N
N
NN
N
NH2
NH2
NH2
N
NN
N
NH NH
N
H
TsCl, K2CO3
H2O
Ts
Ts Ts
Ts
Ts Ts
K2CO3
CH3CN
Ts
Ts Ts
B2H6
. THF
1) 10% HCl/MeOH
2) 6 M aq. NaOH
TsCl, THF
aq. NaOH
Ts
Ts TsTs Ts
Ts
B1
B2

140
Scheme 3.3. The reaction that leads to the formation of the precursor macrocycles.
The precursor macrocycles can be seen in figure 3.1
The preparation of starting materials as well as cyclization reactions went
smoothly and yields (see experimental section for details) are in good agreement
with those of related products reported earlier.32, 34, 44, 105
Problems similar to those
described in section 2.5 (synthesis of target monocyclic compounds) were
encountered in the final step, the detosylation of precursor macrocycles. The use of
strongly acidic conditions for the synthesis of 126 proved unsuccesful, leading to the
formation of byproducts. It is believed that the reason for this is the strained nature of
the precursor macrocycle, 124, which makes it rather sensitive under strongly acidic
conditions. However, the use of metallic sodium yielded 126 almost quantitatively.
Detosylation of 125 under strongly acidic conditions yielded 127 without any
problems. The methods employed in this final step are exactly the same with those
described for monocyclic azaphanes in section 2.5. Compound 128 was easily
synthesized by prolonged heating of 126 in a mixture of paraformaldehyde and
formic acid.
N
N
N
Br Br
Br
NH
NH
NH
N
Ts
Ts
Ts+
K2CO3, CH3CN
N
N
Ts
Ts
Ts
S
S
S
S S S
A B
PRECURSOR
MACROCYCLE
S = or
Ts

141
Figure 3.1. Cryptand precursor macrocycles (124, 125) and target compounds (126,
127, 128) synthesized in this project
3.2 Crystallographic evidence for an attractive intramolecular NH···
interaction
Suitable crystals for X-ray analysis of the precursor macrocycle 124 were
grown by slow diffusion of hexane into a concentrated solution of 124 in chloroform.
The NApical···Centroid distance was found to be only 2.988(8) Å, suggesting that the
N
N
N
N
N
N
N
NN
N
N
NH
NH
N
NH
NH
NH
NH
NHNH
N
NH
N
N
N
N
Me
Me
Me
Ts
Ts
Ts
Ts
Ts
Ts Ts Ts
Ts
124
125
126
127
128

142
only species that would fit inside such a tiny cavity is a proton. Suitable crystals for
X-ray analysis for 126 were grown by slow evaporation of a concentrated solution of
126 in chloroform. Both crystal structures prove the endo-conformation of these
cages. The term endo-conformation implies that the apical nitrogen points inwards
the macrocyclic cavity (figure 3.2). Unfortunately, however, the crystal structure of
126 is disordered, making the final intramolecular contact distances unreliable. The
species afforded after crystallization of 126 with dilute aqueous hydrochloric acid,
was 126·4HCl·2H2O, (figure 3.2). It is significant that this cryptand is crystallized in
its fully protonated form, something which is not usually observed in other, larger
cryptands. For example, crystallization of Dietrich’s octaazacryptand 634, 114
(see
chapter 1, figure 1.18) with concentrated hydrochloric acid yielded the
hexaprotonated species.115
Also, the larger cryptand 127 that will be discussed next,
was crystallized in its fully protonated state only with concentrated hydrobromic
acid.
X-ray analysis revealed the endo-conformation of cryptate 126 as well with
the N-H distance being 0.84(5) Å. Importantly, the N···Centroid distance for this
species is 2.988(8) Å, marginally smaller than the corresponding N···Centroid
distance for the tosylated precursor 124, 2.978(7) Å (figure 3.2). Moreover, the
H···Centroid distance is 2.13(4) Å and the N-H···Centroid angle 178(3). The average
NapexH···CAr distance is 2.56(4), on the threshold of the sum of the van der Waals
radii of carbon and hydrogen.

143
126·4HCl·2H2O 124
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
These parameters suggest that an NH··· intramolecular interaction takes
place between the hydrogen of the ammonium moiety at the top of the azaphane, and
the electron cloud of the aromatic ring. This suggestion is in agreement with
solution (potentiometric and NMR) and theoretical studies. Potentiometric, NMR,
and computational studies regarding this system are discussed in detail in sections
3.3.1, 3.4.1, and 3.5 respectively. It was anticipated that this attractive force would
induce structural changes in the cryptate, compared to its precursor macrocycle.
Indeed, we have measured the distances between each of the C(7), C(8) and C(9)
carbons (next to the arene ring), and the plane defined by the atoms of the arene ring
in each compound (figure 3.3). The corresponding distances are x1: 0.279(10) Å, x2:
0.280(11) Å, and x3: 0.317(11) Å for 124 (average: 0.292(11)). For 126·4HCl·2H2O,
the distances are x1: 0.246(8) Å, x2: 0.257(8) Å and x3: 0.256(7) Å (average:
0.253(8)). Apparently, the average x distance is smaller in 126·4HCl·2H2O than in
124. Moreover, there is a difference between the average Napex···CAr distance in the
cryptate (3.287(7) Å) and the average Napex···CAr distance in the precursor

144
macrobicycle (3.292(8) Å) with that of the cryptate being slightly smaller (table 3.1).
It is evident from these data that, compared to the cavity of the precursor
macrobicycle, the cavity of the cryptate is reduced in size as a result of the attractive
NH··· force. The structural features of the cryptate outside the bicyclic cavity are
also interesting. Each of the NH2
+
protons forms one short hydrogen bond with each
of the six chlorides that surround the cryptand, forming the hydrogen bond network
shown in figure 3.4. The protons of the water molecules are also fully involved in
hydrogen bonding by forming H-O-H···Cl-
and H-O-H···OH2 hydrogen bonds.
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
N N
N
N
x3
x2
x1
C7
C8
C9

145
Figure 3.4. Hydrogen bonding between the NH2
+
protons and the chloride anions
surrounding the protonated ligand 126
NApex···CAr distances for:
a) 124 b) 126·4HCl·2H2O
N···C1: 3.274(8) Å N···C1: 3.280(6) Å
N···C2: 3.324(8) Å N···C1: 3.283(6) Å
N···C3: 3.313(8) Å N···C1: 3.272(7) Å
N···C4: 3.306(9) Å N···C1: 3.292(7) Å
N···C5: 3.272(8) Å N···C1: 3.291(7) Å
N···C6: 3.265(8) Å N···C1: 3.302(7) Å
Mean: 3.292(8) Å Mean: 3.287(7) Å
Table 3.1 Comparison of structural data for 124 and 126·4HCl·2H2O
3.3 Crystal structures of 128 and 128·3HCl
It has been possible to grow crystals of X-ray quality for the methylated
cryptand 128 (figure 3.5). This compound is structurally very similar to the tosylated
precursor 124. An unexpected feature of 128 is that the N···Centroid distance is

146
2.936(5) Å, even shorter than the corresponding distance (2.978(7) Å) observed for
the tetraprotonated unmethylated cryptand 126·4HCl·2H2O. It is believed that crystal
packing effects play also a significant role in determining the N···Centroid distance in
both cases. Given the disordered nature of the crystal structure of 126, efforts were
directed towards the growing of X-ray quality crystals of the hydrochloride salt of
128, so that a direct comparison between the unprotonated and the fully protonated
species could be made. Unfortunately the crystals grown for 128·3HCl·xH2O were of
very poor quality (only the unit cell dimensions of this compound are given in
section 3.6) and they apparently correspond to the triprotonated species. It was not
possible to refine the ammonium protons but the geometry of the crystal structure
suggests that the protonated amine moieties are the ones close to the aromatic ring
with the apical nitrogen being unprotonated. This observation contradicts the
findings of potentiometric studies where 128 was found to behave in the same way as
126. Given the crystal structure of 128·3HCl·xH2O is of trigonal symmetry
(rhombohedral, space group: P3) it is believed that the triprotonated species may fit
this symmetry better, despite the fact that the crystallization experiment was
conducted at pH<2. Therefore, it is assumed that the ligand behaves differently in the
solid state than in solution but the exact reasons for this are not known.
Figure 3.5. Crystal structure of 128. Unexpectedly, the N···Centroid distance is
shorter than that for 126·4HCl·2H2O

147
3.4 Crystal structure of 125
Suitable crystals for X-ray diffraction for 125 were grown by slow diffusion
of pentane in a concentrated solution of the product in dichloromethane. The
tosylated macrobicycle clearly lacks preorganization for the binding of a halide or a
spherical species in general (figure 3.6) and this is reflected by the relatively short
N···Centroid distance (5.872(19) Å). It is anticipated however, that upon protonation
the cavity would become preorganized for a spherical species due to the mutual
repulsive forces between the protonated ammonium sites. The crystal structure
displays high symmetry belonging to the rhombohedral crystal system (for crystal
structure information, see section 3.6).
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
3.5 Crystal structures of polyammonium salts of 127
It has been possible to crystallize compound 127 with the halide anions
fluoride, chloride, bromide, and iodide from an aqueous solution of the
corresponding acid by slow evaporation. In the case of the hydrochloride salt, the
state of protonation the ligand was confirmed by elemental analysis, as the wR2
factor of this crystal structure was rather high (0.3563). A mixed fluoride/ silicon
hexafluoride salt (127·2HF·2H2SiF6·7H2O) resulted from crystallization with

148
hydrofluoric acid, presumably as a result of glass corrosion. Four I3
-
anions
cocrystallized along with the hexaprotonated ligand and two iodide anions in the case
of the polyiodide salt 127·2HI·4HI3. In all cases the macrocycle was crystallized in
its hexaprotonated form with the exception of the bromide salt 127·7HBr·3H2O in
which it was crystallized in its heptaprotonated form. Importantly, in all four cases, a
halide anion is located inside the cavity of the macrocycle. The general structural
characteristics of these compounds are given in section 3.6 and will be discussed in
detail in the following paragraphs.
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
In the crystal structure of 127·2HF·2H2SiF6·7H2O a fluoride anion is located
inside the cavity of the macrocycle. The hexa-protonated ligand cocrystallized along
with two silicon hexafluoride anions as well as with seven water molecules. Silicon
hexafluoride was apparently formed by the corrosion of the glass tube after action of
traces of hydrofluoric acid (for preparation of suitable crystals for X-ray analysis, see
experimental part).
127·2HF·2H2SiF6·7H2O 127·6HCl·4H2O 127·7HBr·3H2O 127·2HI·4HI3
Napex···X-
3.066(3) Å 3.445(7), 3.528(7) Å 3.169(12), 3.187(14) Å 3.786(13) Å
Centr···X-
4.506(3) Å 3.652(8), 3.743(9) Å 3.653(14), 3.675(14) Å 3.692(13) Å
Napex···Centr 7.520(4) Å 7.169(11), 7.185(11) Å 6.804(19), 6.849(18) Å 7.468(18) Å
dav 6.100(4) Å 7.127(14), 7.099(18) Å 7.642(27), 7.207(25) Å 6.808(21) Å

149
(a) (b)
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
Compared with the structure of the tosylated precursor macrocycle 125, the
inclusion of the anion markedly changes the structure of the host. The N···Centroid
distance in this salt is 7.520 Å compared with 5.872 Å in the non-preorganized
tosylated precursor indicating the structural difference imposed to the ligand as a
result of protonation and anion inclusion. The fluoride anion is held by three strong
hydrogen bonds supplied by the three ammonium moieties of the tren unit
(N(4)···F(1): 2.679(3) Å, N(5)···F(1): 2.619(3) Å, N(6)···F(1): 2.646(3) Å). Also,
three CH···F-
short contacts at distances typical for this type of interaction185
take
place: C(8)···F(1): 3.414(3) Å, C(15)···F(1): 3.356(3) Å, C(20)···F(1): 3.297(3) Å.
Interestingly, these interactions complete the coordination sphere of the complexed
fluoride in a manner very similar to that of the complexed fluoride in the case of
Dietrich’s octaazacryptand 6, the ligand displaying the largest binding constants
known for fluoride (figure 3.7).34
The average N···F-
distance for the complexed

150
fluoride in the case of Dietrich’s cryptand is 2.835 Å whereas the corresponding
distance for cryptand 127 is 2.648(3) Å, suggesting a very good match between the
cavity of the newly synthesized cryptand and fluoride anion. Another factor
contributing to the smaller N···F-
distances for 127 compared to those observed for 6
could be purely electrostatic. Indeed, in the case of 6 there are six ammonium sites
(three on the ‘top’ side and three on the ‘bottom’ side of the anion) competing for
hydrogen bonding with fluoride. However, in the case of 127 there are only three
ammonium sites on the ‘top’ side of the anion, competing only with CH···F-
weak
interactions. Besides, the average C···F-
distance between C(8), C(15), C(20) and the
complexed fluoride in the case of 127 is 3.356(3) Å indicating the importance of
weak CH···F-
interactions as well as the topological suitability of the
N[(CH2)2NH(CH2)2NH]3- unit (in the case of 6) or the N[(CH2)2NH(CH2)3]3- unit (in
the case of 127) for the binding of fluoride, although one of the coordination points
for the complexed fluoride is a N[(CH2CH2)NH(CH2CH2CH2) proton rather than a
N[(CH2CH2)NH(CH2CH2CH2) proton (see figure 3.7).
An inclusion complex was also observed in the crystal structure of
127·6HCl·4.5H2O (figure 3.8) which contrasts to the structure of the mixed fluoride/
silicon hexafluoride salt discussed above. There are two crystallographically unique
ligands with a chloride anion entirely encapsulated inside the cavity of each ligand.
Again, the included anions form short hydrogen bonds with the ammonium moieties
of the tren unit. As expected, the N···Cl-
distances are larger as a result of the larger
size of the chloride (they vary between 3.109(8) Å and 3.202(7) Å). A surprising
feature of the chloride complexes is their smaller N···Centroid distances (7.185(11) Å
and 7.169(11) Å) in comparison with that of the mixed fluoride/ silicon hexafluoride
salt (7.520(4) Å). At first sight this seems unusual.

151
(a) (b)
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
The size of the cavity would be expected to increase as the larger size of chloride
would induce a stronger repulsion between the negatively charged anion and the
aromatic ring. However, there is no clear evidence that the inclusion of a larger or a
smaller halide leads to an increase or a decrease of the size of the cryptand. For
example, in the case of Dietrich’s octaazacryptand the apical N···N distance is 6.60 Å
for the chloride complex and 6.65 Å for the fluoride complex.34, 151
The cavity
dimensions for the ‘bis-tren’ (37) fluoride, chloride and bromide complexes are 7.66
Å and 8.02 Å (two crystallographically unique ligands), 7.40 Å and 7.50 Å
respectively.113
In the case of cryptand 127 it is assumed that the larger size of
chloride induces a more spherical shape to the ligand as opposed to an ellipsoidal
one. Indeed, for a shape of a given surface area, a sphere occupies the maximum
volume. This translates to a closer approach between the apical nitrogen and the
centroid for 127. On this rationale, a smaller N···Centroid distance can be explained.

152
The fact that the ligand deviates from the ellipsoidal shape to adopt a more spherical
one, can also be realized by calculating the parameter dav. This is the average of d1,
d2, and d3 intramolecular distances separating the -CH2- carbons situated in the
middle of the -NH2CH2CH2CH2NH2- unit for each ligand (figure 3.9).
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
The dav of the polyprotonated ligands in 127·6HCl·4.5H2O (7.113(16) Å, average
between the two ligands) was found significantly larger than the corresponding dav in
127·2HF·2H2SiF6·7H2O (6.100(4) Å). This is indicative of the increased ‘sphericity’
of the ligand in the case of the chloride salt.
The coordination geometry of the complexed anion is completed with three
CH···Cl-
short contacts for each ligand yielding a binding environment similar to that
observed for the mixed fluoride/ silicon hexafluoride system. The average C···Cl-
distance is 3.563(11) Å suggesting again the importance of weak CH···X-
interactions
in this type of complexes. The overall binding environment, distorted octahedral, is
once more very similar to the one observed for the corresponding hexaprotonated
octaazacryptand 6·6HCl·2.75H2O.115
This time, and despite less competition for
chloride binding, the average N···Cl-
distance for the newly synthesized complex is

153
3.164(8) Å, slightly larger than that observed in 6·6HCl·2.75H2O (3.085 Å), probably
indicative of a better match between the cavity of 6 and chloride than between the
cavity of 127 and chloride, at least in the solid state. Importantly, the coordination
geometry (disordered octahedral) of the included chloride is the same as that of the
fluoride in the crystal structure of 127·2HF·2H2SiF6·7H2O. The included anion is
‘pushed’ further away from the tren ammonium sites, probably as a result of a
geometrical mismatch between the cavity and chloride, as compared with fluoride.
Given the structural changes described above, an even smaller N···Centroid distance
along with a more spherical shape would be expected for the bromide salt of this
cryptand.
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
In 127·7HBr·3H2O there are two crystallographically unique (but different
from each other) ligands in the asymmetric unit, as seen for the chloride salt, and
each one of them encapsulates a bromide anion. However, an important difference
between this salt and the others discussed in this section is that the ligands are fully

154
protonated (figure 3.10). The existence of the seventh proton at the apical nitrogen
has significant consequences in its crystal structure. This time there are two short
Napical-H+
···Br-
hydrogen bonds with Napical···Br-
distances at 3.169(12) Å and
3.187(14) Å for the two ligands. As a result of these interactions and the larger size
of the bromide that requires a more spherical shape on the part of the ligand, the
N···Centroid distances become 6.804(19) Å and 6.849(18) Å, about 0.4 Å shorter
than those observed for the chloride salt and 0.7 Å shorter than those observed for
the fluoride salt. The cryptand is shielding the included bromide in an even more
spherical fashion than that observed for chloride. This is also proved by the even
larger dav distance (7.425(28) Å, average of two ligands) as compared with that of the
chloride (7.113(16) Å, average of two ligands) and the fluoride/ silicon hexafluoride
salt (6.100(4) Å). Interestingly, as a result of a more spherical shape, the
Centroid···Br-
distance becomes even shorter (3.653(14) Å and 3.675(14) Å, as
compared with 4.506(3) Å and on average 3.698(9) Å for the fluoride/ silicon
hexafluoride and the chloride salts respectively. It is useful to make a comparison
between this structure and other structures of protonated tren units with bromide
anions.140
In the case of the monoprotonated tren monobromide, a clear chelate effect
was observed for the tren unit. In contrast, the tetraprotonated tren tetrabromide
displays no chelate effect at all, probably because of the sterical hindrance imposed
by the short NApical-H+
···Br-
hydrogen bond and also because of the mutual repulsion
among the ammonium moieties (N···Br-
: 3.169(12) and 3.187(13) Å for the two
crystallographically unique ligands). As seen above, even shorter contacts exist
between the apical ammonium groups of 127 and the encapsulated bromide anions,
despite the chelated nature of the tren unit in this compound. This strong attractive
NApical-H+
···Br-
force is possibly the major contribution to the small size of the
ligands as compared with all the other structures discussed in this paragraph. Again,
as seen for the mixed fluoride/ silicon hexafluoride and the chloride salts, three
CH···Br-
short contacts complete the coordination environment for each complexed
bromide anion. C···Br-
distances range between 3.644(17) and 3.936(14) Å, typical
for this kind of interactions.
The crystal structure of 127·2HI·4HI3 is the last of the series to be discussed.
Despite the large size of the iodide anion, not only there is still room for it to slip
inside the cavity of the hexaprotonated ligand, but the coordination environment of

155
the complexed anion is not different from those observed in the cryptates discussed
in the paragraphs above. The Napex···I-
distance is larger, as expected from the trend
observed in the structures discussed above. This happens because the ‘tren’ unit of
the macrocycle distances itself from the big iodide anion. Indeed, the N···I-
distances
for the ammonium moieties of the ‘tren’ unit are 3.427(13), 3.441(13), and 3.479(13)
Å. Again, three C-H···I-
weak interactions complete the coordination sphere the
complexed iodide (figure 3.11) with C···I-
distances at 3.620(15), 3.728(13) and
3.740(15) Å. Remarkably the Centroid···N distance is 7.468(18) Å, almost 0.7 Å
larger than the Centroid···N distance observed for the bromide salt. In fact, this
distance can be compared to the corresponding distance for the fluoride/ silicon
hexafluoride mixed salt which is 7.520(4) Å. It is assummed that crystal packing
effects play a significant role in the ‘enlargement’ of the macrobicyclic ligand.
Indeed, as shown in figure 3.12, several I3
-
anions surround the hexaprotonated
ligand in a parallel fashion, forming NH···I-
hydrogen bonds as well as numerous
CH···I-
weak interactions. The fact that the ligand becomes less spherical than in the
case of the bromide and even of the chloride salt, is indicated by the dav parameter as
well. Measured at 6.808(21) Å, it is even smaller than that in the case of the chloride
salt (7.113 Å(16)).
Overall, it is concluded that complexation of a halide anion by the protonated
cryptand 127 in the solid state follows the same pattern irrespective of the complexed
halide. The structural unit N(CH2CH2NH2
+
CH2CH2CH2)3- plays a very important
role on the binding of the halides in the newly synthesized cryptands. Each
complexed halide is coordinated at each ammonium proton and each CH proton that
belongs to the terminal CH2 carbon of this structural unit. Two variations to that rule
are observed in the coordination mode of the complexed fluoride discussed above, as
well as in the coordination mode of bromide where an extra hydrogen bond (NApical-
H+
···Br-
) is observed. Crystal packing effects can also play a significant role in the
geometry of the ligand. Indeed, as seen in the crystal structure of 127·2HI·4HI3, the
N···Centroid distance increases as a result of I3
-
anions aligned parallely to the ligand
and participating in an extensive network of N-H···I-
hydrogen bonds and weaker
C-H···I-
interactions.

156
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 to its ellipsoidal shape
3.6 Potentiometric studies

157
3.6.1 Protonation studies of macrobicyclic azaphanes
Given the clear structural and theoretical evidence (see section 3.5) for the
existence of an NH··· interaction in 126 we sought to examine its effects on the
solution properties of this compound as well. The results of these titrations are given in
table 3.1. The acid-base properties of 127 have to be investigated prior to any
complexation studies for the same reasons stated in section 2.8 for the monocyclic
compounds and were also determined.
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
The basicity of 126 was investigated by potentiometric titration with HCl in the
presence of NaNO3 (figure 3.13). The logK values are 10.21(3), 8.50(4), 7.46(3) and
2.56(3). Changing the anion (Et4NCl) had little effect (logK = 10.12(6), 8.27(9),
7.57(5), 2.89(7)) suggesting that the basicity is not highly influenced by the hydrogen
bonding ability of the anion. These logK values may be compared with the values of
9.90, 9.35, 8.20 and 2 for the primary amine N(CH2CH2NH2)3 which is highly solvated
on protonation at the termini, and those of the newly synthesized cryptand 127 that
contains one tertiary and six secondary amines that cannot engage in NH
interactions. Compound 126 is significantly more basic than tren and 127 and indeed
the first logK value of 10.1 – 10.2 is closer to that normally associated with propylene
bridged species which suffer much less from mutual repulsion between the positive
charges. An important consequence of solvation effects in polar solution is that in
triethylenetriamine-based species protonation occurs initially at the primary or
log K1 log K2 log K3 Log K4 log K5 log K6 log K7 log Ki
126a
126b
10.23(3)
10.12(6)
8.49(5)
8.28(9)
7.46(3)
7.55(5)
2.57(4)
2.90(7)
28.75(15)
28.85(27)
127a
127c
9.50(16)
9.58(19)
9.82(7)
9.50(11)
8.47(7)
7.90(12)
7.61(10)
6.85(11)
7.18(10)
4.99(9)
6.75(6)
3.19(10)
2.37(10)
---
51.70(66)
42.01(72)
128a
10.41(5) 8.18(7) 7.17(5) 3.12(6) 28.88(23)

158
secondary amines and it can be very difficult to protonate the tertiary amine bridgehead
nitrogen atom. However, there is ample evidence for protonation of macrobicyclic
tertiary amines in cases where the proton is stabilised by conventional hydrogen bonds,
particularly NH+
O, with tertiary amine basicity reaching values of 11.0186
or, in one
very small cryptand, 17.8!187
As a control the basicity of the tri-N-methyl derivative 128
was determined in the presence of NaNO3 giving logK values of 10.41(5), 8.18(7),
7.17(5) and 3.12(6) (figure 3.14). The increase in the first logK value is consistent with
intra-cavity protonation since inductive effects will render the cavity more electron rich,
while the decrease in the second and third values is consistent with decreased solvation
of the tertiary amines compared to the secondary amine groups in 126. In conclusion,
potentiometric studies confirm the findings provided by X-ray crystallography and
theoretical calculations that system 126 and consequently system 128 establish the
ability of an aromatic ring to interact with an NH+
moiety and to effectively ‘solvate’ it.
in 0.01 M HNO3/ 0.1M NaNO3. The horizontal axis of the distribution diagrams
represents the volume of 0.1 NaOH solution added to the titrated solution

159
in 0.01 M HNO3/ 0.1M NaNO3
The protonation constants of 127 are shown in table 3.3 (see figure 3.15 for
species distribution). These values are not very different from protonation constants
measured for other cryptands, for instance cryptand 68 (see chapter 1, section
1.3.5.2) as well as a series of related cryptands.188
It seems that the existence of
propylene units balances a greater loss of basicity expected due to mutual coulombic
repulsion and the existence of the aromatic unit. The first three protonation constants
presumably represent the logK values of the amine moieties of the tren unit and
indeed they are close to the corresponding values for the tren amine. The last
protonation constant, corresponding to the apical nitrogen is similar to that found for
tren under the same experimental conditions.

160
Figure 3.15. Distribution diagram for species present in aqueous solution for the
system 127 in 0.01 M HNO3/ 0.1M NaNO3
system 127 in 0.01 M TsOH/ 0.1M TsONa
The protonation behaviour of this ligand was also studied in the presence of
0.01 M TsOH/ 0.1 M TsONa (figure 3.16). As it will be discussed in the following
section, the tosylate anion was chosen because it is less likely to interfere with the
macrocyclic cavity of 127. With the exception of the first basicity constant, all other
basicity constants were found to be smaller than those observed in the presence of

161
0.01 M HNO3/ 0.1 M NaNO3. The last protonation constant was not posible to be
refined in the presence of 0.01M TsOH/ 0.1 M TsONa.
3.6.2 Anion binding studies of 127
Given the inclusive character of all the halide complexes of 127 in the solid
state, pH titrations were conducted in order to investigate the binding behaviour of
this ligand in aqueous solution. The basicity constants of this compound were
investigated again in the presence of 0.01 M TsOH and 0.1 M TsONa as supporting
electrolyte (table 3.3). The system 0.01 M TsOH/ 0.1 M TsONa was preferred over
0.01 HNO3/ 0.1 M NaNO3 as the bulky tosylate anion is less likely to interfere with
the macrocyclic cavity than nitrate anion. pH titrations were then conducted in the
presence of excess of NaF, NaCl, NaBr and NaNO3. No change of the titration curve
was observed in the tiration of 127 in the presence of NaBr or NaNO3. This is
indicative of the formation of complexes with Br-
and NO3
-
in which the anion is not
included within the macrocyclic cavity, contrary to what was observed in the crystal
structure of 127·7HBr·3H2O where an inclusive complex was formed.
F-
Cl-
Br-
NO3
-
LH6X 9.54(12) 4.19(13) - -
LH5X 7.84(8) 3.88(9) - -
LH4X 5.65(12) 2.06(26) - -
LH3X 4.86(9) - - -
Table 3.4. First anion binding constants (logKs) observed for ligand 127 at different
states of protonation
The pH titration data are consistent with crystal structures for the fluoride and
chloride complexes (see figures 3.17 and 3.18 for species distribution for fluoride
and chloride titrations respectively). In fact, remarkably high binding constants,
consistent with the formation of a 1:1 inclusion complex are observed in the presence
of excess of fluoride anion (table 3.4). High binding constants were also observed in
presence of excess of chloride anion. Moreover, 127·6H+
exhibits a strong F-
/Cl-
selectivity (>105
). Binding constants of comparable magnitude (10-11 logarithmic
units) for fluoride were only observed in the case of Dietrich’s octaazacryptand 6.

162
Cryptand 6 which also has nearly perfect design to form a cryptate inclusion
complex, displays an extaordinary F-
/Cl-
selectivity of more than eight logarithmic
units.
titration of 127 with excess of NaF
Although potentiometric and X-ray diffraction studies are in agreement and
consistent with the formation of 1:1 complexes in the case of F-
and Cl-
, no binding is
observed for Br-
anion. In fact, only the binding of Br-
by 127 was studied in aqueous
solution and after it was found insignificant, no titration in the presence of I-
was
performed. The reason for the insignificant binding of Br-
can be traced to the
conditions under which compound 127 was crystallized in the presence of
hydrobromic or hydriodic acid. Concentrated acidic solutions were used for
crystallization experiments. Thus, it is assumed that affinity patterns change
dramatically at very low pH values. This phenomenon was investigated in the case of
Dietrich’s octaazacryptand 6.115
An inclusive complex with chloride was obtained by
treatment with concentrated hydrochloric acid despite the fact that earlier work
suggested an enormous F-
/Cl-
selectivity of more than eight logarithmic units for this
cryptand. Intrigued by this result, the workers investigated the affinity patterns of this
cryptand by NMR techniques to conclude that it displays a dramatic enhancement of

163
its affinity for chloride below pH 2.5. It is believed that compound 127 is subjected
to the same effect at low pH, forming inclusive complexes with bromide and iodide
as well. This behaviour can not be studied by pH titrations because conventional
potentiometric techniques employed are generally considered to be accurate over a
pH range of 2.5-11. Thus, the examination of affinity patterns of polyamine hosts is
not possible at pH<2.5 by pH titrations.
titration of 127 with excess of NaCl
3.7 NMR studies
We sought to confirm the fact that initial protonation (as predicted by
calculations) is at the bridgehead nitrogen in 126 by 1
H NMR titration over a wide pH
range (2 – 13). At pD 13 in D2O compound 126 shows three broad signals associated
with the aliphatic CH2 groups as well as a sharp signal associated with the aryl CH
groups. Remarkably, however, at pD 11 an entirely separate, sharper set of four signals
begins to appear (to give 8 in all) consistent with the presence of a second species with
time averaged C3v symmetry. As the pH is decreased to 7 the contribution from this
species increases until it dominates the spectrum while the other set of resonances
moves gradually downfield, the greatest effect being noted for the benzylic CH2 groups.
At pH 5 the sharper signals decrease in intensity again. Raising the temperature to 90 o
C

164
results in the coalescence of the majority of the resonances into very broad signals. The
high temperature indicates a very high barrier to exchange between the two species. The
presence of these two distinct sets of 1
H NMR signals is surprising. It strongly suggests
slow exchange between intra- and extra-cavity protons and indicates intra-cavity
protonation even at extremely high pH. Slow proton exchange has been noted before
for non-cyclophane cryptands in which the intra-cavity proton is stabilized by NH···O
interactions.177, 187
In other words compound 126 is a remarkably basic proton sponge as
a result of the pseudosolvation of the intra-cavity proton by the cyclophane aromatic
ring.
The 1
H NMR spectrum of 126 reveals further remarkable behaviour at pH 2 at
room temperature. Under these conditions resonances consistent with only a single
species are present, however, every one of the signals assigned to CH2 groups is
doubled indicating a lowering of the molecular symmetry from C3v to C3 and the
freezing out of a chiral species by slowing of the propeller inversion motion, figure
3.19.

165
Figure 3.19. NMR spectra of 126 as a function of pH
This conformation is consistent with the static structures observed crystallographically.
This assignment was confirmed by examination of the spectrum of neutral 126 in
CDCl3 solution. At room temperature the spectrum is broad. At +50 o
C the spectrum
exhibits time averaged C3v symmetry while at –50 o
C a sharp spectrum is observed with
geminal coupling constants of 12.1 Hz for the benzylic CH2 groups for example,
confirming the inequivalence of these protons (figure 3.20). The slow propeller
inversion of 126 gives a further insight into the importance of the NH··· interaction
since it is clear that the rate of inversion depends strongly on the protonation state of the
cyclophane.
1.21.41.61.82.02.22.42.62.83.03.23.43.63.84.04.24.44.6
pH = 13
pH = 11
pH = 9
pH = 7
pH = 5
pH = 2

166
Figure 3.20. VT-NMR of compound 126 in CDCl3
The same propeller inversion is also observed for the methylated cryptand
(figure 3.21) although this time, coupling for the benzylic CH2 groups is observed
only from –40 o
C to –20 o
C with lower coupling constants. For example, at –40 o
C
the geminal coupling constants of the benzylic CH2 groups are 12.0 and 8.9 for 126
and 128 respectively. No propeller inversion was observed for the larger
macrobicyclic cryptand 127.
0.01.02.03.04.05.06.07.08.0
-60
-50
-40
-30
-20
-10
0
10
23
30
40
50
60

167
Figure 3.21. VT-NMR of compound 128 in CDCl3
3.8 Computational studies
Both DFT and MP2 calculations were carried out by Dr. Michael J. Bearpark at
King’s College London and they offer support to the conclusion that strain in the
cyclophane is reduced upon protonation of the bridgehead nitrogen atom. DFT gives
slightly closer agreement with the experimental bond lengths of 125 and
126·4HCl·3H2O. The DFT model of the neutral cryptand 126 indicates that the
compound has approximate C3 symmetry with an endo bridgehead nitrogen atom
exhibiting an N···centroid distance of 3.01 Å. The calculations indicate that upon
monoprotonation at this site the nitrogen atom moves some 0.06 Å closer to the
aromatic ring. In the tetraprotonated species the N atom is 0.02 Å closer still. Gas phase
calculations suggest that the bridgehead is significantly the most favoured site for
monoprotonation, by 14 kcal mol–1
. If solvation effects are taken into account this value
is approximately halved. It is well known that while tertiary amines are more basic than
secondary amines in the gas phase this order is reversed in aqueous solution as a result
1.52.02.53.03.54.04.55.05.56.06.57.07.58.0
-50
-40
-30
-20
0
20
10
30
40
50

168
of solvation effects.177
In this particular case the tethered aromatic ring in 1 is
effectively playing the role of solvent for the intra-cavity proton. The results suggest
that such ‘solvation’ is highly effective. Modelling of 1·4H+
suggests that the geometry
changes little from 1·H+
highlighting the importance of the intra-cavity protonation.
3.10 Crystallographic parameters for new macrobicyclic systems
124 125 126
Formula C36H42N4O6S3 C69H87Cl6N7O12S6 C15H24N4
M 722.95 1611.61 260.38
System Orthorhombic Rhombohedral Rhombohedral
Space group P2(1)2(1)2(1) R3 P6(3)
a/ 8.6574(4) 16.3404(23) 7.9744(7)
b/ 18.3472(10)
c/ 22.6283(15) 28.0178(27) 12.9441(12)
/deg
/deg
/deg
V/ 3
3594.3(12) 6479.0(18) 712.85(14)
Z 8 3 2
No. msd. rflns. 25147 10189 1626
No. un. Rflns 8208 5656 839
R1 (on F, I>2 (I)) 0.1203 0.2118 0.0810
wR2 (on F2
, all data) 0.1891 0.3388 0.1695
126·4HCl·2H2O 127·2HF·2H2SiF6·7H2O 127·6HCl·4.5H2O
Formula C15H32Cl4N4O2 C24H65F14N7O7Si2 C24H60Cl6N7O4.5
M 442.24 885.97 731.51
System Triclinic Monoclinic Triclinic
Space group P-1 P2(1)/n P-1
a/ 9.4427(11) 14.0345(9) 11.2494(8)
b/ 9.9475(14) 15.9137(10) 16.2958(12)
c/ 12.2520(20) 17.6318(11) 21.1945(19)

169
/deg 84.2668(64) 78.3122(27)
/deg 73.4238(70) 96.2392(45) 85.1281(32)
/deg 74.0765(58) 82.6143(40)
V/ 3
1060.4(4) 3914.6(14) 3719.3(13)
Z 2 6 2
No. msd. rflns. 3625 13422 43774
No. un. Rflns 2660 7845 13301
R1 (on F, I>2 (I)) 0.0504 0.0550 0.1420
wR2 (on F2
, all data) 0.1100 0.1405 0.3553
127·7HBr·3H2O 127·2HI·4HI3 128
Formula C24H58Br7N7O3 C24H51I14N7 C18H30N4
M 1052.10 2214.32 302.46
System Triclinic Triclinic Monoclinic
Space group P-1 P-1 C2
a/ 11.2538(4) 11.4033(12) 24.945(5)
b/ 18.0137(8) 11.5662(12) 8.7052(17)
c/ 20.9088(8) 21.966(2) 8.2753(17)
/deg 74.548(3) 85.670(2)
/deg 82.221(2) 83.181(2) 101.79(3)°.
/deg 73.058(3) 61.557(2)
V/ 3
3900.5(14) 2528.8(5) 1759.1(6)
Z 2 2 4
No. msd. rflns. 24842 20906 3001
No. un. Rflns 15500 11340 2092
R1 (on F, I>2 (I)) 0.1135 0.0756 0.0507
wR2 (on F2
, all data) 0.2951 0.1956 0.1196
128·3HCl·xH2O
System Rhombohedral
Space group P3
a/ 15.4534(22)
b/

170
c/
/deg 90
/deg 90
/deg 120
3.11 Hydrogen bond parameters for new macrocyclic systems
126·4HCl·2H2O
____________________________________________________________________
N(1)-H(11)...Cl(2)#1 0.92 2.26(5) 3.172(4) 173(5)
N(1)-H(12)...Cl(4)#2 0.92 2.16(5) 3.054(4) 163(4)
N(2)-H(21)...Cl(1) 1.11(5) 1.93(5) 3.041(4) 178(4)
N(3)-H(32)...Cl(2)#3 0.79(5) 2.32(5) 3.089(6) 165(5)
N(2)-H(22)...Cl(1)#4 0.93(5) 2.23(5) 3.156(5) 178(4)
O(2)-H(201)...Cl(4) 1.11(11) 2.09(12) 3.192(5) 170(8)
O(2)-H(202)...Cl(3)#5 0.91(7) 2.41(7) 3.289(5) 162(6)
O(1)-H(101)*
...Cl(3) 3.226(6)
O(1)-H(102)...O(2)#6 0.82(6) 2.11(7) 2.833(6) 147(7)
____________________________________________________________________
#1 x-1,y,z-1 #2 x,y-1,z #3 -x,-y+1,-z #4 -x,-y,-z
#5 x-1,y,z #6 -x-1,-y+1,-z
127·2HF·2H2SiF6·7H2O
____________________________________________________________________
N(1)-H(11)...F(4) 0.81(3) 2.07(3) 2.858(3) 165(3)
N(1)-H(11)...F(6) 0.81(3) 2.52(3) 3.101(3) 130(3)
N(1)-H(12)...F(2) 0.99(3) 1.68(3) 2.656(3) 169(2)
N(5)-H(52)...F(14)#1 0.94(4) 2.15(4) 3.003(4) 150(3)
N(5)-H(52)...F(13)#1 0.94(4) 2.28(3) 2.978(4) 131(3)
N(5)-H(52)...F(12)#1 0.94(4) 2.47(3) 3.298(4) 147(2)
N(5)-H(51)...F(1) 0.77(3) 1.86(3) 2.619(3) 169(3)
N(6)-H(62)...F(13)#2 0.84(3) 1.95(3) 2.726(3) 154(3)

171
N(6)-H(62)...F(11)#2 0.84(3) 2.39(3) 3.079(3) 139(3)
N(3)-H(31)...O(3)#3 1.00(3) 1.75(4) 2.733(5) 167(3)
N(2)-H(21)...O(4)#1 0.83(3) 1.95(4) 2.771(4) 172(3)
N(3)-H(32)...F(7)#1 0.81(3) 2.06(3) 2.844(4) 164(3)
N(3)-H(32)...F(6)#1 0.81(3) 2.37(3) 2.915(4) 125(3)
N(2)-H(22)...F(2)#4 0.88(3) 1.75(4) 2.620(3) 169(3)
N(4)-H(41)...O(5) 0.96(3) 1.86(4) 2.811(4) 177(3)
N(6)-H(61)...F(1) 1.00(3) 1.67(4) 2.646(3) 168(3)
N(4)-H(42)...F(1) 0.99(4) 1.70(4) 2.679(3) 174(3)
O(1)-H(101) *
...O(3) 2.922
O(1)-H(102) *
...F(8) 3.202
O(2)-H(201)...F(2) 0.96(6) 1.76(6) 2.679(3) 159(5)
O(5)-H(501)...F(5) 0.79(4) 1.97(4) 2.752(3) 174(4)
O(6)-H(601)...O(2)#5 0.63(3) 2.19(3) 2.797(4) 163(4)
O(6)-H(602) *
...F(10) 2.715
O(3)-H(302) *
...N(3)#4 2.733
O(4)-H(402)...F(2) 0.78(4) 1.92(5) 2.674(3) 162(4)
O(2)-H(202)...F(8) 0.80(4) 2.08(4) 2.866(4) 164(4)
O(4)-H(401)...F(9) 0.97(5) 1.74(5) 2.709(3) 176(4)
O(7)-H(702)...O(6) 0.90(5) 1.87(5) 2.772(4) 178(4)
O(5)-H(502)...O(7) 0.83(4) 1.95(5) 2.772(4) 169(4)
O(7)-H(701)...F(3)#6 0.93(8) 2.17(8) 2.956(3) 142(7)
____________________________________________________________________
#1 x-1/2,-y+3/2,z-1/2 #2 -x+1,-y+2,-z #3 -x+3/2,y+1/2,-z-1/2
#4 -x+3/2,y-1/2,-z-1/2 #5 x-1/2,-y+3/2,z+1/2
#6 -x+1,-y+1,-z
127·6HCl·4.5H2O
____________________________________________________________________
N(12)-H(121)...Cl(15)#1 0.92 2.23 3.145(7) 173.9
N(12)-H(122)...Cl(2) 0.92 2.33 3.176(7) 151.9
N(12)-H(122)...O(4) 0.92 2.60 3.113(14) 116.1
N(4)-H(42)...Cl(15) 0.92 2.23 3.143(7) 172.3
N(4)-H(41)...Cl(1) 0.92 2.40 3.202(7) 145.4

172
N(4)-H(41)...O(3)#2 0.92 2.65 3.225(9) 121.1
N(8)-H(82)...Cl(11) 0.92 2.14 3.056(8) 171.7
N(8)-H(81)...Cl(12) 0.92 2.29 3.183(7) 162.4
N(9)-H(91)...Cl(14)#1 0.92 2.27 3.177(8) 171.0
N(9)-H(92)...O(6) 0.92 2.52 3.194(10) 129.9
N(9)-H(92)...Cl(8)#3 0.92 2.66 3.335(8) 130.5
N(1)-H(11)...O(7)#4 0.92 2.49 3.236(8) 138.9
N(1)-H(12)...Cl(14) 0.92 2.19 3.101(9) 171.5
N(11)-H(112)...Cl(2) 0.92 2.26 3.161(8) 164.7
N(11)-H(111)...O(4) 0.92 2.30 3.075(14) 141.1
N(11)-H(111)...Cl(9) 0.92 2.40 3.162(12) 140.4
N(6)-H(61)...Cl(1) 0.92 2.27 3.185(8) 170.1
N(6)-H(62)...O(2)#2 0.92 2.04 2.862(11) 148.8
N(6)-H(62)...O(3)#2 0.92 2.50 3.142(9) 126.9
N(3)-H(31)...Cl(8)#3 0.92 2.14 3.009(9) 157.1
N(3)-H(32)...Cl(12) 0.92 2.24 3.132(8) 163.1
N(2)-H(21)...O(7)#5 0.92 2.28 3.187(10) 168.8
N(2)-H(22)...O(9) 0.92 2.00 2.795(13) 143.3
N(5)-H(51)...Cl(10) 0.92 2.24 3.150(13) 169.1
N(5)-H(52)...Cl(1) 0.92 2.20 3.109(8) 170.2
N(13)-H(131)...Cl(3) 0.92 2.16 3.059(12) 165.6
N(13)-H(132)...Cl(2) 0.92 2.24 3.148(9) 169.5
N(10)-H(101)...O(7) 0.92 2.18 3.071(12) 162.0
N(10)-H(102)...O(8) 0.92 2.65 3.47(7) 147.5
O(1)-H(1C) *
...Cl(6) 3.019
O(1)-H(1D) *
...Cl(7) 3.152
O(2)-H(2C) *
...Cl(6) 3.009
O(2)-H(2D) *
...Cl(5) 2.915
O(3)-H(3C) *
...Cl(11) 3.016
O(3)-H(3D) *
...O(2) 3.051
O(4)-H(4C) *
...Cl(2) 3.142
O(4)-H(4D) *
...N(12) 3.113
O(5)-H(5C) *
...Cl(3) 3.035
O(5)-H(5D) *
...Cl(11) 2.926
O(6)-H(6C) *
...N(10)#2 3.442
O(6)-H(6D) *
...N(1)#1 3.448
O(7)-H(7C) *
...N(1)#6 3.236
O(7)-H(7D) *
...O(5)#1 3.821

173
O(8)-H(8C) *
...Cl(8)#1 3.085
O(8)-H(8D) *
...Cl(3) 2.773
O(9)-H(9C) *
...Cl(14) 3.096
O(9)-H(9D) *
...Cl(15) 3.126
____________________________________________________________________
#1 x,y-1,z #2 x+1,y,z #3 x+1,y-1,z #4 x+1,y+1,z
#5 x,y+1,z #6 x-1,y-1,z
127·6HBr·3H2O
____________________________________________________________________
N(1)-H(1)...Br(1) 0.93 2.26 3.192(13) 175.7
N(11)-H(111)...Br(9)#2 0.92 2.81 3.51(3) 134.3
N(11)-H(111)...Br(17) 0.92 3.05 3.73(3) 131.3
N(11)-H(112)...Br(12) 0.92 2.35 3.22(2) 159.0
N(2)-H(21)...O(1) 0.92 2.41 2.87(2) 111.1
N(2)-H(21)...Br(1) 0.92 2.50 3.331(15) 151.0
N(2)-H(22)...O(2) 0.92 2.02 2.86(3) 152.1
N(2)-H(22)...Br(4)#3 0.92 3.02 3.611(16) 123.8
N(3)-H(31)...Br(1) 0.92 2.48 3.299(13) 148.9
N(3)-H(31)...Br(8)#2 0.92 3.15 3.728(17) 122.8
N(3)-H(32)...Br(5) 0.92 2.34 3.203(17) 157.0
N(3)-H(32)...Br(4) 0.92 2.39 3.264(16) 158.1
N(4)-H(41)...Br(1) 0.92 2.46 3.347(14) 162.9
N(4)-H(42)...Br(6)#1 0.92 2.32 3.197(12) 159.8
N(5)-H(51)...Br(7) 0.92 2.37 3.249(13) 158.8
N(5)-H(52)...Br(6) 0.92 2.46 3.366(14) 169.0
N(6)-H(61)...Br(3)#4 0.92 2.44 3.306(15) 157.9
N(6)-H(62)...Br(13)#5 0.92 2.37 3.264(14) 164.3
N(7)-H(71)...Br(10)#2 0.92 2.66 3.25(3) 122.6
N(7)-H(72)...Br(7)#2 0.92 2.99 3.77(6) 143.8
N(7)-H(72)...Br(9)#2 0.92 2.86 3.44(3) 122.6
N(7)-H(72)...Br(8)#2 0.92 3.30 3.84(5) 119.9
N(8)-H(8)...Br(2) 0.93 2.25 3.172(12) 168.9
N(9)-H(91)...Br(14) 0.92 2.45 3.233(16) 142.7

174
N(9)-H(92)...Br(2) 0.92 2.66 3.460(14) 146.5
N(9)-H(92)...Br(15)#6 0.92 2.69 3.213(13) 116.9
N(10)-H(101)...Br(11)#2 0.92 2.36 3.264(14) 168.1
N(10)-H(102)...Br(2) 0.92 2.52 3.356(12) 150.7
N(10)-H(102)...Br(15)#6 0.92 2.98 3.455(13) 114.0
N(12)-H(121)...Br(16)#3 0.92 2.44 3.246(14) 146.2
N(12)-H(122)...Br(18)#7 0.92 2.37 3.189(17) 147.9
N(13)-H(132)...Br(16) 0.92 2.28 3.187(12) 171.2
N(13)-H(131)...Br(17)#8 0.92 2.43 3.284(14) 153.9
N(14)-H(141)...O(6) 0.92 1.94 2.843(19) 167.9
N(14)-H(142)...Br(11)#7 0.92 2.39 3.291(14) 164.8
O(1)-H(1C) *
...O(2) 2.858
O(1)-H(1D) *
...Br(3)#4 3.204
O(2)-H(2C) *
...O(4) 3.434
O(2)-H(2D) *
...Br(4)#3 2.933
O(3)-H(3C) *
...O(3) 3.493
O(3)-H(3D) *
...Br(11) 3.432
O(4)-H(4C) *
...O(5) 2.396
O(4)-H(4D) *
...O(1)#9 2.720
O(5)-H(5C) *
...O(2)#1 2.680
O(5)-H(5D) *
...Br(14) 3.288
O(6)-H(6C) *
...Br(17)#8 3.328
O(6)-H(6D) *
...Br(11)#2 3.221
____________________________________________________________________
#1 -x+1,-y+1,-z #2 x+1,y,z #3 x-1,y,z #4 -x+2,-y,-z
#5 -x+2,-y,-z+1 #6 -x+1,-y+2,-z+1 #7 -x+1,-y+1,-z+1
#8 -x+2,-y+1,-z+1 #9 x,y+1,z
127·2HI·4HI3
____________________________________________________________________
N(1)-H(1A)...I(6)#3 0.92 2.97 3.711(10) 138.8
N(1)-H(1A)...I(2)#4 0.92 3.00 3.550(11) 120.3
N(1)-H(1B)...I(11)#5 0.92 2.77 3.670(12) 166.9
N(2)-H(2A)...I(6) 0.92 2.75 3.633(11) 160.3

175
N(2)-H(2B)...I(2)#2 0.92 2.50 3.392(10) 162.7
N(3)-H(3A)...I(11)#5 0.92 2.87 3.743(11) 159.1
N(3)-H(3B)...I(2)#5 0.92 2.49 3.385(12) 165.2
N(4)-H(4A)...I(5)#6 0.92 2.80 3.685(13) 162.0
N(4)-H(4B)...I(1) 0.92 2.54 3.429(13) 163.3
N(5)-H(5A)...I(1) 0.92 2.62 3.474(11) 154.5
N(5)-H(5B)...I(14)#2 0.92 3.03 3.675(11) 128.7
N(5)-H(5B)...I(7) 0.92 3.23 3.906(12) 131.7
N(6)-H(6A)...I(1) 0.92 2.59 3.444(13) 153.8
N(6)-H(6B)...I(10)#5 0.92 3.07 3.787(12) 135.6
N(6)-H(6B)...I(9)#5 0.92 3.21 4.050(12) 153.4
____________________________________________________________________
#1 -x,-y+1,-z #2 -x+1,-y,-z+1 #3 x+1,y,z
#4 -x+2,-y,-z+1 #5 -x+1,-y+1,-z+1 #6 x+1,y-1,z
*
Note: Protons denoted with * have not been refined experimentally.

176
CHAPTER 4:
EXPERIMENTAL SECTION
2.1. General
Materials. The starting materials were obtained in the highest purity
available and used without further purification.
NMR Spectra. 1
H and 13
C NMR spectra at room temperature were measured
at King’s College London with a Bruker Avance NMR spectrometer, operating at
360 MHz and 90 MHz respectively and the chemical shifts are reported in ppm
relative to tetramethylsilane. 1
H VT NMR were measured at King’s College London
with a Bruker Avance NMR spectrometer, operating at 400 MHz and the chemical
shifts are reported in ppm relative to tetramethylsilane.
Mass spectra. Fast Atom Bombardment (low resolution) mass spectra were
obtained with a Kratos MS 890 Mass Spectometer, at King’s College London. High
resolution mass spectra were obtained with a Bruker Apex III Mass Spectrometer by
Electron Spray Ionization.
Elemental Analysis for carbon, hydrogen and nitrogen was carried out by the
Elemental Analysis Service at the London Metropolitan University.
Potentiometric titrations: All potentiometric titrations were performed at room
temperature, using carbonate-free NaOH. A Titrino model 736 GP along with a
Metrohm combined glass electrode was used. The protonation constants were
determined from titrations of an approximately 10-3
M ligand solution containing an
excess of HCl or HNO3 or TsOH (0.01 M) in the presence of NaNO3 or Me4NCl or
TsONa to maintain ionic strength at 0.1 M. Anion binding constants for anionic species
X-
were determined from titrations of an approximately 10-3
M ligand solution
containing excess of TsOH (0.01 M or more) in the presence of approximately 0.01 M
of the corresponding salt NaX, and TsONa (0.1 M) to maintain ionic strength at 0.1 M.

177
The range of accurate pH measurements was considered to be 2.5-11. Stability
constants were calculated with the program HYPERQUAD.189
X-ray crystallography. Crystal data and data collection parameters are
summarised in table 2.1 and section 3.11. Crystals were mounted using silicone
grease on a thin glass fibre. All crystallographic measurements were carried out with
a Nonius KappaCCD diffractometer equipped with graphite monochromated Mo-K
radiation using wide and -scans. Data collection temperature was 120 K,
maintained by using an Oxford Cryosystem low temperature device. Integration was
carried out by the Denzo-SMN package.190
Data sets were corrected for Lorentz and
polarization effects and for the effects of absorption (Scalepack)190
and crystal decay
where appropriate. Structures were solved using the direct methods option of
SHELXS-97191
and developed using conventional alternating cycles of least-squares
refinement (SHELXL-97)192
and difference Fourier synthesis with the aid of the
program XSeed.193
In all cases non-hydrogen atoms were refined anisotropically
except for some disordered, while C-H hydrogen atoms were fixed in idealised
positions and allowed to ride on the atom to which they were attached. Hydrogen
atom thermal parameters were tied to those of the atom to which they were attached.
Where possible, non C-H hydrogen atoms were located experimentally and their
positional and isotropic displacement parameters refined. Otherwise a riding model
was adopted. All calculations were carried out on an IBM-PC compatible personal
computer.
In the crystal structure of 109, a disordered chloroform molecule was refined
by assigning a site occupancy factor of 0.333 to the atoms C(1S), Cl(1S), Cl(2S),
Cl(3S).
In the crystal structure of 112, there are two disordered dichloromethane
molecules. In one of them, C(43), C(43A), Cl(2) and Cl(2A) were assigned a site
occupancy factor of 0.5 each. In the other, Cl(3), Cl(3A), Cl(3B), Cl(4), Cl(4A), and
Cl(4B) were assigned a site occupancy factor of 0.333 each.
In the crystal structure of 60, the atoms H(31A), H(31B), H(41A), and
H(41B) were assigned with an occupancy factor of 0.5 each.
In the crystal structure of 61·5HCl·H2O, atom O(1) that belongs to a partially
occupied solvated water molecule site, was refined isotropically.

178
In the crystal structure of 62·2HI·HI3·2I2, all the atoms that belong to the
macrocyclic host (C(1)-C(20), as well as N(1)-N(3) were refined isotropically
because of the poor quality of the crystal.
In the crystal structure of 62·3HI·I2(b), several atoms are disordered: C(8A),
C(8B), C(9A), C(9B), C(10A), C(10B), C(11A), C(11B), C(12A), C(12B), C(13A),
C(13B), C(14A), C(14B), C(15A), C(15B), C(16A), C(16B), C(17A), C(17B),
C(18A), C(18B), C(19A), C(19B), N(1A), N(1B), N(2A), N(2B), N(3A), N(3B),
I(4A), I(4B), I(5A), I(5B) were assigned with a site occupancy factor of 0.5 each.
In the crystal structure of 126, all atoms are disordered. Atoms N(1) and
N(1A) on threefold axis were assigned with a site occupancy factor of 0.166. Atoms
C(1), C(2), C(3), and N(2) were assigned with a fractional occupancy of 0.55
whereas atoms C(1A), C(2A), C(3A), and N(2A) were assigned with a fractional
occupancy of 0.45.
In the crystal structure of 127·6HCl·4.5H2O, chloride atoms Cl(7), Cl(9),
Cl(10), and Cl(13) are disordered and given half occupancy each.
In the crystal structure of 127·7HBr·3H2O, bromide atoms Br(4), Br(5),
Br(7), Br(8), Br(9), Br(10), Br(17), and Br(18) are disordered and given half
occupancy each.
The crystal structure of 128·3HCl·xH2O was of very poor quality, thus only
its unit cell dimensions are given in section 3.6.
4.2 Synthesis
4.2.1 Synthesis of polyaza-metacyclophanes
N,N’,N’’-Tritosyl-1,4,7-triazaheptane (103)
Diethylenetriamine (4.13 g, 40 mmol) and K2CO3 (11.06 g, 80 mmol) were
suspended in water (600 mL) at 80 o
C. To this mixture, tosyl chloride (23.00 g, 121
mmol) was added in batches over a period of 1 h. After addition was complete,
NH2
N
H
NH2 N
H
N
N
HK2CO3
TsCl, H2O
Ts
TsTs

179
vigorous stirring and heating were continued overnight. The tosylated macrocycle
precipitated as a white solid which was filtered under reduced pressure, washed
thoroughly with 500 mL of water and quickly with 50 mL of methanol and dried
under high vacuum (17.89 g, 31.6 mmol, 79% yield).
1
H NMR (CDCl3): 7.69 (d, J = 8.3, 4H), 7.57 (d, J = 8.3, 2H), 7.38 (d, J =
8.3, 4H), 7.35 (d, J = 8.3, 2H), 5.72 (t, J = 6.2, 2H), 3.05 (t, J = 6.6, 4H), 2.92 (pt, J =
6.5, 4H), 2.43 (s, 6H), 2.41 (s, 3H); 13
C NMR (CD3CN):143.37, 143.13, 136.81,
136.49, 129.52, 129.44, 126.80, 126.55, 48.64, 41.59, 20.21; MS m/z (FAB) 566
([M + H]+
). Anal. Calcd for C25H31S3O6N3: C, 53.08%; H, 5.52%; N, 7.42%. Found:
C, 52.97%; H, 5.56%; N, 7.41%.
N,N’,N’’-Tritosyl-1,5,9-triazanonane (104)
Dipropylenetriamine (5.25 g, 40 mmol), tosyl chloride (23.00 g, 121 mmol)
and K2CO3 (11.06 g, 80 mmol) were reacted by following the same procedure with
that for the synthesis of 103. After work-up, 104 was isolated as a white solid (16.16
g, 27.2 mmol, 68% yield).
1
8.2, 4H), 7.27 (d, J = 8.2, 4H), 3.10 (t, J = 6.7, 4H), 2.95 (pt, J = 6.2, 4H), 2.42 (s,
3H), 2.41 (s, 6H), 1.71 (m, J = 6.4, 4H); 13
C NMR (CDCl3): 144.16, 144.83, 137.15,
135.77, 130.31, 130.16, 127.48, 127.41, 47.18, 40.46, 29.60, 21.96; MS m/z (FAB)
594 ([M + H]+
); Anal. Calcd for C27H35S3O6N3: C, 54.61%; H, 5.94%; N, 7.08%.
Found: C, 54.75%; H, 5.83%; N, 6.94%.
NH N NHNH2 N
H
NH2
TsK2CO3
TsCl, H2O
Ts
Ts

180
N,N’,N’’-Tritosyl-1,8,15-triazadecapentane (105)
Dihexylenetriamine (8.62 g, 40 mmol), tosyl chloride (23.00 g, 121 mmol)
that for the synthesis of 103. After work-up, 105 was isolated as a brown sticky solid
(19.53 g, 28.8 mmol, 72% yield).
1
H NMR (DMSO-d6): 7.66 (d, J = 8.2, 4H), 7.48 (d, J = 8.2, 2H), 7.46 (d, J =
8.2, 4H), 7.38 (d, J = 8.2, 2H), 2.96 (m, 4H), 2.65 (m, 4H), 2.38 (s, 6H), 2.29 (s, 3H),
1.31 (m, 8H), 1.14 (m, 8H); 13
C NMR (CDCl3): 141.31, 141.10, 134.91, 134.66,
127.69, 127.64, 125.05, 46.26, 40.97, 27.39, 26.56, 23.93, 19.52, 19.49; MS m/z
(FAB) 678 ([M + H]+
); Anal. Calcd for C33H47S3O6N3: C, 58.46%; H, 6.99%; N,
6.20%. Found: C, 58.43%; H, 6.91%; N, 6.18%.
N,N’,N’’,N’’’-Tetratosyl-1,4,7,10-tetraazadecane (106)
Triethylenetetramine (5.85 g, 40 mmol), tosyl chloride (23.00 g, 121 mmol)
that for the synthesis of 103. After work-up, 106 was isolated as a white solid (21.06
g, 27.6 mmol, 69% yield).
N
NH NH
N
H
NH2NH2
K2CO3
TsCl, H2O
Ts Ts
Ts
NH2
N
H
N
H
NH2
NH
N
N
NH
K2CO3
TsCl, H2O
Ts
Ts
Ts
Ts

181
1
H NMR (CD3CN): 7.75 (d, J = 8.2, 4H), 7.73 (d, J = 8.2, 4H), 7.34 (d,
J = 8.2, 4H), 7.31 (d, J = 8.2, 4H), 5.50 (t, 2H), 3.42 (s, 4H), 3.21 (t, 4H), 3.16 (pt,
4H), 2.45 (s, 6H), 2.42 (s, 6H); 13
C NMR (CDCl3): 143.91, 143.12, 137.60, 135.54,
49.02, 48.32, 41.93, 21.34, 21.32; MS m/z (FAB) 763 ([M + H]+
); Anal. Calcd for
C34H42S4O8N4: C, 53.52%; H, 5.55%; N, 7.34%. Found: C, 53.41%; H, 5.49%; N,
7.29%.
N,N’,N’’,N’’’-Tetratosyl-1,5,8,12-tetraazadodecane (107)
1,2-bis(3-aminopropylamino)ethane (6.97 g, 40 mmol), tosyl chloride (23.00
g, 121 mmol) and K2CO3 (11.06 g, 80 mmol) were reacted by following the same
procedure as that for the synthesis of 103. After work-up, 107 was isolated as a white
solid (23.41 g, 29.6 mmol, 74% yield).
1
H NMR (DMSO-d6): 7.74 (d, J = 8.2, 4H), 7.68 (d, J = 8.2, 4H), 7.34 (d,
J = 8.2, 4H), 7.31 (d, J = 8.2, 4H), 5.35 (b, 2H), 3.24 (s, 4H), 3.17 (t, J = 6.8, 4H),
2.99 (b, 4H), 2.46 (s, 6H), 2.43 (s, 6H), 2.26 (pt, 4H); 13
C NMR (CDCl3): 144.32,
143.83, 137.12, 135.47, 130.39, 130.16, 127.62, 127.41, 49.29, 47.52, 40.36, 29.39,
21.96, 21.92; MS m/z (FAB) 791 ([M + H]+
); Anal. Calcd for C36H46S4O8N4: C,
54.66%; H, 5.86%; N, 7.08%. Found: C, 54.60%; H, 5.85%; N, 6.88%.
N,N’,N’’,N’’’,N’’’’-Pentatosyl-1,4,7,10,13-pentaazadecatriane (108)
NH2
N
H
N
H
NH2
N
H
N
N N
H
K2CO3
TsCl, H2O Ts
Ts
Ts
Ts
NH2
N
H
N
H
N
H
NH2
NH
N
N
N
NH
Et2O, NaOH
TsCl, H2O
Ts
Ts
Ts
TsTs

182
Tosyl chloride (40 g, 0.211 mol), H2O (40 mL), and diethyl ether were stirred
and cooled to 0 o
C in an ice bath. To this mixture, a solution of
tetraethylenepentamine (7.97 g, 42 mmol) and NaOH (10 g, 0.25 mol) in H2O (80
mL) was added dropwise over a period of 1 hr. The reaction mixture was stirred
further for 3 hr at room temperature. The precipitate was filtered and then washed
with diethyl ether and water. Recrystallization from hot CHCl3/MeOH afforded 108
as white powder (16.55 g, 17 mmol, 41% yield).
1
8.3, 4H), 7.38 (d, J = 8.3, 2H), 7.34 (d, J = 8.3, 4H), 7.29 (d, J = 8.3, 4H), 5.54 (b,
2H), 3.38 (b, 8H), 3.20 (b, 8H), 2.48 (s, 3H), 2.45 (s, 6H), 2.42 (s, 6H); 13
C NMR
(CDCl3): 144.41, 144.34, 143.87, 136.92, 135.13, 134.88, 130.46, 130.38, 130.16,
127.92, 127.86, 127.55; MS m/z (FAB) 961 ([M + H]+
); Anal. Calcd for
7.18%.
Tosylated amine 103 (10.70 g, 18.9 mmol) and K2CO3 (52.24 g, 378 mmol)
were suspended in refluxing CH3CN (700 mL). To this mixture, a solution of
1,3-bis(bromomethyl)-benzene (5.00g, 18.9 mmol) in CH3CN (700 mL) was added
dropwise. After the addition was complete, the suspension was refluxed and stirred
for 36 h and then filtered. The solvent was removed and the crude product was
purified by column chromatography on silica (Toluene/AcOEt: 85/15). The product
was obtained as a white solid (9.36 g, 14.0 mmol, 74% yield). Suitable crystals for
X-ray analysis were obtained as colourless blocks after slow diffusion of hexane into
a solution of the product in chloroform for a few days (for crystal data, see table 2.1).
1
H NMR (CDCl3): 7.72 (d, J = 8.2, 4H), 7.64 (d, J = 8.2, 2H), 7.14-7.40 (m,
4H), 7.35 (d, J = 8.2, 4H), 7.28 (d, J = 8.2, 2H), 4.21 (s, 4H), 3.04 (t, 4H), 2.58 (t,
4H), 2.46 (s, 6H), 2.42 (s, 3H); 13
C NMR (CDCl3): 142.55, 142.35, 134.93, 134.45,
N
N
N
Br
Br
NH
N
NH
Ts
Ts
Ts
+
Ts
Ts
Ts
K2CO3
CH3CN

183
133.83, 129.87, 129.52, 129.07, 128.71, 128.60, 125.96, 125.88, 53.19, 52.22, 49.17,
46.06, 20.32, 20.29; MS m/z (FAB) 668 ([M + H]+
); Anal. Calcd for C33H37S3O6N3:
C, 59.37%; H, 5.59%; N, 6.29%. Found: C, 59.50%; H, 5.47%; N, 6.26%.
By following a procedure similar to that described for the synthesis of 109,
tosylated amine 104 (11.23 g, 18.9 mmol), K2CO3 (52.24 g, 378 mmol) and
1,3-bis(bromomethyl)-benzene (5.00g, 18.9 mmol) yielded 110 as a white solid (9.87
g, 14.2 mmol, 75% yield). Suitable crystals for X-ray analysis were obtained as
colorless blocks in the same manner as for 109 (for crystal data, see table 2.1).
1
4H), 7.35 (d, J = 8.2, 4H), 7.16 (d, J = 8.2, 2H), 4.18 (s, 4H), 3.07 (t, J = 6.8, 4H),
2.86 (t, J = 7.3, 4H), 2.45 (s, 6H), 2.41 (s, 3H), 1.35 (m, 4H); 13
C NMR (CDCl3):
143.87, 143.53, 137.57, 135.59, 130.12, 129.93, 129.76, 129.71, 129.69, 129.24,
127.41, 127.27, 54.46, 47.97, 47.94, 29.34, 21.74, 21.68; MS m/z (FAB) 696
([M + H]+
); Anal. Calcd for C35H36S3O6N3: C, 60.42%; H, 5.94%; N, 6.04%. Found:
C, 60.37%; H, 5.88%; N, 5.94%.
N
N
N
Br
Br
NH N NH
Ts
Ts
Ts+
Ts
Ts
Ts
K2CO3
CH3CN

184
tosylated amine 105 (12.81 g, 18.9 mmol), 2CO3 (52.24 g, 378 mmol) and
1,3-bis(bromomethyl)-benzene (5.00 g, 18.9 mmol) yielded 111 as a white solid
(11.20 g, 14.34 mmol, 76% yield). 1
H NMR (CDCl3): 7.65 (d, J = 8.3, 4H), 7.54 (d,
J = 8.3, 2H), 7.27 (d, J = 8.2, 2H), 7.11-7.24 (m, 4H), 7.21 (d, J = 8.2, 2H), 4.15 (s,
4H), 2.97 (t, J = 7.6, 4H), 2.79 (t, J = 6.41, 4H), 2.38 (s, 6H), 2.34 (s, 3H), 1.27 (m,
4H), 1.13 (m, 8H), 1.03 (m, 4H); 13
C NMR (CDCl3): 143.78, 143.52, 137.75, 136.66,
135.73, 130.21, 129.98, 129.39, 127.97, 127.93, 127.67, 127.56, 53.27, 50.57, 49.92,
29.52, 28.95, 27.03, 26.50, 21.93, 21.88; MS m/z (FAB) 781 ([M + H]+
); Anal. Calcd
for C41H53S3O6N3: C, 63.13%; H, 6.85%; N, 5.39%. Found: C, 63.02%; H, 6.85%; N,
5.28%.
Br
Br
N
N
N
N
NH NH
Ts
Ts
Ts
+
Ts Ts
Ts
K2CO3
CH3CN

185
(11.11 g, 12.9 mmol, 68% yield). Suitable crystals for X-ray analysis were obtained
as colorless blocks in tha same manner as for 109 (for crystal data, see table 2.1).
1
4H), 7.37 (d, J = 8.2, 4H), 7.31 (d, J = 8.2, 4H), 4.13 (s, 4H), 2.98 (t, J = 5.3, 4H),
2.89 (t, J = 5.6, 4H), 2.68 (s, 4H), 2.47 (s, 6H), 2.44 (s, 6H); 13
C NMR (CDCl3):
144.37, 144.12, 137.03, 135.90, 134.80, 130.40, 130.25, 129.99, 129.31, 127.88,
127.81, 54.82, 50.15, 49.21, 48.28, 21.98, 21.97; MS m/z (FAB) 865 ([M + H]+
);
Anal. Calcd for C42H48S4O8N4: C, 58.31%; H, 5.59%; N, 6.48%. Found: C, 58.39%;
H, 5.54%; N, 6.43%.
N
N N
NNH
N
N
NH
Br
Br
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
K2CO3
CH3CN
+
N
N
N
N
Br
Br
N
H
N
N N
H
Ts
Ts
Ts
Ts
K2CO3
CH3CN
+
Ts
Ts
Ts
Ts

186
(11.98 g, 13.42 mmol, 71% yield). Suitable crystals for X-ray analysis were
obtained as colorless blocks in the same manner as for 109 (for crystal data, see table
2.1).
1
4H), 7.37 (d, J = 8.2, 4H), 7.33 (d, J = 8.2, 4H), 4.17 (s, 4H), 3.11 (t, J = 7.2, 4H),
2.94 (t, J = 7.0, 4H), 2.66 (s, 4H), 2.46 (s, 6H), 2.44 (s, 6H), 1.41 (m, 4H); 13
C NMR
(CDCl3): 144.24, 144.10, 138.09, 135.65, 135.05, 130.45, 130.27, 129.46, 128.58,
127.92, 127.72, 54.68, 48.66, 48.59, 48.50, 29.50, 22.03; MS m/z (FAB) 893
([M + H]+
C, 59.06%; H, 5.63%; N, 6.05%.
N,N’,N’’,N’’’N’’’’-Pentatosyl-2,5,8,11,14-pentaaza[15]metacyclophane
(114)
(8.77 g, 8.25 mmol, 69 % yield). Suitable crystals for X-ray analysis were obtained
as colorless blocks in the same manner as for 109 (for crystal data, see table 2.1).
1
8.3, 2H), 7.48 (d, J = 8.2, 2H), 7.36 (d, J = 8.3, 4H), 7.34 (d, J = 8.3, 4H), 7.24 (m,
1H), 7.17 (d, J = 8.5, 2H), 7.04 (s, 1H), 4.25 (s, 4H), 3.18 (b, 4H), 3.13 (b, 4H), 3.02
(b, 8H), 2.47 (s, 6H), 2.46 (s, 3H), 2.45 (s, 6H); 13
C NMR (CDCl3): 144.49, 144.21,
144.14, 136.95, 135.89, 135.31, 134.14, 130.32, 130.01, 128.68, 128.60, 128.00,
127.89, 127.82, 53.91, 51.17, 50.26, 49.99, 47.75, 21.97; MS m/z (FAB) 1063
([M + H]+
C, 57.81%; H, 5.73%; N, 6.70%.
NN
N N
N
Br
Br
NH
N
N
N
NH
Ts Ts
Ts+
Ts
Ts TsTs
Ts Ts
Ts
K2CO3
CH3CN

187
A mixture of tosylated amine 113 (2.00 g, 2.24 mmol), phenol (4.0 g, 42.50
mmol) and 60 mL of 48% aqueous HBr was stirred and heated to reflux for 72 h.
After cooling to room temperature, the mixture was repeatedly washed with
chloroform. The aqueous phase was cooled to 0 o
C and sodium hydroxide was added
slowly until the pH of the solution became at least 12. The product was extracted in
chloroform which was removed under high vacuum to afford the free amine as a
waxy solid (0.32 g, 1.16 mmol, 52% yield). Suitable cystals for X-ray analysis of the
fluoride, chloride and bromide salts of 60 were obtained in two ways: Either from a
solution of this material in the corresponding diluted acid after a few days by slow
evaporation or by slow diffusion of acetone into a concentrated solution of 60 in the
corresponding diluted acid. The species 60·3HClO4·HBr·H2O was synthesized after a
mixture of 60 and perchloric acid was accidentally treated with fumes of
hydrobromic acid inside a fume cubpoard (for crystal data, see table 2.1). Suitable
cystals for X-ray analysis of the free amine 60 were obtained by slow evaporation of
a concentrated solution of 60 in chloroform.
1
H NMR (CDCl3): 7.34 (s, 1H), 7.18 (t, J = 7.4, 1H), 7.04 (d, J = 7.6, 2H),
3.73 (s, 4H), 2.62-2.66 (m, 4H), 2.61 (s, 4H), 1.73 (s, b, 4H), 1.60-1.67 (m, 4H); 13
C
NMR (CDCl3): 140.78, 128.79, 127.70, 127.30, 54.48, 50.38, 50.00, 48.79, 29.87;
HRMS calcd for C16H29N4 [M]+
277.2387, found 277.2363.
N
H
NH
NH
NH
N
N
N
N
Ts
Ts
Ts
Ts
48% HBr
PhOH

188
2,5,8,11,14-pentaaza[15]metacyclophane (61)
114 (2.00 g, 1.88 mmol), phenol (4.0 g, 42.50 mmol) and 60 mL of 48% aqueous
HBr afforded 61 as a waxy solid (0.43 g, 1.47 mmol, 78% yield). Suitable cystals for
X-ray analysis of the chloride (two structures), bromide and iodide salts of 61 were
obtained in a similar manner as for 60 (for crystal data, see table 2.1). 1
H NMR
(CDCl3): 7.54 (s, 1H), 7.12 (t, J = 7.4, 1H), 7.00 (d, J = 7.3, 2H), 3.73 (s, 4H), 2.65-
2.76 (m, 16H), 2.32 (b, 5H); 13
C NMR (CDCl3): 141.16, 128.26, 127.23, 126.84,
53.96, 49.65, 49.53, 49.52, 48.99; HRMS calcd for C16H30N5 [M]+
292.2496, found
292.2491.
HBr afforded 62 as a viscous oil (0.33 g, 1.05 mmol, 41% yield). Suitable cystals for
X-ray analysis of three different polyiodide salts of 62 were obtained in a similar
manner as for 60 (for crystal data, see table 2.1). Compound 62 is difficult to handle
N
H
N
H
N
H
N
H
NH
NN
N N
N
Ts Ts
Ts
Ts Ts
48 aq. HBr
PhOH
N
N
N
N
H
N
H
NH
Ts
Ts
Ts
48% aq. HBr
PhOH

189
because of its viscous nature. Thus, for analytical purposes the perchlorate salt was
obtained in the following manner: Perchloric acid was added dropwise into a
concentrated solution of 62 in ethanol. The solution was left in the refrigerator
overnight, the precipitate was filtered under suction and then dried under high
vacuum.
Spectrometric data of the free amine: 1
H NMR (CDCl3): 7.27 (s, 1H), 7.20
(m, 1H), 7.08 (d, J = 6.6, 2H), 3.74 (s, 4H), 2.51 (t, J = 6.7, 8H), 1.31-1.46 (m, 8H),
1.25 (b, 11H); 13
C NMR (CDCl3): 138.89, 126.82, 125.85, 125.30, 51.98, 46.58,
46.31, 27.98, 26.90, 24.75, 24.42; MS m/z (FAB) 318 ([M + H]+
); Anal. Calcd for
the perchlorate salt, C20H35N3Cl3O12: C, 38.63%; H, 6.16%; N, 6.76%. Found: C,
38.74%; H, 6.26%; N, 6.65%.
HBr afforded 60 as a waxy solid (0.40 g, 1.94 mmol, 65% yield). Suitable crystals
for X-ray analysis of this material were obtained by slow diffusion of n-hexane
into a solution of 115 in chloroform after a few days (for crystal data, see table 2.1).
1
3.83 (s, 4H), 2.66 (t, J = 5.1, 4H), 2.45 (s, b, 3H), 2.06 (s, b, 4H); 13
C NMR (CDCl3):
142.28, 127.60, 126.31, 125.80, 53.40, 48.27, 47.67; HRMS calcd for C12H19N3 [M]+
206.1652, found 206.1654.
N
H
NH
N
H
N
N
N
Ts
Ts
Ts
48% aq. HBr
PhOH

190
HBr afforded 116 as a viscous oil (0.48 g, 2.07 mmol, 72% yield). Suitable cystals
for X-ray analysis of the chloride, bromide and iodide salts of 116 were obtained
in a similar manner as for 60 (for crystal data, see table 2.1). Compound 116 is
difficult to handle because of its viscous nature. Thus, for analytical purposes its
perchlorate salt was prepared in the same manner as that described for compound 62.
1
3.81 (s, 4H), 2.71 (t, J = 5.6, 4H), 2.47 (t, J = 5.9, 4H), 1.79 (s, b, 3H), 1.64 (m, 4H);
13
C NMR for 116·3HClO4·3H2O (D2O): 131.92, 131.76, 131.66, 49.93, 42.58,
42.33, 20.84; MS m/z (FAB) 234 ([M + H]+
); Anal. Calcd for the perchlorate salt
C14H28N3Cl3O15: C, 28.76%; H, 4.83%; N, 7.19%. Found: C, 28.64%; H, 4.87%; N,
7.17%.
N
H
N
H
NH
N
N
N
Ts
Ts
Ts
48% aq. HBr
PhOH
N
H
N
H N
H
NH
N
N N
N
Ts
Ts
Ts
Ts
48% aq. HBr
PhOH

191
HBr afforded 117 as a waxy solid (0.40 g, 1.62 mmol, 70% yield). Suitable cystals
for X-ray analysis of the chloride and bromide salts of 117 were obtained in a
similar manner as for 60 (for crystal data, see table 2.1).
1
3.84 (s, 4H), 2.77-2.80 (m, 4H), 2.71-2.73 (m, 8H), 1.99 (s, b, 4H); 13
C NMR
(CDCl3): 141.59, 128.32, 127.23, 127.11, 53.12, 49.03, 49.01, 48.23; HRMS calcd
for C14H25N4 [M]+
249.2074, found 249.2077.
4.2.2 Synthesis of polyaza-macrobicycles
Trimethyl 1,3,5-Benzenetricarboxylate (118)
Benzenetricarboxylic acid (10.0 g, 47.5 mmol), methanol (200 mL) and
concentrated sulfuric acid (2.5 mL) were mixed and then refluxed for 24 h. The
solvent was evaporated and the residue was dissolved in chloroform (200 mL) and
then washed with a saturated solution of potassium carbonate (250 mL). The solvent
was removed under reduced pressure to afford 118 as a white powder (10.91 g, 37.2
mmol, 92%).
1
H NMR (CDCl3): 8.88 (s, 3H), 4.00 (s, 9H); 13
C NMR (CDCl3): 165.82,
135.00, 131.59, 53.03; MS m/z (FAB) 253 ([M + H]+
); Anal. Calcd for C12H12O6: C,
57.14%; H, 4.80%; Found: C, 57.18%; H, 4.82%.
O O
OOH
OHOH
MeO OMe
OMe
O O
O
CH3OH, H2SO4

192
1,3,5-Tribromo-trimethylbenzene (119)
6.00 g (222 mmol) of lithium aluminium hydride was added to 600 mL of dry
THF. Then, 15 g (59.5 mmol) of 118 in 600 mL of dry THF was added dropwise at
room temperature under vigorous stirring and an atmosphere of N2. After dropwise
addition was completed the mixture was heated to reflux for 24h. The excess of
reducing agent was destroyed by slow addition of water, and the solvent was
evaporated. Then, 450 mL of a 48% HBr solution and 750 mL of toluene was added
and heated to reflux for 24 h. The organic layer was separated and the aqueous
portion was extracted several times with diethyl ether. The organic layers were
combined and removed under reduced pressure. The crude material was purified
through a short column of silica with a 1/1 mixture of n-hexane/toluene. The solvents
were evaporated under high vacuum to afford 19.12 g (53.6 mmol, 90% yield) of
119. 1
H NMR (CDCl3): 7.36 (s, 3H), 4.46 (s, 6H); 13
C NMR (CDCl3): 139.45,
129.99, 32.62; MS m/z (FAB) 357 ([M + H]+
); Anal. Calcd. for C9H9Br3: C, 30.54%;
H, 2.54%. Found: C, 30.12%; H, 2.55%.
Tris-[2-(tosyl)-ethyl]-amine (120)
O O
OMeO
OMeOMe
Br Br
Br
1) LiAlH4, THF
2) 48% aq. HBr, toluene
N
NH2NH2
NH2
N
NHNH
NH
TsCl, K2CO3
H2O
Ts
Ts Ts

193
Tris(2-aminoethyl)amine (4.83 g, 33.0 mmol) was dissolved in 70 mL of
water containing 4.23 g (106 mmol) NaOH. To this solution, p-toluenesulfonyl
chloride (19.17 g, 100 mmol) in 60 mL ether was added dropwise with vigorous
stirring at room temperature. After the addition was complete, stirring was continued
for 2 h and the reaction mixture was allowed to stand for 12 h. The white solid which
precipitated was filtered, washed with copious amounts of water and dried under
high vacuum to afford 120 as a white powder (16.28 g, 26.7 mmol, 81% yield). 1
H
NMR (CDCl3): 7.78 (d, J = 8.3, 6H), 7.27 (d, J = 8.3, 6H), 5.96 (b, 3H), 2.90 (b, 6H),
2.48 (b, 6H), 2.40 (s, 9H); 13
C NMR (CDCl3): 143.70, 137.15, 130.18, 127.59, 54.55,
41.16, 21.92; MS m/z (FAB) 609 ([M + H]+
); Anal. Calcd for C27H36S3O6N4: C,
53.27%; H, 5.96%; N, 9.20%. Found: C, 53.31%; H, 5.89%; N, 9.15%.
____________________________________________________________________
3,3’,3’’-Tritosyl-6,6’,6’-nitrilotri(3-azahexanenitrile) (121)
A mixture of 120, (15.0 g, 24.6 mmol), acrylonitrile (5.3 mL, 81.3 mmol),
K2CO3 (11.2 g, 81.3 mmol) and 200 mL of CH3CN were heated at 70 o
C and stirred
for 3 days. Upon cooling, H2O (1 L) and CHCl3 (650 mL) were added, and the
aqueous phase was washed with CHCl3 (3 x 200 mL). The combined organic layers
were dried under high vacuum and the residue was recrystallized from MeOH/
CH3Cl to afford the product as white solid (16.6 g, 22.9 mmol, 93% yield).
1
H NMR (CDCl3): 7.67 (d, J = 8.3, 6H), 7.28 (d, J = 8.3, 6H), 3.33 (t, J = 6.8,
6H), 3.20 (t, J = 6.8, 6H), 2.80 (t, J = 7.5, 6H), 2.63 (t, J = 6.7, 6H), 2.37 (s, 9H); 13
C
NMR (CDCl3): 149.23, 140.94, 135.57, 132.68, 124.33, 58.52, 52.21, 50.51, 26.58,
23.72; MS m/z (FAB) 727 ([M + H]+
); Anal. Calcd for C36H45S3O6N7: C, 56.30%; H,
5.91%; N, 12.77%. Found: C, 56.22%; H, 5.85%; N, 12.70%.
N
NHNH
NH
N
NN
N
N
N
N
N
Ts
Ts Ts
Ts
Ts Ts
+ 3
K2CO3
CH3CN

194
3,3’,3’’-Tritosyl-6,6’,6’-nitrilotri(3-azahexylamine) (122)
121 (7.27 g, 10 mmol) was dissolved in a solution of B2H6 in THF (200 mL,
1.0 M) and heated to reflux for 12 h under N2. After cooling to r.t., MeOH (30 mL)
was added slowly to destroy excess B2H6 and the solvents were evaporated. The
residue was dissolved in 2.5 M HCl/MeOH (300 mL) and refluxed for 3 h. The
solvents were evaporated, the residue partitioned between CHCl3 (250 mL) and 1 M
NaOH (150 mL) and the aqueous layer was extracted with CHCl3 (2 x 150 mL). The
organic layers were combined and dried under high vacuum to afford the crude
amine as a viscous oil which was used directly to the next step.
N
NN
N
N
N
N
N
NN
N
NH2 NH2
NH2
Ts
Ts Ts
Ts
Ts Ts
B2H6
. THF
1) 10% HCl/MeOH
2) 6 M aq. NaOH

195
N,N’,N’’-3,3’,3’’-Hexatosyl-6,6’,6’-nitrilotri(3-azahexylamine) (123)
122 afforded directly from the prevous step was dissolved in THF (150
mL)/CH2Cl2 (15 mL). To this mixture, Et3N (15.6 mL, 112 mmol) and TsCl (6.23 g,
32 mmol) in 20 mL THF was added over 10 min, and the mixture was stirred for 12
h at room temperature. The solvents were evaporated and the residue was partitioned
between CHCl3 and H2O. The aqueous layer was extracted with CHCl3 (2 x 150 mL)
and the organic layers were combined and dried under under high vacuum. The
residue was purified by column chromatography on silica (CH2Cl2) to afford 123 as a
powder (4.86 g, 4.5 mmol, 45% yield).
1
8.3, 6H), 7.33 (d, J = 8.3, 6H), 2.99 (b, 6H), 2.91 (b, 6H), 2.75 (b, 6H), 2.48 (s, 9H),
2.46 (s, 9H), 0.87 (b, 12H); 13
C NMR (CDCl3): 144.04, 143.65, 137.12, 136.00,
130.32, 130.08, 127.58, 127.39, 54.33, 47.90, 47.49, 40.61, 29.35, 21.91, 21.89; MS
m/z (FAB) 1228 ([M + H]+
); Anal. Calcd for C57H75S6O12N7: C, 55.72%; H, 6.15%;
N, 6.84%. Found: C, 55.74%; H, 6.00%; N, 7.34%.
N
NN
N
NH2 NH2
NH2
N
NN
N
NH NH
N
H
Ts
Ts Ts
TsCl, THF
aq. NaOH
Ts
Ts TsTs Ts
Ts

196
5,11,16-Tris-(toluene-4-sulfonyl)-5,8,11,16-tetraaza- tricyclo[6.6.4.1 3,13
]
nonadeca-1(14),2,13(19)-triene (124)
120 (7.00 g, 19.6 mmol) and a2CO3 (80.0 g, 755 mmol) were suspended in
refluxing CH3CN (700 mL). To this mixture, a solution of 119 (11.94 g, 19.6 mmol)
in CH3CN (700 mL) was added dropwise. After the addition was complete, the
suspension was refluxed and stirred for 36 h and then filtered. The solvent was
removed and the crude product was purified by column chromatography on silica
(Toluene/AcOEt: 85/15) and then by recrystallization from THF. The product was
obtained as a white crystalline solid (2.36 g, 3.26 mmol, 17% yield).
Suitable crystals for X-ray analysis were obtained as colorless blocks in the
same manner as for 109 (for crystal data, see section 3.11).
1
H NMR (CDCl3): 7.67 (d, J = 8.2, 6H), 7.33 (d, J = 8.2, 6H), 7.21 (s, 3H),
4.18 (b, 6H), 2.81 (b, 6H), 2.44 (s, 9H), 1.93 (b, 6H); 13
C NMR (CDCl3): 143.69,
138.57, 135.22, 133.12, 129.95, 127.00, 59.46, 54.89, 46.00, 21.54; MS m/z (FAB)
723 ([M + H]+
); Anal. Calcd for C36H42S3O6N4: C, 59.81%; H, 5.86%; N, 7.75%.
Found: C, 59.61%; H, 5.68%; N, 7.82%.
N
N
N
N
N
NHNH
NH
Br Br
Br
Ts
Ts
Ts
Ts
Ts Ts
+ K2CO3, CH3CN

197
5,9,15,19,24,28-Hexakis-(toluene-4-sulfonyl)-5,9,12,15,19,24,28-heptaaza-
tricyclo[10.10.8.1 3,21
]hentriaconta-1(22),2,21(31)-triene (125)
tosylated amine 123 (5.50 g, 4.48 mmol), Cs2CO3 (80 g, 245.5 mmol) and 119 (1.60
g, 4.48 mmol) yielded 125 as a white crystalline solid (1.13 g, 0.49 mmol, 19 %
yield). The same reaction performed with K2CO3 gave only 11% yield. Suitable
crystals for X-ray analysis were obtained as colorless blocks in the same manner as
for 109 (for crystal data, see section 3.11).
1
H NMR (CDCl3): 7.68 (d, J = 8.2, 6H), 7.62 (d, J = 8.2, 6H), 7.57 (s, 3H),
7.25 (m, 12H), 4.12 (s, 6H), 3.15 (b, 6H), 3.06 (b, 6H), 2.84 (b, 6H), 2.44 (b, 6H),
2.36 (s, 9H), 2.33 (s, 9H), 1.62 (b, 6H); 13
C NMR (CDCl3): 144.02, 143.74, 135.35,
134.78, 130.24, 130.14, 128.80, 128.38, 127.98, 127.60, 56.12, 55.41, 49.30, 48.96,
45.20, 27.73, 21.91; MS m/z (FAB) 1315 ([M + H]+
); Anal. Calcd for
6.39%.
N
NN
N
NH NH
N
H
Br Br
Br
N
N
N
NN
N
N
Ts
Ts Ts
+
Cs2CO3
CH3CN
Ts
Ts
Ts Ts Ts
Ts
Ts
TsTs

198
5,8,11,16-Tetraaza-tricyclo[6.6.4.13,13
]nonadeca-1(14),2,13(19)-triene
(126)
HBr afforded 126 as a waxy solid (0.35 g, 1.33 mmol, 48% yield). Suitable crystals
for X-ray analysis of the free amine were obtained by slow evaporation of a
solution of 126 in chloroform (for crystal data, see section 3.11). Suitable cystals for
X-ray analysis of the chloride salt of 126 were obtained in a similar manner as for 60
(for crystal data, see section 3.11).
1
H NMR (CDCl3): 7.01 (s, 3H), 3.71 (b, 6H), 2.49 (b, 6H), 1.79 (b, 6H); 13
C
NMR (CDCl3): 142.50, 131.18, 63.14, 55.38, 44.64; HRMS calcd for C15H25N4
[M+H]+
261.2078, found 261.2079.
5,9,12,15,19,24,28-Heptaaza-tricyclo[10.10.8.13,21
]hentriaconta-
1(22),2,21(31)-triene (127)
N
N
N
N
NH
NH
N
NH
Ts
Ts
Ts
48% aq. HBr
PhOH
N
N
N
NN
N
N
NH
NH
NH
NHNH
N
NH
Ts
Ts
Ts Ts Ts
Ts
48% aq. HBr
PhOH

199
125 (0.5 g, 0.38 mmol), phenol (2.0 g, 21.25 mmol) and 30 mL of 48% aqueous HBr
afforded 127 as a waxy solid (80 mg, 0.19 mmol, 50% yield). Suitable cystals for
X-ray analysis of the halide salts of 127 were obtained in a manner similar to that
described for other halide salts in previous paragraphs (for crystal data, see section
3.11).
1
H NMR (CDCl3): 7.20 (s, 3H), 3.84 (s, 6H), 2.63 (b, 12H), 2.57 (b, 12H),
2.40 (b, 6H), 1.53 (b, 6H); 13
C NMR (CDCl3): 141.78, 126.71, 54.23, 53.44, 49.04,
47.79, 47.41, 31.74; HRMS calcd for C23
13
C1H45N7Na [M+H]+
455.3662, found
455.3650.
5,11,16-Trimethyl-5,8,11,16-tetraaza-tricyclo[6.6.4.1*3,13*]nonadecane
(128)
126 (0.10 g, 0.38 mmol), formic acid (2 mL) and paraformaldehyde (0.25 g)
were stirred and refluxed for 72 h under nitrogen. The residue, after reaching room
temperature was diluted with water, then basified with NaOH and then extracted with
chloroform. The solvent was evaporated under high vaccum to give 128 as a pale
yellow solid (0.10 g, 0.34 mmol, 90% yield). Suitable crystals for X-ray analysis of
the free amine were obtained by slow evaporation of a solution of 128 in chloroform
(for crystal data, see section 3.11).
1
H NMR (CDCl3): 7.07 (s, 3H), 3.53 (b, 6H), 2.43 (s, 9H), 2.24 (b, 6H), 1.58
(b, 6H); 13
C NMR (CDCl3): 140.69, 132.93, 65.07, 60.69, 53.88, 49.18; HRMS calcd
for C18H31N4 [M]+
303.2543, found 303.2526.
NH
NH
N
NH
N
N
N
N
Me
Me
Me(CH2O)n
HCOOH

200
CHAPTER 5:
CONCLUSION
The original aim of the project was the synthesis and study of macrocyclic
and macrobicyclic azaphane receptors possessing specific coordination geometries
for anionic species, especially halides. During the course of the project, attention was
also turned to an unusual NH··· interaction observed in one of the smallest
macrobicyclic azaphanes ever synthesized.
Synthesis of monocyclic meta-azaphanes proved challenging particularly at
the last stage where removal of the tosyl group was required. X-ray studies indicated
good size match between the largest of these hosts, especially 61 and 62 and halides.
The hosts display a ditopic binding mode with one halide placed at the ‘top’ side and
one at the ‘bottom’ side of the macrocyclic ring. Generally, the ‘complexed’ anions
display similar coordination environments with those observed in our previous
crystallographic studies.140, 141
The basicity behaviour of these species is similar to
that observed for para-azaphanes and related compounds. Unfortunately, no binding
was established in aqueous solution after conducting pH titrations, probably due to
the fact that binding is too weak to be detected by this method.
Synthesis of bicyclic azaphanes proved more challenging as more steps are
required. For compound 126, particular interest was paid to an intramolecular NH···
interaction, the first of its kind ever observed in an artificial macrocyclic system.
This interaction was confirmed by X-ray, solution (potentiometric and NMR) and
computational studies.
Compound 127 yields inclusion complexes with all four halides in its hexa-
or heptaprotonated form. X-ray studies suggest that the tren unit plays a very
important role in keeping the halide anions firmly inside the cavity. In general, there
is a binding pattern according to which the complexed halide is coordinated at each
ammonium proton and each CH proton that belongs to the terminal CH2 carbon of
the structural unit N(CH2CH2NH2
+
CH2CH2CH2)3-. The tiny fluoride anion deviates
slightly from that rule. The geometry of the macrobicyclic cavity was found to be
influenced not only by the size of the complexed halide but also by its protonation
state and crystal packing effects. Remarkably high binding constants were

201
established by means of pH titrations for fluoride and chloride despite the fact that
X-ray studies show the existance of only three charge assisted hydrogen bonds
between the ‘complexed’ halides and the ammonium moieties of the ligand. X-ray
studies revealed the formation of inclusive 1:1 complexes. The ammonium moieties
involved in hydrogen bonding with the ‘trapped’ halides are exclusively those
belonging to the ‘tren’ unit of the macrocycle. Solution studies showed that basicity
constants of 127 are in good agreement with those observed for related
macrobicyclic species. Compound 127 in its hexa-protonated form displays high
selectivity for fluoride over chloride (logKF
-
/ logKCl
-
> 5) whereas no binding in
aqueous solution was found to take place for Br-
and NO3
-
.

202
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212
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This Ph.D. thesis is accompanied by a CD-ROM which includes crystallographic
information (.hkl, .cif, .res and .rtf files) for all new crystal structures as well as
titrations data (.con, .par and .ppd files) referring to potentiometric titrations
conducted in this project. Titrations data can be accessed with the use of the program
HYPERQUAD.189

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