Macrocyclic Ligands - Web del Profesor

Macrocyclic Ligands
Kristin Bowman-James
University of Kansas, Lawrence, KS, USA
1 Introduction 1
2 Classification of Ligands 1
3 Synthesis 5
4 Thermodynamics and Structural Aspects 9
5 Applications 17
6 Related Articles 18
7 References 18
Glossary
Bis-macrocycles: two macrocycles joined together
Calixarenes: basket-shaped macrocycles with phenyl
backbones
Catenands: two interlocked macrocycles
Compartmental ligands: macrocycles with ‘compartments’
for housing more than one substrate
Crown ethers: polyoxa macrocycles
Cryptands: bicyclic macrocycles with aza bridgeheads
Cyclidenes: lacunar tetraaza macrocycles
Expanded porphyrins: macrocycles based on pyrrolic
frameworks
Lariat ethers: crown ethers with pendant chains
Sepulchrates: bicyclic caged macrocycles
Spherands: macrocycles with phenyl backbones
Abbreviations
Polyaza macrocycles: [n]aneNm: n = Number of ring atoms;
Nm = Number of nitrogen atoms; Polyoxa macrocycles: ncrown-m:
n = Number of ring atoms; m = Number of oxygen
atoms; TRI = Tribenzo[b,f ,j][1,5,9]triazacyclododecine;
TAAB = Tetrabenzo[b,f ,j,n][1,5,9,13]tetraazacyclohexadecine.
1 INTRODUCTION
Macrocyclic ligands are defined as cyclic molecules
generally consisting of organic frames into which heteroatoms,
capable of binding to substrates, have been interspersed.
Some reports of ‘synthetic’ macrocycles (as opposed to the
naturally occurring species such as porphyrins, corrins, and
chlorins) appeared as early as 1936, when the first synthesis of
1,4,8,11-tetraazacyclotetradecane was reported. 1 Nonetheless,
the field only began to blossom in the early 1960s with the
pioneering work of Busch 2 and Curtis’ discovery of the nickelmediated
condensation of [Ni(en)3] 2+ with acetone. 3 The
early macrocycles were synthesized with an eye to mimicking
biologically occurring macrocycles such as the porphyrins,
corrins, chlorins, and, more recently, the corphins.
Another area of macrocyclic development began in the late
1960s and initial applications were focused toward modeling
biological processes such as ion transport. These macrocycles
initially included the oxygen-based crown ethers of Pedersen, 4
and the mixed oxygen–nitrogen bicyclic cryptands of Lehn, 5
both of which exhibit high selectivity toward alkali and
alkaline earth metal ions. Several years later, the concept
of ‘preorganized’ cavities resulted in the synthesis of the
cavitands by Cram. 6
Since its birth, the development of macrocyclic chemistry
has proceeded along two lines:
1. as models of the naturally occurring macrocyclic systems,
containing predominantly nitrogen donor atoms; and
2. as receptors designed for recognition and supramolecular
chemistry, with a variety of donor atoms and recognition
capabilities.
Macrocyclic chemistry has expanded phenomenally since
the 1960s to provide exciting and novel chemistry. The award
of the 1987 Nobel Prize in Chemistry to Pedersen, Lehn,
and Cram is testimony to the importance of this rapidly
expanding field.
In such a large subject, this article can only focus on
certain aspects, namely those that involve complexation
with inorganic substrates. We only consider the synthetic
macrocycles, with emphasis on transition metal complexation.
Aza, oxa, and, to a lesser extent, thia and phospha
macrocycles are also covered. The naturally occurring
porphyrins, corrins, corphins, chlorins, and phthalocyanins, 7
as well as the cyclodextrins, 8 are not included. Because of the
general complexity of macrocyclic systems and the resulting
complicated systematic names, commonly used abbreviations
or simplified names will be employed. This review will
encompass the synthesis, thermodynamics, structure, and
applications of macrocyclic ligands.
2 CLASSIFICATION OF LIGANDS
Two major areas of complexation have developed over
the years with regard to synthetic macrocycles. Those with
nitrogen, sulfur, phosphorus, and arsenic tend predominantly
to form traditional covalent coordination complexes with
transition metal ions. A notable exception to this tendency,
however, is the rapidly expanding chemistry of the

2 MACROCYCLIC LIGANDS
polyammonium macrocycles, which are capable of forming
a variety of complexes with anionic substrates. Oxygenderived
macrocycles are noted for complexation with alkali
and alkaline earth metal ions, as well as with organic cations
and molecular substrates. In this latter situation, associations
tend to be electrostatic in nature, and in many instances
hydrogen-bonding interactions are vital to complex formation.
Macrocyclic ligands will be classified, for the purposes of
this article, as rings with at least nine members and three or
more donor atoms. In a number of cases of unique structural
units, elegant descriptive names have developed, which more
appropriately describe the macrocyclic shape. Macrocycles
will be classified as to donor types and, within the donor
types, specific classifications of macrocycles will be noted
where applicable.
2.1 Polyaza Macrocycles (1)–(10) 9–18
2.1.1 Simple Polyaza Macrocycles
Until recently, the tetraaza macrocycles, such as (1)
(cyclam) and related ligands with extensive varieties of
modifications including differing degrees of saturation and
ring size (2), had been the most studied, primarily because
of the relationship of these molecules to naturally occurring
tetraaza macrocycles, such as the porphyrins and corrins.
Currently, with interest in metal–metal interactions, increased
activity has occurred in the area of larger macrocycles
capable of incorporating more than one metal ion, such as
(3) ([24]aneN8). 18 Interest in the smaller triaza macrocycles,
such as (4) ([9]aneN3) and its variations, has also accelerated
in recent years. 14 Added to the simple polyaza macrocycles has
been the effort to achieve functionalized macrocycles in order
to expand the chemistry of these ligands by combining the
rigid structural aspects of the macrocyclic ring with the more
flexible and kinetically labile properties of pendant chains, as
in (5). 11
NH
NH
(1)
HN
HN
2.1.2 Cyclidenes
N
N
(2)
N
N
Me
Me
NH
NH
NH HN
NH
(3)
HN
HN
HN
Cyclidenes (6) are a subset of the polyaza macrocycles
and are the lacunar ligands first synthesized and extensively
NH HN
H
N
(4)
HO 2C
HO 2C
N
N
(5)
N
N
CO2H
CO2H
studied by Busch. 19 They coordinate a single metal ion and
maintain a ‘persistent void’ which allows access to small
molecules within the vaulted cavity.
N
N
2.1.3 Sepulchrates
N
N
N
N
R
R
NH HN
NH
NH HN
HN
R
(6) (7)
Sepulchrates (7) are polyaza cage macrocycles. They are
noted for their exceptionally strong hold on encapsulated metal
ions. 20
2.1.4 Expanded Porphyrins
Expanded porphyrins are macrocycles based on the pyrrolic
backbone of porphyrins, but are expanded in size to achieve a
larger cavity (8) 21 or binucleating capabilities (9). 22
NH
N
N
N
N
N
N
NH NH
HN
HN
(8) (9)
N
N

2.1.5 Bis-Macrocycles
Bis-macrocycles (10) provide another mechanism for
achieving complexation of more than one metal ion. They
are joined by a bridge linking two simple macrocycles. 13,23
Me
N N
N
N
(CH 2) 2
N
Me
(10)
2.2 Polythia, Polyphospha, and Polyarsa Macrocycles
Polythia macrocycles (11), the thioether analogs of the
crown ethers, have been known since the 1930s. 24 These are
the most extensively studied macrocycles in line after the
polyoxa and polyaza macrocycles.
S
S
S
S
N
(11) (12)
The ‘pure’ polyphospha macrocycles (12) (as opposed to
the mixed donor phospha macrocycles) were first reported in
1975. 25 These macrocycles have been found to complex a
variety of transition metals, but have not received the same
attention as the more readily accessible polyaza and polyoxa
macrocycles.
The polyarsa macrocycles (13) comprise one of the least
common type of macrocycles. 26
P
P
P
P
As
As
As
MACROCYCLIC LIGANDS 3
(13)
2.3 Mixed Donor Macrocycles
As
As
As
2.3.1 Simple Mixed Donor Macrocycles
The simple mixed donor macrocycles (14) at one time were
the major source of study of the influence of the incorporation
of ‘soft’ phosphorus and arsenic donors into macrocycles. 27
Mixed oxygen–nitrogen macrocycles have been studied quite
extensively, since they serve as bridges for examining the
coordination tendencies of the aza macrocycles and the oxa
crown ethers. 13
P
P
2.3.2 Cryptands
O
O
HN
HN
HN
N
O
O O
O
(14) (15)
Cryptands (15) are bicyclic macrocycles which can contain
a variety of donor atoms with bridgehead nitrogen atoms. 5
They are highly selective for alkali and alkaline earth
metal ions.
2.3.3 Compartmental Ligands
Compartmental ligands (16) are macrocyclic ligands (as
well as nonmacrocyclic ligands) which contain ‘compartments’
for housing more than one metal ion. 28 Only the
macrocyclic counterparts will be treated here.
O
O
N

4 MACROCYCLIC LIGANDS
N
N
2.3.4 Catenands
Me
N OH N
N
OH
Me
(16)
O
O O
O
O
O
O O
O
O
(17)
Catenands (17) are interlocked macrocyclic ligands, which
complex a variety of metal ions. 29
2.4 Polyoxa Macrocycles
Polyoxa macrocycles, known more commonly as the crown
ethers, comprise an extensive area of research, with a repertoire
of types and variations. 30 Some of these macrocycles have
been utilized predominantly for purposes other than metal ion
complexation, and these will not be discussed in depth in this
review. Included in this latter category are the polycarbonyls, 31
polylactones, 32 polylactams 33 and carcerands. 34
2.4.1 Polyether Macrocycles
Polyether macrocycles (18) are the simplest of the polyoxa
macrocycles. The commonly used name for these macrocycles
is the crown ethers, due to their crown-like structure in the
solid state. These molecules have been extensively studied
N
O
O
N
N
O
O
O
O
(18)
as complexing agents for the alkali and alkaline earth metal
ions. 30
2.4.2 Lariat Ethers
The lariat ethers comprise a subset of the polyether
macrocycles, and are identified by their pendant chains. 35
They can be categorized as either N-pivot (19) orC-pivot
(20), depending on which type of atom the chain is attached.
As for their polyether parents, much of the focus on these
macrocycles has been on complexation of alkali and alkaline
earth metal ions.
O
O
O
O
(19)
N
O
2.4.3 Spherands and Hemispherands
O
O
O
O
O
O
(20)
O
O
MeO
These consist of an arrangement of phenyl groups which
provide a preorganized cavity for complexation, 36 e.g. (21)
and (22).
Me Me
Me
Me
OMe
OMe MeO
OMe MeO
OMe
Me
(21)
Me

Me
2.4.4 Calixarenes
O
Me
OMe
OMe MeO
O
(22)
Calixarenes (23) are the macrocyclic result of condensations
between phenols and formaldehyde 37 and have been
referred to as the most easily accessible molecular basket. 38
t-Bu
t-Bu
OH
OH HO
OH
t-Bu
(23)
H 2N
H2N
O
NH
H
N
HN
Me
t-Bu
NH 2
NH2
NH
NH
NH
NH
3 SYNTHESIS
3.1 Polyaza Macrocycles
MACROCYCLIC LIGANDS 5
3.1.1 Conventional (Nontemplate) Syntheses
Reviews of synthetic procedures can be found for tridentate
and pentadentate macrocyclic ligands with nitrogen donors,
mixed nitrogen donors, and sulfur donor macrocycles, 39 the
techniques of which can be expanded to other ring sizes. The
general procedures will be summarized below.
Cyclic secondary amines, [n]aneNm, are generally prepared
by macrocyclization reactions known as the Richman–Atkins
procedure. 40 These reactions involve ring closure by
condensation of two precursor fragments of the cyclic
molecule. In general, one fragment consists of a salt
of a sulfonamide, while the other contains two terminal
leaving groups, which can vary in identity and include
chloride, bromide, hydroxide, or, more often, a sulfonate ester
(Scheme 1). The reaction is performed in polar aprotic solvents
and may involve high dilution techniques. Simplified routes
to tri-, tetra-, and pentaaza systems have been described. 41 A
handy synthetic technique for the smaller triaza ring has been
described by Alder, where the macrocycle is built by using
a single carbon as template. 42 Treatises on the synthesis of
pyridine-containing macrocycles 43 and imidazole-containing
macrocycles 44 have also been reported.
Functionalized macrocycles (5) with additional ligating
components attached as pendant arms have been an area
of focus in efforts to expand the chemistry of macrocyclic
receptors by incorporating additional recognition sites.
Synthetic techniques for N-functionalized, C-functionalized,
NTs
TsN −
Scheme 1
Ts
N
TsN
OMs MsO
HN
NTs TsN
HN
HN
− NTs

6 MACROCYCLIC LIGANDS
and bis-macrocycles are known. 11 N-Alkylation, the more
common of the functionalization routes, is usually achieved
by alkylation or acylation of the amino nitrogens using
a variety of agents such as chloroacetic acid, ethylene
oxide, acrylonitrile, and formaldehyde. 11 Routes for selective
alkylations are known, including the use of selective protection
and deprotection techniques. 45
Bis-macrocycles (10), another extension of the concept of
functionalized macrocycles, can be made by several different
methods. One of the more commonly used is the condensation
of two precursor chains already joined by the linker. 23
Bis-macrocycles also can be formed from cyclam (1) asa
by-product bis-macrocycle in low yield (24). 46
NH
NH
HN
HN
(24)
NH
NH
3.1.2 Template-Mediated Syntheses
HN
HN
Metal ion template mediation in macrocyclic synthesis has
been a part of the field since its inception, its importance
having been realized early in the development of this area.
Two specific roles for the metal ion in template reactions have
been proposed. These are, in turn, kinetic and thermodynamic
in origin. 47 In the kinetic template effect, the arrangement of
ligands already coordinated to the metal ion provides control
in a subsequent condensation during which the macrocycle
is formed. The thermodynamic effect serves to promote
stabilization of a structure which would not be favored in
the absence of a metal ion. Schiff base condensations tend
to be dependent on this latter type of template effect. Some
of the more routine and general synthetic procedures will be
described here. A more in-depth treatment can be found in a
review by Curtis, with particular emphasis on general methods
as well as modifications of preformed macrocycles. 48
Carbonyl compounds are commonly used precursors for
the polyaza macrocycles, as in the classic synthesis of
the Curtis ligand from the condensation of acetone with
Ni(en)3 (Scheme 2). 3 2,6-Diacetylpyridine has provided the
Ni
H2
N
N
H 2
3
O
N
HN
Ni
Scheme 2
NH
N
+
HN
HN
Ni
N
N
Me
N
Me
O O
+
H2N NH2 N
H
small M n+
large M n+
Scheme 3
Me
N
Me
N
M
N
Me
N
Me
N
M
N
Me
NH HN
precursor for a number of pyridine-derived imine macrocycles
(Scheme 3), where smaller metal ions as templates tend to
implement the formation of 1:1 condensates, while larger
metal ions allow for 2:2 stoichiometries. 49 Schiff base
condensations can be considered as another variation of
the carbonyl condensations (Scheme 4). 50 The expanded
porphyrins (8) and(9) 21,22 and the compartmental ligands
(16) 28 are usually synthesized by Schiff base condensations.
In some instances the macrocyclic analog cannot be obtained
via other methods. This is true for the self-condensation of
o-aminobenzaldehyde, which can yield both tridentate (TRI)
and tetradentate (TAAB) macrocycles (25) and(26). 51
N N
N
(25)
N
N
N
(26)
Template-assisted condensations of amines with formaldehyde
yield a wide variety of macrocyclic products. Sepulchrates
(7) can be synthesized from the template-assisted
condensation of [Co(en)3] 3+ with formaldehyde and ammonia
under basic conditions. 20 Primary aldehydes other than
formaldehyde have also been used. 52 Caged metal ion complexes
in which the metal ion is used as a template are normally
N
N
N H
M
N
N
Me

N
N
CHO
H2N +
CHO
H2N
M n+
extremely inert, so much so that removal of the metal is often
impossible. Nonmetal template syntheses of polyaza cages
have also been reported. 53 A number of interesting variations
utilizing the template-assisted condensation of formaldehyde
and amines have also resulted in structurally new macrocycles
such as (27). 54
Me
N
NH HN
N N
N
(27)
3.2 Polythia, Polyphospha, and Polyarsa Macrocycles
One of the reasons for the relative ‘late-blooming’ of the
thioether macrocycles can be found in synthetic difficulties.
While the polyaza and polyoxa macrocycles can often utilize
template effects in controlling the critical condensations,
polythia condensations are more limited in this area. In
general, these macrocycles are made from condensation of the
appropriate polythiane with a dibromoalkane (Scheme 5). 55
Synthetic procedures and yields have been greatly enhanced by
the addition of high dilution techniques. 56,57 A cage-like sulfur
macrocycle has been reported as an analog of the nitrogencontaining
sepulchrates (28). 58 Mixed nitrogen–sulfur cages
can also be obtained. 58
S
S
N
S
S
N
(28)
N
S
S
Scheme 4
N
N N
M M
N
N N
Ph
N
N
S S
SNa NaS
+
Br Br
P P
Ni
PH HP
Ph Ph
+
Br Br
Ph
MACROCYCLIC LIGANDS 7
Scheme 5
Scheme 6
Ph
S S
S S
P P
Ph
Ni
Ph
P P
Ph
Polyphospha macrocycles can be made via template
condensations of coordinated polyphosphine ligands and
dibromoalkanes (Scheme 6). 59,60
Polyarsa macrocycles can be made by the reaction of
lithiated polyarsanes with a dichloroalkane (Scheme 7). 26,60
3.3 Mixed Donor Macrocycles
Simple mixed donor macrocycles, such as aza–oxa,
aza–thia, oxa–thia, and analogous phospha and arsa analogs
are generally achieved via combinations of the routes used for
synthesis of the ‘pure’ donor analogs. Since the possibilities
are so extensive they will not be treated here, but are found
elsewhere. 16,60 New mixed donor phosphorus techniques
have been devised for phospha–thia and phospha–aza
macrocycles. 61,62

8 MACROCYCLIC LIGANDS
PhAs As(Ph)Li
As(Ph)Li
+
Cl Cl
Scheme 7
PhAs
As
Ph
AsPh
Cryptands are usually synthesized via sequential condensations
between a diamine and an acid chloride, which
yields a diamide, followed by reduction with LiAlH4
to give the macromonocycle. Condensation with another
H2N O O NH2 O O
Cl O O Cl
HN
O O
O O
NH
HN
+
O O
Cl O O Cl
N
O O
O O
O O
O
O O
O
equivalent of acyl chloride will yield the bicyclic precursor,
which can be reduced by B2H6 to give the bicycle
(Scheme 8). 5
Compartmental ligands (16) are derived from diketonates
and triketonates and are usually synthesized from Schiff base
reactions of the ketone with a diamine. 28
Catenands (17) are also made using the metal ion template
effect. A bis-complex is formed from an α,α ′ -disubstituted
o-phenanthroline. Then the initial product is treated with a
diiodoalkane to accomplish the ring closure. 29
3.4 Polyoxa Macrocycles
Polyethers were originally synthesized by template
assistance from an oligo(ethylene glycol), monoglyme, and
potassium t-butoxide (Scheme 9). 4
O O
HN
NH
O O
O O
NH
N
O O
O
N
Scheme 8
O
O O
O
O
N
B2H 6
LAH

HO O O OH
+
Cl O O Cl
Scheme 9
Spherands and hemispherands (21)and(22) are synthesized
by ring closure reactions of aryllithium with Fe(acac)3, often
using high dilution techniques. 36
Calixarenes (23) are obtained from base-catalyzed condensations
of p-substituted phenols with formaldehyde. 37
4 THERMODYNAMICS AND STRUCTURAL
ASPECTS
4.1 Introduction
4.1.1 The Macrocyclic Effect
This term refers to the amazing stability of macrocyclic
ligands. It was initially described in studies of tetraaza
macrocycles with copper(II). 63 For polyaza macrocycles this
effect has been attributed to both entropic and enthalpic
considerations and considerable controversy raged for a
number of years as to which was the predominant factor. 64,65
The conflicting reports are now realized to be extremely
dependent on the experimental methods used for the
determination of the thermodynamic parameters. Two main
types of technique have been employed, each of which has its
strengths and weaknesses: the calorimetric titration method
and the use of the temperature variation of the stability
constants. The controversy has been largely settled by more
recent studies. 66,67 Important contributions to the enthalpic
term are now attributed to a number of factors, including
solvation and conformation changes upon bond formation.
Likewise, the entropic considerations include the number of
species present and particularly solvation effects. Detailed
discussions of the historical development can be found. 13,17
Related to the macrocyclic effect are the decreased rates
of dissociation observed for macrocyclic complexes. Busch
and co-workers have coined a term to describe these longterm
stabilities incurred by synthetic macrocycles: multiple
juxtapositional fixedness. The premise is that straight-chain
ligands can undergo dissociative displacements in consecutive
steps starting at one end of the ligand and finishing with the
opposite end. This is not the case for macrocyclic ligands, for
which each dissociated donor is still held in proximity to the
metal ion by the rest of the ligand framework. 68
O
O
O
O
O
O
MACROCYCLIC LIGANDS 9
The macrocyclic effect has been observed for polyaza,
polythia, and polyoxa, as well as mixed donor atom,
macrocycles. 69
4.1.2 Selectivity
The selectivity of a macrocycle for either a metal ion or
another substrate is critically dependent on the structure of
the macrocycle and electronic effects, i.e. the types of donor
atoms. Some of the important aspects are described below.
1. The number of binding sites is perhaps one of the
most crucial influences on the binding properties of the
substrate. Electronic effects of the binding of macrocycles
with substrates are charge, polarity, and polarizability
of the binding sites. For metal ion binding, this means
ion pair interactions for negatively charged ligands,
ion–dipole and ion–induced dipole interactions for
neutral ligands, and the hard–soft acid–base criteria.
Nitrogen, phosphorus, and sulfur donors are noted for
their complexation of transition metal ions. Oxygen is
more likely to complex alkali or alkaline earth metal ions.
2. The arrangement of the binding sites should be such as to
maximize the potential ligand–metal ion interactions. In
this regard the selection of spacers between donor atoms
to allow for the formation of five- and six-member chelate
rings has been the most utilized.
3. The preferred conformations of the macrocycles dictate
its propensity to bind a metal ion internally or externally
to the cavity. The propensity of the lone pair to point in
or out of the cavity is also a deciding factor. Hence, it is
not always a foregone conclusion that the metal ion will
be bound within the macrocyclic cavity.
4. The identity of the macrocyclic framework also plays
a major role in structure. For example, saturated
hydrocarbon chains provide considerably more flexibility
than incorporated aromatic units. Likewise the presence
of other functional groups, such as amides or esters, serve
to stiffen the macrocyclic framework. Decreasing the
flexibility of the macrocycle by adding selected ‘shaping
groups’ is the theory behind preorganization, so important
in the cavitands. Another method of creating rigidity is to
increase the dimensionality of the macrocycle, inherent in
cryptand selectivities.
5. The size of the macrocyclic cavity also plays a large role in
governing the flexibility of the ligand, and its propensity
for metal ion binding.
Since the focus of this article is primarily on transition metal
chemistry, the structural aspects related to complexation of
transition metals will be emphasized, and other aspects of
complexation will only be briefly treated.
In addition to the traditional measurement of thermochemical
properties, molecular mechanics calculations are now
available to supplement and correlate with experimental findings.
An extensive review which links the large data base of

10 MACROCYCLIC LIGANDS
thermodynamic and kinetic data with items such as ring size,
number and arrangement of ligand binding sites, and solvent
effects, for all types of donor atoms including coronands,
cryptands, spherands, and nitrogen donors can be found. 69 A
more recent series of molecular mechanics calculations have
added to this base of thermochemical data and point to structural
factors affecting complex stabilities from the viewpoint
of steric strain. 70
4.2 Polyaza Macrocycles
An extensive review of the thermodynamic aspects of
polyaza macrocycles has been reported. 17 Other reviews
include the chemistry of tridentate and pentadentate aza
macrocycles, 16 1,4,7-triazacyclononane and derivatives, 14 and
polyaza macrocycles with pendant chains. 11 In general, the
polyaza macrocycles form extremely stable complexes with
transition metals of the later transition series, but show reduced
affinity for alkali and alkaline earth metal ions compared to
the oxa macrocycles.
4.2.1 Triaza Macrocycles
One of the simplest and smallest of the polyaza macrocycles
according to definition is 1,4,7-triazacyclononane (4). The
geometrical constraints of the triaza macrocycles are such
that they do not allow for the incorporation of the metal ion
within the macrocyclic ring. Hence, these macrocycles are
facially coordinated in either a mono- or bis-ligand complex
with a variety of metal ions. 14 The macrocyclic effect is
observed, and the stability constants of the complexes follow
the Irving–Williams Series. 17 Both microcalorimetric 71 and
stability constant determinations at different temperatures 72
indicate that the effect is most probably enthalpic in origin.
The triaza macrocycles also form extremely stable complexes
with the heavier main group metals (such as Ga III , In III ,
Tl I ,andTl III ) as well as transition metals. The chemistry
of this macrocycle and its derivatives is wide in scope and
is treated extensively in a review which includes the base
compound and its N-functionalized derivatives. 14 Depending
on the appendages employed in N-functionalization, three
more coordination sites are potentially available, rounding out
the coordination to pseudooctahedral.
The formation of dinuclear and higher nuclearity species
is common for the mono-coordinated triazacyclononane, with
bridging acetates, hydroxides, and oxides being very common.
Extensive studies of the chemistry of the variety of bridged
species have been made using the relatively substitutionally
inert chromium(III) ion. Different dimers and trimers have
been isolated and structurally characterized, as in (29) and
(30). 73,74 Higher nuclear clusters such as an octanuclear iron
system are relevant as a model for the iron storage protein
ferritin (see Iron Proteins for Storage & Transport & their
Synthetic Analogs). 75
N
N
Cr
N O
H
O
O
H
O
(29)
N
Cr
O
N
N
N
N
N
Cr
N
H
O N
O
H Cr
OH
Cr
N
N
(30)
A more ‘preorganized’ ligand system is derived from the
self-condensation of o-aminobenzaldehyde. 51 The tridentate
form of the ligand (25) (TRI) imparts considerable
inertness toward substitution. For example, the salts of
the [Ni(TRI)(H2O)3] 2+ ion can be resolved into optical
isomers. 76 A copper(II) complex of the methyl-substituted
tetradentate macrocycle Me4TAAB, in which bis-coordination
occurs, displays a dynamic Jahn–Teller distortion based on
crystallographic evidence. 77
4.2.2 Tetraaza Macrocycles
Because of the potential relationship to the naturally
occurring porphyrins and porphyrin-analog macrocycles, the
tetraaza macrocycles have been the focus of much attention.
Tetraaza macrocycles often, but not always, form a coplanar
arrangement of the four nitrogen donors. Empirical force field
calculations of free macrocycles from 12- to 16-membered
rings indicate that cyclam (1) exhibits the least strain with the
best planarity. A straightforward assessment of the relationship
of hole size to selectivity is complicated by the conformational
flexibility of the ligands. Results of studies for the tetraaza
macrocycles show that hole size does not appear to be the
predominant factor in metal ion discrimination. Rather, the
selectivity of these macrocycles is governed by the relative
stability of the conformers of the macrocycle which have
different metal ion size preferences. An interesting observation
regarding the relationship of the tetraaza macrocycles with
regard to hole size and metal ion selectivity can be found
for the most studied of the simple tetraaza macrocycles,
cyclam. Cyclam is proposed to have five configurational
isomers, based on the orientation of the amine hydrogens.
From molecular mechanics calculations, where the best M–N
distance is calculated as that giving the minimum energy,
the trans-III analog of [12]aneN4 (31) is found to have an
extremely high strain energy of 19.7 kcal mol −1 with a best-fit
M–N distance of 1.81 ˚A, compared to the trans-I form (32)
(10.8 kcal mol −1 and 2.11 ˚A, respectively). 70,78 In general, the
larger, more flexible, planar coordination is provided by the
trans-I conformer, and often if a metal is too large for the
macrocyclic cavity, it will coordinate lying out of the plane of
the donor atoms. When the metal ion is not incorporated into
the macrocyclic plane, the factors influencing stability are the
same as for the acyclic aza analogs, namely that for larger
metal ions, as the size of the chelate ring increases from five
N
N

to six, the complex stability decreases. A detailed discussion
of the thermodynamics of changing chelate sizes for tetraaza
macrocycles can be found. 17,78
M N
N
H H
H
H
H
H N
M
N N
N
(31) (32)
N
N
H
H
An elegant example of the importance of conformational
changes in tetradentate macrocycles is the blue to yellow
conversion observed for nickel(II) complexes. The yellow
form is the low-spin square planar complex NiL 2+ , while the
blue form is high-spin pseudooctahedral [NiL(H2O)2] 2+ .In
the blue to yellow conversion the Ni–N bonds contract, which
compensates for the breaking of the axial Ni–OH2 bonds. The
reaction is controlled by entropy, and the addition of an inert
salt is such as to favor the dissociation of the water molecules.
At equilibrium in aqueous solution, both [12]aneN4 (cyclam)
(1) and the 15-membered analog, [15]aneN4, have 99% of
the high-spin form present, while the 13- and 14-membered
macrocycles exist in predominantly the low-spin square planar
form (87 and 71%, respectively). 79
For the nonplanar octahedral cis-coordinated macrocycles
[n]aneN4, changes in the ligand field correlate well with the
analogous ligand field strengths for nonmacrocyclic analogs,
specifically as related to the chelate ring size. A general rule
of thumb is that increasing the chelate ring size from five
to six increases the stability of complexes of smaller metals
compared to larger metal ions. The origin of this effect can be
attributed to increases in ring strain energy when metal ions
larger than tetrahedral carbon are part of the ring. 78 For the
planar-coordinated macrocycles, the equatorial ligand field,
as anticipated, is dependent on the ring size. These findings
have been related to the calculation of the optimum hole size
permitting the macrocycle to adopt its most preferable endo
configuration. Thus, it has been found that the macrocyclic
hole size increases by 10–15 pm for each increment in n for
[n]aneN4. 79
In order to introduce a greater rigidity into the
flexible polyaza macrocycles and to implement greater
hole size–metal ion size match correlations, reinforced
macrocycles such as (33) have been created, which contain
fused diaza rings. 80 Crystallographic results for the nickel(II)
complex indicate that the Ni–N bonds are shortened from
the strain-free value of 1.91 ˚A for diamagnetic nickel to
1.86 ˚A. Ligand field strength is also found to increase, and
this has been suggested as being due to the compression
of the bond lengths 80 as well as the presence of tertiary
nitrogen donors. 78 In a more recent comparative study of
nickel macrocycles with two fused 1,3-diazacyclohexane rings
(35) compared to two fused 1,3-diazacyclopentane rings (34),
MACROCYCLIC LIGANDS 11
structural results revealed weaker ligand field strengths for the
1,3-diazacyclohexane compared to 1,3-diazacyclopentane. 54
N
N
NH HN
(33)
N
NH
N
N
(34)
HN
N
N
NH
N
N
(35)
HN
Attempts to achieve macrocycles that are capable of
stabilizing highly oxidized transition metal complexes has
led to the design of ‘noninnocent’ ligands. 81 The structures of
high-valent chromium(V) oxo species with the two tetraamido
N ligands (36)and(37) were determined. Both structures were
found to contain distinctly nonplanar amide groups, and in
(36) all four amides are nonplanar.
O
NH
NH
O
HN
HN
O
Cl Cl
NH
N
O NH HN O
(36) (37)
HN
Polyaza macrocycles with pendant arms have been studied
extensively, in particular with respect to protonation and
complexation as well as to the kinetics of metal complex
formation. These aspects are treated in a review by Kaden. 11
Of particular interest is the fact that metal complex formation
constants of macrocycles with pendant carboxylates can be
10 3 to 10 4 times higher than for the unsubstituted analogs.
4.2.3 Higher Polyaza Macrocycles
Transition metal complexes of the larger polyaza
macrocyclic ligands have been less extensively studied than
for the smaller ring systems. For the pentaaza macrocycles,
[15]aneN5 with ethylene bridges appears to form the most
stable complexes with most metal ions. 17 Structural data
for a variety of pentaaza macrocyclic complexes have
been reviewed. 16 The N–H bonds as well as the different
sized chelate rings must be considered in calculating the

12 MACROCYCLIC LIGANDS
number of possible isomers. For each of the complexes,
three configurations of the in-plane N–H bonds are possible:
(38), (39), and (40). Crystallographic data indicate that
most of the complexes with pentadentate macrocycles have
pseudooctahedral geometries. Pentadentate macrocycles also
tend to stabilize unusual oxidation states. For example, the
nickel(II) complexes of [15]aneN5 (41), [16]aneN5 (42), and
one of the isomers of [17]aneN5 (43), are readily oxidized
to the Ni III analogs. Also, there is little dependence of E1/2
values on the macrocyclic ring size, which has been attributed
to the absence of in-plane ring size effects. 16
NH
H N N H N
N
H
N
M
N
N
N
H
N
M
N
N
N
N
M
N
N
H
H
(38) meso–syn (39) meso–anti (40) racemic
NH HN
NH
HN
NH
NH HN
NH
HN
NH
NH HN
NH
(41) (42) (43)
HN
The hexaaza [18]aneN6 forms complexes with transition
metal ions and with certain alkali and alkaline earth and
lanthanide ions. 82 For the higher aza macrocycles with
seven or more donor atoms, dinuclear complexes become
possible. A systematic investigation of both the structural
and thermodynamic aspects of copper complexes formed with
the larger polyaza macrocycles from heptaaza to dodecaaza
has been published. 18 All of the macrocycles were found to
form hydroxo species as well as polynuclear complexes. A
number of structures have been determined for the higher
polyaza macrocycles, both in complexed and noncomplexed
forms, and structures range from highly boat shaped to nearly
planar. 18,50,83,84
A review of macrocycles possessing subheterocyclic rings
has appeared, which includes pyridine, furan, and thiophene. 85
In a study of formation constants for transition metal ions
with pyridine- and furan-containing macrocycles, (44) and
(45), it was found that the pyridine macrocycles follow the
Irving–Williams series and bind even more effectively than
their saturated analogs (i.e. [18]aneN6 and [18]aneN4O2). The
furan analogs showed little tendency to bind, which has been
attributed to the increased rigidity of the furan ring. 86
NH
NH
N
N
HN
4.2.4 Anion Coordination
NH
HN NH
O
O
(44) (45)
HN
HN
While the initial interest in polyaza macrocycles involved
metal ion coordination, the finding in 1968 by Simmons 87
that diaza bicyclic catapinands can incorporate halide ions
into their cavity opened the door on a vast new area of
chemistry, that of anion complexation. The thermodynamics
of anion binding can be divided into several different
areas: that of simple inorganic anions; more complex
carboxylate and polycarboxylates; corresponding phosphates,
polyphosphates, and nucleotides; and culminating in anionic
metal complexes. 17,88–90 Binding is accomplished via both
electrostatic and hydrogen-bonding interactions between the
protonated macrocyclic amines and the anionic substrates.
The general trend appears to be that the increased flexibility
of larger polyammonium macrocycles tends to facilitate
complexation of more complex anionic substrates.
The results of studies for complexes formed between
polyammonium macrocycles and transition metal complex
anions indicate that cation–anion electrostatic attraction is a
crucial factor in complexation reactions and serves to regulate
the stoichiometry of the complexes formed. Hydrogenbonding,
size, and conformational factors also play major
roles. 89 Anions can be incorporated in or out of the ring.
Two illustrative examples are metal ion complexes with the
octaprotonated macrocycle H8[30]aneN10 (46). In the complex
with Co(CN)6 3− , the anion lies outside the macrocycle. The
PdCl4 2− complex is a true ‘inclusion’ situation, however, in
which the PdCl4 2− is situated along the minor axis of the
macrocyclic cavity, and the Cl atoms are out of the frame,
forming strong hydrogen bonds with the polyammonium
sites. 90
4.2.5 Cyclidenes
Crystallographic results for the cyclidenes (6) show that
a wide variety of structural ranges can result from designed
modifications of the lacunar cavity (or void). 91 The affinity
of the cobalt(II) complexes of the cyclidenes for molecular
oxygen was found to be very dependent on the identity of the
overhead bridge and was found to increase with increasing
bridge length. Further design has also allowed for expanding

NH
NH
NH
NH
NH
NH
(46)
HN
HN
HN
HN
the capability of these macrocycles beyond simple oxygen
binding to oxygenase activity observed for the cytochrome
P-450s. This has been achieved by adding piperazine ‘risers’
to increase the cavity size (9 ˚A high) as well as increasing the
hydrophobicity of the molecules, and by adding anthracene
and durene ‘roofs’. The crystal structure of the anthracenebridged
derivative shows that the macrocycle is indeed capable
of hosting an acetonitrile molecule.
4.2.6 Sepulchrates
Sepulchrates (7) are the most noted of the caged
macrocyclic ligands and are the nitrogen analogs of the
cryptands. The Co–N distances are 1.99 ˚AforCo III and 2.16 ˚A
for Co II from crystallographic data, and do not vary greatly
from other cobalt amines. 20
4.2.7 Expanded Porphyrins
A review of expanded porphyrin ligands can be found. 92
The texaphyrins (8) can be considered as 22-π-electron
benzannulene systems with an 18-π-electron delocalization
path, based on crystal structure data as well as NMR.
The cadmium complex of the macrocycle is found to be
planar with pentadentate coordination of the macrocycle to
cadmium, which becomes seven-coordinate as a result of
axial coordination to two pyridine molecules. The cavity is
nearly circular with a center-to-nitrogen distance of 2.39 ˚A.
Because of the larger size of this macrocycle, metal ion
coordination is generally seen with the larger transition metals
and lanthanides.
A more flexible expanded porphyrin is the ‘accordion’
porphyrin (9). 22 The structural aspects of this macrocycle
illustrate the importance of flexibility in achieving unanticipated
structures. The free-base macrocycle is elliptical with
the inclusion of two water molecules (47), while the dicopper(II)
complex is highly distorted by means of exo and endo
orientations of the imine groups (48).
N 3
N
N N
Cu
MACROCYCLIC LIGANDS 13
Ph
NHNH
O
N
H HN
N H H N
O
HN HN
N
Ph
(47)
(48)
N
N
Cu
N
N3
4.3 Polythia and Polyphospha Macrocycles
4.3.1 Polythia Macrocycles
The coordination chemistry of thioether macrocycles has
expanded greatly only since the mid-1980s, as seen by a number
of reviews. 55,93–95 The macrocyclic effect is also noted for
thioethers, but to a lesser extent than some of the other macrocyclic
ligands. This is due primarily to the reorganizational
energy requirements, since a number of the free-ligand thia
macrocycles have a tendency to adopt ‘exodentate’ conformations
in the uncomplexed form, where the sulfurs are pointed
out of the macrocycle (49). Macrocyclic thioethers must then
undergo a reorganization of their exo lone pairs in order to
incorporate metal ions within the cavity. It was found in a study
of the complexation of a number of open-chain thia ligands and
thia macrocycles that the enthalpy changes were essentially
identical for both macrocyclic and nonmacrocyclic ligands.
Hence, the favorable macrocyclic effect is more attributable to
the entropy changes in the sulfur macrocycles. 96 The smaller
trithia analog of the extensively studied nitrogen donor triazacyclononane
does not require such organization and, as such,
has been extensively studied itself. 55 Because of the preference
for exodentate sulfurs, metal ion coordination in many
cases is external to the cavity (50). 97 A comprehensive review
of the structural aspects of thia macrocycles can be found. 55
Considerable effort has been made with regard to
conformation analysis of crown thioethers. It has been found
that ligand strain is most evident in torsion angles, whereby
an examination of the deviations from the optimum values of
N

14 MACROCYCLIC LIGANDS
S
S
S
S Cl
Cl
Hg
S
S
(49) (50)
S
S
Hg Cl
Cl
60 ◦ for gauche or 180 ◦ for anti configurations can lead to an
assessment of the overall strain in the molecules. 93
Examination of the influence of ring size has been
reported for the 12- to 16-membered tetrathia systems with
copper(II). 96,98 The results indicate a marked interrelationship
between ring size and stability. The stability peaks at 14membered
rings, and the rings are large enough to incorporate
the copper only for the 14- to 16-membered systems.
Results from the correlation of stability constants in
conjunction with redox data have led to insights regarding the
coordination chemistry of thia macrocycles. For example, the
electrochemical behavior of a number of copper(II)/(I) redox
couples has been investigated, 99 and redox potentials as well
as protonation and stability constants of Cu I species were
determined for a number of tetradentate and pentadentate thiaderived
macrocycles with thia- and mixed thia–aza rings with
the basic backbones (51)and(52). Results of the examination
of the stability constants in conjunction with the Cu II/I redox
potentials indicate that the stability constants for the Cu I
oxidation state are relatively constant regardless of the mixing
in of nitrogen donor atoms. Hence, the dramatic increase in
the Cu II/I redox potential which is observed in the presence of
the sulfur macrocycles can be attributed to a destabilization of
the Cu II state rather than stabilization of the Cu I state, contrary
to popular belief from the hard–soft acid–base system.
S S
S
S
S
S S
S
(51) (52)
In order to force binding of trithia structural units into
an endodentate conformation, one strategy has been to add
rigid xylyl groups into the ring to limit the flexibility (53). 100
While the conformation of the free ligands is exodentate,
a number of transition metal complexes of this ligand have
been found to exhibit endodentate coordination, including Mo,
Cu, Ag, Pd, and Rh. Results for the bis-macrocyclic silver
complex with a variety of noncoordinating anions, indicate
that the conformational interconversions of the ligand are low
in energy.
S
S
S
(53)
S
S
S
S
(54)
Thiophene units have also been incorporated into the thia
crowns (54). 101
4.3.2 Polyphospha Macrocycles
Phosphorus macrocycles can exist in a variety of
conformations, a number of which are stable. The barrier
for inversion of phosphate is 146.4 kJ mol −1 . 102 Hence there
are five conformations possible for the tetraphosphorus
macrocycle (12). Two are preferred: the one in which the
macrocyclic benzo groups are trans (55) and that in which
they are cis (56). 60,103
P
P
P
P
(55) (56)
4.4 Mixed Donor Macrocycles
4.4.1 Simple Mixed Donors
Much of the work in this area has been reported by Lindoy
and co-workers, who have performed extensive studies on the
role of hole size in complex stability and rates of complex
formation. 13,27,104 Bradshaw, Krakowiak, and Izatt have
published an extensive text on the synthesis of aza crowns. 105
A review of tri- and pentadentate macrocyclic ligands also
includes mixed donor results as well as the influence of
pendant arms. 16 Due to the numerous ramifications of this
area, a few key findings will be cited for the simplest
systems.
A major focus in the study of mixed metal ion systems
has been to examine metal ion discrimination. In particular,
two specific mechanisms can be attributed to metal
ion discrimination: macrocyclic hole size and what Lindoy
has termed as a ‘dislocation’ mechanism. The key to this
S
S
P
P
P
P

mechanism is the assumption that coordination geometry
preferences can be suddenly changed at some point along
a series of ligands where gradual changes in the ligand
framework are made. Because these changes can occur at
different points for different metal ions, discrimination can
be achieved. A particularly appealing aspect of the mixed
donor aza–oxa systems is the lower ligand field which they
provide, which then tends to minimize spin state changes.
These systems are treated in a comprehensive review of
O3N2, O2N3, and other pentadentate macrocycles with N, O,
S heteroatoms. 104
Examples of the use of synthetic mixed donor macrocycles
in heavy metal ion separations are found in the discrimination
of silver from lead. A number of studies indicate that
the inclusion of sulfur in macrocyclic sequestering agents
shifts the discrimination to silver. 104 An example of this
is seen with (57) and (58). For the aza–oxa macrocycle
(57) the log K is 5.9 for both silver and lead ions,
while the thia-incorporated ligand (58) complexes silver
more efficiently (log K = 9.9) compared to lead (log
K = 5.7). 106,107
NH
O O
HN
NH
S S
O
O
(57) (58)
HN
The larger mixed aza–oxa, aza–thia, and aza–and
oxa–phospha macrocycles are noted for their ability to
complex more than one metal ion and to alter the magnetic
properties of bimetallic complexes. 108–110 An example of
tri-metal coordination is the tricopper complex of a 27member
ring system (59). 108 A classic series of dicopper
complexes which illustrates the influence of donor atoms
on magnetism are the dicopper structures (60)–(62). 110 The
magnetic properties were found to be extremely dependent
on the mode of azide coordination, which is thought to be
influenced by the orientation of the orbitals on the metal ions.
In complex (60), the two copper ions are ferromagnetically
coupled with a triplet ground state; in (61), the metal ions
are antiferromagnetically coupled; and in (62), the two copper
ions are not coupled.
4.4.2 Cryptands
Cryptands (15) are noted for their highly selective
complexation of alkaline earth metal ions, and for their
ring size–metal ion match ability. 5 The thermodynamic
properties of these macrocycles have been extensively
investigated, and results indicate that the high stability of the
N
H
N
H
O
Cu
HOH O
HN Cu Cu NH
HN NH
O
(59)
H
N
N3
O
N3
H
N
HN Cu Cu
N3
N
H
O
(61)
N
H
N 3
NH
MACROCYCLIC LIGANDS 15
HN
N 3
O
Cu
O
O
N
N
N
N
N
N
O
(60)
S
N3 N N N
S
O
Cu
O
S
S
N 3
NH
HN Cu Cu NH
N
N N N3
(62)
bicyclic macrocycles compared to their monocyclic analogs is
enthalpic in origin. 88
4.4.3 Compartmental Ligands
Compartmental ligands (16) provide extensive opportunities
for multiple metal ion complexation. An example of a
mixed donor ligand incorporating different metal ions is the
macrocyclic trinucleating ligand (63), which is capable of
complexing two ‘soft’ donor metal centers in addition to a
‘hard’ alkali or alkaline earth metal. 111
4.5 Oxa Macrocycles
4.5.1 Crown Ethers
In the crown ethers (18) the interactions between the ligand
and metal ion are considered to be more electrostatic in nature,
rather than the covalent binding observed for the transition
metal complexes of the aza, thia, and phospha macrocycles.
The thermodynamic properties of these macrocycles have
been extensively studied, with numerous reviews covering
complexation, selectivity, and structural aspects, some with
extensive tables of thermodynamic data. 69,70,112–119 Considerable
efforts have been made to correlate the interrelationship
between cavity size of the macrocycles and stability of alkali
and alkaline earth metal complexes. From X-ray and CPK
models, cavity radii are determined as 0.86–0.92 ˚A for 15crown-5
(64), 1.34–1.43 ˚A for 18-crown-6 (65), and about
1.7 ˚A for 21-crown-7 (66). 69 For complex formation between
the alkali metal ions and 18-crown-6, the maximum stability

16 MACROCYCLIC LIGANDS
O
S
O
N N
Cu
O O
O
N
Ba
Cu
(63)
occurs for the potassium ion, which has a radius of 1.38 ˚A, thus
correlating well with the cavity radius. However, 18-crown-6
forms extremely stable complexes with all of the alkali and
alkaline earth metal ions. Hence, Gokel argues that the data
indicate that the hole size concept is inapplicable, since the
binding constants for sodium, potassium, ammonium, and
calcium ions are the largest for the 18-crown-6 compared to
almost all of the other simple crown ethers. 119 Hancock has
proposed that chelate ring size is the critical factor, and that the
high stabilities observed for the crown ethers with large metal
ions is a result of the presence of five-membered chelate rings.
Thus the high affinity of these macrocycles for the potassium
ion is explained by the fact that potassium is the right size for
the five-membered chelate rings of the crown ethers. 78
O
O
O
(64)
O
O
O
O
O
(65)
O
O
O
N
O
O
S
O
O
O
O
O
(66)
A number of reviews of the structural aspects of crown
ethers can be found. 115–117 These structures vary considerably
in complexity. An example of the flexibility of the crown ethers
can be seen in the variation in the structures as a result of ring
size of three different benzo crowns. When the cavity of the
O
O
O
crown matches the radius of the metal ion, the metal ion can be
readily incorporated in the cavity, such as in the structure of the
rubidium thiocyanate complex with the dibenzo-18-crown-6
(67). In cases where the cavity of the crown is too large to
surround the metal ion snugly, a folded structure can result,
as with the dibenzo-30-crown-10 (68) and the potassium ion.
For very large metal ions incapable of fitting into smaller
macrocyclic cavities, sandwich-type structures can occur, as
in the benzo-15-crown-5 (69) with the potassium ion. 115
O
O
O
O
O
O
(67)
O
O
O O O
O O O
O
(68)
O
O O
(69)
Molecular mechanics studies indicate that the lowest energy
conformer of the uncomplexed ligand is not necessarily
that required for complexation, i.e. oxygen donors may be
exodentate as in the thia macrocycles. This means that in order
for complex formation to occur, the ligand must undergo both
reorganization as well as desolvation. A general rule of thumb
with respect to size, however, is that the larger macrocycles
are more flexible and subject to adaptability, while the smaller
macrocycles are more rigid and, in that sense, ‘preorganized’.
Cram has provided an excellent treatise on preorganization. 118
His principle of preorganization is that ‘the more highly
hosts and guests are organized for binding and low solvation
prior to their complexation, the more stable will be their
complexes.’ 118 �G values for a variety of macrocyclic oxygen
donors indicate that the ‘prearranged’ ligands in general bind
O
O
O

their guests more strongly and are, in sequence, the spherands
> cryptaspherands ≈ cryptands > hemispherands > crown
ethers. 116
A useful correlation of enthalpy–entropy considerations for
complexation has been shown by Inoue, Liu, and Hakushi. 113
The treatment reflects enthalpy–entropy relationships for
given types of ligands. The general concept is that as the
enthalpic contributions become strong, a higher level of
organization is obtained, which will result in unfavorable
entropy changes. For a given type of system with similar
entropic versus enthalpic considerations, the T�S and �H
values determined for a series of ligands should thus exhibit
a linear relationship. This is found for the macrocyclic crown
ethers, the cryptands, lariat ethers, and bis-crown ethers, as
well as the acyclic polyethers known as podands. The slopes
are all positive with high correlation coefficients. Gokel has
suggested that these slopes can be used to assess the ligand
flexibility: glymes and podands (0.86) > crown ethers (0.76)
> cryptands (0.51). 119
4.5.2 Lariat Ethers
The lariat ethers (19) and (20) known to date consist
of macrocycles with many different types of podand
groups, and much of their complexation chemistry involves
electrostatic binding of guests. Reviews of both structural and
thermodynamic aspects of the lariat ethers can be found. 120–122
The trends are noted to be relatively similar for both the
carbon-pivot and nitrogen-pivot types of lariat ethers. Binding
strengths and selectivities are dependent on ring size and in
general increase as ligand size increases. Strong selectivities
are noted for the potassium ion, as in the crown ethers.
4.5.3 Spherands and Hemispherands
The spherands (21) were specifically designed using the
concept of ‘preorganization’ wherein the oxygen donors are
arranged in an enforced spherical cavity. Totally prearranged
(spherand) and partially arranged (hemispherand, (22))
complexes are possible. 118 Due to the structural restraints
imposed by the rigidly joined phenyl rings, the spherands are
considered to be highly ‘preorganized’ binding sites. In these
macrocycles the lone pair of electrons will always be pointed
toward the center of the macrocyclic cavity.
4.5.4 Calixarenes
The calixarenes (23) are also highly preorganized
molecules which are capable of forming different
conformational isomers. The conformational flexibility is
determined by the size of the ring, with the preferred conformation
becoming more planar as the ring size increases. 37
5 APPLICATIONS
MACROCYCLIC LIGANDS 17
As macrocyclic chemistry has developed, the variety and
scope of the applications of these molecules have continued
to multiply. This concluding section is an attempt to provide
an overview of only three of the applications of synthetic
macrocycles. A particularly insightful treatment can be
found in the Nobel Lecture of Jean-Marie Lehn, 123 which
describes the concept of supramolecular chemistry from
simple recognition, to cation and anion receptors, multiple
recognition, catalysis, transport, and molecular devices.
5.1 Ion Transport
Ion transport, especially cation transport, was one of the
early focal points in macrocyclic chemistry, revolving primarily
around the crown ethers and cryptands. Later efforts have
been to provide switches to control the rates of cation transport.
Two examples of the types of switches that have been
developed include photo switches using cryptands, 124 and
electrochemical switches using anthraquinone-derived lariat
ethers. 125
Related to transport capabilities is the use of synthetic
macrocycles in analytical chemistry. Because of their selective
complexation of a variety of cations, the crown ethers and
related macrocycles have been widely used for separations
and analyses. 126
While transport efforts have largely involved metal
cations, more recent developments have led to the use of
macrocycles for transport of more complex molecules such as
nucleosides. 127
5.2 Catalysis
Catalysis can be broken down into a number of areas,
depending on the substrate and the catalytic reaction. One of
the prime areas of the initial effort in catalysis has been small
molecule activation, such as oxygen with a number of transition
metal ion macrocycles 128,129 and carbon dioxide, the latter
particularly with cobalt(I) and nickel(I) macrocycles. 130,131
Once the polyammonium macrocycles were found to be able
to recognize substrates other than metal ions, other catalysis
applications evolved. For example, phosphoryl transfer catalysis
with simple polyammonium macrocycles has become
quite accessible. 132
5.3 Magnetic Resonance Imaging
Macrocyclic complexes have gained recognition in
magnetic resonance imaging. 133,134 In order to be effective
imaging agents, complexes must provide a significant
enhancement in the proton relaxation rates of water,
as well as be nontoxic, and thermodynamically stable.
Hence, macrocyclic ligands with pendant carboxylates, such

18 MACROCYCLIC LIGANDS
as (5), have been examined primarily because of their
thermodynamic stability.
6 RELATED ARTICLES
Ammonia & N-donor Ligands; Mixed Donor Ligands
P-donor Ligands; S-donor Ligands; Water & O-donor Ligands.
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