Macrocyclic Ligands - Web del Profesor
Macrocyclic Ligands - Web del Profesor
Macrocyclic Ligands - Web del Profesor
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<strong>Macrocyclic</strong> <strong>Ligands</strong><br />
Kristin Bowman-James<br />
University of Kansas, Lawrence, KS, USA<br />
1 Introduction 1<br />
2 Classification of <strong>Ligands</strong> 1<br />
3 Synthesis 5<br />
4 Thermodynamics and Structural Aspects 9<br />
5 Applications 17<br />
6 Related Articles 18<br />
7 References 18<br />
Glossary<br />
Bis-macrocycles: two macrocycles joined together<br />
Calixarenes: basket-shaped macrocycles with phenyl<br />
backbones<br />
Catenands: two interlocked macrocycles<br />
Compartmental ligands: macrocycles with ‘compartments’<br />
for housing more than one substrate<br />
Crown ethers: polyoxa macrocycles<br />
Cryptands: bicyclic macrocycles with aza bridgeheads<br />
Cyclidenes: lacunar tetraaza macrocycles<br />
Expanded porphyrins: macrocycles based on pyrrolic<br />
frameworks<br />
Lariat ethers: crown ethers with pendant chains<br />
Sepulchrates: bicyclic caged macrocycles<br />
Spherands: macrocycles with phenyl backbones<br />
Abbreviations<br />
Polyaza macrocycles: [n]aneNm: n = Number of ring atoms;<br />
Nm = Number of nitrogen atoms; Polyoxa macrocycles: ncrown-m:<br />
n = Number of ring atoms; m = Number of oxygen<br />
atoms; TRI = Tribenzo[b,f ,j][1,5,9]triazacyclododecine;<br />
TAAB = Tetrabenzo[b,f ,j,n][1,5,9,13]tetraazacyclohexadecine.<br />
1 INTRODUCTION<br />
<strong>Macrocyclic</strong> ligands are defined as cyclic molecules<br />
generally consisting of organic frames into which heteroatoms,<br />
capable of binding to substrates, have been interspersed.<br />
Some reports of ‘synthetic’ macrocycles (as opposed to the<br />
naturally occurring species such as porphyrins, corrins, and<br />
chlorins) appeared as early as 1936, when the first synthesis of<br />
1,4,8,11-tetraazacyclotetradecane was reported. 1 Nonetheless,<br />
the field only began to blossom in the early 1960s with the<br />
pioneering work of Busch 2 and Curtis’ discovery of the nickelmediated<br />
condensation of [Ni(en)3] 2+ with acetone. 3 The<br />
early macrocycles were synthesized with an eye to mimicking<br />
biologically occurring macrocycles such as the porphyrins,<br />
corrins, chlorins, and, more recently, the corphins.<br />
Another area of macrocyclic development began in the late<br />
1960s and initial applications were focused toward mo<strong>del</strong>ing<br />
biological processes such as ion transport. These macrocycles<br />
initially included the oxygen-based crown ethers of Pedersen, 4<br />
and the mixed oxygen–nitrogen bicyclic cryptands of Lehn, 5<br />
both of which exhibit high selectivity toward alkali and<br />
alkaline earth metal ions. Several years later, the concept<br />
of ‘preorganized’ cavities resulted in the synthesis of the<br />
cavitands by Cram. 6<br />
Since its birth, the development of macrocyclic chemistry<br />
has proceeded along two lines:<br />
1. as mo<strong>del</strong>s of the naturally occurring macrocyclic systems,<br />
containing predominantly nitrogen donor atoms; and<br />
2. as receptors designed for recognition and supramolecular<br />
chemistry, with a variety of donor atoms and recognition<br />
capabilities.<br />
<strong>Macrocyclic</strong> chemistry has expanded phenomenally since<br />
the 1960s to provide exciting and novel chemistry. The award<br />
of the 1987 Nobel Prize in Chemistry to Pedersen, Lehn,<br />
and Cram is testimony to the importance of this rapidly<br />
expanding field.<br />
In such a large subject, this article can only focus on<br />
certain aspects, namely those that involve complexation<br />
with inorganic substrates. We only consider the synthetic<br />
macrocycles, with emphasis on transition metal complexation.<br />
Aza, oxa, and, to a lesser extent, thia and phospha<br />
macrocycles are also covered. The naturally occurring<br />
porphyrins, corrins, corphins, chlorins, and phthalocyanins, 7<br />
as well as the cyclodextrins, 8 are not included. Because of the<br />
general complexity of macrocyclic systems and the resulting<br />
complicated systematic names, commonly used abbreviations<br />
or simplified names will be employed. This review will<br />
encompass the synthesis, thermodynamics, structure, and<br />
applications of macrocyclic ligands.<br />
2 CLASSIFICATION OF LIGANDS<br />
Two major areas of complexation have developed over<br />
the years with regard to synthetic macrocycles. Those with<br />
nitrogen, sulfur, phosphorus, and arsenic tend predominantly<br />
to form traditional covalent coordination complexes with<br />
transition metal ions. A notable exception to this tendency,<br />
however, is the rapidly expanding chemistry of the
2 MACROCYCLIC LIGANDS<br />
polyammonium macrocycles, which are capable of forming<br />
a variety of complexes with anionic substrates. Oxygenderived<br />
macrocycles are noted for complexation with alkali<br />
and alkaline earth metal ions, as well as with organic cations<br />
and molecular substrates. In this latter situation, associations<br />
tend to be electrostatic in nature, and in many instances<br />
hydrogen-bonding interactions are vital to complex formation.<br />
<strong>Macrocyclic</strong> ligands will be classified, for the purposes of<br />
this article, as rings with at least nine members and three or<br />
more donor atoms. In a number of cases of unique structural<br />
units, elegant descriptive names have developed, which more<br />
appropriately describe the macrocyclic shape. Macrocycles<br />
will be classified as to donor types and, within the donor<br />
types, specific classifications of macrocycles will be noted<br />
where applicable.<br />
2.1 Polyaza Macrocycles (1)–(10) 9–18<br />
2.1.1 Simple Polyaza Macrocycles<br />
Until recently, the tetraaza macrocycles, such as (1)<br />
(cyclam) and related ligands with extensive varieties of<br />
modifications including differing degrees of saturation and<br />
ring size (2), had been the most studied, primarily because<br />
of the relationship of these molecules to naturally occurring<br />
tetraaza macrocycles, such as the porphyrins and corrins.<br />
Currently, with interest in metal–metal interactions, increased<br />
activity has occurred in the area of larger macrocycles<br />
capable of incorporating more than one metal ion, such as<br />
(3) ([24]aneN8). 18 Interest in the smaller triaza macrocycles,<br />
such as (4) ([9]aneN3) and its variations, has also accelerated<br />
in recent years. 14 Added to the simple polyaza macrocycles has<br />
been the effort to achieve functionalized macrocycles in order<br />
to expand the chemistry of these ligands by combining the<br />
rigid structural aspects of the macrocyclic ring with the more<br />
flexible and kinetically labile properties of pendant chains, as<br />
in (5). 11<br />
NH<br />
NH<br />
(1)<br />
HN<br />
HN<br />
2.1.2 Cyclidenes<br />
N<br />
N<br />
(2)<br />
N<br />
N<br />
Me<br />
Me<br />
NH<br />
NH<br />
NH HN<br />
NH<br />
(3)<br />
HN<br />
HN<br />
HN<br />
Cyclidenes (6) are a subset of the polyaza macrocycles<br />
and are the lacunar ligands first synthesized and extensively<br />
NH HN<br />
H<br />
N<br />
(4)<br />
HO 2C<br />
HO 2C<br />
N<br />
N<br />
(5)<br />
N<br />
N<br />
CO2H<br />
CO2H<br />
studied by Busch. 19 They coordinate a single metal ion and<br />
maintain a ‘persistent void’ which allows access to small<br />
molecules within the vaulted cavity.<br />
N<br />
N<br />
2.1.3 Sepulchrates<br />
N<br />
N<br />
N<br />
N<br />
R<br />
R<br />
NH HN<br />
NH<br />
NH HN<br />
HN<br />
R<br />
(6) (7)<br />
Sepulchrates (7) are polyaza cage macrocycles. They are<br />
noted for their exceptionally strong hold on encapsulated metal<br />
ions. 20<br />
2.1.4 Expanded Porphyrins<br />
Expanded porphyrins are macrocycles based on the pyrrolic<br />
backbone of porphyrins, but are expanded in size to achieve a<br />
larger cavity (8) 21 or binucleating capabilities (9). 22<br />
NH<br />
N<br />
N<br />
N<br />
N<br />
N<br />
N<br />
NH NH<br />
HN<br />
HN<br />
(8) (9)<br />
N<br />
N
2.1.5 Bis-Macrocycles<br />
Bis-macrocycles (10) provide another mechanism for<br />
achieving complexation of more than one metal ion. They<br />
are joined by a bridge linking two simple macrocycles. 13,23<br />
Me<br />
N N<br />
N<br />
N<br />
(CH 2) 2<br />
N<br />
Me<br />
(10)<br />
2.2 Polythia, Polyphospha, and Polyarsa Macrocycles<br />
Polythia macrocycles (11), the thioether analogs of the<br />
crown ethers, have been known since the 1930s. 24 These are<br />
the most extensively studied macrocycles in line after the<br />
polyoxa and polyaza macrocycles.<br />
S<br />
S<br />
S<br />
S<br />
N<br />
(11) (12)<br />
The ‘pure’ polyphospha macrocycles (12) (as opposed to<br />
the mixed donor phospha macrocycles) were first reported in<br />
1975. 25 These macrocycles have been found to complex a<br />
variety of transition metals, but have not received the same<br />
attention as the more readily accessible polyaza and polyoxa<br />
macrocycles.<br />
The polyarsa macrocycles (13) comprise one of the least<br />
common type of macrocycles. 26<br />
P<br />
P<br />
P<br />
P<br />
As<br />
As<br />
As<br />
MACROCYCLIC LIGANDS 3<br />
(13)<br />
2.3 Mixed Donor Macrocycles<br />
As<br />
As<br />
As<br />
2.3.1 Simple Mixed Donor Macrocycles<br />
The simple mixed donor macrocycles (14) at one time were<br />
the major source of study of the influence of the incorporation<br />
of ‘soft’ phosphorus and arsenic donors into macrocycles. 27<br />
Mixed oxygen–nitrogen macrocycles have been studied quite<br />
extensively, since they serve as bridges for examining the<br />
coordination tendencies of the aza macrocycles and the oxa<br />
crown ethers. 13<br />
P<br />
P<br />
2.3.2 Cryptands<br />
O<br />
O<br />
HN<br />
HN<br />
HN<br />
N<br />
O<br />
O O<br />
O<br />
(14) (15)<br />
Cryptands (15) are bicyclic macrocycles which can contain<br />
a variety of donor atoms with bridgehead nitrogen atoms. 5<br />
They are highly selective for alkali and alkaline earth<br />
metal ions.<br />
2.3.3 Compartmental <strong>Ligands</strong><br />
Compartmental ligands (16) are macrocyclic ligands (as<br />
well as nonmacrocyclic ligands) which contain ‘compartments’<br />
for housing more than one metal ion. 28 Only the<br />
macrocyclic counterparts will be treated here.<br />
O<br />
O<br />
N
4 MACROCYCLIC LIGANDS<br />
N<br />
N<br />
2.3.4 Catenands<br />
Me<br />
N OH N<br />
N<br />
OH<br />
Me<br />
(16)<br />
O<br />
O O<br />
O<br />
O<br />
O<br />
O O<br />
O<br />
O<br />
(17)<br />
Catenands (17) are interlocked macrocyclic ligands, which<br />
complex a variety of metal ions. 29<br />
2.4 Polyoxa Macrocycles<br />
Polyoxa macrocycles, known more commonly as the crown<br />
ethers, comprise an extensive area of research, with a repertoire<br />
of types and variations. 30 Some of these macrocycles have<br />
been utilized predominantly for purposes other than metal ion<br />
complexation, and these will not be discussed in depth in this<br />
review. Included in this latter category are the polycarbonyls, 31<br />
polylactones, 32 polylactams 33 and carcerands. 34<br />
2.4.1 Polyether Macrocycles<br />
Polyether macrocycles (18) are the simplest of the polyoxa<br />
macrocycles. The commonly used name for these macrocycles<br />
is the crown ethers, due to their crown-like structure in the<br />
solid state. These molecules have been extensively studied<br />
N<br />
O<br />
O<br />
N<br />
N<br />
O<br />
O<br />
O<br />
O<br />
(18)<br />
as complexing agents for the alkali and alkaline earth metal<br />
ions. 30<br />
2.4.2 Lariat Ethers<br />
The lariat ethers comprise a subset of the polyether<br />
macrocycles, and are identified by their pendant chains. 35<br />
They can be categorized as either N-pivot (19) orC-pivot<br />
(20), depending on which type of atom the chain is attached.<br />
As for their polyether parents, much of the focus on these<br />
macrocycles has been on complexation of alkali and alkaline<br />
earth metal ions.<br />
O<br />
O<br />
O<br />
O<br />
(19)<br />
N<br />
O<br />
2.4.3 Spherands and Hemispherands<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
(20)<br />
O<br />
O<br />
MeO<br />
These consist of an arrangement of phenyl groups which<br />
provide a preorganized cavity for complexation, 36 e.g. (21)<br />
and (22).<br />
Me Me<br />
Me<br />
Me<br />
OMe<br />
OMe MeO<br />
OMe MeO<br />
OMe<br />
Me<br />
(21)<br />
Me
Me<br />
2.4.4 Calixarenes<br />
O<br />
Me<br />
OMe<br />
OMe MeO<br />
O<br />
(22)<br />
Calixarenes (23) are the macrocyclic result of condensations<br />
between phenols and formaldehyde 37 and have been<br />
referred to as the most easily accessible molecular basket. 38<br />
t-Bu<br />
t-Bu<br />
OH<br />
OH HO<br />
OH<br />
t-Bu<br />
(23)<br />
H 2N<br />
H2N<br />
O<br />
NH<br />
H<br />
N<br />
HN<br />
Me<br />
t-Bu<br />
NH 2<br />
NH2<br />
NH<br />
NH<br />
NH<br />
NH<br />
3 SYNTHESIS<br />
3.1 Polyaza Macrocycles<br />
MACROCYCLIC LIGANDS 5<br />
3.1.1 Conventional (Nontemplate) Syntheses<br />
Reviews of synthetic procedures can be found for tridentate<br />
and pentadentate macrocyclic ligands with nitrogen donors,<br />
mixed nitrogen donors, and sulfur donor macrocycles, 39 the<br />
techniques of which can be expanded to other ring sizes. The<br />
general procedures will be summarized below.<br />
Cyclic secondary amines, [n]aneNm, are generally prepared<br />
by macrocyclization reactions known as the Richman–Atkins<br />
procedure. 40 These reactions involve ring closure by<br />
condensation of two precursor fragments of the cyclic<br />
molecule. In general, one fragment consists of a salt<br />
of a sulfonamide, while the other contains two terminal<br />
leaving groups, which can vary in identity and include<br />
chloride, bromide, hydroxide, or, more often, a sulfonate ester<br />
(Scheme 1). The reaction is performed in polar aprotic solvents<br />
and may involve high dilution techniques. Simplified routes<br />
to tri-, tetra-, and pentaaza systems have been described. 41 A<br />
handy synthetic technique for the smaller triaza ring has been<br />
described by Alder, where the macrocycle is built by using<br />
a single carbon as template. 42 Treatises on the synthesis of<br />
pyridine-containing macrocycles 43 and imidazole-containing<br />
macrocycles 44 have also been reported.<br />
Functionalized macrocycles (5) with additional ligating<br />
components attached as pendant arms have been an area<br />
of focus in efforts to expand the chemistry of macrocyclic<br />
receptors by incorporating additional recognition sites.<br />
Synthetic techniques for N-functionalized, C-functionalized,<br />
NTs<br />
TsN −<br />
Scheme 1<br />
Ts<br />
N<br />
TsN<br />
OMs MsO<br />
HN<br />
NTs TsN<br />
HN<br />
HN<br />
− NTs
6 MACROCYCLIC LIGANDS<br />
and bis-macrocycles are known. 11 N-Alkylation, the more<br />
common of the functionalization routes, is usually achieved<br />
by alkylation or acylation of the amino nitrogens using<br />
a variety of agents such as chloroacetic acid, ethylene<br />
oxide, acrylonitrile, and formaldehyde. 11 Routes for selective<br />
alkylations are known, including the use of selective protection<br />
and deprotection techniques. 45<br />
Bis-macrocycles (10), another extension of the concept of<br />
functionalized macrocycles, can be made by several different<br />
methods. One of the more commonly used is the condensation<br />
of two precursor chains already joined by the linker. 23<br />
Bis-macrocycles also can be formed from cyclam (1) asa<br />
by-product bis-macrocycle in low yield (24). 46<br />
NH<br />
NH<br />
HN<br />
HN<br />
(24)<br />
NH<br />
NH<br />
3.1.2 Template-Mediated Syntheses<br />
HN<br />
HN<br />
Metal ion template mediation in macrocyclic synthesis has<br />
been a part of the field since its inception, its importance<br />
having been realized early in the development of this area.<br />
Two specific roles for the metal ion in template reactions have<br />
been proposed. These are, in turn, kinetic and thermodynamic<br />
in origin. 47 In the kinetic template effect, the arrangement of<br />
ligands already coordinated to the metal ion provides control<br />
in a subsequent condensation during which the macrocycle<br />
is formed. The thermodynamic effect serves to promote<br />
stabilization of a structure which would not be favored in<br />
the absence of a metal ion. Schiff base condensations tend<br />
to be dependent on this latter type of template effect. Some<br />
of the more routine and general synthetic procedures will be<br />
described here. A more in-depth treatment can be found in a<br />
review by Curtis, with particular emphasis on general methods<br />
as well as modifications of preformed macrocycles. 48<br />
Carbonyl compounds are commonly used precursors for<br />
the polyaza macrocycles, as in the classic synthesis of<br />
the Curtis ligand from the condensation of acetone with<br />
Ni(en)3 (Scheme 2). 3 2,6-Diacetylpyridine has provided the<br />
Ni<br />
H2<br />
N<br />
N<br />
H 2<br />
3<br />
O<br />
N<br />
HN<br />
Ni<br />
Scheme 2<br />
NH<br />
N<br />
+<br />
HN<br />
HN<br />
Ni<br />
N<br />
N<br />
Me<br />
N<br />
Me<br />
O O<br />
+<br />
H2N NH2 N<br />
H<br />
small M n+<br />
large M n+<br />
Scheme 3<br />
Me<br />
N<br />
Me<br />
N<br />
M<br />
N<br />
Me<br />
N<br />
Me<br />
N<br />
M<br />
N<br />
Me<br />
NH HN<br />
precursor for a number of pyridine-derived imine macrocycles<br />
(Scheme 3), where smaller metal ions as templates tend to<br />
implement the formation of 1:1 condensates, while larger<br />
metal ions allow for 2:2 stoichiometries. 49 Schiff base<br />
condensations can be considered as another variation of<br />
the carbonyl condensations (Scheme 4). 50 The expanded<br />
porphyrins (8) and(9) 21,22 and the compartmental ligands<br />
(16) 28 are usually synthesized by Schiff base condensations.<br />
In some instances the macrocyclic analog cannot be obtained<br />
via other methods. This is true for the self-condensation of<br />
o-aminobenzaldehyde, which can yield both tridentate (TRI)<br />
and tetradentate (TAAB) macrocycles (25) and(26). 51<br />
N N<br />
N<br />
(25)<br />
N<br />
N<br />
N<br />
(26)<br />
Template-assisted condensations of amines with formaldehyde<br />
yield a wide variety of macrocyclic products. Sepulchrates<br />
(7) can be synthesized from the template-assisted<br />
condensation of [Co(en)3] 3+ with formaldehyde and ammonia<br />
under basic conditions. 20 Primary aldehydes other than<br />
formaldehyde have also been used. 52 Caged metal ion complexes<br />
in which the metal ion is used as a template are normally<br />
N<br />
N<br />
N H<br />
M<br />
N<br />
N<br />
Me
N<br />
N<br />
CHO<br />
H2N +<br />
CHO<br />
H2N<br />
M n+<br />
extremely inert, so much so that removal of the metal is often<br />
impossible. Nonmetal template syntheses of polyaza cages<br />
have also been reported. 53 A number of interesting variations<br />
utilizing the template-assisted condensation of formaldehyde<br />
and amines have also resulted in structurally new macrocycles<br />
such as (27). 54<br />
Me<br />
N<br />
NH HN<br />
N N<br />
N<br />
(27)<br />
3.2 Polythia, Polyphospha, and Polyarsa Macrocycles<br />
One of the reasons for the relative ‘late-blooming’ of the<br />
thioether macrocycles can be found in synthetic difficulties.<br />
While the polyaza and polyoxa macrocycles can often utilize<br />
template effects in controlling the critical condensations,<br />
polythia condensations are more limited in this area. In<br />
general, these macrocycles are made from condensation of the<br />
appropriate polythiane with a dibromoalkane (Scheme 5). 55<br />
Synthetic procedures and yields have been greatly enhanced by<br />
the addition of high dilution techniques. 56,57 A cage-like sulfur<br />
macrocycle has been reported as an analog of the nitrogencontaining<br />
sepulchrates (28). 58 Mixed nitrogen–sulfur cages<br />
can also be obtained. 58<br />
S<br />
S<br />
N<br />
S<br />
S<br />
N<br />
(28)<br />
N<br />
S<br />
S<br />
Scheme 4<br />
N<br />
N N<br />
M M<br />
N<br />
N N<br />
Ph<br />
N<br />
N<br />
S S<br />
SNa NaS<br />
+<br />
Br Br<br />
P P<br />
Ni<br />
PH HP<br />
Ph Ph<br />
+<br />
Br Br<br />
Ph<br />
MACROCYCLIC LIGANDS 7<br />
Scheme 5<br />
Scheme 6<br />
Ph<br />
S S<br />
S S<br />
P P<br />
Ph<br />
Ni<br />
Ph<br />
P P<br />
Ph<br />
Polyphospha macrocycles can be made via template<br />
condensations of coordinated polyphosphine ligands and<br />
dibromoalkanes (Scheme 6). 59,60<br />
Polyarsa macrocycles can be made by the reaction of<br />
lithiated polyarsanes with a dichloroalkane (Scheme 7). 26,60<br />
3.3 Mixed Donor Macrocycles<br />
Simple mixed donor macrocycles, such as aza–oxa,<br />
aza–thia, oxa–thia, and analogous phospha and arsa analogs<br />
are generally achieved via combinations of the routes used for<br />
synthesis of the ‘pure’ donor analogs. Since the possibilities<br />
are so extensive they will not be treated here, but are found<br />
elsewhere. 16,60 New mixed donor phosphorus techniques<br />
have been devised for phospha–thia and phospha–aza<br />
macrocycles. 61,62
8 MACROCYCLIC LIGANDS<br />
PhAs As(Ph)Li<br />
As(Ph)Li<br />
+<br />
Cl Cl<br />
Scheme 7<br />
PhAs<br />
As<br />
Ph<br />
AsPh<br />
Cryptands are usually synthesized via sequential condensations<br />
between a diamine and an acid chloride, which<br />
yields a diamide, followed by reduction with LiAlH4<br />
to give the macromonocycle. Condensation with another<br />
H2N O O NH2 O O<br />
Cl O O Cl<br />
HN<br />
O O<br />
O O<br />
NH<br />
HN<br />
+<br />
O O<br />
Cl O O Cl<br />
N<br />
O O<br />
O O<br />
O O<br />
O<br />
O O<br />
O<br />
equivalent of acyl chloride will yield the bicyclic precursor,<br />
which can be reduced by B2H6 to give the bicycle<br />
(Scheme 8). 5<br />
Compartmental ligands (16) are derived from diketonates<br />
and triketonates and are usually synthesized from Schiff base<br />
reactions of the ketone with a diamine. 28<br />
Catenands (17) are also made using the metal ion template<br />
effect. A bis-complex is formed from an α,α ′ -disubstituted<br />
o-phenanthroline. Then the initial product is treated with a<br />
diiodoalkane to accomplish the ring closure. 29<br />
3.4 Polyoxa Macrocycles<br />
Polyethers were originally synthesized by template<br />
assistance from an oligo(ethylene glycol), monoglyme, and<br />
potassium t-butoxide (Scheme 9). 4<br />
O O<br />
HN<br />
NH<br />
O O<br />
O O<br />
NH<br />
N<br />
O O<br />
O<br />
N<br />
Scheme 8<br />
O<br />
O O<br />
O<br />
O<br />
N<br />
B2H 6<br />
LAH
HO O O OH<br />
+<br />
Cl O O Cl<br />
Scheme 9<br />
Spherands and hemispherands (21)and(22) are synthesized<br />
by ring closure reactions of aryllithium with Fe(acac)3, often<br />
using high dilution techniques. 36<br />
Calixarenes (23) are obtained from base-catalyzed condensations<br />
of p-substituted phenols with formaldehyde. 37<br />
4 THERMODYNAMICS AND STRUCTURAL<br />
ASPECTS<br />
4.1 Introduction<br />
4.1.1 The <strong>Macrocyclic</strong> Effect<br />
This term refers to the amazing stability of macrocyclic<br />
ligands. It was initially described in studies of tetraaza<br />
macrocycles with copper(II). 63 For polyaza macrocycles this<br />
effect has been attributed to both entropic and enthalpic<br />
considerations and considerable controversy raged for a<br />
number of years as to which was the predominant factor. 64,65<br />
The conflicting reports are now realized to be extremely<br />
dependent on the experimental methods used for the<br />
determination of the thermodynamic parameters. Two main<br />
types of technique have been employed, each of which has its<br />
strengths and weaknesses: the calorimetric titration method<br />
and the use of the temperature variation of the stability<br />
constants. The controversy has been largely settled by more<br />
recent studies. 66,67 Important contributions to the enthalpic<br />
term are now attributed to a number of factors, including<br />
solvation and conformation changes upon bond formation.<br />
Likewise, the entropic considerations include the number of<br />
species present and particularly solvation effects. Detailed<br />
discussions of the historical development can be found. 13,17<br />
Related to the macrocyclic effect are the decreased rates<br />
of dissociation observed for macrocyclic complexes. Busch<br />
and co-workers have coined a term to describe these longterm<br />
stabilities incurred by synthetic macrocycles: multiple<br />
juxtapositional fixedness. The premise is that straight-chain<br />
ligands can undergo dissociative displacements in consecutive<br />
steps starting at one end of the ligand and finishing with the<br />
opposite end. This is not the case for macrocyclic ligands, for<br />
which each dissociated donor is still held in proximity to the<br />
metal ion by the rest of the ligand framework. 68<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
MACROCYCLIC LIGANDS 9<br />
The macrocyclic effect has been observed for polyaza,<br />
polythia, and polyoxa, as well as mixed donor atom,<br />
macrocycles. 69<br />
4.1.2 Selectivity<br />
The selectivity of a macrocycle for either a metal ion or<br />
another substrate is critically dependent on the structure of<br />
the macrocycle and electronic effects, i.e. the types of donor<br />
atoms. Some of the important aspects are described below.<br />
1. The number of binding sites is perhaps one of the<br />
most crucial influences on the binding properties of the<br />
substrate. Electronic effects of the binding of macrocycles<br />
with substrates are charge, polarity, and polarizability<br />
of the binding sites. For metal ion binding, this means<br />
ion pair interactions for negatively charged ligands,<br />
ion–dipole and ion–induced dipole interactions for<br />
neutral ligands, and the hard–soft acid–base criteria.<br />
Nitrogen, phosphorus, and sulfur donors are noted for<br />
their complexation of transition metal ions. Oxygen is<br />
more likely to complex alkali or alkaline earth metal ions.<br />
2. The arrangement of the binding sites should be such as to<br />
maximize the potential ligand–metal ion interactions. In<br />
this regard the selection of spacers between donor atoms<br />
to allow for the formation of five- and six-member chelate<br />
rings has been the most utilized.<br />
3. The preferred conformations of the macrocycles dictate<br />
its propensity to bind a metal ion internally or externally<br />
to the cavity. The propensity of the lone pair to point in<br />
or out of the cavity is also a deciding factor. Hence, it is<br />
not always a foregone conclusion that the metal ion will<br />
be bound within the macrocyclic cavity.<br />
4. The identity of the macrocyclic framework also plays<br />
a major role in structure. For example, saturated<br />
hydrocarbon chains provide considerably more flexibility<br />
than incorporated aromatic units. Likewise the presence<br />
of other functional groups, such as amides or esters, serve<br />
to stiffen the macrocyclic framework. Decreasing the<br />
flexibility of the macrocycle by adding selected ‘shaping<br />
groups’ is the theory behind preorganization, so important<br />
in the cavitands. Another method of creating rigidity is to<br />
increase the dimensionality of the macrocycle, inherent in<br />
cryptand selectivities.<br />
5. The size of the macrocyclic cavity also plays a large role in<br />
governing the flexibility of the ligand, and its propensity<br />
for metal ion binding.<br />
Since the focus of this article is primarily on transition metal<br />
chemistry, the structural aspects related to complexation of<br />
transition metals will be emphasized, and other aspects of<br />
complexation will only be briefly treated.<br />
In addition to the traditional measurement of thermochemical<br />
properties, molecular mechanics calculations are now<br />
available to supplement and correlate with experimental findings.<br />
An extensive review which links the large data base of
10 MACROCYCLIC LIGANDS<br />
thermodynamic and kinetic data with items such as ring size,<br />
number and arrangement of ligand binding sites, and solvent<br />
effects, for all types of donor atoms including coronands,<br />
cryptands, spherands, and nitrogen donors can be found. 69 A<br />
more recent series of molecular mechanics calculations have<br />
added to this base of thermochemical data and point to structural<br />
factors affecting complex stabilities from the viewpoint<br />
of steric strain. 70<br />
4.2 Polyaza Macrocycles<br />
An extensive review of the thermodynamic aspects of<br />
polyaza macrocycles has been reported. 17 Other reviews<br />
include the chemistry of tridentate and pentadentate aza<br />
macrocycles, 16 1,4,7-triazacyclononane and derivatives, 14 and<br />
polyaza macrocycles with pendant chains. 11 In general, the<br />
polyaza macrocycles form extremely stable complexes with<br />
transition metals of the later transition series, but show reduced<br />
affinity for alkali and alkaline earth metal ions compared to<br />
the oxa macrocycles.<br />
4.2.1 Triaza Macrocycles<br />
One of the simplest and smallest of the polyaza macrocycles<br />
according to definition is 1,4,7-triazacyclononane (4). The<br />
geometrical constraints of the triaza macrocycles are such<br />
that they do not allow for the incorporation of the metal ion<br />
within the macrocyclic ring. Hence, these macrocycles are<br />
facially coordinated in either a mono- or bis-ligand complex<br />
with a variety of metal ions. 14 The macrocyclic effect is<br />
observed, and the stability constants of the complexes follow<br />
the Irving–Williams Series. 17 Both microcalorimetric 71 and<br />
stability constant determinations at different temperatures 72<br />
indicate that the effect is most probably enthalpic in origin.<br />
The triaza macrocycles also form extremely stable complexes<br />
with the heavier main group metals (such as Ga III , In III ,<br />
Tl I ,andTl III ) as well as transition metals. The chemistry<br />
of this macrocycle and its derivatives is wide in scope and<br />
is treated extensively in a review which includes the base<br />
compound and its N-functionalized derivatives. 14 Depending<br />
on the appendages employed in N-functionalization, three<br />
more coordination sites are potentially available, rounding out<br />
the coordination to pseudooctahedral.<br />
The formation of dinuclear and higher nuclearity species<br />
is common for the mono-coordinated triazacyclononane, with<br />
bridging acetates, hydroxides, and oxides being very common.<br />
Extensive studies of the chemistry of the variety of bridged<br />
species have been made using the relatively substitutionally<br />
inert chromium(III) ion. Different dimers and trimers have<br />
been isolated and structurally characterized, as in (29) and<br />
(30). 73,74 Higher nuclear clusters such as an octanuclear iron<br />
system are relevant as a mo<strong>del</strong> for the iron storage protein<br />
ferritin (see Iron Proteins for Storage & Transport & their<br />
Synthetic Analogs). 75<br />
N<br />
N<br />
Cr<br />
N O<br />
H<br />
O<br />
O<br />
H<br />
O<br />
(29)<br />
N<br />
Cr<br />
O<br />
N<br />
N<br />
N<br />
N<br />
N<br />
Cr<br />
N<br />
H<br />
O N<br />
O<br />
H Cr<br />
OH<br />
Cr<br />
N<br />
N<br />
(30)<br />
A more ‘preorganized’ ligand system is derived from the<br />
self-condensation of o-aminobenzaldehyde. 51 The tridentate<br />
form of the ligand (25) (TRI) imparts considerable<br />
inertness toward substitution. For example, the salts of<br />
the [Ni(TRI)(H2O)3] 2+ ion can be resolved into optical<br />
isomers. 76 A copper(II) complex of the methyl-substituted<br />
tetradentate macrocycle Me4TAAB, in which bis-coordination<br />
occurs, displays a dynamic Jahn–Teller distortion based on<br />
crystallographic evidence. 77<br />
4.2.2 Tetraaza Macrocycles<br />
Because of the potential relationship to the naturally<br />
occurring porphyrins and porphyrin-analog macrocycles, the<br />
tetraaza macrocycles have been the focus of much attention.<br />
Tetraaza macrocycles often, but not always, form a coplanar<br />
arrangement of the four nitrogen donors. Empirical force field<br />
calculations of free macrocycles from 12- to 16-membered<br />
rings indicate that cyclam (1) exhibits the least strain with the<br />
best planarity. A straightforward assessment of the relationship<br />
of hole size to selectivity is complicated by the conformational<br />
flexibility of the ligands. Results of studies for the tetraaza<br />
macrocycles show that hole size does not appear to be the<br />
predominant factor in metal ion discrimination. Rather, the<br />
selectivity of these macrocycles is governed by the relative<br />
stability of the conformers of the macrocycle which have<br />
different metal ion size preferences. An interesting observation<br />
regarding the relationship of the tetraaza macrocycles with<br />
regard to hole size and metal ion selectivity can be found<br />
for the most studied of the simple tetraaza macrocycles,<br />
cyclam. Cyclam is proposed to have five configurational<br />
isomers, based on the orientation of the amine hydrogens.<br />
From molecular mechanics calculations, where the best M–N<br />
distance is calculated as that giving the minimum energy,<br />
the trans-III analog of [12]aneN4 (31) is found to have an<br />
extremely high strain energy of 19.7 kcal mol −1 with a best-fit<br />
M–N distance of 1.81 ˚A, compared to the trans-I form (32)<br />
(10.8 kcal mol −1 and 2.11 ˚A, respectively). 70,78 In general, the<br />
larger, more flexible, planar coordination is provided by the<br />
trans-I conformer, and often if a metal is too large for the<br />
macrocyclic cavity, it will coordinate lying out of the plane of<br />
the donor atoms. When the metal ion is not incorporated into<br />
the macrocyclic plane, the factors influencing stability are the<br />
same as for the acyclic aza analogs, namely that for larger<br />
metal ions, as the size of the chelate ring increases from five<br />
N<br />
N
to six, the complex stability decreases. A detailed discussion<br />
of the thermodynamics of changing chelate sizes for tetraaza<br />
macrocycles can be found. 17,78<br />
M N<br />
N<br />
H H<br />
H<br />
H<br />
H<br />
H N<br />
M<br />
N N<br />
N<br />
(31) (32)<br />
N<br />
N<br />
H<br />
H<br />
An elegant example of the importance of conformational<br />
changes in tetradentate macrocycles is the blue to yellow<br />
conversion observed for nickel(II) complexes. The yellow<br />
form is the low-spin square planar complex NiL 2+ , while the<br />
blue form is high-spin pseudooctahedral [NiL(H2O)2] 2+ .In<br />
the blue to yellow conversion the Ni–N bonds contract, which<br />
compensates for the breaking of the axial Ni–OH2 bonds. The<br />
reaction is controlled by entropy, and the addition of an inert<br />
salt is such as to favor the dissociation of the water molecules.<br />
At equilibrium in aqueous solution, both [12]aneN4 (cyclam)<br />
(1) and the 15-membered analog, [15]aneN4, have 99% of<br />
the high-spin form present, while the 13- and 14-membered<br />
macrocycles exist in predominantly the low-spin square planar<br />
form (87 and 71%, respectively). 79<br />
For the nonplanar octahedral cis-coordinated macrocycles<br />
[n]aneN4, changes in the ligand field correlate well with the<br />
analogous ligand field strengths for nonmacrocyclic analogs,<br />
specifically as related to the chelate ring size. A general rule<br />
of thumb is that increasing the chelate ring size from five<br />
to six increases the stability of complexes of smaller metals<br />
compared to larger metal ions. The origin of this effect can be<br />
attributed to increases in ring strain energy when metal ions<br />
larger than tetrahedral carbon are part of the ring. 78 For the<br />
planar-coordinated macrocycles, the equatorial ligand field,<br />
as anticipated, is dependent on the ring size. These findings<br />
have been related to the calculation of the optimum hole size<br />
permitting the macrocycle to adopt its most preferable endo<br />
configuration. Thus, it has been found that the macrocyclic<br />
hole size increases by 10–15 pm for each increment in n for<br />
[n]aneN4. 79<br />
In order to introduce a greater rigidity into the<br />
flexible polyaza macrocycles and to implement greater<br />
hole size–metal ion size match correlations, reinforced<br />
macrocycles such as (33) have been created, which contain<br />
fused diaza rings. 80 Crystallographic results for the nickel(II)<br />
complex indicate that the Ni–N bonds are shortened from<br />
the strain-free value of 1.91 ˚A for diamagnetic nickel to<br />
1.86 ˚A. Ligand field strength is also found to increase, and<br />
this has been suggested as being due to the compression<br />
of the bond lengths 80 as well as the presence of tertiary<br />
nitrogen donors. 78 In a more recent comparative study of<br />
nickel macrocycles with two fused 1,3-diazacyclohexane rings<br />
(35) compared to two fused 1,3-diazacyclopentane rings (34),<br />
MACROCYCLIC LIGANDS 11<br />
structural results revealed weaker ligand field strengths for the<br />
1,3-diazacyclohexane compared to 1,3-diazacyclopentane. 54<br />
N<br />
N<br />
NH HN<br />
(33)<br />
N<br />
NH<br />
N<br />
N<br />
(34)<br />
HN<br />
N<br />
N<br />
NH<br />
N<br />
N<br />
(35)<br />
HN<br />
Attempts to achieve macrocycles that are capable of<br />
stabilizing highly oxidized transition metal complexes has<br />
led to the design of ‘noninnocent’ ligands. 81 The structures of<br />
high-valent chromium(V) oxo species with the two tetraamido<br />
N ligands (36)and(37) were determined. Both structures were<br />
found to contain distinctly nonplanar amide groups, and in<br />
(36) all four amides are nonplanar.<br />
O<br />
NH<br />
NH<br />
O<br />
HN<br />
HN<br />
O<br />
Cl Cl<br />
NH<br />
N<br />
O NH HN O<br />
(36) (37)<br />
HN<br />
Polyaza macrocycles with pendant arms have been studied<br />
extensively, in particular with respect to protonation and<br />
complexation as well as to the kinetics of metal complex<br />
formation. These aspects are treated in a review by Kaden. 11<br />
Of particular interest is the fact that metal complex formation<br />
constants of macrocycles with pendant carboxylates can be<br />
10 3 to 10 4 times higher than for the unsubstituted analogs.<br />
4.2.3 Higher Polyaza Macrocycles<br />
Transition metal complexes of the larger polyaza<br />
macrocyclic ligands have been less extensively studied than<br />
for the smaller ring systems. For the pentaaza macrocycles,<br />
[15]aneN5 with ethylene bridges appears to form the most<br />
stable complexes with most metal ions. 17 Structural data<br />
for a variety of pentaaza macrocyclic complexes have<br />
been reviewed. 16 The N–H bonds as well as the different<br />
sized chelate rings must be considered in calculating the
12 MACROCYCLIC LIGANDS<br />
number of possible isomers. For each of the complexes,<br />
three configurations of the in-plane N–H bonds are possible:<br />
(38), (39), and (40). Crystallographic data indicate that<br />
most of the complexes with pentadentate macrocycles have<br />
pseudooctahedral geometries. Pentadentate macrocycles also<br />
tend to stabilize unusual oxidation states. For example, the<br />
nickel(II) complexes of [15]aneN5 (41), [16]aneN5 (42), and<br />
one of the isomers of [17]aneN5 (43), are readily oxidized<br />
to the Ni III analogs. Also, there is little dependence of E1/2<br />
values on the macrocyclic ring size, which has been attributed<br />
to the absence of in-plane ring size effects. 16<br />
NH<br />
H N N H N<br />
N<br />
H<br />
N<br />
M<br />
N<br />
N<br />
N<br />
H<br />
N<br />
M<br />
N<br />
N<br />
N<br />
N<br />
M<br />
N<br />
N<br />
H<br />
H<br />
(38) meso–syn (39) meso–anti (40) racemic<br />
NH HN<br />
NH<br />
HN<br />
NH<br />
NH HN<br />
NH<br />
HN<br />
NH<br />
NH HN<br />
NH<br />
(41) (42) (43)<br />
HN<br />
The hexaaza [18]aneN6 forms complexes with transition<br />
metal ions and with certain alkali and alkaline earth and<br />
lanthanide ions. 82 For the higher aza macrocycles with<br />
seven or more donor atoms, dinuclear complexes become<br />
possible. A systematic investigation of both the structural<br />
and thermodynamic aspects of copper complexes formed with<br />
the larger polyaza macrocycles from heptaaza to dodecaaza<br />
has been published. 18 All of the macrocycles were found to<br />
form hydroxo species as well as polynuclear complexes. A<br />
number of structures have been determined for the higher<br />
polyaza macrocycles, both in complexed and noncomplexed<br />
forms, and structures range from highly boat shaped to nearly<br />
planar. 18,50,83,84<br />
A review of macrocycles possessing subheterocyclic rings<br />
has appeared, which includes pyridine, furan, and thiophene. 85<br />
In a study of formation constants for transition metal ions<br />
with pyridine- and furan-containing macrocycles, (44) and<br />
(45), it was found that the pyridine macrocycles follow the<br />
Irving–Williams series and bind even more effectively than<br />
their saturated analogs (i.e. [18]aneN6 and [18]aneN4O2). The<br />
furan analogs showed little tendency to bind, which has been<br />
attributed to the increased rigidity of the furan ring. 86<br />
NH<br />
NH<br />
N<br />
N<br />
HN<br />
4.2.4 Anion Coordination<br />
NH<br />
HN NH<br />
O<br />
O<br />
(44) (45)<br />
HN<br />
HN<br />
While the initial interest in polyaza macrocycles involved<br />
metal ion coordination, the finding in 1968 by Simmons 87<br />
that diaza bicyclic catapinands can incorporate halide ions<br />
into their cavity opened the door on a vast new area of<br />
chemistry, that of anion complexation. The thermodynamics<br />
of anion binding can be divided into several different<br />
areas: that of simple inorganic anions; more complex<br />
carboxylate and polycarboxylates; corresponding phosphates,<br />
polyphosphates, and nucleotides; and culminating in anionic<br />
metal complexes. 17,88–90 Binding is accomplished via both<br />
electrostatic and hydrogen-bonding interactions between the<br />
protonated macrocyclic amines and the anionic substrates.<br />
The general trend appears to be that the increased flexibility<br />
of larger polyammonium macrocycles tends to facilitate<br />
complexation of more complex anionic substrates.<br />
The results of studies for complexes formed between<br />
polyammonium macrocycles and transition metal complex<br />
anions indicate that cation–anion electrostatic attraction is a<br />
crucial factor in complexation reactions and serves to regulate<br />
the stoichiometry of the complexes formed. Hydrogenbonding,<br />
size, and conformational factors also play major<br />
roles. 89 Anions can be incorporated in or out of the ring.<br />
Two illustrative examples are metal ion complexes with the<br />
octaprotonated macrocycle H8[30]aneN10 (46). In the complex<br />
with Co(CN)6 3− , the anion lies outside the macrocycle. The<br />
PdCl4 2− complex is a true ‘inclusion’ situation, however, in<br />
which the PdCl4 2− is situated along the minor axis of the<br />
macrocyclic cavity, and the Cl atoms are out of the frame,<br />
forming strong hydrogen bonds with the polyammonium<br />
sites. 90<br />
4.2.5 Cyclidenes<br />
Crystallographic results for the cyclidenes (6) show that<br />
a wide variety of structural ranges can result from designed<br />
modifications of the lacunar cavity (or void). 91 The affinity<br />
of the cobalt(II) complexes of the cyclidenes for molecular<br />
oxygen was found to be very dependent on the identity of the<br />
overhead bridge and was found to increase with increasing<br />
bridge length. Further design has also allowed for expanding
NH<br />
NH<br />
NH<br />
NH<br />
NH<br />
NH<br />
(46)<br />
HN<br />
HN<br />
HN<br />
HN<br />
the capability of these macrocycles beyond simple oxygen<br />
binding to oxygenase activity observed for the cytochrome<br />
P-450s. This has been achieved by adding piperazine ‘risers’<br />
to increase the cavity size (9 ˚A high) as well as increasing the<br />
hydrophobicity of the molecules, and by adding anthracene<br />
and durene ‘roofs’. The crystal structure of the anthracenebridged<br />
derivative shows that the macrocycle is indeed capable<br />
of hosting an acetonitrile molecule.<br />
4.2.6 Sepulchrates<br />
Sepulchrates (7) are the most noted of the caged<br />
macrocyclic ligands and are the nitrogen analogs of the<br />
cryptands. The Co–N distances are 1.99 ˚AforCo III and 2.16 ˚A<br />
for Co II from crystallographic data, and do not vary greatly<br />
from other cobalt amines. 20<br />
4.2.7 Expanded Porphyrins<br />
A review of expanded porphyrin ligands can be found. 92<br />
The texaphyrins (8) can be considered as 22-π-electron<br />
benzannulene systems with an 18-π-electron <strong>del</strong>ocalization<br />
path, based on crystal structure data as well as NMR.<br />
The cadmium complex of the macrocycle is found to be<br />
planar with pentadentate coordination of the macrocycle to<br />
cadmium, which becomes seven-coordinate as a result of<br />
axial coordination to two pyridine molecules. The cavity is<br />
nearly circular with a center-to-nitrogen distance of 2.39 ˚A.<br />
Because of the larger size of this macrocycle, metal ion<br />
coordination is generally seen with the larger transition metals<br />
and lanthanides.<br />
A more flexible expanded porphyrin is the ‘accordion’<br />
porphyrin (9). 22 The structural aspects of this macrocycle<br />
illustrate the importance of flexibility in achieving unanticipated<br />
structures. The free-base macrocycle is elliptical with<br />
the inclusion of two water molecules (47), while the dicopper(II)<br />
complex is highly distorted by means of exo and endo<br />
orientations of the imine groups (48).<br />
N 3<br />
N<br />
N N<br />
Cu<br />
MACROCYCLIC LIGANDS 13<br />
Ph<br />
NHNH<br />
O<br />
N<br />
H HN<br />
N H H N<br />
O<br />
HN HN<br />
N<br />
Ph<br />
(47)<br />
(48)<br />
N<br />
N<br />
Cu<br />
N<br />
N3<br />
4.3 Polythia and Polyphospha Macrocycles<br />
4.3.1 Polythia Macrocycles<br />
The coordination chemistry of thioether macrocycles has<br />
expanded greatly only since the mid-1980s, as seen by a number<br />
of reviews. 55,93–95 The macrocyclic effect is also noted for<br />
thioethers, but to a lesser extent than some of the other macrocyclic<br />
ligands. This is due primarily to the reorganizational<br />
energy requirements, since a number of the free-ligand thia<br />
macrocycles have a tendency to adopt ‘exodentate’ conformations<br />
in the uncomplexed form, where the sulfurs are pointed<br />
out of the macrocycle (49). <strong>Macrocyclic</strong> thioethers must then<br />
undergo a reorganization of their exo lone pairs in order to<br />
incorporate metal ions within the cavity. It was found in a study<br />
of the complexation of a number of open-chain thia ligands and<br />
thia macrocycles that the enthalpy changes were essentially<br />
identical for both macrocyclic and nonmacrocyclic ligands.<br />
Hence, the favorable macrocyclic effect is more attributable to<br />
the entropy changes in the sulfur macrocycles. 96 The smaller<br />
trithia analog of the extensively studied nitrogen donor triazacyclononane<br />
does not require such organization and, as such,<br />
has been extensively studied itself. 55 Because of the preference<br />
for exodentate sulfurs, metal ion coordination in many<br />
cases is external to the cavity (50). 97 A comprehensive review<br />
of the structural aspects of thia macrocycles can be found. 55<br />
Considerable effort has been made with regard to<br />
conformation analysis of crown thioethers. It has been found<br />
that ligand strain is most evident in torsion angles, whereby<br />
an examination of the deviations from the optimum values of<br />
N
14 MACROCYCLIC LIGANDS<br />
S<br />
S<br />
S<br />
S Cl<br />
Cl<br />
Hg<br />
S<br />
S<br />
(49) (50)<br />
S<br />
S<br />
Hg Cl<br />
Cl<br />
60 ◦ for gauche or 180 ◦ for anti configurations can lead to an<br />
assessment of the overall strain in the molecules. 93<br />
Examination of the influence of ring size has been<br />
reported for the 12- to 16-membered tetrathia systems with<br />
copper(II). 96,98 The results indicate a marked interrelationship<br />
between ring size and stability. The stability peaks at 14membered<br />
rings, and the rings are large enough to incorporate<br />
the copper only for the 14- to 16-membered systems.<br />
Results from the correlation of stability constants in<br />
conjunction with redox data have led to insights regarding the<br />
coordination chemistry of thia macrocycles. For example, the<br />
electrochemical behavior of a number of copper(II)/(I) redox<br />
couples has been investigated, 99 and redox potentials as well<br />
as protonation and stability constants of Cu I species were<br />
determined for a number of tetradentate and pentadentate thiaderived<br />
macrocycles with thia- and mixed thia–aza rings with<br />
the basic backbones (51)and(52). Results of the examination<br />
of the stability constants in conjunction with the Cu II/I redox<br />
potentials indicate that the stability constants for the Cu I<br />
oxidation state are relatively constant regardless of the mixing<br />
in of nitrogen donor atoms. Hence, the dramatic increase in<br />
the Cu II/I redox potential which is observed in the presence of<br />
the sulfur macrocycles can be attributed to a destabilization of<br />
the Cu II state rather than stabilization of the Cu I state, contrary<br />
to popular belief from the hard–soft acid–base system.<br />
S S<br />
S<br />
S<br />
S<br />
S S<br />
S<br />
(51) (52)<br />
In order to force binding of trithia structural units into<br />
an endodentate conformation, one strategy has been to add<br />
rigid xylyl groups into the ring to limit the flexibility (53). 100<br />
While the conformation of the free ligands is exodentate,<br />
a number of transition metal complexes of this ligand have<br />
been found to exhibit endodentate coordination, including Mo,<br />
Cu, Ag, Pd, and Rh. Results for the bis-macrocyclic silver<br />
complex with a variety of noncoordinating anions, indicate<br />
that the conformational interconversions of the ligand are low<br />
in energy.<br />
S<br />
S<br />
S<br />
(53)<br />
S<br />
S<br />
S<br />
S<br />
(54)<br />
Thiophene units have also been incorporated into the thia<br />
crowns (54). 101<br />
4.3.2 Polyphospha Macrocycles<br />
Phosphorus macrocycles can exist in a variety of<br />
conformations, a number of which are stable. The barrier<br />
for inversion of phosphate is 146.4 kJ mol −1 . 102 Hence there<br />
are five conformations possible for the tetraphosphorus<br />
macrocycle (12). Two are preferred: the one in which the<br />
macrocyclic benzo groups are trans (55) and that in which<br />
they are cis (56). 60,103<br />
P<br />
P<br />
P<br />
P<br />
(55) (56)<br />
4.4 Mixed Donor Macrocycles<br />
4.4.1 Simple Mixed Donors<br />
Much of the work in this area has been reported by Lindoy<br />
and co-workers, who have performed extensive studies on the<br />
role of hole size in complex stability and rates of complex<br />
formation. 13,27,104 Bradshaw, Krakowiak, and Izatt have<br />
published an extensive text on the synthesis of aza crowns. 105<br />
A review of tri- and pentadentate macrocyclic ligands also<br />
includes mixed donor results as well as the influence of<br />
pendant arms. 16 Due to the numerous ramifications of this<br />
area, a few key findings will be cited for the simplest<br />
systems.<br />
A major focus in the study of mixed metal ion systems<br />
has been to examine metal ion discrimination. In particular,<br />
two specific mechanisms can be attributed to metal<br />
ion discrimination: macrocyclic hole size and what Lindoy<br />
has termed as a ‘dislocation’ mechanism. The key to this<br />
S<br />
S<br />
P<br />
P<br />
P<br />
P
mechanism is the assumption that coordination geometry<br />
preferences can be suddenly changed at some point along<br />
a series of ligands where gradual changes in the ligand<br />
framework are made. Because these changes can occur at<br />
different points for different metal ions, discrimination can<br />
be achieved. A particularly appealing aspect of the mixed<br />
donor aza–oxa systems is the lower ligand field which they<br />
provide, which then tends to minimize spin state changes.<br />
These systems are treated in a comprehensive review of<br />
O3N2, O2N3, and other pentadentate macrocycles with N, O,<br />
S heteroatoms. 104<br />
Examples of the use of synthetic mixed donor macrocycles<br />
in heavy metal ion separations are found in the discrimination<br />
of silver from lead. A number of studies indicate that<br />
the inclusion of sulfur in macrocyclic sequestering agents<br />
shifts the discrimination to silver. 104 An example of this<br />
is seen with (57) and (58). For the aza–oxa macrocycle<br />
(57) the log K is 5.9 for both silver and lead ions,<br />
while the thia-incorporated ligand (58) complexes silver<br />
more efficiently (log K = 9.9) compared to lead (log<br />
K = 5.7). 106,107<br />
NH<br />
O O<br />
HN<br />
NH<br />
S S<br />
O<br />
O<br />
(57) (58)<br />
HN<br />
The larger mixed aza–oxa, aza–thia, and aza–and<br />
oxa–phospha macrocycles are noted for their ability to<br />
complex more than one metal ion and to alter the magnetic<br />
properties of bimetallic complexes. 108–110 An example of<br />
tri-metal coordination is the tricopper complex of a 27member<br />
ring system (59). 108 A classic series of dicopper<br />
complexes which illustrates the influence of donor atoms<br />
on magnetism are the dicopper structures (60)–(62). 110 The<br />
magnetic properties were found to be extremely dependent<br />
on the mode of azide coordination, which is thought to be<br />
influenced by the orientation of the orbitals on the metal ions.<br />
In complex (60), the two copper ions are ferromagnetically<br />
coupled with a triplet ground state; in (61), the metal ions<br />
are antiferromagnetically coupled; and in (62), the two copper<br />
ions are not coupled.<br />
4.4.2 Cryptands<br />
Cryptands (15) are noted for their highly selective<br />
complexation of alkaline earth metal ions, and for their<br />
ring size–metal ion match ability. 5 The thermodynamic<br />
properties of these macrocycles have been extensively<br />
investigated, and results indicate that the high stability of the<br />
N<br />
H<br />
N<br />
H<br />
O<br />
Cu<br />
HOH O<br />
HN Cu Cu NH<br />
HN NH<br />
O<br />
(59)<br />
H<br />
N<br />
N3<br />
O<br />
N3<br />
H<br />
N<br />
HN Cu Cu<br />
N3<br />
N<br />
H<br />
O<br />
(61)<br />
N<br />
H<br />
N 3<br />
NH<br />
MACROCYCLIC LIGANDS 15<br />
HN<br />
N 3<br />
O<br />
Cu<br />
O<br />
O<br />
N<br />
N<br />
N<br />
N<br />
N<br />
N<br />
O<br />
(60)<br />
S<br />
N3 N N N<br />
S<br />
O<br />
Cu<br />
O<br />
S<br />
S<br />
N 3<br />
NH<br />
HN Cu Cu NH<br />
N<br />
N N N3<br />
(62)<br />
bicyclic macrocycles compared to their monocyclic analogs is<br />
enthalpic in origin. 88<br />
4.4.3 Compartmental <strong>Ligands</strong><br />
Compartmental ligands (16) provide extensive opportunities<br />
for multiple metal ion complexation. An example of a<br />
mixed donor ligand incorporating different metal ions is the<br />
macrocyclic trinucleating ligand (63), which is capable of<br />
complexing two ‘soft’ donor metal centers in addition to a<br />
‘hard’ alkali or alkaline earth metal. 111<br />
4.5 Oxa Macrocycles<br />
4.5.1 Crown Ethers<br />
In the crown ethers (18) the interactions between the ligand<br />
and metal ion are considered to be more electrostatic in nature,<br />
rather than the covalent binding observed for the transition<br />
metal complexes of the aza, thia, and phospha macrocycles.<br />
The thermodynamic properties of these macrocycles have<br />
been extensively studied, with numerous reviews covering<br />
complexation, selectivity, and structural aspects, some with<br />
extensive tables of thermodynamic data. 69,70,112–119 Considerable<br />
efforts have been made to correlate the interrelationship<br />
between cavity size of the macrocycles and stability of alkali<br />
and alkaline earth metal complexes. From X-ray and CPK<br />
mo<strong>del</strong>s, cavity radii are determined as 0.86–0.92 ˚A for 15crown-5<br />
(64), 1.34–1.43 ˚A for 18-crown-6 (65), and about<br />
1.7 ˚A for 21-crown-7 (66). 69 For complex formation between<br />
the alkali metal ions and 18-crown-6, the maximum stability
16 MACROCYCLIC LIGANDS<br />
O<br />
S<br />
O<br />
N N<br />
Cu<br />
O O<br />
O<br />
N<br />
Ba<br />
Cu<br />
(63)<br />
occurs for the potassium ion, which has a radius of 1.38 ˚A, thus<br />
correlating well with the cavity radius. However, 18-crown-6<br />
forms extremely stable complexes with all of the alkali and<br />
alkaline earth metal ions. Hence, Gokel argues that the data<br />
indicate that the hole size concept is inapplicable, since the<br />
binding constants for sodium, potassium, ammonium, and<br />
calcium ions are the largest for the 18-crown-6 compared to<br />
almost all of the other simple crown ethers. 119 Hancock has<br />
proposed that chelate ring size is the critical factor, and that the<br />
high stabilities observed for the crown ethers with large metal<br />
ions is a result of the presence of five-membered chelate rings.<br />
Thus the high affinity of these macrocycles for the potassium<br />
ion is explained by the fact that potassium is the right size for<br />
the five-membered chelate rings of the crown ethers. 78<br />
O<br />
O<br />
O<br />
(64)<br />
O<br />
O<br />
O<br />
O<br />
O<br />
(65)<br />
O<br />
O<br />
O<br />
N<br />
O<br />
O<br />
S<br />
O<br />
O<br />
O<br />
O<br />
O<br />
(66)<br />
A number of reviews of the structural aspects of crown<br />
ethers can be found. 115–117 These structures vary considerably<br />
in complexity. An example of the flexibility of the crown ethers<br />
can be seen in the variation in the structures as a result of ring<br />
size of three different benzo crowns. When the cavity of the<br />
O<br />
O<br />
O<br />
crown matches the radius of the metal ion, the metal ion can be<br />
readily incorporated in the cavity, such as in the structure of the<br />
rubidium thiocyanate complex with the dibenzo-18-crown-6<br />
(67). In cases where the cavity of the crown is too large to<br />
surround the metal ion snugly, a folded structure can result,<br />
as with the dibenzo-30-crown-10 (68) and the potassium ion.<br />
For very large metal ions incapable of fitting into smaller<br />
macrocyclic cavities, sandwich-type structures can occur, as<br />
in the benzo-15-crown-5 (69) with the potassium ion. 115<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
(67)<br />
O<br />
O<br />
O O O<br />
O O O<br />
O<br />
(68)<br />
O<br />
O O<br />
(69)<br />
Molecular mechanics studies indicate that the lowest energy<br />
conformer of the uncomplexed ligand is not necessarily<br />
that required for complexation, i.e. oxygen donors may be<br />
exodentate as in the thia macrocycles. This means that in order<br />
for complex formation to occur, the ligand must undergo both<br />
reorganization as well as desolvation. A general rule of thumb<br />
with respect to size, however, is that the larger macrocycles<br />
are more flexible and subject to adaptability, while the smaller<br />
macrocycles are more rigid and, in that sense, ‘preorganized’.<br />
Cram has provided an excellent treatise on preorganization. 118<br />
His principle of preorganization is that ‘the more highly<br />
hosts and guests are organized for binding and low solvation<br />
prior to their complexation, the more stable will be their<br />
complexes.’ 118 �G values for a variety of macrocyclic oxygen<br />
donors indicate that the ‘prearranged’ ligands in general bind<br />
O<br />
O<br />
O
their guests more strongly and are, in sequence, the spherands<br />
> cryptaspherands ≈ cryptands > hemispherands > crown<br />
ethers. 116<br />
A useful correlation of enthalpy–entropy considerations for<br />
complexation has been shown by Inoue, Liu, and Hakushi. 113<br />
The treatment reflects enthalpy–entropy relationships for<br />
given types of ligands. The general concept is that as the<br />
enthalpic contributions become strong, a higher level of<br />
organization is obtained, which will result in unfavorable<br />
entropy changes. For a given type of system with similar<br />
entropic versus enthalpic considerations, the T�S and �H<br />
values determined for a series of ligands should thus exhibit<br />
a linear relationship. This is found for the macrocyclic crown<br />
ethers, the cryptands, lariat ethers, and bis-crown ethers, as<br />
well as the acyclic polyethers known as podands. The slopes<br />
are all positive with high correlation coefficients. Gokel has<br />
suggested that these slopes can be used to assess the ligand<br />
flexibility: glymes and podands (0.86) > crown ethers (0.76)<br />
> cryptands (0.51). 119<br />
4.5.2 Lariat Ethers<br />
The lariat ethers (19) and (20) known to date consist<br />
of macrocycles with many different types of podand<br />
groups, and much of their complexation chemistry involves<br />
electrostatic binding of guests. Reviews of both structural and<br />
thermodynamic aspects of the lariat ethers can be found. 120–122<br />
The trends are noted to be relatively similar for both the<br />
carbon-pivot and nitrogen-pivot types of lariat ethers. Binding<br />
strengths and selectivities are dependent on ring size and in<br />
general increase as ligand size increases. Strong selectivities<br />
are noted for the potassium ion, as in the crown ethers.<br />
4.5.3 Spherands and Hemispherands<br />
The spherands (21) were specifically designed using the<br />
concept of ‘preorganization’ wherein the oxygen donors are<br />
arranged in an enforced spherical cavity. Totally prearranged<br />
(spherand) and partially arranged (hemispherand, (22))<br />
complexes are possible. 118 Due to the structural restraints<br />
imposed by the rigidly joined phenyl rings, the spherands are<br />
considered to be highly ‘preorganized’ binding sites. In these<br />
macrocycles the lone pair of electrons will always be pointed<br />
toward the center of the macrocyclic cavity.<br />
4.5.4 Calixarenes<br />
The calixarenes (23) are also highly preorganized<br />
molecules which are capable of forming different<br />
conformational isomers. The conformational flexibility is<br />
determined by the size of the ring, with the preferred conformation<br />
becoming more planar as the ring size increases. 37<br />
5 APPLICATIONS<br />
MACROCYCLIC LIGANDS 17<br />
As macrocyclic chemistry has developed, the variety and<br />
scope of the applications of these molecules have continued<br />
to multiply. This concluding section is an attempt to provide<br />
an overview of only three of the applications of synthetic<br />
macrocycles. A particularly insightful treatment can be<br />
found in the Nobel Lecture of Jean-Marie Lehn, 123 which<br />
describes the concept of supramolecular chemistry from<br />
simple recognition, to cation and anion receptors, multiple<br />
recognition, catalysis, transport, and molecular devices.<br />
5.1 Ion Transport<br />
Ion transport, especially cation transport, was one of the<br />
early focal points in macrocyclic chemistry, revolving primarily<br />
around the crown ethers and cryptands. Later efforts have<br />
been to provide switches to control the rates of cation transport.<br />
Two examples of the types of switches that have been<br />
developed include photo switches using cryptands, 124 and<br />
electrochemical switches using anthraquinone-derived lariat<br />
ethers. 125<br />
Related to transport capabilities is the use of synthetic<br />
macrocycles in analytical chemistry. Because of their selective<br />
complexation of a variety of cations, the crown ethers and<br />
related macrocycles have been wi<strong>del</strong>y used for separations<br />
and analyses. 126<br />
While transport efforts have largely involved metal<br />
cations, more recent developments have led to the use of<br />
macrocycles for transport of more complex molecules such as<br />
nucleosides. 127<br />
5.2 Catalysis<br />
Catalysis can be broken down into a number of areas,<br />
depending on the substrate and the catalytic reaction. One of<br />
the prime areas of the initial effort in catalysis has been small<br />
molecule activation, such as oxygen with a number of transition<br />
metal ion macrocycles 128,129 and carbon dioxide, the latter<br />
particularly with cobalt(I) and nickel(I) macrocycles. 130,131<br />
Once the polyammonium macrocycles were found to be able<br />
to recognize substrates other than metal ions, other catalysis<br />
applications evolved. For example, phosphoryl transfer catalysis<br />
with simple polyammonium macrocycles has become<br />
quite accessible. 132<br />
5.3 Magnetic Resonance Imaging<br />
<strong>Macrocyclic</strong> complexes have gained recognition in<br />
magnetic resonance imaging. 133,134 In order to be effective<br />
imaging agents, complexes must provide a significant<br />
enhancement in the proton relaxation rates of water,<br />
as well as be nontoxic, and thermodynamically stable.<br />
Hence, macrocyclic ligands with pendant carboxylates, such
18 MACROCYCLIC LIGANDS<br />
as (5), have been examined primarily because of their<br />
thermodynamic stability.<br />
6 RELATED ARTICLES<br />
Ammonia & N-donor <strong>Ligands</strong>; Mixed Donor <strong>Ligands</strong><br />
P-donor <strong>Ligands</strong>; S-donor <strong>Ligands</strong>; Water & O-donor <strong>Ligands</strong>.<br />
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