Macrocyclic Ligands

Kristin Bowman-James
University of Kansas, Lawrence, KS, USA

1 2 3 4 5 6 7

Introduction Classication of Ligands Synthesis Thermodynamics and Structural Aspects Applications Related Articles References

1 1 5 9 17 18 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

chlorins) appeared as early as 1936, when the rst synthesis of 1,4,8,11-tetraazacyclotetradecane was reported.1 Nonetheless, the eld only began to blossom in the early 1960s with the pioneering work of Busch2 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 eld. 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 simplied names will be employed. This review will encompass the synthesis, thermodynamics, structure, and applications of macrocyclic ligands.

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.

2 CLASSIFICATION OF LIGANDS 1 INTRODUCTION Macrocyclic ligands are dened 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 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

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 classied, 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 classied as to donor types and, within the donor types, specic classications of macrocycles will be noted where applicable. 2.1 Polyaza Macrocycles (1)(10)918 2.1.1 Simple Polyaza Macrocycles Until recently, the tetraaza macrocycles, such as (1) (cyclam) and related ligands with extensive varieties of modications 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 exible and kinetically labile properties of pendant chains, as in (5).11

HO2C NH H N (4) HN HO2C

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 R NH NH HN R N N NH HN HN R (7)

N (6)

2.1.3 Sepulchrates 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

Me NH HN NH HN N N N N Me (1) (2)

NH HN NH NH HN HN NH HN (3)

NH NH N N NH N N N N HN HN N N

2.1.2 Cyclidenes Cyclidenes (6) are a subset of the polyaza macrocycles and are the lacunar ligands rst synthesized and extensively
(8)

(9)

MACROCYCLIC LIGANDS

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
As

As

As As

Me

As

As

(13)

N N (CH2)2 N N

2.3 Mixed Donor Macrocycles

2.3.1 Simple Mixed Donor Macrocycles The simple mixed donor macrocycles (14) at one time were the major source of study of the inuence 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

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.

O P P O HN HN HN N O (15) O O O O O N

S S

S S

P P

P P

(14)

2.3.2 Cryptands
(11) (12)

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.

The pure polyphospha macrocycles (12) (as opposed to the mixed donor phospha macrocycles) were rst 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

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.

MACROCYCLIC LIGANDS

Me
O O

O O O O (18)

N N

OH OH

N N

as complexing agents for the alkali and alkaline earth metal ions.30
Me (16)

2.4.2 Lariat Ethers The lariat ethers comprise a subset of the polyether macrocycles, and are identied by their pendant chains.35 They can be categorized as either N-pivot (19) or C-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 N N O

N N

O
O

O N O O O

O O O MeO

O O

O
O O O (20)

(17)

(19)

2.3.4 Catenands Catenands (17) are interlocked macrocyclic ligands, which complex a variety of metal ions.29 2.4 Polyoxa Macrocycles

2.4.3 Spherands and Hemispherands These consist of an arrangement of phenyl groups which provide a preorganized cavity for complexation,36 e.g. (21) and (22).
Me

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 polylactams33 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

Me OMe OMe MeO OMe MeO OMe Me

Me

Me

Me (21)

MACROCYCLIC LIGANDS
Me

3 SYNTHESIS 3.1 Polyaza Macrocycles 3.1.1 Conventional (Nontemplate) Syntheses

O

Me OMe OMe MeO O O (22)

Me

2.4.4 Calixarenes Calixarenes (23) are the macrocyclic result of condensations between phenols and formaldehyde37 and have been referred to as the most easily accessible molecular basket.38

t-Bu

OH t-Bu OH HO OH t-Bu

t-Bu (23)

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. Simplied 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 macrocycles43 and imidazole-containing macrocycles44 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,
Ts N NTs TsN MsO
NTs

H N H2N NH2

OMs H2N NH HN NH2 TsN

NTs TsN

NH NH NH NH HN HN HN

Scheme 1

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) as a by-product bis-macrocycle in low yield (24).46

small Mn+

Me N

N M N H N

Me

Me O

N O

Me

+
Me H2N N H NH2
large Mn+

Me N N NH N M N M N HN N Me

NH HN NH HN (24)

NH HN NH HN
Scheme 3

Me

3.1.2 Template-Mediated Syntheses Metal ion template mediation in macrocyclic synthesis has been a part of the eld since its inception, its importance having been realized early in the development of this area. Two specic 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 modications 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

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 N N

N N

(25) H2 N Ni N H2
3

(26)

N Ni HN

NH N

HN Ni HN

N N

Scheme 2

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

MACROCYCLIC LIGANDS

CHO H2N N N

N
Mn+

N N

N M M N N N

+
H2N CHO

Scheme 4

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 (27)
Ph

S S S S S

SNa NaS Br

Br

Scheme 5

N N

Ph

P Ni PH

P HP

Ph Ph Ph Ph P P Ni P Ph P Ph

+
Br Br

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 difculties. 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
N S S S S N (28) S S

Scheme 6

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

MACROCYCLIC LIGANDS

PhAs

As(Ph)Li As(Ph)Li

+
Cl Cl

PhAs As Ph

AsPh

equivalent of acyl chloride will yield the bicyclic precursor, which can be reduced by B2 H6 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 , -disubstituted o-phenanthroline. Then the initial product is treated with a diiodoalkane to accomplish the ring closure.29

Scheme 7

3.4 Polyoxa Macrocycles 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 Polyethers were originally synthesized by template assistance from an oligo(ethylene glycol), monoglyme, and potassium t -butoxide (Scheme 9).4

O H2N O Cl O O NH2 O O O O Cl O HN

O
LAH

NH O O

O HN O O HN O O O NH

O NH O

O N O

O O O O

O N
B2H6

+
O Cl O O Cl

O O

O N O O O

O N

Scheme 8

MACROCYCLIC LIGANDS

O HO O O OH O O Cl O

O O O

+
Cl O

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 inuences 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 ve- 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 exibility than incorporated aromatic units. Likewise the presence of other functional groups, such as amides or esters, serve to stiffen the macrocyclic framework. Decreasing the exibility 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 exibility 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 briey treated. In addition to the traditional measurement of thermochemical properties, molecular mechanics calculations are now available to supplement and correlate with experimental ndings. An extensive review which links the large data base of

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 conicting 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 xedness. The premise is that straight-chain ligands can undergo dissociative displacements in consecutive steps starting at one end of the ligand and nishing 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

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 afnity for alkali and alkaline earth metal ions compared to the oxa macrocycles.

N N Cr N O

H O O H O (29)

N N Cr O N N N

N Cr N

H N O O H Cr OH Cr N N (30)

N N

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)(H2 O)3 ]2+ ion can be resolved into optical isomers.76 A copper(II) complex of the methyl-substituted tetradentate macrocycle Me4 TAAB, in which bis-coordination occurs, displays a dynamic Jahn Teller distortion based on crystallographic evidence.77 4.2.2 Tetraaza Macrocycles

4.2.1 Triaza Macrocycles One of the simplest and smallest of the polyaza macrocycles according to denition 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 microcalorimetric71 and stability constant determinations at different temperatures72 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 GaIII , InIII , TlI , and TlIII ) 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

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 eld 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 exibility 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 ve congurational isomers, based on the orientation of the amine hydrogens. From molecular mechanics calculations, where the best MN 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 mol1 with a best-t compared to the trans-I form (32) MN distance of 1.81 A, respectively).70,78 In general, the (10.8 kcal mol1 and 2.11 A, larger, more exible, 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 inuencing 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 ve

MACROCYCLIC LIGANDS

11

to six, the complex stability decreases. A detailed discussion of the thermodynamics of changing chelate sizes for tetraaza macrocycles can be found.17,78
H M N N (31) H H H N N (32) N M NH H

structural results revealed weaker ligand eld strengths for the 1,3-diazacyclohexane compared to 1,3-diazacyclopentane.54

N N N N NH N (33) (34) HN N N

N HN N

H H N N

NH HN

NH N (35)

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 NiL2+ , while the blue form is high-spin pseudooctahedral [NiL(H2 O)2 ]2+ . In the blue to yellow conversion the NiN bonds contract, which compensates for the breaking of the axial NiOH2 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 eld correlate well with the analogous ligand eld strengths for nonmacrocyclic analogs, specically as related to the chelate ring size. A general rule of thumb is that increasing the chelate ring size from ve 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 eld, as anticipated, is dependent on the ring size. These ndings have been related to the calculation of the optimum hole size permitting the macrocycle to adopt its most preferable endo conguration. 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 exible 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 NiN bonds are shortened from for diamagnetic nickel to the strain-free value of 1.91 A Ligand eld strength is also found to increase, and 1.86 A. this has been suggested as being due to the compression of the bond lengths80 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),

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.
Cl O NH HN Cl

NH HN NH HN

NH HN

(36)

(37)

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 103 to 104 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 NH 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 congurations of the in-plane NH 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 NiIII 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

N NH HN NH

O HN

NH N

HN

NH O

HN

(44)

(45)

H N H N

N N M N N H N H

N N M N

H N

4.2.4 Anion Coordination

N N M N

(38) mesosyn

(39) mesoanti

H (40) racemic

NH HN NH NH (41) HN

NH HN NH NH (42) HN

NH HN NH NH (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]aneN4 O2 ). The furan analogs showed little tendency to bind, which has been attributed to the increased rigidity of the furan ring.86

While the initial interest in polyaza macrocycles involved metal ion coordination, the nding in 1968 by Simmons87 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.17,8890 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 exibility 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 modications of the lacunar cavity (or void).91 The afnity 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

MACROCYCLIC LIGANDS

13

NH NH NH NH NH NH (46) HN HN HN HN NH

Ph

NH NH O HN NH HN O HN HN Ph

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 high) as well as increasing the to increase the cavity size (9 A 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.

(47)

N N3 N Cu

N N (48)

N Cu N3 N N

4.2.6 Sepulchrates Sepulchrates (7) are the most noted of the caged macrocyclic ligands and are the nitrogen analogs of the for CoIII and 2.16 A cryptands. The CoN distances are 1.99 A II for Co from crystallographic data, and do not vary greatly from other cobalt amines.20

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.55,9395 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

4.2.7 Expanded Porphyrins A review of expanded porphyrin ligands can be found.92 The texaphyrins (8) can be considered as 22- -electron benzannulene systems with an 18- -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 exible expanded porphyrin is the accordion porphyrin (9).22 The structural aspects of this macrocycle illustrate the importance of exibility 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).

14

MACROCYCLIC LIGANDS

S S

S S

Hg

Cl Cl S S S (53) S S (54) S S S

S S (49)

Cl Cl

Hg

S S (50)

60 for gauche or 180 for anti congurations can lead to an assessment of the overall strain in the molecules.93 Examination of the inuence 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 CuI 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 CuII/I redox potentials indicate that the stability constants for the CuI oxidation state are relatively constant regardless of the mixing in of nitrogen donor atoms. Hence, the dramatic increase in the CuII/I redox potential which is observed in the presence of the sulfur macrocycles can be attributed to a destabilization of the CuII state rather than stabilization of the CuI state, contrary to popular belief from the hard soft acid base system.

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 mol1 .102 Hence there are ve 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

P P

P P

(55)

(56)

4.4 Mixed Donor Macrocycles

S S S S S S (51) (52) S S S

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 inuence of pendant arms.16 Due to the numerous ramications of this area, a few key ndings 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 specic mechanisms can be attributed to metal ion discrimination: macrocyclic hole size and what Lindoy has termed as a dislocation mechanism. The key to this

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 exibility (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.

MACROCYCLIC LIGANDS

15

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 eld which they provide, which then tends to minimize spin state changes. These systems are treated in a comprehensive review of O3 N2 , O2 N3 , 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 efciently (log K = 9.9) compared to lead (log K = 5.7).106,107

N H O HN Cu

N H O NH HN N3 O Cu O

H OH Cu Cu HN O (59) NH

O N N N N N N O (60)

O N3 Cu O NH

H N N3 HN Cu N3

H N N3 Cu NH N3 N H HN

S N N N Cu N N N S

S Cu S NH N3

N3 N H O (61)

(62)

O NH O (57)

O HN

S NH O (58)

S HN

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.69,70,112119 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 for 15models, cavity radii are determined as 0.86 0.92 A for 18-crown-6 (65), and about crown-5 (64), 1.34 1.43 A for 21-crown-7 (66).69 For complex formation between 1.7 A the alkali metal ions and 18-crown-6, the maximum stability

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.108110 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 inuence 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 inuenced 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

16

MACROCYCLIC LIGANDS

N Cu O O S O O Cu N Ba

N O O S

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 tting into smaller macrocyclic cavities, sandwich-type structures can occur, as in the benzo-15-crown-5 (69) with the potassium ion.115

O O N

O O O (67)

O O

(63)
O

O O O

thus occurs for the potassium ion, which has a radius of 1.38 A, 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 ve-membered chelate rings. Thus the high afnity of these macrocycles for the potassium ion is explained by the fact that potassium is the right size for the ve-membered chelate rings of the crown ethers.78

O O O (68) O

O O O O O

(69) O O O O O O O O O O O O O O O O O O

(64)

(65)

(66)

A number of reviews of the structural aspects of crown ethers can be found.115117 These structures vary considerably in complexity. An example of the exibility 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

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 exible 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

MACROCYCLIC LIGANDS

17

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 reects 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 coefcients. Gokel has suggested that these slopes can be used to assess the ligand exibility: 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.120122 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.

5 APPLICATIONS 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

4.5.3 Spherands and Hemispherands The spherands (21) were specically 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.

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 macrocycles128,129 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 signicant enhancement in the proton relaxation rates of water, as well as be nontoxic, and thermodynamically stable. Hence, macrocyclic ligands with pendant carboxylates, such

4.5.4 Calixarenes The calixarenes (23) are also highly preorganized molecules which are capable of forming different conformational isomers. The conformational exibility is determined by the size of the ring, with the preferred conformation becoming more planar as the ring size increases.37

18

MACROCYCLIC LIGANDS 22. F. V. Acholla, F. Takusagawa, and K. B. Mertes, J. Am. Chem. Soc., 1985, 107, 6902. 23. I. Murase, K. Hamada, and S. Kida, Inorg. Chim. Acta, 1981, 54, L171.

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.

24. N. B. Tucker and E. E. Reid, J. Am. Chem. Soc., 1933, 55, 775. 25. L. Horner, H. Kunz, and P. Walach, Phosphorus Relat. Group B Elem., 1975, 6, 63. 26. J. Ennen and T. Kauffmann, Angew. Chem., Int. Ed. Engl., 1981, 28, 118. 27. L. Lindoy, in Cation Binding by Macrocycles, eds. Y. Inoue and G. W. Gokel, Dekker, New York, 1990, Chap. 16, p. 599. 28. D. E. Fenton, U. Casellato, P. A. Vigato, and M. Vidali, Inorg. Chim. Acta, 1982, 62, 57. 29. C. O. Dietrich-Buchecker, J.-M. Kern, and J.-P. Sauvage, J. Am. Chem. Soc., 1984, 106, 3043. 30. Y. Inoue and G. W. Gokel eds, Cation Binding by Macrocycles, Dekker, New York, 1990. 31. I. Tabushi, Y. Kobuki, and T. Nishiya, Tetrahedron Lett., 1979, 20, 3515. 32. A. Shanzer, J. Libman, and F. Frolow, J. Am. Chem. Soc., 1981, 103, 7339. 33. E. Schwartz and A. Shanzer, J. Chem. Soc., Chem. Commun., 1981, 634. 34. D. J. Cram, S. Karbach, Y. H. Kim, L. Baczynskyj, and W. Kalleymeyn, J. Am. Chem. Soc., 1985, 107, 2575. 35. G. W. Gokel, D. M. Dishong, and C. J. Diamond, J. Chem. Soc., Chem. Commun., 1980, 1053. 36. D. J. Cram, Angew. Chem., Int. Ed. Engl., 1986, 25, 1039. 37. C. D. Gutsche, in Calixarenes, ed. G. F. Stoddart, Royal Society Chemistry, Cambridge, MA, 1989. 38. C. D. Gutsche, I. Alam, M. Iqbal, T. Mangiaco, K. C. Nam, J. Rogers, and K. A. See, J. Inclusion Phenom., 1989 7, 61. 39. R. Bhula, P. Osvath, and D. C. Weatherburn, Coord. Chem. Rev., 1988, 91, 89. 40. J. E. Richman and T. J. Atkins, J. Am. Chem. Soc., 1974, 96, 2268. 41. F. Chavez and A. D. Sherry, J. Org. Chem., 1989, 54, 2990. 42. R. W. Alder, R. W. Mowlam, D. J. Vachon, and G. R. Weisman, J. Chem. Soc., Chem. Commun., 1992, 507. 43. M. W. Hosseini, J. Comarmond, and J.-M. Lehn, Helv. Chim. Acta, 1989, 72, 1066. 44. Y.-D. Choi and J. P. Street, J. Org. Chem., 1992, 57, 1258. 45. L. Qian, Z. Sun, M. P. Mertes, and K. B. Mertes, J. Org. Chem., 1991, 56, 4904. 46. E. K. Bareeld, D. Chueng, D. vanDerveer, and F. Wagner, J. Chem. Soc., Chem. Commun., 1981, 302. 47. M. C. Thompson and D. H. Busch, J. Am. Chem. Soc., 1964, 86, 3651.

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