smc007

Cooperativity and the Chelate, Macrocyclic andCryptate Effects

Richard W. Taylor1, Rowshan Ara Begum2, Victor W. Day2, andKristin Bowman-James21University of Oklahoma, Norman, OK, USA2University of Kansas, Lawrence, KS, USA

1 Introduction 12 Supramolecular Coordination Chemistry 23 Transition Metal Coordination Chemistry 34 Supramolecular Chemistry 85 Conclusions 24Acknowledgments 25References 25

1 INTRODUCTION

Cooperativity and the chelate, macrocyclic and cryptateeffects are terms that were coined at different times duringthe twentieth century. Cooperativity involves a processwhere multiple (two or more) binding sites interact to binda guest. It is considered to be positive when the stabilityof the resulting complex is greater than the sum of theindividual interactions. However, there are also examplesof negative cooperativity, where the process of interactionof the binding sites gives energetically unfavorable results,usually from undesirable steric or electronic effects. Thischapter is devoted primarily to a discussion of positivecooperativity that involves the chelate, macrocyclic, andcryptate effects, all of which utilize the interaction of twoor more binding sites in tandem to achieve more stable

hostguest complexes. A key historical example of positivecooperativity is found in the metalloprotein hemoglobin.This exceptionally efficient oxygen transport protein bindsup to four O2 molecules sequentially at different sites. Eachadditional O2 binds with higher affinity than the previousone due to changes induced in the tertiary structure of themetalloprotein by the previous binding events.1

The chelate effect refers to enhanced stabilities achievedin complexes where binding of a ligand (potentially referredto as a host) to a guest (traditionally a metal ion) is sta-bilized by the presence of more than one binding site onthe ligand. The macrocyclic and cryptate effects build onthe properties found for the chelate effect as a result ofincreased dimensionality and structure that is provided tothe binding process. The macrocyclic effect reflects the ele-vated stability of macrocyclic complexes by virtue of aclosed ring system that binds a metal ion or other guestat multiple sites. In this case, the ligand is even less readilyreleased or dissociated because of the constraints placed onmovement of any one binding site by virtue of the closedring. The cryptate effect involves the highest form of com-plex, or hostguest, stability as a result of the increaseddimensionality provided by the bicyclic (or higher ordercyclic) cage.

In the beginning of the increased cognizance of thedifferent types of chemical influences that multiple bindingsites can impart, the focus was totally on transition metalcoordination complexes. Indeed, for the majority of theseeffects (with the exception perhaps of the cryptate effect),supramolecular chemistry was not even on the radar screen.Now, however, decades after the term supramolecularwas coined by the now Nobel Laureate Jean-Marie Lehn,2

Supramolecular Chemistry: From Molecules to Nanomaterials, Online 2012 John Wiley & Sons, Ltd.This article is 2012 John Wiley & Sons, Ltd.This article was published in the Supramolecular Chemistry: From Molecules to Nanomaterials in 2012 by John Wiley & Sons, Ltd.DOI: 10.1002/9780470661345.smc007

2 Concepts

= Donor site= Acceptor site

Acyclic (podand)No preorganization Chelate effect Macrocyclic effect

Cryptand effect

Increasing organization

Figure 1 A pictorial representation of effect of increasing host organization with increasingly restricted binding of a guest withinchelate, macrocyclic, and cryptand ligands.

it is evident that the same phenomena can be attributed tosupramolecular chemistry.

Another influence on binding, both in transition metalchemistry and supramolecular chemistry, is the role of pre-organization. Preorganization tends to enhance cooperativ-ity, since it infers that a host is already conformationally setin place for the most efficient binding (Figure 1). In gen-eral, preorganization is mandated for the constrained cyclichosts, both macrocyclic and macrobicyclic, that force a pre-ordained structure, such as in porphyrins. However, it canalso occur at the chelate level, in a conformational rigid-ity (e.g., donor groups appended to a phenyl ring in cispositions) and/or proximal H-bonding effects (e.g., in 2,6-diamidopyridine groups, where the pyridine NH groups aredrawn inward to H bond with the pyridine nitrogen atom).Preorganization is discussed in detail in another chapter (seeComplementarity and Preorganization, Concepts), but isstill an important contributor to the effects described here.

Prior to exploring various aspects of cooperativity and itsinfluence on the chelate, macrocyclic and cryptate effect, itis important to understand the role of coordination chem-istry as it relates to both transition metal and supramolecularchemistry. What follows is an explanation of this relation-ship that includes both bonding similarities and differences.

2 SUPRAMOLECULAR COORDINATIONCHEMISTRY

In the late 1800s, the visionary Alfred Werner predicted theactual structures of transition metal coordination complexesin the absence of X-ray crystallography or other definitivestructural tools.3 He put forth the hypothesis that transitionmetal ions had not just one, but two valencies. The firstwould be the oxidation number of the metal ion, +1, +2,+3, and so on, that would require a sufficient complementof counterions to satisfy the neutrality principle. However,

beyond the necessity of achieving neutrality, Werner pro-posed that transition metal ions possessed a secondaryvalence. This would be a coordination number governedby neutral species (e.g., H2O or NH3 molecules), anions(e.g., Cl, CN, CH3CO2), and even more complex lig-and frameworks that could donate a lone pair (or pairs)of electrons to the metal ion, forming dative or coordinatecovalent bonds. This proclamation revolutionized transitionmetal chemistry and provided the basis for the new and stillexpanding field of coordination chemistry.

In the mid-twentieth century with the birth of supramolec-ular chemistry, scientists began exploring the influence ofweaker (compared with covalent bonds) supramolecularinteractions. A new and vibrant field of chemistry has nowevolved from almost unnoticed beginnings. Supramolecu-lar chemistry includes a plethora of possible hostguestsystems held together by noncovalent forces, and in manyinstances H bonds. These systems represent the primaryfocus of this chapter, although, because of the groundworklaid by the chemistry of transition metal complexes, aspectsof traditional coordination chemistry are also included.

Although binding modes are considerably differentbetween transition metals, cations, anions, and even in therarer case, neutral molecules, there are nonetheless strik-ing similarities if a broader view of binding is considered.Some specific examples are shown in Figure 2. In transi-tion metal complexes, coordinate covalent bonds are formed

R3N: Mn+R2O:

R2O:

Mn+

HNH2R+

R3NH :An

M = Transition metalM = Nontransition metalA = Anion

(a)(b)

(c)

(d)

Figure 2 Comparison of binding modes for transition metalions, cations, and anions.


Cooperativity and chelate, macrocyclic and cryptate effects 3

between the ligand electron pair donors and the metal ion(Figure 2a). These donations lead to interesting stabiliza-tions (known as crystal field stabilization) because of the(usually) unfilled d orbitals on the metal ions.4 For othercationic species, a similar donation of the lone electron pairscan occur, either to a nontransition metal ion (potentiallyelectrostatic but still involving electron pair interactions) orto a multiatomic cation such as ammonium ion (electro-static and H bonding) (Figure 2b and c).5 For anions, theelectron pair donation is reversed and the flow proceedsfrom the anion to the ligand hydrogen atoms, that is, Hbonding (Figure 2d).

This chapter addresses cooperativity and the chelate,macrocyclic and cryptate effects by examining the corol-laries and differences between transition metal and supra-molecular coordination. These four effects have beenresponsible for many of the exciting developments insupramolecular chemistry, from simple sensor and seques-tration agents to more complex molecular self-assembliesand functional molecular machines and devices. The fol-lowing sections describe the evolution and the interre-lations of the four effects, beginning with the transitionmetal basics that laid the groundwork starting in the1940s (Section 3) as shown in Figure 2(a), and progress-ing to the supramolecular aspects (Section 4) as shown inFigure 2(b)(d). The latter section begins first with non-transition metal (ionic) examples, which started to mate-rialize in the 1970s, and progresses to nonmetal (H bond)hosts and guests that are still being formulated. Throughoutthis chapter, the terms host (receptor) and ligand are usedinterchangeably, where the term ligand refers to the speciesmaking up the secondary valence of transition metals intransition metal coordination chemistry.

3 TRANSITION METALCOORDINATION CHEMISTRY

3.1 Chelate effect

In traditional coordination chemistry, chelates (from theGreek word for claw, , chele`) refer to complexeswith a ligand that contains more than one donor atom. Thenumber of donor atoms in a given ligand is referred to as thedenticity (from the Latin dentis for teeth). The chelate effectwas first coined in the 1940s6, 7 led by Schwarzenbach, insome of the formative years of coordination chemistry. Thearea began to flourish in the 1950s, when researchers, suchas Martell and Calvin,8 Bjerrum,9 and Schwarzenbach,10were able to examine complex solution equilibria.11

As noted above, a chelator is a ligand that has morethan one donor atom that is capable of binding to a metal

ion simultaneously. For example, ethylenediamine (en) orbipyridine (bipy) can form a complex with Cu2+ where bothamine nitrogens are coordinated to the metal ion forminga five-membered chelate ring. In a majority of cases, thenumerical value of the complexation constant for a chelateligand with n donor atoms is larger than the comparableoverall stability constant for a complex consisting ofthe same number of unidentate ligands with the samedonor atom. This phenomenon (enhanced stability constant)has been termed the chelate effect.6, 7 For example, theformation constant (K1) for the reaction of Cu2+ with en(K1 = 2.5 1010) may be compared with overall constant(2) for the reaction of two molecules of the monodentateligands NH3 (2 = 6.8 107) or CH3NH2 (2 = 3.2 107) as shown in (13).

Cu2+ + en Cu(en)2+

K1 = [Cu(en)2+]/[Cu2+][en] (1)Cu2+ + 2NH3 Cu(NH3)22+

2 = [Cu(NH3)22+]/[Cu2+][NH3]2 (2)Cu2+ + 2CH3NH2 Cu(CH3NH2)22+

2 = [Cu(CH3NH2)22+]/[Cu2+][CH3NH2]2 (3)

Figure 3 shows some simple chelators and their comparablemonodentate reference ligands. The ligands chosen arethe simple mono- and bidentate amines often used insupramolecular and self-assembled structures, especiallythe pyridine derivatives.

The energetics of the chelate effect become more clearupon examining both the formation constants and ther-modynamic parameters of the two nickel(II) reactions12 (4and 5):

[Ni(H2O)6]2+ + 6NH3 = [Ni(NH3)6]2+ + 6H2O (4) 109,G = 51.8 kJ mol1,H = 100 kJ mol1,S = 163 J mol1K1

[Ni(H2O)6]2+ + 3en = [Ni(en)3]2+ + 6H2O (5) 1018,G = 101.8 kJ mol1,H = 117 kJ mol1,S = 42 J mol1K1

There are many factors to be considered in examiningthe enhanced stability provided by chelating ligands. Theseinclude both thermodynamic and kinetic effects. Thermo-dynamically, an early explanation was that the origin of theeffect was entropic in nature. This can be seen by compar-ing reactions in (4 and 5). The number of species in solutionremains the same before and after the reaction in (4), andthe overall G is favorable at 51.8 kJ mol1. In (5), how-ever, the four reactant species are replaced by seven product


4 Concepts

Monodentate

NH3Ammine N

Pyridinepy

Bidentate

H2N NH2 N NEthylenediamine

en2,2'-Bipyridine

bipy

O O

CH3

Acetate

N N

H3C CH3

O

O

N HO OPicolinate Dimethylglyoximate

DMGTetradentate

CH3NH2Methylamine

NH HN

NH2 H2N

NH HN

NH2 H2N

1,4,7,10-Triethylenetetraminetrien

1,4,8,11-Triethylenetetramine2,3,2-tet

Tridentate

NN

N

2,2',2''-Terpyridineterpy

Figure 3 Monodentate and chelating ligands and abbreviations.

ions/molecules, contributing to more disorder and an evenmore favorable (more positive) entropy situation. (Coun-terions remain the same in both so are not included inthis count.) Thus, the less negative S for (5) comparedto (4), in addition to a slightly more favorable H , resultsin almost doubling the G (G = H TS).

Another consideration is the cooperative influence ofchelating ligands. In the 1970s, Busch termed this effectmultiple juxtapositional fixedness (MJF).13, 14 When agroup of monodentate ligands is attached to a metal ion,dissociation becomes rather simple, since the individualligands are not tied to each other (Figure 4a). However,in bi- and multidentate ligands, such is not the case. For abidentate ligand, upon dissociation of one donor, the freedend is still held in proximity due to the coordination of thesecond donor (Figure 4b). Hence, there is more opportunityfor the ligand to recombine with the metal ion as opposedto dissociating. By increasing the denticity, this effectbecomes even greater, since complete dissociation wouldrequire multiply tethered donors to be released from themetal ion (Figure 4c). Thus, binding sites in multidentateligands are considered to be fixed to their juxtapositionedcounterparts.

The MJF effect, which involves the kinetic aspect ofthe stability of these complexes, is also operative uponthe initial binding of ligands. In both cases, cooperativityis involved, because the binding of the donor atom underconsideration depends on the binding of previous donoratoms in the same ligand. The process of losing ordissociating the entire macrocycle, which is a totally closedring, thus becomes even more difficult, and is the origin of

MNH3NH3

H3NH3N

MH2N

HNNH

NH

MNH3H3N

H3N NH3

MNH2HN

NH

NH

MNH3

H3NH3N NH3

MHN

HNNH

NH

MHNNNH NH

M

HN

NNH NH

MNH2HN

NH H2N

(a)

(b)

(c)

MHNNN N M

HN

NN N

(d)

M NNNH NH

M

HN

NNH NH2

M NNN N

M

HN

NN HN

Figure 4 Schematic diagrams showing the dissociation path-ways and the influence of the MJF effect in the case of(a) monodentate (no effect), and increasing effect in (b) bidentate,(c) tetradentate, and (d) macrocyclic ligands.



the macrocyclic effect to be discussed in the next section(Figure 4d).

It should be noted, however, that a fundamental problemwith quantitatively calculating the chelate effect fromKchelate/mono is that the equilibrium constants do nothave the same molecularity when expressed in molar units(i.e., K1 = M1 and 2 = M2).15 Indeed, the (numerical)chelate effect almost disappears when the concentrations areexpressed as mole fractions, with similar findings observedin gas-phase measurements. This same problem arises inthe supramolecular chelate effect, and will be described ingreater detail in Section 4. However, in the solution phase,the reaction of complexes containing monodentate ligandswith chelating ligands usually results in a favorable bindingconstant, as observed for the displacement of ammines in[Ni(NH3)6]2+ with en (6).11, 12

[Ni(NH3)6]2+ + 3en = [Ni(en)3]2+ + 6NH3log K = 8.76 (6)

Table 1 lists formation constants with selected metal ionsas an illustration of the chelate effect for transition metalions. The structures of the ligands and their abbreviationsare shown in Figure 3. In the table, the chelate effect isdefined as log K = log K1 log n, which is equivalentto log Kexch for the exchange reaction (7)

M(L)n + Ln M(Ln) + nLKexch = [M(Ln)][L]n/[M(L)n][Ln] (7)

where Ln is a chelating ligand with n identical donor atomsand L is the monodentate reference ligand.

Table 1 covers many of the important considerations ofthe chelate effect in transition metal complexes. It is dividedto show examples of two-coordinate, three-coordinate, andfour-coordinate binding constants. First, examination of thedata shows that the chelate effect is not confined to a par-ticular metalligand system, as seen for Ni2+ and Cu2+,and is operable for both aliphatic and aromatic amines.For simple bidentate ligands such as en and bipy, thechelate effect ranges from 2.27 for Ni(en)2+ to 3.94 forNi(bipy)2+, and is larger for bipy than en with the samemetal ion.

As noted earlier, the chelate effect also increases withincreasing number of rings. Transition metal chemists haveapplied a very simplified approach to the chelate effectfor linear polyamines, expressed in (8), that corrects forinductive effects (pKa(CH3NH2)/pKa(NH3)).11

LogK1 (polydentate ligand)

= 1.152 log n (unidentate ligand)+ (n 1) log 55.5 n = denticity (8)

Table 1 Complex formation constants for reactions of metal ions with multidentate ligandsand their unidentate analogs.16

Number Reaction: Two-coordinate Log Kn(n)a (Kcalc)b log Kc (#)d

1 Ni2+ + 2NH3 Ni(NH3)22+ 5.08 (2) 2 Ni2+ + en Ni(en)2+ 7.35 (K1) (7.58) 2.27 (1)3 Ni2+ + 2py Ni(py)22+ 3.10 (2) 4 Ni2+ + bipy Ni(bipy)2+ 7.04 (K1) 3.94 (3)5 Cu2+ + 2NH3 Cu(NH3)22+ 7.83 (2) 6 Cu2+ + 2CH3NH2 Cu(CH3NH2)22+ 7.51 (2) 7 Cu2+ + en Cu(en)2+ 10.40 (K1) (10.76) 2.57 (5); 2.89 (6)8 Cu2+ + 2py Cu(py)22+ 4.45 (2) 9 Cu2+ + bipy Cu(bipy)2+ 8.00 (K1) 3.55 (8)

Reaction: Three-coordinate10 Ni2+ + 3py Ni(py)32+ 3.71 (3) 11 Ni2+ + terpy Ni(terpy)2+ 10.7 (K1) 7.0 (10)

Reaction: Four-coordinate12 Cu2+ + 4NH3 Cu(NH3)42+ 13.0 (4) 13 Cu2+ + 2en Cu(en)22+ 19.6 (K1) 6.6 (10)14 Cu2+ + trien Cu(trien)2+ 20.05 (K1) (20.20) 7.0 (10)15 Cu2+ + 2,3,2-tet Cu(2,3,2-tet)2+ 23.2 (K1) 10.2 (10)aK1 and n defined in (1 and 2).bKcalc refers to the K calculated using (8).clog K = log Kchelate log Kunidentate.d (#) refers to the number of reaction that is being compared.


6 Concepts

The latter term, (n 1) log 55.5, derives from the factthat when coordinated water molecules are replaced bychelating ligands, the increase in the number of moleculesin solution causes an increase in the entropy in theamount S = nR ln 55.5 = 33.4n J mol1 K1, where nrefers to the number of chelate rings. As noted for theen and trien systems in Table 1 for both Cu2+ and Ni2+ions, this approximation works quite well for the linearpolyamines.11, 12

Also note as seen in Table 1, the chelate effect increaseswith an increase in the number of chelate rings for agiven metal ion, but this can be offset by cumulative ringstrain for some metal ion complexes. This is illustrated bycomparison of the formation constants for Cu2+ complexeswith NH3, en, trien, and 2,3,2-tet given for #1215 inTable 1. The log K values, compared to log 4 (NH3),are 6.6, 7.0, and 10.2 for two en ligands, trien, and 2,3,2-tet, respectively. However, the increase in log K is muchgreater for 2,3,2-tet, where a six-membered chelate ringis formed by coordination of the metal ion to the twointerior nitrogen atoms. The observed increase in stabilityhas been ascribed to the lessening of ring strain due tothe expanded six-membered chelate ring in 2,3,2-tet.11, 12 Itshould be noted, however, that the actual strain associatedwith ring size will also depend on the size of the metalion. For transition metal ions, in considering ring sizesfrom four to seven, a four-membered ring is the moststrained (as in acetate); a five-membered ring (as in en) isoptimal for larger transition metal ions; and six- and seven-membered rings allow for increasing flexibility, but theyare more favorable for binding with smaller ions. Theseobservations derive mainly from differences in bond lengthsand bond angles that give rise to greater or lesser strain inthe cyclic systems.11 Additionally, it should be noted thatthe distances from the transition metal ions to the liganddonors are greater than distances between atoms in theligand (usually around 2.0 A compared with 1.41.5 A),which influences the strain introduced by various ring sizes.

Another level of cooperativity can be observed for thechelate effect in terms of bonding of additional chelatingligands, as seen in the examples below. In coordinationchemistry, a simple form of cooperativity can be observedin the successive complex formation constants (KMLn) forcertain metalligand complexation reactions (9 and 10).

Mx+ + Ly MLxy

KML1 = [MLxy]/[Mx+][Ly] (9)MLxy + Ly MLx2y2KML2 = [MLx2y2 ]/[MLxy][Ly] (10)

In addition to sequential binding effects of multiplechelates, other mitigating factors can play a role in the

FeN

N

N

N

O H O

O O

Im

Im

Im = NNHH

(a) (b)

Fe

Figure 5 (a) Structure of the Fe(DMG)2(Im)2 complex and(b) electron density map for the Fe(DMG)2 pseudomacrocyclicring around the iron atom with contours at increments of 0.5 e/Astarting at 0.2 e/A.

binding of ligands to transition metals. For example, themagnitude of the equilibrium constants generally decreasesas successive ligands coordinate to the metal center due toa combination of statistical, electrostatic, and steric factors;that is, KML1 > KML2.17 For example, when M = Ca2+and L = picolinate anion, a bidentate ligand, K1 = 380 forbinding of the first ligand, and K2 = 24.3 for the secondligand.18 On the other hand, the Cu2+ and Zn2+ complexeswith dimethylglyoxime (DMG, also a bidentate ligand),show cooperative behavior in metal complex formation. Inthis case, the ligand readily deprotonates and forms twoH bonds, which results in the formation of a pseudomacrocyclic ligand. K2 K1 by factors of 32 and 16for the Cu2+ and Zn2+ complexes, respectively.19 Twointramolecular hydrogen bonds between the oxygen atomsof the coordinated ligands are responsible for this effectand have been verified by X-ray crystallography.20, 21The electron density diagram for the di-imidazole iron(II)complex with dimethylglyoximate,22 synthesized as anearly model of the heme iron proteins, nicely illustratesthe pseudomacrocyclic effect (Figure 5).

3.2 Macrocyclic effect

Macrocyclic chemistry had its beginnings in the 1960s.In 1962, Curtis published the first tetraaza macrocycle.23However, the first planned synthesis of a macrocyclic ligand(and complex) came two years later, when Busch reportedthe use of a kinetic template effect and nickel(II) ionto achieve a mixed aza-, thia-donor macrocyclic ligand24(Figure 6). Early macrocycles by Busch and others weregenerally based on nitrogen donor groups and were oftenused as models for the naturally occurring macrocycles suchas the porphyrins.

As the field of macrocyclic chemistry grew, so did therealization that macrocyclic complexes, particularly transi-tion metal complexes, exhibited enhanced stabilities overnoncyclic systems, even those with multiple chelate rings.



NiSN

N S

R Br

Br

R = CH3, C2H5, C5H11

+CH2Cl2

NiSN

N S

R

Figure 6 Final step of the reaction sequence resulting in theformation of the first planned macrocyclic ligand by a kinetictemplate effect.24

This meant that transition metal complexes that were kinet-ically labile and therefore not very easy to study on normaltime scales could be made increasingly inert so as to enableroom temperature study of the chemistry. This finding ledMargerum and Cabbiness to coin the term macrocycliceffect, for the increased stability of macrocyclic com-plexes over their acyclic counterparts.25 The origins of themacrocyclic effect have been a subject of discussion for anumber of years, and aspects of the following four fac-tors undoubtedly play a role.26 Macrocyclic ligands areoften preorganized in a fashion that readily allows for com-plexation. Solvation of the donor atoms is possibly less inthe more limited macrocyclic cavity. The basicity of themacrocyclic ligands is influenced by the inductive effectsof the bridges between the donor atoms, which increasesthe donor capabilities in macrocyclic ligands. Last but notleast, the electron repulsion from the constrained donor loneelectron pairs in macrocycles is eased upon metal ion coor-dination. The macrocyclic and cryptand ligands discussedin this chapter are depicted in Figure 7 along with theircommon names.

In terms of thermodynamics, the role of entropy versusenthalpy has been hotly debated. Log K and thermody-namic values are provided in Table 2. As can be seen fromthe thermodynamic parameters provided in the table, itbecomes evident that the macrocyclic effect is primarilyenthalpic in origin. This is dependent, however, on com-paring systems without steric strain, which naturally addsother mitigating factors to the thermodynamics.

3.3 Cryptate effect

Probably the most famous cryptands are those first reportedby Lehn in 1969.27, 28 These will be described in the sectionon supramolecular chemistry (Section 4). However, transi-tion metal cryptands were reported several years later, theclathrates and sepulchrates of Sargeson and coworkers29, 30(Figure 7). The sepulcrates derive from a hexamine cage-like structure that encloses around a metal ion. They areactually a class of clathrochelates, the term clathro beingderived from the Latin word meaning lattice. However,Sargeson named the ligand sepulchrates, more or less inkeeping with the tone of the crypt in cryptand. This groupof complexes has been studied at length because of the easewith which the captured metal ions undergo rapid redoxchanges in addition to a high complex stability.30 Manyof these complexes are also excellent oxidizing agents inthe higher oxidation states. A number of other cryptand-like macrocycles and their transition metal complexes havebeen synthesized, including the lacunar (dry cave) ligandsof Busch used to bind small molecules such as oxygen31(Figure 4). There are a number of variations on this theme,with polycyclic macrocycles of many shapes and varieties.However, since the focus of this review is on supramolec-ular chemistry, the reader is directed to a review of someof these interesting transition metal complexes.32

NH

NH

HN

HN

NH

NH

HN

HN

N

N

N

NNH

NH

R N

R

R N

R

R

CyclamSepulchrate

Lacunar ligand

Figure 7 Macrocyclic and cryptand ligands.

Table 2 Complex formation constants and thermodynamic parameters for the macrocyclic effect forCu(II), Ni(II), and Zn(II) with cyclic and acyclic tetraamines.a

Complex log K (log K) G (G) H (H) TS (TS)

Cu(2,3,2-tet)2+ 23.2 132.1 115.9 16.2 Cu(cyclam)2+ 26.5 3.3 151.8 19.7 135.6 19.7 16.2 0Ni(2,3,2-tet)2+ 15.5 90.4 77.9 12.5 Ni(cyclam)2+ 19.4 3.9 (3) 110.9 20.5 100.9 23.0 10.0 2.5Zn(2,3,2-tet)2+ 12.6 72.3 49.8 22.5 Zn(cyclam)2+ 15.5 2.9 (5) 87.1 14.8 61.9 12.1 26.2 3.7aH2O at 25 C11; values of the G,H , and TS in kJ mol1; macrocyclic effect = (log K) = log Kcyclam log K2,3,2-tet;(X) = Xcyclam X2,3,2-tet.


8 Concepts

4 SUPRAMOLECULAR CHEMISTRY

Various aspects of cooperativity and the chelate, macro-cyclic and cryptate effect are described in this section forsupramolecular complexes. As noted in Figure 2, there aretwo general types of interactions, electrostatic and H bond-ing, included in this sectionhowever, in all cases theseare noncovalent in nature. Three types of guests will bedescribed: metal ions of the nontransition metal variety (pri-marily electrostatic interactions, Figure 2b), and nonmetal-lic cationic and anionic guests (potentially electrostatic andH-bonding interactions, Figure 2c and d). Both nonmetal-lic cationic and anionic guests utilize their H-bond donoras well as acceptor sites. Each of the sections below, onchelate, macrocyclic, and cryptate effects, will include sev-eral examples of two or more different types of guests.

4.1 Background

In supramolecular chemistry, stable hostguest complexesare built on multiple, simultaneous noncovalent interac-tions.33 This is because a single supramolecular interaction,being beyond the covalent or dative bond, is inherentlyweaker than the coordinative covalent or dative bond thatis found in transition metal chemistry. Hence, stability isenhanced by the additive effect of multiple hostguestinteractions. However, as Schneider points out, referringto the additivity of noncovalent bonding there is alsoa chelation influence when the interactions emanate froma single host (or ligand), as seen in transition metals. Inessence, polytopic hosts can bind to either monotopic orpolytopic guests, the latter situation of particular importancein hostguest chemistry, where an organic or inorganicguest may have more than one binding site. These principlesare abundant in biology, where hostguest chemistry is themodus operandi for enzyme and protein interactions withtheir substrates, among other important processes includingantibodyantibody interactions. Complementarity, as seenin the chelate effect for transition metal complexes, alsoplays an important role. The fit of the guest to the hostshould be as favorable as possible; otherwise, the full bene-fit of the chelate enhancement effect in binding by multipleinteractions is lost.

Thus, for example, in a simple system where the poly-topic host and guest match each other (Figure 8), the totalfree energy of the interaction, Gtot, is obtained by thesum of the free energies of the individual interactions whereH1G1 refers to the binding site H1 of the host and G1 of theguest, and so on (11). However, the overall binding con-stant Ktot is not the product of the individual binding con-stants, because Ktot is in units of M1, while if each individ-ual constant is multiplied, the Ktot would have dimensions

H1 H2 H3 H4 H5

Host

G1 G2 G3 G4 G5

Guest

Figure 8 Schematic representation of multiple hostguest-binding site interactions.

Mn where n would be the number of pairwise contacts,in this case five. In actuality, the same problem occurs forGtot as well, since if treated separately, each of the Gvalues would involve a significant entropy term, where onlyone entropy term would be involved in the Gtot. In orderto circumvent this problem, the same solution as applied tothe transition metal quandary can be applied to supramolec-ular chemistry. Namely, when expressed as molar fractionsinstead of molarities, the equilibrium constants becomedimensionless. This involves multiplying the molar con-centrations of an 1 M aqueous solution of the solute bya factor of 1/55.5 to obtain molar fractions. When substi-tuted in the multiple equilibrium equations and solving, theresulting dimensionless Ktot is obtained (12).

G = GH1G1 + GH2G2 + GH3G3+ GH4G4 + GH5G5 (11)

Ktot = (55.5)1KH1G1KH2G2KH3G3KH4G4KH5G5 (12)

Note first that (11) assumes complete additivity of theeffects. Nonetheless, the snowballing effect of multipleinteractions can be easily seen. It should be noted, however,that there are a number of factors that weigh in whendetermining the additivity of multiple binding events,especially for entropic considerations. These include, forexample, ion pair versus neutral interactions; solvation anddesolvation effects; and the phase under study, gas orsolution among others. Nonetheless, it does appear that theexperimental values of G additivity hold in general whenrotational entropy is not compromised on complexation,solvation and desolvation effects are comparable for eachbinding site, and partnering host and guest sites are able tobind without inducing significant strain.33

Over and above the chelate effect in supramolecularchemistry, macrocyclic and cryptand hosts take advantageof a combination of effects that serve to leverage theirbinding capability (Figure 1). For example, because of pre-organization effects of the closed cyclic systems, imme-diately more contact with the guestespecially spheri-cal guestsoccurs. Solvation effects are also important.In acyclic hosts, the binding sites are readily available



to the solvent, which then requires additional rearrange-ment upon complexation of a subsequent guest. As thedimensionality increases, the binding sites can be moreshielded, allowing for less rearrangement upon guest bind-ing (Figure 9). Even so, acyclic chelates benefit from thechelate effect once they start wrapping or binding a guestin their multiple sites. Macrocyclic and macrobicyclic orpolycyclic hosts not only benefit from the chelate effect, buthave the macrocyclic and, for the higher order hosts, thecryptate effect in their favor. On the other hand, with orga-nization comes more repulsion, for example between thelone electron pairs in the crowns and cryptands in Figure 9.Repulsion is subsequently eased upon binding of a guest.The binding constants (log K) for a series of ionophores areprovided in Table 3. They are listed in order of increasingpreorganization as shown in Figure 10.

The following sections provide examples of cooperativityas it relates to the chelate, macrocyclic, and cryptate effectsfor supramolecular complexes of both cations and anions.

4.2 Cations

Perhaps the most apparent similarities with transitionmetal complexes are the main group metal ions and theirsupramolecular complexes. Here, the progression from thechelate to macrocyclic to cryptate effect can be readily rec-ognized and the thermodynamics are, for the most-part,established. The term ionophore is often used for this classof hosts, originating from its use in biology for lipid-solublemolecules that serve as vehicles for transporting ions acrossmembranes.

4.2.1 Chelate effectNature utilizes the chelate effect often in the naturallyoccurring ionophores. For example, the polyether car-boxylic acid ionophore A23187 (calcimycin) behaves asa monoanionic tridentate ligand (Figure 11a). For Ca2+the equilibrium constants KML1 and KML2 are 2.5 106

H3COO O O O OCH3

Acycle = podand Relaxed conformation results inhigh solvation of lone pairs andminimal electronelectron repulsion.

O OO

O

O O

Macrocycle (crown ether)

Lessened solvation of lone pairsand increased repulsion oflone pairs pointing inward.

O O

N

O

N

O

O O

O O

O

O

O

O

O O

O

O

O

OCH3 H3C

Macrobicycle (cryptand)

Limited solvation of lone pairsin cavity but lone pair repulsionin the cavity is retained.

O O

N

O

N

O

O O

Figure 9 Preorganization effects in the binding of a spherical ion by the non-preorganized pentaglyme, and the effect of increasingorganization progressing down the series to macrocyclic and cryptand hosts. (Redrawn from Ref. 34. John Wiley & Sons, Ltd., 2009.)

Table 3 Stability constants (log K) in methanol at 25 C for the binding of alkali metal ionswith ionophores that have increasingly complex design and dimension.33

Ionophore Li+ Na+ K+ Rb+ Cs+

Pentaglyme 1.5 2.2 Tripod

10 Concepts

O O

N

O

N

O

O O

O O

O

O

O

O

O O

O

O

O

O

NO O O

O

O

O

OO

OO

OO

Pentaglyme2.2 (K+)

Tripod2.3 (K+)

[18]crown-66.08 (K+)

[2.2.2]10.8 (K+)

Spherand16 (Li+), 14.4 (Na+)

Increasing preorganization

Incr

easi

ng p

reor

gani

zatio

n

OO

O

HA(A)4AH4.4 (Li+)

4

Figure 10 Schematic showing relationship between binding constants of hosts of increasing preorganization and K+ ion. (Redrawnfrom Ref. 34. John Wiley & Sons, Ltd, 2009.)

N

O O O NH

O OH

NH

H3C

H3C

H3CH

CH3

H

(a)

HH3C O

(b)Figure 11 (a) Chemdraw diagram of the ionophore A23187 and (b) X-ray structure of Ca(A23187)2 showing interligand andintraligand H bonds.

and KML2 = 6.3 107, respectively, and KML2/KML1 =25.2.36 Similar cooperative effects have been observedfor complexes of A23187 with Mg2+, Sr2+, and Ba2+.An explanation for the enhanced binding of the sec-ond ligand to M(A23187)+ is the formation of H bondsbetween the pyrrole NH of one ligand to a carboxylateoxygen atom on the other ligand (similar to the situa-tion in the DMG transition metal complex described ear-lier), as shown in Figure 11(b).37 In recent years, therehas been an increasing level of activity in the design ofsupramolecular systems that display cooperative behavioreither in their (self) assembly or in response to stim-uli. In addition to H bonds and other noncovalent inter-actions, the formation of metal ionligand complexes is

often employed in the construction and/or operation of suchsystems.

An example of a metal ion acting as a template bringingtogether two acyclic ethers is observed for the synthesisof the Li+ complex of the spherand (Figure 12).38, 39 Cramand coworkers used the Li-assisted ring closure tactic toform the Li-encapsulated spherand in 28% yield. Note howwell the lithium ion fits into the cyclic cavity. As seen inTable 3 and Figure 12, the fit of the lithium ion in thiscavity is so good that this macrocycle, despite only beingmonocyclic, displays an extremely high binding constantfor lithium ion, about 500 times greater than for the largersodium ion. This demonstrates the benefits of the influenceof preorganization.



BrBrO

OO

OO

OO

OO

1. BuLi2. Fe(acac)33. EDTA44. HCl

acac =O O

Li+ Cl

(a)

(b) (c)

Figure 12 (a) Template effect utilizing Li+ in the synthesis of the spherand as the LiCl salt and (b) side and (c) overhead views ofthe crystal structure for the complex.

0.78 0.97 1.33 1.48 1.67Ionic radius ()

O O

OO

OO

O

OO

O

O O

O

O OO

O O

O

OO

O

[12]crown-41.201.50

[15]crown-51.702.20

[18]crown-62.603.20

[21]crown-73.404.30

Li+ Na+ K+ Rb+ Cs+

Crown namehole size ()

Figure 13 Depiction of alkali metal ions and their relative ionic radii, along with a series of crown ethers ranging from [12]crown-4through [21]crown-7, with their approximate hole size. (Data from Ref. 46.)

4.2.2 Macrocyclic effectIn a seminal 1967 paper by Pedersen, the exceptional sta-bility of macrocyclic crown ether complexes with alkalimetal ions was reported.40 What followed was the birth ofa new area of macrocyclic chemistry, one not involvingtransition metal complexes but focused more on organicchemistry. The field of supramolecular chemistry was justbeginning to blossom. Perhaps the most studied of thesemacrocycles is the [18]crown-6. Nomenclature for the sim-ple crown ethers derives from a simple notation that refersto the number of atoms in the ring enclosed in brackets,

followed by the type of macrocycle, crown, followed bythe number of ether oxygen atoms, in this case 6. Earlystudies showed that in the simple rings, the affinity for thealkali metal ions seemed to be dependent on the ratio ofthe radius of the cation to the size of the macrocyclic cav-ity41, 42 (Figure 13). However, upon more intense scrutinyusing ion selective electrode (ISE) measurements, Gokelpointed out in 198343 that all crown ethers are selective forK+ ion, and in particular that [18]crown-6 is selective forall ions. In part, the ambiguity in binding affinities was aproblem arising from data obtained under a variety of con-ditions.43, 44 Binding constants for crown ethers ranging in


12 Concepts

Table 4 Binding constants (log K) in methanol at 25 C for selected cations with crown andlariat ethers.

Crown Na+ K+ Ca2+ NH4+

[12]crown-443 1.7 1.74 nd 1.3[15]crown-543 3.24 3.43 2.36 3.03[18]crown-643 4.35 6.08 3.90 4.14[21]crown-743 2.54 4.35 2.80 3.27[2.2]N(CH3)245 3.62 5.0 4.20 [2.2]BME47 4.57 5.30 4.48 [2.2]BHE48 4.87 5.08

size from [12]crown-4 to [21]crown-7 with the ions K+,Na+, Ca2+, and NH4+ are shown in Table 4. As noted byGokel, the data indicate that [18]crown-6 has the highestselectivity for all the ions studied, and that K+ appears tobe the best guest, in terms of maximum binding. Size ofthe guest, number of interactions, as well as solvation (thefree energy of solvation K+ < Na+) were all cited as play-ing important roles in the complexation process. Ring sizestill matters, however, a complementarity of fit is desirable,which is what is found for K+ and [18]crown-6.44, 45

A number of interesting variations in metal ioncrownether interactions can be seen by examining the crystalstructure data for metal ion complexes, and is covered in anexcellent review of the structural aspects of the crown ethersby Steed.46 For example, it should be noted that the totallyencapsulated structure is not the only one observed forK+ ion with [18]crown-6, but rather a number of differentstructures exist. This is an aspect of monocycle hostguestcomplexes that sets this group of ligands apart from bicyclicand polycyclic systems. The openness above and below thehost allows for egress of the guest as well as for additionaltypes of interactions, sometimes involving more than oneligand. For example, in the Li+ complex (Figure 14a)a sandwich with two [12]crown-4 molecules is formed;the Li+ in the [18]crown-6 in one of the independentmolecules (Figure 14b) has a THF (tetrahydrofuran) solventmolecule associated with it (not shown); and the Rb+complex (Figure 14c) also has other molecules surrounding

the host and guest within bonding interaction (not shown).The result of this openness is illustrated in the rates forformation of the complexes, and the reverse release ofguests, which for monocycles are both relatively fast, butthe reverse reaction is still significantly slower than forchelating ligands.

Of interest for comparison purposes, the cyclododecadep-sipeptide ionophore valinomycin, formed from amino andhydroxyl acids, is highly selective for K+, yet the hostdoes not encapsulate the ion within a single macrocyclicring. Rather it wraps around in a threefold saddle-like shape(Figure 15), that from the top view (Figure 15a) resemblesthe [18]crown-6 with the sixfold interaction of its oxygenbinding sites.52 However, in this case, three donor sites aresymmetrically placed around the top half of the ion, andthree around the bottom half. This type of wrapping effectepitomizes the concept of cooperativity in its simplest form,the use of multiple binding sites to effect a superlativelystrong interaction between host and guest.

Understanding that the fast onoff kinetics of thecrown ethers could be a drawback, Gokel, noting theefficiency imparted by the flexibility of valinomycin,added appendages containing additional donor atoms tothe crowns in order to further trap guests in the macro-cycle. Because the macrocycle with its arm resembled therope used for lassos, Gokel named the extended macrocy-cles the lariat ethers.53 A series of simple analogs to the

(a) (b) (c)

Figure 14 Side views of the crystal structures of Li+ with (a) [12]crown-4,49 (b) [18]crown-6,50 and (c) Rb+ with [18]crown-6.51



ONH

HN

NH

OOH

N

NH

OHN

O

O

O

O

OO

O

O

O

O

OO

Valinomycin

(a)

(b) (c)

Figure 15 (a) Chemdraw picture showing the structure of valinomycin and (b) overhead and (c) side views of the crystal structure ofthe K+ complex.

N

O O

N

O O

H3C CH3 N

O O

N

O O

RO OR

[2.2]NCH3 R = H [2.2]BHER = CH3 [2.2]BME

N

O O

N

O O

O OCH3

[2.2.2]open

CH3

Figure 16 Chemdraw diagrams of [2.2]NCH3 and lariat ethers.

crown ethers are shown in Figure 16 and the binding con-stants of these macrocycles with selected alkali metal ionsand Ca2+ are compared with the original crown ethers inTable 4. The nomenclature used for these lariat ethers willbe derived from the one used for the cryptands that denotesthe number of ether oxygen atoms in each of the arms.

Here, the two arms are separated by the bridgeheadamine, and the pendant group designation follows. Hence,the N-methylated analog is [2.2]NCH3. The macrocycleswith the pendant hydroxyethyl and methoxyethyl groups are[2.2]BHE (B, bibrachial (two arms); HE, hydroxyethyl) and[2.2]BME (ME, methoxyethyl), respectively. The mono-cyclic analog [2.2]NCH3 is slightly poorer as a host for thealkali metal ions compared to the [18]crown-6, but betterfor Ca2+. However, the other two lariat ethers show slightlyhigher affinities for Na+ and Ca2+, but less for K+. As canbe seen for the crystal structures (Figure 17),54 the orien-tations of the two side chains can be either syn or anti.Nonetheless, the effect that Gokel desired was achievedwith the more flexible lariats, a cryptand-like cavity. Gokellater extended this additional cooperativity effect to utilizethese systems for biological applications such as ion trans-port, in which multiple cooperative interactions serve tomove an ion along a channel membrane.44

Tables 5 and 6 provide the thermodynamic perspective ofthe binding differences between a simple acyclic polyether,pentaglyme, and the macrocyclic corollary, 18-crown-6.In Table 5, it is readily apparent that the macrocyclic


14 Concepts

(a) (b) (c)

Figure 17 Crystal structures of K+ in (a) the syn form of [2.2]BHE, (b) the syn form of [2.2]BME, (c) and the anti form of [2.2]BME.

Table 5 Macrocyclic effect for four polyether and polyphenoxy ligands shown in Figure 10.

Number Reaction log K (log K)a (#)b

1 K+ + pentaglyme K(pentaglyme)+ 2.1c 2 K+ + [18]crown-6 K([18]crown-6)+ 6.1c 4.0 (1)3 Ba2+ + pentaglyme Ba(pentaglyme)2+ 2.3c 4 Ba2+ + 18-crown-6 Ba(18-crown-6)2+ 7.0c 4.7 (3)5 Na+ + HA(A)4AH Na(HA(A)4AH)+ 9.7 (5)7 Li+ + spherand (Li(spherand)+ >16.8d >12.4 (5)a(log K) = log Kcyclic log Kacyclic.bNumber of reaction that is being compared in parenthesis.cIn methanol.55d In CHCl3 saturated with H2O, K values obtained from K = kf/kd.35

Table 6 Comparison of the macrocyclic effect and differences in the thermodynamic parame-ters for complexes of selected alkali and divalent metal ions with pentaglyme and [18]crown-6.a

Metal ion (log K)b (G)c (H)c (TS)c

Na+ 2.9 16.1 15.5 0.63K+ 4.0 23.0 2.5 20.1Rb+ 3.4 19.5 2.89 16.4Cs+ 2.6 15.3 11.0 3.89Ba2+ 4.7 25.4 23.3 2.01Pb2+ 4.8 27.2 18.6 8.37aIn methanol at 25 C, taken from Table A4 in Ref. 33, Ref. 55, or calculated from G.b(log K) = log K[18]cr-6 log Kpenta.c(X) = X[18]cr-6 Xpenta,(G),(H),(TS) in kJ mol1.

effect enhances the binding by more than several ordersof magnitude. An especially convincing case is that of thespherand, which is possibly the epitomy of the concept ofpreorganization, showing incredible binding despite its twodimensionality, that is, monocyclic as opposed to bicyclicor polycyclic.

It is particularly interesting to compare the thermody-namic aspects of supramolecular chemistry with transi-tion metal chemistry (Tables 2 and 6). If similar chemistryholds, the macrocyclic effect should be primarily enthalpicin origin. As can be seen from Table 6, the (H) val-ues show that the effect is primarily enthalpic for Na+,Cs+, Ba2+, and Pb2+, ranging from negative teens for the

mononegatively charged ions to the negative twenties forthe dipositively charged ions. On the other hand, for K+and Rb+ the trend is reversed, and it would appear that thefavorable (G) is primarily entropic in origin. These val-ues can be compared to the values for 2,3,2-tet and cyclamthat illustrate this effect is primarily enthalpic in origin fortransition metal ions (Table 2).

Crown ethers and their derivatives also display a coop-erative, multisite binding of molecular cations as well asmetal ions. Here, H-bonding and electrostatic interactionsplay a role. The number of H bonds will also influence theaffinities, as evidenced in the simple ammonium series, withNH4+ about equal to CH3NH3+ (log K = 4.27 and 4.25,



O

ON

O

OO

O O

(a) (b) (c)

Figure 18 (a) Chemdraw diagram of the pyridine-containingcrown, and (b) overhead and (c) side views of the crystal struc-tures of benzylammonium ion bound to the crown.

respectively) > (CH3)2NH2+ (log K = 1.76), reflecting thecooperative additivity of binding sites.55 As can be seenfrom the crystal structure of a simple benzylamine com-plex with a pyridine-containing crown, the amine groupdips into the crown, and forms H-bond interactions with all

six potential donor groups (Figure 18). For more informa-tion about molecular cation guest complexes, the reader isurged to see reviews by Gokel et al.44 and Schneider.56

Another interesting example of cooperativity and themacrocyclic effect involves the taco complex of Gibsonand coworkers.57 Inspired by the formation of pseudoro-taxanes (threaded macrocycles) using paraquats reportedby Stoddart and coworkers in the late 1980s,58 Gibson andcoworkers capitalized on the more flexible bending capabil-ity of larger crown ethers to drive rotaxane formation in acooperative-like binding sequence (Figure 19). They foundthat when they closed the crown to capture a guest inside, a100-fold increase in the binding constant, K , was achieved.Two of the structures of the crown are shown in Figure 20,one with a H-bonding group linking the two hydroxyl sites,and one with a covalent chain closing off the cavity. As canbe seen in the latter structure, a water molecule also man-ages to fit in the cavity, pushing the paraquat guest to theback of the host.

Figure 19 Schematic representation of the complexation of paraquat by the flexible difunctionalized crown ether.

O O O O O

OOOOOR

R

N NH3C CH3R = CH2OHR/R = O(CH2CH2O)4

(a)

(b) (c)

+ +

Figure 20 (a) Chemdraw diagram of the reaction of the large crown ether with the paraquat guest, and crystal structures of (b) theparaquat guest in the crown complex (R = CH2OH), closed off by H bonding between the hydroxyl groups and a CF3CO2 ion, and(c) a covalently closed cryptand/crown (R/R = O(CH2CH2OCH2CH2O)2 complex.


16 Concepts

Table 7 Stability constants (log K)a for chloride salts of alkali and alkaline-earth metal ions with cryptands in H2O.

Metal ion (ionic radius, A)

Cryptand Cavity Li+ Na+ K+ Rb+ Cs+ Mg2+ Ca2+ Sr2+ Ba2+size (A)c (0.86) (1.12) (1.44) (1.58) (1.84) (0.87) (1.18) (1.32) (1.49)

[2.1.1] 0.8 4.30 2.80


which differ in terms of steric requirements and donor atombasicity.64 As a result, the [2.2.2]open may not exhibit theoptimal structure within the acyclic analogs. The bibrachial[2.2]BHE brings additional complications with pendentarms that can adopt either syn or anti orientations withrespect to the plane of the macrocycle in the metal ioncomplexes. X-ray structures of the Na+ and K+ complexesreveal that 2.2-BHE adopts the syn form for both cationsalthough the related host with methoxy termini has bothsyn and anti conformations54 as shown in Figure 17 forthe K+ ion. The simple monocyclic derivative, [2.2]NCH3with an N2O4 donor atom set, has tertiary nitrogen atomsas do the cryptands and lariat ethers in the table, and is thusmore suited for a comparison than [18]-crown-6. While thebinding constants for the lariat ethers are also provided inTable 4, those are in methanol, and slightly different fromthose determined in the mixed methanol/water solution inTable 8.

For [2.2.2]open the only data available are for Na+ andK+ in 95 : 5 M/W, and the cryptate effects (log Kcryp)are 3.86 and 4.95 for Na+ and K+, respectively, similar tothose found with the [2.2]N(CH3)2, but 318 times lowerthan those of 2.2-BHE. It thus appears that [2.2]BHE is theclosest corollary in terms of binding affinities compared tothe cryptand [2.2.2], although in most cases, a significantcryptate effect is seen in progressing from the macrocycleto the cryptand. In summary, while affinities do depend

to some extent on the number of binding sites, as seenthroughout this chapter, maximizing cooperativity dependson a number of other circumstances, including steric andpreorganization effects.

Large cryptate effects are also observed in water asshown in Table 9, which provides additional thermody-namic information. The cryptate effect (log Kcryp) is againsubstantial, varying from 2.4 to 5.3. The predominant con-tribution to G for the complexes of [2.2.2] is the gener-ally strikingly large, negative enthalpic term.

4.2.4 Kinetic aspects

It is of interest now to consider the kinetics of complexformation (kf) and dissociation (kd) of chelate, macrocyclic,and cryptate complexes and how these are related tothe type of ligand structure. Table 10 lists kf and kdvalues for chelating (#13), macrocyclic (#4 and 5), andcryptand (#68) ligands and the appropriate referencecompounds. For the chelate effect, the reactions of Ni2+with py, bipy, and terpy show very little difference inkf values. On the other hand, the values of kd decreaseby factors of 2 105 and 2 109, for bipy and terpy,respectively. A similar effect is seen in a comparison ofthe reactions of Cu2+ ion with the thioether macrocycle[14]aneS4 (ane denoting a saturated carbon macrocycleand S4 the four sulfur donor atoms) and its acyclic

Table 8 Complex formation constants for reactions of Mn+ with cryptand [2.2.2] and open-chain or monocyclic analogs and the cryptate effect.a

log K (log Kcryp)b

Ligand Na+ K+ Ca2+ Sr2+ Ba2+

[2.2.2]59 7.21 (- - - -) 9.75 (- - - -) 7.60 (- - - -) 11.5 (- - - -) 12.0 (- - - -)[2.2.2]open59 3.35 (3.86) 4.80 (4.95) [2.2]BHE65 4.60 (2.61) 5.28 (4.47) 7.60 (0.0) 8.44 (3.06) 8.94 (3.06)[2.2]N(CH3)247, 59, 65 3.30 (3.91) 4.47 (5.28) 4.65 (2.95) 6.66 (4.84) 6.68 (5.32)aIn 95/5 methanolwater at 25 C.bCryptate effect = log Kcryp = log K2.2.2 log Kanalog, given in parentheses.

Table 9 Complex formation constants and thermodynamic parameters for cryptand [2.2.2] and [2.2] BHE.a

Mn+ [2.2]BHE66 [2.2.2]67

log K H TS log K (log K)b H (H) TS (TS)

Sr2+ 4.0 10 12 8.3 4.3 44.4 34 2.7 9Ba2+ 5.3 18 13 9.7 4.4 59.9 42 4.6 17Pb2+ 9.2 34 18 12.4 3.2 57.8 24 12.6 5Ag2+ 7.2 36 5 9.6 2.4 53.6 18 1.3 4aIn H2O at 25 C, H and TS are in kJ mol1.bCryptate effect = log K = log K2.2.2 log K2.2-BHE,(X) = X2.2.2 X2.2-BHE.


18 Concepts

Table 10 Rate constants for the formation and dissociation of chelate, macrocyclic, andcryptate complexes along with the corresponding complexes of reference ligandsa .48, 6871

Complex Solvent log K kf, M1 s1 kd, s1

Ni(pyr)2+ H2O 2.0 4.0 103 40Ni(bipy)2+ H2O 7.0 1.6 103 2.1 104Ni(terpy)2+ H2O 10.7 1.3 103 2.5 108Cu((CH3)2-2,3,2-S4)2+ H2O 2.0 4.2 106 4.5 104Cu([14]aneS4)2+ H2O 4.3 1.3 105 11.0Na([2.2]BME)+ CH3OH 4.6 9.0 107 2.4 103Na([2.2]BHE)+ CH3OH 4.9 3.0 108 4.1 103Na[2.2.2]+ CH3OH 8.0 2.7 108 2.9a25 C.

(CH3)2-2,3,2-S4

S S

S S

[14]aneS4

S S

S S

Figure 22 Cyclic tetrathiaether [14]aneS4 and its acyclic analog(CH3)2-2,3,2-S4.

counterpart (CH3)2-2,3,2-S4 (Figure 22) where kf decreasesabout 30-fold, but kd decreases by a factor of 4000for the macrocycle compared to its linear analog. Finally,comparison of the kinetics for the Na+ complexes of [2.2.2]with the lariat analogs [2.2]BHE and [2.2]BME show thatkf varies by only a factor of 3 while kd for [2.2.2] is about1000 times smaller than that of the lariat macrocycles. Forthe chelate, macrocyclic and cryptate effects, it is clear thatthe most pronounced change for each class of ligand occursfor the dissociation rates, where decreases of 103 105 occurfor the more ordered ligands, while the formation rateconstants vary only by an order of magnitude or less.

4.3 Anions

Cooperativity is also seen for anion coordination chemistryin terms of the chelate, macrocyclic and cryptate effects.However, the area has been less extensively studied thanfor the transition metals and supramolecular metal ionhostguest chemistry. Some examples, primarily structuralwith a smattering of binding constants, which illustrate theimportance of cooperativity in anion coordination chemistryare provided below.

4.3.1 Chelate effectThe chelate effect is also seen for anion hosts. In thiscase, there exists more than one class of chelate formation.

First, in anion coordination opportunities exist for chela-tion within a single functional group, that is, urea, thiourea,guanidinium, and indolocarbazole (Figure 23ac). Onemight say that the urea/thiourea, guanidinium, and indo-locarbazole-containing ligands have preorganized mini-chelate cooperative binding sites. Another type of preor-ganization is provided by a pyridine (Figure 23d), where Hbonding tends to draw the NH groups into an appropriateconformation for binding.

This mini-chelate effect leads to the finding that even asingle urea-containing host can form a hostguest complex(albeit rather weak). An example is shown for the urea-containing host linked to two nitrobenzenes (providingadditional electron withdrawing enhancement of H bondingfor the urea) (Figure 24), although as noted by the authors,this is probably primarily an electrostatic interaction. Theacetate complex shows a 1 : 1 stoichiometry. The bindingenergy for a variety of anions is really related to the basicityof the anion, which is seen to be acetate > benzoate> H2PO4 > NO2 > HSO4 > NO3. Nonetheless, it ismost probably the inherent chelation effect that evenallows for the isolation of the simple acetate structure.An interesting and seemingly recurring phenomenon is thatthe basicity of fluoride ion in organic solvents is strongenough to result in deprotonatation of one of the urea NHgroups, activating the host for conversion of carbon dioxideto bicarbonate in the presence of water. Thus, a bicarbonatecomplex is also obtained with this simple ligand. Althoughnot shown in the figure, a dimeric structure is actuallyformed with H bonding between two bicarbonate guests.72

Another preorganization ploy was successfully employedby Anslyn and coworkers. The design concept behind thetris-imidazolium cyclophane-derived tripodal ligand was touse the ethyl groups to force the H-binding donors all in onedirection for maximized chelation.73 This would promotethe formation of an up-down-up-down-up-down pattern ofsubstituents. While the coordinating imidazolium groupsall did point in the same direction in the structure withtricarballate (Figure 25), one of the ethyl groups disobeyed



HN C

XNH HN C

NNH

Urea (X = O)Thiourea (X = S) Guanidinium

HN

Indolocarbazole

HN

NO

HN

O

HN

2,6-Diamidopyridine

(a) (c)(b) (d)

+

R R

Figure 23 Examples of mini- and preorganized chelates in anion coordination.

NH

NH

O2N NO2O

(a)

(b) (c)

Figure 24 (a) Chemdraw diagram of the simple urea acycle, and (b) the acetate, and (c) bicarbonate complexes.

NHHN

HN

NHHN

NH

HN

HN

NH

+

+

+O2C CO2O2C

(a) (b)

Figure 25 (a) Chemdraw diagram of the imidazolium host and(b) the tricarballate complex.

common sense and also oriented in an up direction. Thehost binds carballate with extremely high affinity in aqueousconditions, Ka 7 103.

An example of a more systematic examination of theinfluence of additional chelate rings was published by Wu,Yang, and coworkers.74 Four complexes were reported,where R = p-nitrophenyl or naphthalene. The tris-urea lig-and (Figure 26a) was designed based on the correlation withthe generally strong metal-binding tridentate terpyridine lig-and. The high affinity of the tris-urea ligand in DMSO forSO42 was dramatically decreased when a trace amountof water (0.5%) was added to the solvent. As a result, theauthors decided to increase the number of binding sites tobenefit from the cumulative chelate effect of the chelateeffect and hydrophobic effects in order to circumvent thelarge hydration energy of sulfate ion (Figure 26b). How-ever, despite the complementarity observed in the crystal

NH

NH

O

NH HNO

NH HN

O

R R

NH

NH

O

NH HNO

NH HN

O

R

NH

NHOR(a) (b)

(c)

Figure 26 Chemdraw diagrams of (a) the tris-urea and (b) thetetrakis-urea acycles, and (c) the sulfate complex with the tetrakis-urea host.

structure (Figure 26c), 1H NMR studies in DMDO-d6 +0.5% H2O indicated a lessened affinity of the tetrakis-ureas.


20 Concepts

These findings were explained by the authors as due toa better conformational complementarity between the tris-urea and the sulfate.

4.3.2 Macrocyclic effectA number of years ago, one of the first indications thatthe synthetic polyammonium macrocycles would be ableto go beyond simple recognition of anionic substrates waspublished by Lehn, Mertes, and coworkers in 1983.75 Theexcitement surrounding the discovery of this chemistrywas that these simple cyclic systems could mimic thenaturally occurring ATPases by catalyzing the hydrolysis ofATP at physiological pHs in aqueous solution. The utilityof these simple macrocycles can be attributed to severalaspects: (i) they operate in water, (ii) due to their cyclicnature the hosts are polyprotonated under physiological pHconditions, (iii) one of the reaction pathways involves acovalent intermediate as a result of the presence of an aminenucleophile, and (iv) the rates of reaction are enhanced uponthe addition of certain metal ions as seen for the Mg2+-dependence of the ATPases.76

One of the superior cyclic systems in this regard is the[24]N6O2 (N6O2 reflecting the heteroatoms in the ring)shown in Figure 27. The reaction sequence proceeds asdepicted in the figure. This simple macrocyclic systemclearly illustrates the importance of cooperativity in bind-ing, both by the macrocyclic ammonium sites and by theaddition of an ion capable of chelation to the ATP. At pH7, the macrocycle is predominantly tetraprotonated, servingto complement the primarily tetranionic ATP at that pH.The role of the metal ion is thought to be in preorganizing(through chelation) the structure of the guest for suitablebinding with the host and/or by stabilizing the intermediatephosphoramidate formation. In their polyprotonated forms,these macrocycles also hydrolyze nucleotides and polyphos-phates in the absence of metal ions, but often at slower

Table 11 Comparison of binding constants for the cyclic andacyclic tetraamide hosts.

Anions K(M1) (TAM) K(M1) (TAA)

Cl 1930 45Br 150 AcO 3240 160H2PO4 7410 346 (223)aaBinding constant for the NH group not tethered to the methylene chain.

rates, and the covalent phosphoramidate is more fleeting,sometimes not appearing at all.

An example of inducing preorganization is evident in the2,6-diamidopyridine hosts of Jurczak and coworkers. In anelegant study, the researchers compared anion binding ofthe tetraamide macrocycle (TAM) with trimethylene bridges(Figure 28b) with the corresponding tetraamide acycle(TAA) (Figure 28a).77 They also studied macrocycles withdifferent chain lengths between the amide groups, butfound that the trimethylene host was superior to the others.Binding constants were determined in DMSO-d6 by NMRtitration techniques for the macrocycle and acycle, andthe results indicated that the macrocyclic host displayedaffinities approximately 20 times higher than the acyclicanalog (Table 11). Note that in the crystal structure ofthe acyclic unbound host, despite the rather zigzag shape,for each pyridine group the two adjacent amides pointinward, exhibiting H-bonding interactions with the pyridinenitrogen (Figure 28c). In the acyclic complex with Cl,the cavity is open somewhat (Figure 28d), and clearlynot as symmetrical in the binding of its guest as in themacrocyclic case (Figure 28e). Interesting as well is thefact that binding constants for the anions in the acycle varydepending on which NH group is used for the measurement.It is slightly less for the free methyl amides not connectedby the trimethylene chain, as seen for H2PO4.

HN

NH2 O

NH2O NH2

NH2

NNN

NNH2

O OH

OHOPOP

OPO

O

OO

OO

O

_

_

_

_

NH HN

NH2 O

NH2O

HN

NH2NH2

NNN

NNH2

O OH

OHOPOP

O OO

OO

+

+

PO

OO

+ HPO42Mg2+, Ca2+, La3+

pH 7

H2OpH 7

H2OADP HN

NH2 O

NH2O

HN

NH2NH2

+

++

+

+

++

++

+

_

_

_

Figure 27 The reaction sequence between the tetraprotonated [24]N6O2 leading to the hydrolysis of ATP and formation of inorganicphosphate.



N OO

HNNH

N OO

HNNH

N OO

HNNH

N OO

HNNH

(a) (b)

(c) (d) (e)

Figure 28 Chemdraw diagrams of the (a) acyclic ligand host(TAA) and (b) cyclic host (TAM); perspective views of (c) theuncomplexedacycle and chloride complexes of the (d) acycle and(e) macrocycle.

A simple lariat crown ether, reported by Barboiu andcoworkers, consists of a benzo[15]crown-5 base with anappended urea lariat (Figure 29).78 The ligand displaysa dual host binding effect that is allosteric in nature(Figure 29a). Sodium ion brings the two crown ethers inproximity, which also allows the lariats to be positionedfor coordination to a chloride guest. The distance betweenthe two binding sites, that is, the Na Cl distance, is 9.05 A(Figure 29b). The authors observed the effective transportof sodium salts of highly hydrophilic anions with the lariat

host that was contrary to the Hofmeister series, the latter ofwhich is the general trend of transport in order of decreasinghydrophilicity.

4.3.3 Cryptate effectLehn and coworkers provided the first evidence of encap-sulated multiatomic anion binding in the hexaprotonatedaza cryptand known as bis-tren (Figure 30).79 The authorsnoted that the cigar-shaped cavity provided an excellentcomplementarity for the linear azide ion. The bis-tren hostdisplays a high affinity for N3 ion in water (log K = 4.3for hexaprotonated form of the macrocycle) with the ter-minal nitrogen atoms on the N3 each interacting with thethree protonated amine hydrogen atoms. This finding ledLehn to propose that the ligand was suitable for bindingother linear triatomic guests, such as bifluoride, although acrystal structure was never isolated.

A number of years later, the BowmanJames group wasable to isolate an encapsulated bifluoride as well as an azidecomplex in a somewhat more complex octaamide tricyclicligand formed by connecting two macrocycles with ethylenelinkers80, 81 (Figure 31). The two structures are essentiallyisomorphous, indicating the preorganization of the tricyclefor small linear anions. While the host looks somewhatflexible, to date only two conformations of the host have

NH2N

NH2

NH2

N

H2N

H2N

H2N

O

O

O

NN N

+

+

++

+

+

Figure 30 Chemdraw diagram of the azide complex in bis-tren.

+

O

O

OO

O

NH

NH

O Na+2 Cl

(a)

(b)

Figure 29 (a) Schematic drawing showing a generic allosteric, cooperative interaction of the two macrocycles binding first Na+(magenta) followed by Cl (green), and (b) Chemdraw diagram of the allosteric lariat crown ether reaction with NaCl with the crystalstructure of the resulting NaCl complex.


22 Concepts

NNH NHO

O O

O

NNH NH

N

NHNHN O

OO

O

NHNHN

N

(a)

(b) (c)

Figure 31 (a) Chemdraw diagram of the tricyclic host, and perspective views of the (b) azide and (c) bifluoride complexes.

been isolated in the solid state, one of which is with pseudo-S4 symmetry as in the azide and bifluoride structures. A freebase form has also been characterized crystallographically,and is isomorphous with the two anion structures. Thestability of the conformation in both structures can beattributed to an extended H-bond network that works itsway around the inside cavity through the pyridine, amide,and amine moieties.

Lehn and coworkers published an expanded host capa-ble of binding dicarboxylates, such as terephthalate(Figure 32ac).82, 83 The design was such that the hostdisplayed an amazing affinity for terephthalate over otherdicarboxylates (1.5 104 dm3 mol1 in aqueous solutionat pH 6 and 20 C). Binding constants for the other diacidswere in the range of 103 dm3 mol1. This affinity bringshome the point that in addition to the number of bind-ing sites, a complementary fit of host and guest is vitallyimportant.

More recently, the BowmanJames group synthesizedanother multitopic host that showed selectivity for a num-ber of dicarboxylates (Figure 32df).84 This ligand is anexpanded version of the octaamide tricycle that binds biflu-oride and azide, with 12 amides potentially available for Hbonding with guests, that is, a dodecaamide tricycle. Theligand makes use of the extra four amide linkages in theterephthalate complex by binding two water molecules inthe side pockets of the host. Two water corks have theappearance of holding the terephthalate in place.

A famous supramolecular host named the soccer ballligand in view of its similarity in terms of symmetry tothe soccerball (or in European terminology football) usedin sports (Figure 33)8588 illustrates the versatility of some

of these hosts. By virtue of its design, the soccer ballhas tetrahedral sites for H bonding, ideal for guests withtetrahedral binding sites, either from sp3-hybridized lonepairs or from hydrogen atoms. In its tetraprotonated form,the soccer ball ligand encapsulates Cl (Figure 33a). Whenneutral it binds the tetrahedral ammonium ion, NH4+. Thecomplementarity and cooperativity of all eight bindingsites is utilized in the NH4+ complex. The nitrogen lonepairs, at the vertices of a tetrahedron, are perfectly matchedto H bond with the hydrogen atoms of the ammoniumion. This leaves the oxygen atoms situated for electrostaticinteractions with the positive nitrogen center at positionsthat bisect the HNH bonds. In its diprotonated form, thesoccer ball host binds H2O internally. Here again, the hostcan adapt to the guest by its degree of protonation, with Hbonding between the two lone pairs of the ligand and theH2O hydrogen atoms, while the other two NH groups arepoised at the other tetrahedral sites for H bonding with theoxygen atom lone pairs.62

4.4 The chemistry beyond

Decades have now passed since the birth of supramolec-ular chemistry, and the field has evolved and continuesto evolve far beyond its humble beginnings. A hint ofthe limitless possibilities was first expressed in the famous1959 Caltech talk of Richard Feynman,89 Theres plentyof room at the bottom. The lecture provided what becamea roadmap to nanotechnology. And what better source ofchemistry for this roadmap, but the supramolecular fieldthat began just a few short years later? For several decades



NHNHN O

OO

O

NHNHN

N

NH

N

HNN

NNH NHO

O O

O

NNH NH

N

HN

NH

O

OO

O(d)

N

NH

NH

HN

HN

N

HNHN

(a)

(b)

(c)

(e)

(f)

Figure 32 Chemdraw diagrams of the hosts, (a) and (d); and top, (b) and (e), and side, (c) and (f), views of the cyclophane cryptandand the octaaza tricycle with terephthalate, respectively. In (e), the water molecules are not shown for clarity, but to emphasize thesimilar positioning of the terephthalate.

now, researchers, starting with a handful of groups, andexpanding to many, have been engaged in the developmentof artificial-molecular level machineries. Supramolecularcomplexes such as rotaxanes (threaded macrocycles) andcatenanes (interlinked macrocycles), which are mechani-cally interrelated, potentially have applications as molec-ular switches and machines using cooperative noncovalent

bonding interactions. The details of the chemistry and appli-cability of this fantastic arena is beyond the scope of thischapter and is treated elsewhere in this compendium inthe volumes on Self-Assembly and Supramolecular Devices.Nonetheless, the scope of cooperativity, assisted by thechelate and macrocyclic effects, is illustrated by pro-viding three simple examples of its extended impacts


24 Concepts

O

OHN

O

++

+

HN

ONH+

O

NH

ON

O

+HN

ONH+

O

NO

ON

O

N

ON

O

NOOO O O

(a) (b) (c)

Figure 33 Chemdraw views depicting the structures of the(a) chloride, (b) water, and (c) ammonium complexes of theversatile soccer ball ligand.

in intertwined supramolecular molecules and molecularmachines.

Sauvage and coworkers have been engaged in the studyof molecular topology, an important consideration in theroadmap to molecular devices. Molecular knots are intrigu-ing to chemists because of their interlinking nature, andof the many different kinds of knots, the trefoil knotis the simplest. Because of its intricate interwoven pat-tern, this beautiful knot has had a historical presence inart as well as in scientific fields. A trefoil knot is obtainedby locking together the two ends of a regular (or over-hand) knot (Figure 34a). The Sauvage group first reportedthe Cu(I)-templated synthesis of molecular trefoil knots,and the crystal structure of elegant dicopper(I) complex isshown in Figure 34(b).90 These dicopper(I) knots are alsochiral, apparently resolving upon crystallization.

Two back-to-back reports in 1988 by Stoddart92, 93served to catapult the field of molecular devices forward.The two communications described the concept of using-electron-deficient hosts, in this case a cyclobis(paraquat-p-phenylene) cyclophane, to bind -electron-rich guestssuch as a diphenol-derived ether. A year earlier, thegroup had described the reverse, a -electron-rich host and

-electron deficient guest.58 The structure of the hydro-quinone dimethyl ether complex with the paraquat host(Figure 35a) indicates the threading of the cyclic quadru-ply charged host by the guest molecule that illustratedthe potential of the hosts as the precursors to molecularmachines.

The early electron-rich and electron poor hostguestcomplexes of Stoddart and coworkers led to molecularmachines such as the mixed paraquat and crown cate-nane (Figure 35b and c).58, 94 In this very simple cate-nane, a cyclobis(paraquat-p-phenylene) is interlocked withbis-paraphenylene-34-crown-10. The interactive forces aremechanical and include only noncovalent, electrostaticbonding interactions and London dispersive forces. Therings undergo degenerate simultaneous conformationalchanges due to the two identical recognition sites in eachmacrocycle, and resulting in a rotation of each ring withinthe cavity of the other (Figure 35b). The crystal structure(Figure 35c) depicts the solid-state structure, confirmingthe interlocked ring systems. Cooperativity is inherent inthese exquisitely dynamic intertwined systems, which canbe further modified by placing nonidentical recognition sitesin the macrocycles, resulting in further refinement of theswitching capabilities of these molecular devices.

5 CONCLUSIONS

All supramolecular complexes are examples of cooperativ-ity in a sense, and there are so many very elegant ones fromwhich to choose, that only a few have been selected for thischapter. When based on metal ionligand interactions, thedesign of cooperative or self-assembling systems utilizescertain properties of the ligand and metal ion. For the for-mer, these include the number, type, and arrangement of

(a) (b)

Figure 34 (a) Picture of a trefoil knot drawn using POVRAY91 and (b) a molecular trefoil knot containing two copper(I) centers.



N

N

N

N

O O O O O

OOOOO

+

+

+

+

(a)

(b) (c)

Figure 35 (a) Inclusion complexes of [cyclobis(paraquat-p-phenylene)]4+ with hydroquinone dimethyl ether, (b) Chemdraw depictionof the ring rotations in paraquat-derived catenane, and (c) perspective view of the X-ray structure.

donor atoms as well as Lewis base properties. In the caseof metal ions, the coordination number, geometry (squareplanar, tetrahedral, octahedral), and Lewis acid propertiesare important. The formation of complexes (both metal ionand supramolecular) with multidentate (chelating) ligandsplays a crucial role in a number of cooperative processessuch as template synthesis, the behavior of allosteric recep-tor systems, as well as the assembly of two-dimensionalgrids, three-dimensional cages, nanoscale reactors (contain-ers), molecular switches, and molecular machines. Metalionligand interactions may be utilized to convert a lig-and from an acyclic to a macrocyclic or bi(poly)cyclicstructure.95 These multidentate chelating ligands may haveincreasingly enhanced binding properties and/or selectivityfor the desired guest compared to an equivalent number oftheir unidentate counterparts. The phenomena describingthis enhancement emanate from the widespread existenceof the chelate, macrocyclic and cryptate effects that are allleveraged by cooperativity.

The concepts of the chelate, macrocyclic and cryptateeffects have come a long way since their original coinage.Together with a better understanding of the role of coop-erativity in these chemical trends and the addition of

supramolecular chemistry to the field, our understandingof chemical processes has led and will continue to lead tobetter insight to the design of a wide variety of utilizablechemical systems at the molecular level.

ACKNOWLEDGMENTS

K.B.-J. gratefully acknowledges support from the NationalScience Foundation CHE-0809736.

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26 Concepts

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