SMC 007

Cooperativity and the Chelate, Macrocyclic and
Cryptate Effects
Richard W. Taylor1 , Rowshan Ara Begum2 , Victor W. Day2 , and
Kristin Bowman-James2
1
2
University of Oklahoma, Norman, OK, USA

University of Kansas, Lawrence, KS, USA
1 Introduction
2 Supramolecular Coordination Chemistry
3 Transition Metal Coordination Chemistry
4 Supramolecular Chemistry
5 Conclusions
Acknowledgments
References
1
2
3
8
24
25
25
INTRODUCTION
Cooperativity and the chelate, macrocyclic and cryptate

effects are terms that were coined at different times during
the twentieth century. Cooperativity involves a process
where multiple (two or more) binding sites interact to bind
a guest. It is considered to be positive when the stability
of the resulting complex is greater than the sum of the
individual interactions. However, there are also examples
of negative cooperativity, where the process of interaction
of the binding sites gives energetically unfavorable results,
usually from undesirable steric or electronic effects. This
chapter is devoted primarily to a discussion of positive
cooperativity that involves the chelate, macrocyclic, and
cryptate effects, all of which utilize the interaction of two
or more binding sites in tandem to achieve more stable
hostguest complexes. A key historical example of positive

cooperativity is found in the metalloprotein hemoglobin.
This exceptionally efficient oxygen transport protein binds
up to four O2 molecules sequentially at different sites. Each
additional O2 binds with higher affinity than the previous
one due to changes induced in the tertiary structure of the
metalloprotein by the previous binding events.1
The chelate effect refers to enhanced stabilities achieved
in complexes where binding of a ligand (potentially referred
to as a host) to a guest (traditionally a metal ion) is stabilized by the presence of more than one binding site on
the ligand. The macrocyclic and cryptate effects build on
the properties found for the chelate effect as a result of
increased dimensionality and structure that is provided to
the binding process. The macrocyclic effect reflects the elevated stability of macrocyclic complexes by virtue of a
closed ring system that binds a metal ion or other guest
at multiple sites. In this case, the ligand is even less readily
released or dissociated because of the constraints placed on
movement of any one binding site by virtue of the closed
ring. The cryptate effect involves the highest form of complex, or hostguest, stability as a result of the increased
dimensionality provided by the bicyclic (or higher order
cyclic) cage.
In the beginning of the increased cognizance of the
different types of chemical influences that multiple binding
sites can impart, the focus was totally on transition metal
coordination complexes. Indeed, for the majority of these
effects (with the exception perhaps of the cryptate effect),
supramolecular chemistry was not even on the radar screen.
Now, however, decades after the term supramolecular
was 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
Concepts
Increasing organization
Acyclic (podand)
No preorganization
Macrocyclic effect
Chelate effect
Cryptand effect
= Donor site
= Acceptor site
Figure 1 A pictorial representation of effect of increasing host organization with increasingly restricted binding of a guest within
chelate, macrocyclic, and cryptand ligands.
it is evident that the same phenomena can be attributed to

supramolecular chemistry.
Another influence on binding, both in transition metal
chemistry and supramolecular chemistry, is the role of preorganization. Preorganization tends to enhance cooperativity, since it infers that a host is already conformationally set
in place for the most efficient binding (Figure 1). In general, preorganization is mandated for the constrained cyclic
hosts, both macrocyclic and macrobicyclic, that force a preordained structure, such as in porphyrins. However, it can
also occur at the chelate level, in a conformational rigidity (e.g., donor groups appended to a phenyl ring in cis
positions) and/or proximal H-bonding effects (e.g., in 2,6diamidopyridine groups, where the pyridine NH groups are
drawn inward to H bond with the pyridine nitrogen atom).
Preorganization is discussed in detail in another chapter (see
Complementarity and Preorganization, Concepts), but is
still an important contributor to the effects described here.
Prior to exploring various aspects of cooperativity and its
influence on the chelate, macrocyclic and cryptate effect, it
is important to understand the role of coordination chemistry as it relates to both transition metal and supramolecular
chemistry. What follows is an explanation of this relationship that includes both bonding similarities and differences.
SUPRAMOLECULAR COORDINATION
CHEMISTRY
In the late 1800s, the visionary Alfred Werner predicted the

actual structures of transition metal coordination complexes
in the absence of X-ray crystallography or other definitive
structural tools.3 He put forth the hypothesis that transition
metal ions had not just one, but two valencies. The first
would be the oxidation number of the metal ion, +1, +2,
+3, and so on, that would require a sufficient complement
of counterions to satisfy the neutrality principle. However,
beyond the necessity of achieving neutrality, Werner proposed that transition metal ions possessed a secondary
valence. This would be a coordination number governed
by neutral species (e.g., H2 O or NH3 molecules), anions
(e.g., Cl , CN , CH3 CO2 ), and even more complex ligand frameworks that could donate a lone pair (or pairs)
of electrons to the metal ion, forming dative or coordinate
covalent bonds. This proclamation revolutionized transition
metal chemistry and provided the basis for the new and still
expanding field of coordination chemistry.
In the mid-twentieth century with the birth of supramolecular chemistry, scientists began exploring the influence of
weaker (compared with covalent bonds) supramolecular
interactions. A new and vibrant field of chemistry has now
evolved from almost unnoticed beginnings. Supramolecular chemistry includes a plethora of possible hostguest
systems held together by noncovalent forces, and in many
instances H bonds. These systems represent the primary
focus of this chapter, although, because of the groundwork
laid by the chemistry of transition metal complexes, aspects
of traditional coordination chemistry are also included.
Although binding modes are considerably different
between transition metals, cations, anions, and even in the
rarer case, neutral molecules, there are nonetheless striking similarities if a broader view of binding is considered.
Some specific examples are shown in Figure 2. In transition metal complexes, coordinate covalent bonds are formed
M n+
R3N:
Mn +
R2O:
(a)
(d)
R2O:
M = Transition metal
M = Nontransition metal
A = Anion
:An
R3NH
(b)
HNH2
R+
(c)
Figure 2 Comparison of binding modes for transition metal

ions, cations, and anions.
DOI: 10.1002/9780470661345.smc007
Cooperativity and chelate, macrocyclic and cryptate effects

between the ligand electron pair donors and the metal ion
(Figure 2a). These donations lead to interesting stabilizations (known as crystal field stabilization) because of the
(usually) unfilled d orbitals on the metal ions.4 For other
cationic species, a similar donation of the lone electron pairs
can occur, either to a nontransition metal ion (potentially
electrostatic but still involving electron pair interactions) or
to a multiatomic cation such as ammonium ion (electrostatic and H bonding) (Figure 2b and c).5 For anions, the
electron pair donation is reversed and the flow proceeds
from the anion to the ligand hydrogen atoms, that is, H
bonding (Figure 2d).
This chapter addresses cooperativity and the chelate,
macrocyclic and cryptate effects by examining the corollaries and differences between transition metal and supramolecular coordination. These four effects have been
responsible for many of the exciting developments in
supramolecular chemistry, from simple sensor and sequestration agents to more complex molecular self-assemblies
and functional molecular machines and devices. The following sections describe the evolution and the interrelations of the four effects, beginning with the transition
metal basics that laid the groundwork starting in the
1940s (Section 3) as shown in Figure 2(a), and progressing to the supramolecular aspects (Section 4) as shown in
Figure 2(b)(d). The latter section begins first with nontransition metal (ionic) examples, which started to materialize in the 1970s, and progresses to nonmetal (H bond)
hosts and guests that are still being formulated. Throughout
this chapter, the terms host (receptor) and ligand are used
interchangeably, where the term ligand refers to the species
making up the secondary valence of transition metals in
transition metal coordination chemistry.
3.1
TRANSITION METAL
COORDINATION CHEMISTRY
Chelate effect
In traditional coordination chemistry, chelates (from the

Greek word for claw, ,
chel`e) refer to complexes
with a ligand that contains more than one donor atom. The
number of donor atoms in a given ligand is referred to as the
denticity (from the Latin dentis for teeth). The chelate effect
was first coined in the 1940s6, 7 led by Schwarzenbach, in
some of the formative years of coordination chemistry. The
area began to flourish in the 1950s, when researchers, such
as Martell and Calvin,8 Bjerrum,9 and Schwarzenbach,10
were able to examine complex solution equilibria.11
As noted above, a chelator is a ligand that has more
than one donor atom that is capable of binding to a metal
ion simultaneously. For example, ethylenediamine (en) or

bipyridine (bipy) can form a complex with Cu2+ where both
amine nitrogens are coordinated to the metal ion forming
a five-membered chelate ring. In a majority of cases, the
numerical value of the complexation constant for a chelate
ligand with n donor atoms is larger than the comparable
overall stability constant for a complex consisting of
the same number of unidentate ligands with the same
donor atom. This phenomenon (enhanced stability constant)
has been termed the chelate effect.6, 7 For example, the
formation 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 monodentate
ligands NH3 ( 2 = 6.8 107 ) or CH3 NH2 ( 2 = 3.2
107 ) as shown in (13).
Cu2+ + en Cu(en)2+
K1 = [Cu(en)2+ ]/[Cu2+ ][en]
2+
Cu
+ 2NH3 Cu(NH3 )2
(1)
2+
2 = [Cu(NH3 )2 2+ ]/[Cu2+ ][NH3 ]2
(2)
Cu2+ + 2CH3 NH2 Cu(CH3 NH2 )2 2+

2 = [Cu(CH3 NH2 )2 2+ ]/[Cu2+ ][CH3 NH2 ]2
(3)
Figure 3 shows some simple chelators and their comparable

monodentate reference ligands. The ligands chosen are
the simple mono- and bidentate amines often used in
supramolecular and self-assembled structures, especially
the pyridine derivatives.
The energetics of the chelate effect become more clear
upon examining both the formation constants and thermodynamic parameters of the two nickel(II) reactions12 (4
and 5):
[Ni(H2 O)6 ]2+ + 6NH3 = [Ni(NH3 )6 ]2+ + 6H2 O
(4)
10 , G = 51.8 kJ mol ,
9
H = 100 kJ mol1 , S = 163 J mol1 K1

[Ni(H2 O)6 ]2+ + 3en = [Ni(en)3 ]2+ + 6H2 O
(5)
1018 , G = 101.8 kJ mol1 ,

H = 117 kJ mol1 , S = 42 J mol1 K1
There are many factors to be considered in examining
the enhanced stability provided by chelating ligands. These
include both thermodynamic and kinetic effects. Thermodynamically, an early explanation was that the origin of the
effect was entropic in nature. This can be seen by comparing reactions in (4 and 5). The number of species in solution
remains the same before and after the reaction in (4), and
the overall G is favorable at 51.8 kJ mol1 . In (5), however, the four reactant species are replaced by seven product
DOI: 10.1002/9780470661345.smc007
Concepts
Monodentate
NH3
Ammine
CH3NH2
Methylamine
N
Pyridine
py
Bidentate
CH3
O
H2N
Acetate
H3C
O
NH2
Ethylenediamine 2,2'-Bipyridine
en
bipy
N
Picolinate
Tridentate
CH3
N
N
HO
O
Dimethylglyoximate
DMG
Tetradentate
NH
HN
NH
HN
NH2
H2N
NH2
H2N
N
N
2,2',2''-Terpyridine
terpy
Figure 3
1,4,7,10-Triethylenetetramine 1,4,8,11-Triethylenetetramine
trien
2,3,2-tet
Monodentate and chelating ligands and abbreviations.
ions/molecules, contributing to more disorder and an even

more favorable (more positive) entropy situation. (Counterions remain the same in both so are not included in
this count.) Thus, the less negative S for (5) compared
to (4), in addition to a slightly more favorable H , results
in almost doubling the G (G = H T S).
Another consideration is the cooperative influence of
chelating ligands. In the 1970s, Busch termed this effect
multiple juxtapositional fixedness (MJF).13, 14 When a
group of monodentate ligands is attached to a metal ion,
dissociation becomes rather simple, since the individual
ligands are not tied to each other (Figure 4a). However,
in bi- and multidentate ligands, such is not the case. For a
bidentate ligand, upon dissociation of one donor, the freed
end is still held in proximity due to the coordination of the
second donor (Figure 4b). Hence, there is more opportunity
for the ligand to recombine with the metal ion as opposed
to dissociating. By increasing the denticity, this effect
becomes even greater, since complete dissociation would
require multiply tethered donors to be released from the
metal ion (Figure 4c). Thus, binding sites in multidentate
ligands are considered to be fixed to their juxtapositioned
counterparts.
The MJF effect, which involves the kinetic aspect of
the stability of these complexes, is also operative upon
the initial binding of ligands. In both cases, cooperativity
is involved, because the binding of the donor atom under
consideration depends on the binding of previous donor
atoms in the same ligand. The process of losing or
dissociating the entire macrocycle, which is a totally closed
ring, thus becomes even more difficult, and is the origin of
NH3
H3N
M NH
H3 N
3
NH3
H3N
H3N M NH3
NH3
H3N
H3N M
NH3
(a)
H
N H2N
N M N
H
H
H
N
N M N
H
H
NH2
H
N M
N H N
2
H
(b)
H
N
N HN
N M N
H
H
NH2
N
N
N M N
H
H
N
N M N
H
H
H
N
N
N M
H
(c)
H
N
N HN
N M N
(d)
H
H
N
N
M
N
N
H
H
NH2
N
N
N M N
N
N M N
H
N
N
N M HN
Figure 4 Schematic diagrams showing the dissociation pathways 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.
DOI: 10.1002/9780470661345.smc007

the macrocyclic effect to be discussed in the next section
(Figure 4d).
It should be noted, however, that a fundamental problem
with quantitatively calculating the chelate effect from
Kchelate / mono is that the equilibrium constants do not
have 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 are
expressed as mole fractions, with similar findings observed
in gas-phase measurements. This same problem arises in
the supramolecular chelate effect, and will be described in
greater detail in Section 4. However, in the solution phase,
the reaction of complexes containing monodentate ligands
with chelating ligands usually results in a favorable binding
constant, 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+ + 6NH3
log K = 8.76
(6)
Table 1 lists formation constants with selected metal ions

as an illustration of the chelate effect for transition metal
ions. The structures of the ligands and their abbreviations
are shown in Figure 3. In the table, the chelate effect is
defined as log K = log K1 log n , which is equivalent
to log Kexch for the exchange reaction (7)
M(L)n + Ln M(Ln) + nL

Kexch = [M(Ln)][L] /[M(L)n ][Ln]
n
Reaction: Two-coordinate
1
2
3
4
5
6
7
8
9
Ni2+ + 2NH3 Ni(NH3 )2 2+

Ni2+ + en Ni(en)2+
Ni2+ + 2py Ni(py)2 2+
Ni2+ + bipy Ni(bipy)2+
Cu2+ + 2NH3 Cu(NH3 )2 2+
Cu2+ + 2CH3 NH2 Cu(CH3 NH2 )2 2+
Cu2+ + en Cu(en)2+
Cu2+ + 2py Cu(py)2 2+
Cu2+ + bipy Cu(bipy)2+
LogK1 (polydentate ligand)

= 1.152 log n (unidentate ligand)
+ (n 1) log 55.5
n = denticity
10
11
Ni + 3py Ni(py)3 2+
Ni2+ + terpy Ni(terpy)2+
12
13
14
15
Cu2+ + 4NH3 Cu(NH3 )4 2+

Cu2+ + 2en Cu(en)2 2+
Cu2+ + trien Cu(trien)2+
Cu2+ + 2,3,2-tet Cu(2,3,2-tet)2+
Log Kn ( n )a (Kcalc )b
log K c (#)d
5.08
7.35
3.10
7.04
7.83
7.51
10.40
4.45
8.00
2.27 (1)
3.94 (3)
2.57 (5); 2.89 (6)
3.55 (8)
( 2 )
(K1 ) (7.58)
( 2 )
(K1 )
( 2 )
( 2 )
(K1 ) (10.76)
( 2 )
(K1 )
Reaction: Three-coordinate
2+
3.71 ( 3 )
10.7 (K1 )
7.0 (10)
Reaction: Four-coordinate
aK
13.0 ( 4 )
19.6 (K1 )
20.05 (K1 ) (20.20)
23.2 (K1 )
6.6 (10)
7.0 (10)
10.2 (10)
and n defined in (1 and 2).

refers to the K calculated using (8).
c log K = log K
chelate log Kunidentate .
d (#) refers to the number of reaction that is being compared.
bK
(7)
where Ln is a chelating ligand with n identical donor atoms

and L is the monodentate reference ligand.
Table 1 covers many of the important considerations of
the chelate effect in transition metal complexes. It is divided
to show examples of two-coordinate, three-coordinate, and
four-coordinate binding constants. First, examination of the
data shows that the chelate effect is not confined to a particular 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, the
chelate effect ranges from 2.27 for Ni(en)2+ to 3.94 for
Ni(bipy)2+ , and is larger for bipy than en with the same
metal ion.
As noted earlier, the chelate effect also increases with
increasing number of rings. Transition metal chemists have
applied a very simplified approach to the chelate effect
for linear polyamines, expressed in (8), that corrects for
inductive effects (pKa (CH3 NH2 )/pKa (NH3 )).11
Table 1 Complex formation constants for reactions of metal ions with multidentate ligands
and their unidentate analogs.16
Number
calc
DOI: 10.1002/9780470661345.smc007
(8)
Concepts
The latter term, (n 1) log 55.5, derives from the fact

that when coordinated water molecules are replaced by
chelating ligands, the increase in the number of molecules
in solution causes an increase in the entropy in the
amount S = nR ln 55.5 = 33.4n J mol1 K1 , where n
refers to the number of chelate rings. As noted for the
en and trien systems in Table 1 for both Cu2+ and Ni2+
ions, this approximation works quite well for the linear
polyamines.11, 12
Also note as seen in Table 1, the chelate effect increases
with an increase in the number of chelate rings for a
given metal ion, but this can be offset by cumulative ring
strain for some metal ion complexes. This is illustrated by
comparison of the formation constants for Cu2+ complexes
with NH3 , en, trien, and 2,3,2-tet given for #1215 in
Table 1. The log K values, compared to log 4 (NH3 ),
are 6.6, 7.0, and 10.2 for two en ligands, trien, and 2,3,2tet, respectively. However, the increase in log K is much
greater for 2,3,2-tet, where a six-membered chelate ring
is formed by coordination of the metal ion to the two
interior nitrogen atoms. The observed increase in stability
has been ascribed to the lessening of ring strain due to
the expanded six-membered chelate ring in 2,3,2-tet.11, 12 It
should be noted, however, that the actual strain associated
with ring size will also depend on the size of the metal
ion. For transition metal ions, in considering ring sizes
from four to seven, a four-membered ring is the most
strained (as in acetate); a five-membered ring (as in en) is
optimal for larger transition metal ions; and six- and sevenmembered rings allow for increasing flexibility, but they
are more favorable for binding with smaller ions. These
observations derive mainly from differences in bond lengths
and bond angles that give rise to greater or lesser strain in
the cyclic systems.11 Additionally, it should be noted that
the distances from the transition metal ions to the ligand
donors are greater than distances between atoms in the
compared with 1.41.5 A),
ligand (usually around 2.0 A

which influences the strain introduced by various ring sizes.
Another level of cooperativity can be observed for the
chelate effect in terms of bonding of additional chelating
ligands, as seen in the examples below. In coordination
chemistry, a simple form of cooperativity can be observed
in the successive complex formation constants (KMLn) for
certain metalligand complexation reactions (9 and 10).
Mx+ + Ly MLxy
KML1 = [MLxy ]/[Mx+ ][Ly ]
(9)
x2y
MLxy + Ly ML2
x2y
KML2 = [ML2
]/[MLxy ][Ly ]
(10)
In addition to sequential binding effects of multiple

chelates, other mitigating factors can play a role in the
Im O
N
N
Fe
N
O
(a)
Fe
N
Im
O
H
Im =
NH
N
(b)
Figure 5 (a) Structure of the Fe(DMG)2 (Im)2 complex and

(b) electron density map for the Fe(DMG)2 pseudomacrocyclic
ring around the iron atom with contours at increments of 0.5 e /A
starting at 0.2 e /A.
binding of ligands to transition metals. For example, the

magnitude of the equilibrium constants generally decreases
as successive ligands coordinate to the metal center due to
a 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 for
binding of the first ligand, and K2 = 24.3 for the second
ligand.18 On the other hand, the Cu2+ and Zn2+ complexes
with dimethylglyoxime (DMG, also a bidentate ligand),
show cooperative behavior in metal complex formation. In
this case, the ligand readily deprotonates and forms two
H bonds, which results in the formation of a pseudo
macrocyclic ligand. K2 K1 by factors of 32 and 16
for the Cu2+ and Zn2+ complexes, respectively.19 Two
intramolecular hydrogen bonds between the oxygen atoms
of the coordinated ligands are responsible for this effect
and have been verified by X-ray crystallography.20, 21
The electron density diagram for the di-imidazole iron(II)
complex with dimethylglyoximate,22 synthesized as an
early model of the heme iron proteins, nicely illustrates
the pseudomacrocyclic effect (Figure 5).
3.2
Macrocyclic effect
Macrocyclic chemistry had its beginnings in the 1960s.

In 1962, Curtis published the first tetraaza macrocycle.23
However, the first planned synthesis of a macrocyclic ligand
(and complex) came two years later, when Busch reported
the use of a kinetic template effect and nickel(II) ion
to achieve a mixed aza-, thia-donor macrocyclic ligand24
(Figure 6). Early macrocycles by Busch and others were
generally based on nitrogen donor groups and were often
used as models for the naturally occurring macrocycles such
as the porphyrins.
As the field of macrocyclic chemistry grew, so did the
realization that macrocyclic complexes, particularly transition metal complexes, exhibited enhanced stabilities over
noncyclic systems, even those with multiple chelate rings.
DOI: 10.1002/9780470661345.smc007
3.3
R
S
Ni
Br
CH2Cl2 R
Cryptate effect
N
Ni
Br
R = CH3, C2H5, C5H11
Figure 6 Final step of the reaction sequence resulting in the

formation of the first planned macrocyclic ligand by a kinetic
template effect.24
This meant that transition metal complexes that were kinetically labile and therefore not very easy to study on normal
time scales could be made increasingly inert so as to enable
room temperature study of the chemistry. This finding led
Margerum and Cabbiness to coin the term macrocyclic
effect, for the increased stability of macrocyclic complexes over their acyclic counterparts.25 The origins of the
macrocyclic effect have been a subject of discussion for a
number of years, and aspects of the following four factors undoubtedly play a role.26 Macrocyclic ligands are
often preorganized in a fashion that readily allows for complexation. Solvation of the donor atoms is possibly less in
the more limited macrocyclic cavity. The basicity of the
macrocyclic ligands is influenced by the inductive effects
of the bridges between the donor atoms, which increases
the donor capabilities in macrocyclic ligands. Last but not
least, the electron repulsion from the constrained donor lone
electron pairs in macrocycles is eased upon metal ion coordination. The macrocyclic and cryptand ligands discussed
in this chapter are depicted in Figure 7 along with their
common names.
In terms of thermodynamics, the role of entropy versus
enthalpy has been hotly debated. Log K and thermodynamic values are provided in Table 2. As can be seen from
the thermodynamic parameters provided in the table, it
becomes evident that the macrocyclic effect is primarily
enthalpic in origin. This is dependent, however, on comparing systems without steric strain, which naturally adds
other mitigating factors to the thermodynamics.
Probably the most famous cryptands are those first reported

by Lehn in 1969.27, 28 These will be described in the section
on supramolecular chemistry (Section 4). However, transition metal cryptands were reported several years later, the
clathrates and sepulchrates of Sargeson and coworkers29, 30
(Figure 7). The sepulcrates derive from a hexamine cagelike structure that encloses around a metal ion. They are
actually a class of clathrochelates, the term clathro being
derived from the Latin word meaning lattice. However,
Sargeson named the ligand sepulchrates, more or less in
keeping with the tone of the crypt in cryptand. This group
of complexes has been studied at length because of the ease
with which the captured metal ions undergo rapid redox
changes in addition to a high complex stability.30 Many
of these complexes are also excellent oxidizing agents in
the higher oxidation states. A number of other cryptandlike macrocycles and their transition metal complexes have
been synthesized, including the lacunar (dry cave) ligands
of 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 supramolecular chemistry, the reader is directed to a review of some
of these interesting transition metal complexes.32
R
R
NH HN
NH NH HN
NH HN
NH NHHN
Cyclam
Sepulchrate
R
Lacunar ligand
Figure 7
Macrocyclic and cryptand ligands.
Table 2 Complex formation constants and thermodynamic parameters for the macrocyclic effect for
Cu(II), Ni(II), and Zn(II) with cyclic and acyclic tetraamines.a
Complex
Cu(2,3,2-tet)2+
Cu(cyclam)2+
Ni(2,3,2-tet)2+
Ni(cyclam)2+
Zn(2,3,2-tet)2+
Zn(cyclam)2+
log K
(log K)
G
(G)
H
(H )
T S
23.2
26.5
15.5
19.4
12.6
15.5
3.3
3.9 (3)
2.9 (5)
132.1
151.8
90.4
110.9
72.3
87.1
19.7
20.5
14.8
115.9
135.6
77.9
100.9
49.8
61.9
19.7
23.0
12.1
16.2
16.2
12.5
10.0
22.5
26.2
(T S)
2.5
3.7
a H O at 25 C11 ; values of the G, H , and T S in kJ mol1 ; macrocyclic effect = (log K) = log K
2
cyclam
log K2,3,2-tet ; (X) = Xcyclam X2,3,2-tet .
DOI: 10.1002/9780470661345.smc007
Concepts
SUPRAMOLECULAR CHEMISTRY
Various aspects of cooperativity and the chelate, macrocyclic and cryptate effect are described in this section for
supramolecular complexes. As noted in Figure 2, there are
two general types of interactions, electrostatic and H bonding, included in this sectionhowever, in all cases these
are noncovalent in nature. Three types of guests will be
described: metal ions of the nontransition metal variety (primarily electrostatic interactions, Figure 2b), and nonmetallic cationic and anionic guests (potentially electrostatic and
H-bonding interactions, Figure 2c and d). Both nonmetallic cationic and anionic guests utilize their H-bond donor
as well as acceptor sites. Each of the sections below, on
chelate, macrocyclic, and cryptate effects, will include several examples of two or more different types of guests.
4.1
Background
In supramolecular chemistry, stable hostguest complexes

are built on multiple, simultaneous noncovalent interactions.33 This is because a single supramolecular interaction,
being beyond the covalent or dative bond, is inherently
weaker than the coordinative covalent or dative bond that
is found in transition metal chemistry. Hence, stability is
enhanced by the additive effect of multiple hostguest
interactions. However, as Schneider points out, referring
to the additivity of noncovalent bonding there is also
a chelation influence when the interactions emanate from
a single host (or ligand), as seen in transition metals. In
essence, polytopic hosts can bind to either monotopic or
polytopic guests, the latter situation of particular importance
in hostguest chemistry, where an organic or inorganic
guest may have more than one binding site. These principles
are abundant in biology, where hostguest chemistry is the
modus operandi for enzyme and protein interactions with
their substrates, among other important processes including
antibodyantibody interactions. Complementarity, as seen
in the chelate effect for transition metal complexes, also
plays an important role. The fit of the guest to the host
should be as favorable as possible; otherwise, the full benefit of the chelate enhancement effect in binding by multiple
interactions is lost.
Thus, for example, in a simple system where the polytopic host and guest match each other (Figure 8), the total
free energy of the interaction, Gtot , is obtained by the
sum of the free energies of the individual interactions where
H1 G1 refers to the binding site H1 of the host and G1 of the
guest, and so on (11). However, the overall binding constant Ktot is not the product of the individual binding constants, because Ktot is in units of M1 , while if each individual constant is multiplied, the Ktot would have dimensions
Host
H1
H2
H3
H4
H5
G1
G2
G3
G4
G5
Guest
Figure 8 Schematic representation of multiple hostguestbinding site interactions.
Mn where n would be the number of pairwise contacts,

in this case five. In actuality, the same problem occurs for
Gtot as well, since if treated separately, each of the G
values would involve a significant entropy term, where only
one entropy term would be involved in the Gtot . In order
to circumvent this problem, the same solution as applied to
the transition metal quandary can be applied to supramolecular chemistry. Namely, when expressed as molar fractions
instead of molarities, the equilibrium constants become
dimensionless. This involves multiplying the molar concentrations of an 1 M aqueous solution of the solute by
a factor of 1/55.5 to obtain molar fractions. When substituted in the multiple equilibrium equations and solving, the
resulting dimensionless Ktot is obtained (12).
G = GH1 G1 + GH2 G2 + GH3 G3
+ GH4 G4 + GH5 G5
(11)
Ktot = (55.5)1 KH1 G1 KH2 G2 KH3 G3 KH4 G4 KH5 G5 (12)

Note first that (11) assumes complete additivity of the
effects. Nonetheless, the snowballing effect of multiple
interactions can be easily seen. It should be noted, however,
that there are a number of factors that weigh in when
determining the additivity of multiple binding events,
especially for entropic considerations. These include, for
example, ion pair versus neutral interactions; solvation and
desolvation effects; and the phase under study, gas or
solution among others. Nonetheless, it does appear that the
experimental values of G additivity hold in general when
rotational entropy is not compromised on complexation,
solvation and desolvation effects are comparable for each
binding site, and partnering host and guest sites are able to
bind without inducing significant strain.33
Over and above the chelate effect in supramolecular
chemistry, macrocyclic and cryptand hosts take advantage
of a combination of effects that serve to leverage their
binding capability (Figure 1). For example, because of preorganization effects of the closed cyclic systems, immediately more contact with the guestespecially spherical guestsoccurs. Solvation effects are also important.
In acyclic hosts, the binding sites are readily available
DOI: 10.1002/9780470661345.smc007

to the solvent, which then requires additional rearrangement upon complexation of a subsequent guest. As the
dimensionality increases, the binding sites can be more
shielded, allowing for less rearrangement upon guest binding (Figure 9). Even so, acyclic chelates benefit from the
chelate effect once they start wrapping or binding a guest
in their multiple sites. Macrocyclic and macrobicyclic or
polycyclic hosts not only benefit from the chelate effect, but
have the macrocyclic and, for the higher order hosts, the
cryptate effect in their favor. On the other hand, with organization comes more repulsion, for example between the
lone 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 are
provided in Table 3. They are listed in order of increasing
preorganization as shown in Figure 10.
The following sections provide examples of cooperativity
as it relates to the chelate, macrocyclic, and cryptate effects
for supramolecular complexes of both cations and anions.
4.2
Cations
Perhaps the most apparent similarities with transition

metal complexes are the main group metal ions and their
supramolecular complexes. Here, the progression from the
chelate to macrocyclic to cryptate effect can be readily recognized and the thermodynamics are, for the most-part,
established. The term ionophore is often used for this class
of hosts, originating from its use in biology for lipid-soluble
molecules that serve as vehicles for transporting ions across
membranes.
4.2.1 Chelate effect

Nature utilizes the chelate effect often in the naturally
occurring ionophores. For example, the polyether carboxylic acid ionophore A23187 (calcimycin) behaves as
a monoanionic tridentate ligand (Figure 11a). For Ca2+
the equilibrium constants KML1 and KML2 are 2.5 106
O
H3CO
Acycle = podand
OCH3
Relaxed conformation results in

high solvation of lone pairs and
minimal electron electron repulsion.
O
O
O
CH3 H3C
O
O
O
Lessened solvation of lone pairs

O and increased repulsion of
lone pairs pointing inward.
O
O
O
O
Macrocycle (crown ether)

O
N O
O
O
O N
Limited solvation of lone pairs

in cavity but lone pair repulsion
in the cavity is retained.
O
N O
O
O
O N
O
Macrobicycle (cryptand)
Figure 9 Preorganization effects in the binding of a spherical ion by the non-preorganized pentaglyme, and the effect of increasing
organization 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 ions
with ionophores that have increasingly complex design and dimension.33
Ionophore
Pentaglyme
Tripod
Valinomycin
[18]Crown-6
[2.2.2]Cryptand
Spheranda
a
Li+
Na+
K+
Rb+
Cs+
<2
<0.7
0
2.6
>16.8
1.5
2.2
0.9
4.4
8.0
14.1
2.2
2.3
4.7
6.1
10.8
<2
5.2
5.4
9.0
4.4
4.7
4.4
In CDCl3 saturated with H2 O.35
DOI: 10.1002/9780470661345.smc007
10
Concepts
Increasing preorganization
Pentaglyme
2.2 (K+)
Tripod
2.3 (K+)
O
N O
O
O
O
Increasing preorganization
[18]crown-6
6.08 (K+)
HA(A)4AH
4.4 (Li+)
O
O N
O
O
O
O
O
O
[2.2.2]
10.8 (K+)
Spherand
16 (Li+), 14.4 (Na+)
Figure 10 Schematic showing relationship between binding constants of hosts of increasing preorganization and K+ ion. (Redrawn
from Ref. 34. John Wiley & Sons, Ltd, 2009.)
H3C
H3C
O H
H3C
N
H
O
O O
CH3
H
NH
H3C H O
OH
(a)
(b)
Figure 11 (a) Chemdraw diagram of the ionophore A23187 and (b) X-ray structure of Ca(A23187)2 showing interligand and
intraligand H bonds.
and KML2 = 6.3 107 , respectively, and KML2 /KML1 =

25.2.36 Similar cooperative effects have been observed
for complexes of A23187 with Mg2+ , Sr2+ , and Ba2+ .
An explanation for the enhanced binding of the second ligand to M(A23187)+ is the formation of H bonds
between the pyrrole NH of one ligand to a carboxylate
oxygen atom on the other ligand (similar to the situation in the DMG transition metal complex described earlier), as shown in Figure 11(b).37 In recent years, there
has been an increasing level of activity in the design of
supramolecular systems that display cooperative behavior
either in their (self) assembly or in response to stimuli. In addition to H bonds and other noncovalent interactions, the formation of metal ionligand complexes is
often employed in the construction and/or operation of such

systems.
An example of a metal ion acting as a template bringing
together two acyclic ethers is observed for the synthesis
of the Li+ complex of the spherand (Figure 12).38, 39 Cram
and coworkers used the Li-assisted ring closure tactic to
form the Li-encapsulated spherand in 28% yield. Note how
well the lithium ion fits into the cyclic cavity. As seen in
Table 3 and Figure 12, the fit of the lithium ion in this
cavity is so good that this macrocycle, despite only being
monocyclic, displays an extremely high binding constant
for lithium ion, about 500 times greater than for the larger
sodium ion. This demonstrates the benefits of the influence
of preorganization.
DOI: 10.1002/9780470661345.smc007
Br
Br
O
1. BuLi
2. Fe(acac)3
O
O +O
Li
O
O
O
3. EDTA
4. HCl
acac =
O
(a)
11
Cl
(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 of
the crystal structure for the complex.
Ionic radius ()
O
O
Li+
Na+
K+
Rb+
Cs+
0.78
0.97
1.33
1.48
1.67
O
O
O
O
O
O
Crown name
hole size ()
[12]crown-4
1.20 1.50
[15]crown-5
1.70 2.20
O
O
[18]crown-6
2.60 3.20
O
O
[21]crown-7
3.40 4.30
Figure 13 Depiction of alkali metal ions and their relative ionic radii, along with a series of crown ethers ranging from [12]crown-4
through [21]crown-7, with their approximate hole size. (Data from Ref. 46.)
4.2.2 Macrocyclic effect

In a seminal 1967 paper by Pedersen, the exceptional stability of macrocyclic crown ether complexes with alkali
metal ions was reported.40 What followed was the birth of
a new area of macrocyclic chemistry, one not involving
transition metal complexes but focused more on organic
chemistry. The field of supramolecular chemistry was just
beginning to blossom. Perhaps the most studied of these
macrocycles is the [18]crown-6. Nomenclature for the simple crown ethers derives from a simple notation that refers
to the number of atoms in the ring enclosed in brackets,
followed by the type of macrocycle, crown, followed by

the number of ether oxygen atoms, in this case 6. Early
studies showed that in the simple rings, the affinity for the
alkali metal ions seemed to be dependent on the ratio of
the radius of the cation to the size of the macrocyclic cavity41, 42 (Figure 13). However, upon more intense scrutiny
using ion selective electrode (ISE) measurements, Gokel
pointed out in 198343 that all crown ethers are selective for
K+ ion, and in particular that [18]crown-6 is selective for
all ions. In part, the ambiguity in binding affinities was a
problem arising from data obtained under a variety of conditions.43, 44 Binding constants for crown ethers ranging in
DOI: 10.1002/9780470661345.smc007
12
Concepts
Table 4 Binding constants (log K) in methanol at 25 C for selected cations with crown and
lariat ethers.
Crown
Na+
K+
Ca2+
NH4 +
[12]crown-443
[15]crown-543
[18]crown-643
[21]crown-743
[2.2]N(CH3 )2 45
[2.2]BME47
[2.2]BHE48
1.7
3.24
4.35
2.54
3.62
4.57
4.87
1.74
3.43
6.08
4.35
5.0
5.30
5.08
nd
2.36
3.90
2.80
4.20
4.48
1.3
3.03
4.14
3.27
size from [12]crown-4 to [21]crown-7 with the ions K+ ,

Na+ , Ca2+ , and NH4 + are shown in Table 4. As noted by
Gokel, the data indicate that [18]crown-6 has the highest
selectivity for all the ions studied, and that K+ appears to
be the best guest, in terms of maximum binding. Size of
the guest, number of interactions, as well as solvation (the
free energy of solvation K+ < Na+ ) were all cited as playing important roles in the complexation process. Ring size
still 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 ioncrown
ether interactions can be seen by examining the crystal
structure data for metal ion complexes, and is covered in an
excellent review of the structural aspects of the crown ethers
by Steed.46 For example, it should be noted that the totally
encapsulated structure is not the only one observed for
K+ ion with [18]crown-6, but rather a number of different
structures exist. This is an aspect of monocycle hostguest
complexes that sets this group of ligands apart from bicyclic
and polycyclic systems. The openness above and below the
host allows for egress of the guest as well as for additional
types of interactions, sometimes involving more than one
ligand. 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 independent
molecules (Figure 14b) has a THF (tetrahydrofuran) solvent
molecule associated with it (not shown); and the Rb+
complex (Figure 14c) also has other molecules surrounding
(a)
Figure 14
(b)
the host and guest within bonding interaction (not shown).

The result of this openness is illustrated in the rates for
formation of the complexes, and the reverse release of
guests, which for monocycles are both relatively fast, but
the reverse reaction is still significantly slower than for
chelating ligands.
Of interest for comparison purposes, the cyclododecadepsipeptide ionophore valinomycin, formed from amino and
hydroxyl acids, is highly selective for K+ , yet the host
does not encapsulate the ion within a single macrocyclic
ring. Rather it wraps around in a threefold saddle-like shape
(Figure 15), that from the top view (Figure 15a) resembles
the [18]crown-6 with the sixfold interaction of its oxygen
binding sites.52 However, in this case, three donor sites are
symmetrically placed around the top half of the ion, and
three around the bottom half. This type of wrapping effect
epitomizes the concept of cooperativity in its simplest form,
the use of multiple binding sites to effect a superlatively
strong interaction between host and guest.
Understanding that the fast onoff kinetics of the
crown ethers could be a drawback, Gokel, noting the
efficiency imparted by the flexibility of valinomycin,
added appendages containing additional donor atoms to
the crowns in order to further trap guests in the macrocycle. Because the macrocycle with its arm resembled the
rope used for lassos, Gokel named the extended macrocycles the lariat ethers.53 A series of simple analogs to the
(c)
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
DOI: 10.1002/9780470661345.smc007
N
H
O
O
HN
O
NH
13
O
O
Valinomycin
O
O
HN
O
NH
O
O
H
N
(a)
(b)
O
O
(c)
Figure 15 (a) Chemdraw picture showing the structure of valinomycin and (b) overhead and (c) side views of the crystal structure of
the K+ complex.
H3C N
O
N CH3 RO
N
O
[2.2]NCH3
OR
R = H [2.2]BHE
R = CH3 [2.2]BME
O
O
OCH3
N CH3
O
[2.2.2]open
Figure 16
Chemdraw diagrams of [2.2]NCH3 and lariat ethers.
crown ethers are shown in Figure 16 and the binding constants of these macrocycles with selected alkali metal ions
and Ca2+ are compared with the original crown ethers in
Table 4. The nomenclature used for these lariat ethers will
be derived from the one used for the cryptands that denotes
the number of ether oxygen atoms in each of the arms.
Here, the two arms are separated by the bridgehead

amine, and the pendant group designation follows. Hence,
the N-methylated analog is [2.2]NCH3 . The macrocycles
with the pendant hydroxyethyl and methoxyethyl groups are
[2.2]BHE (B, bibrachial (two arms); HE, hydroxyethyl) and
[2.2]BME (ME, methoxyethyl), respectively. The monocyclic analog [2.2]NCH3 is slightly poorer as a host for the
alkali metal ions compared to the [18]crown-6, but better
for Ca2+ . However, the other two lariat ethers show slightly
higher affinities for Na+ and Ca2+ , but less for K+ . As can
be seen for the crystal structures (Figure 17),54 the orientations of the two side chains can be either syn or anti.
Nonetheless, the effect that Gokel desired was achieved
with the more flexible lariats, a cryptand-like cavity. Gokel
later extended this additional cooperativity effect to utilize
these systems for biological applications such as ion transport, in which multiple cooperative interactions serve to
move an ion along a channel membrane.44
Tables 5 and 6 provide the thermodynamic perspective of
the 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
DOI: 10.1002/9780470661345.smc007
14
Concepts
(a)
Figure 17
(b)
(c)
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
1
2
3
4
5
6
7
K+ + pentaglyme K(pentaglyme)+
K+ + [18]crown-6 K([18]crown-6)+
Ba2+ + pentaglyme Ba(pentaglyme)2+
Ba2+ + 18-crown-6 Ba(18-crown-6)2+
Na+ + HA(A)4 AH Na(HA(A)4 AH)+
Na+ + spherand (Na(spherand)+
Li+ + spherand (Li(spherand)+
2.1c
6.1c
2.3c
7.0c
<4.4d
14.1d
>16.8d
(log K)a (#)b
4.0
4.7
>9.7
>12.4
(1)
(3)
(5)
(5)
= log Kcyclic log Kacyclic .

Number of reaction that is being compared in parenthesis.
c In methanol.55
d In CHCl saturated with H O, K values obtained from K = k /k .35
3
2
f d
a (log K)
b
Table 6 Comparison of the macrocyclic effect and differences in the thermodynamic parameters for complexes of selected alkali and divalent metal ions with pentaglyme and [18]crown-6.a
Metal ion
Na+
K+
Rb+
Cs+
Ba2+
Pb2+
(log K)b
(G)c
(H )c
2.9
4.0
3.4
2.6
4.7
4.8
16.1
23.0
19.5
15.3
25.4
27.2
15.5
2.5
2.89
11.0
23.3
18.6
(T S)c
0.63
20.1
16.4
3.89
2.01
8.37
In methanol at 25 C, taken from Table A4 in Ref. 33, Ref. 55, or calculated from G.
(log K) = log K[18]cr-6 log Kpenta .
c (X) = X
1
[18]cr-6 Xpenta , (G), (H ), (T S) in kJ mol .
a
b
effect enhances the binding by more than several orders

of magnitude. An especially convincing case is that of the
spherand, which is possibly the epitomy of the concept of
preorganization, showing incredible binding despite its two
dimensionality, that is, monocyclic as opposed to bicyclic
or polycyclic.
It is particularly interesting to compare the thermodynamic aspects of supramolecular chemistry with transition metal chemistry (Tables 2 and 6). If similar chemistry
holds, the macrocyclic effect should be primarily enthalpic
in origin. As can be seen from Table 6, the (H ) values 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 for

the dipositively charged ions. On the other hand, for K+
and Rb+ the trend is reversed, and it would appear that the
favorable (G) is primarily entropic in origin. These values can be compared to the values for 2,3,2-tet and cyclam
that illustrate this effect is primarily enthalpic in origin for
transition metal ions (Table 2).
Crown ethers and their derivatives also display a cooperative, multisite binding of molecular cations as well as
metal ions. Here, H-bonding and electrostatic interactions
play a role. The number of H bonds will also influence the
affinities, as evidenced in the simple ammonium series, with
NH4 + about equal to CH3 NH3 + (log K = 4.27 and 4.25,
DOI: 10.1002/9780470661345.smc007
O
O
six potential donor groups (Figure 18). For more information about molecular cation guest complexes, the reader is
urged to see reviews by Gokel et al.44 and Schneider.56
Another interesting example of cooperativity and the
macrocyclic effect involves the taco complex of Gibson
and coworkers.57 Inspired by the formation of pseudorotaxanes (threaded macrocycles) using paraquats reported
by Stoddart and coworkers in the late 1980s,58 Gibson and
coworkers capitalized on the more flexible bending capability of larger crown ethers to drive rotaxane formation in a
cooperative-like binding sequence (Figure 19). They found
that when they closed the crown to capture a guest inside, a
100-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 can
be seen in the latter structure, a water molecule also manages to fit in the cavity, pushing the paraquat guest to the
back of the host.
N
O
O
O
(a)
(b)
(c)
Figure 18 (a) Chemdraw diagram of the pyridine-containing

crown, and (b) overhead and (c) side views of the crystal structures of benzylammonium ion bound to the crown.
respectively) > (CH3 )2 NH2 + (log K = 1.76), reflecting the

cooperative additivity of binding sites.55 As can be seen
from the crystal structure of a simple benzylamine complex with a pyridine-containing crown, the amine group
dips into the crown, and forms H-bond interactions with all
Figure 19
15
Schematic representation of the complexation of paraquat by the flexible difunctionalized crown ether.
R
R
O
R = CH2OH
R/R = O(CH2CH2O)4
H3C N
N CH3
(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) the
paraquat guest in the crown complex (R = CH2 OH), closed off by H bonding between the hydroxyl groups and a CF3 CO2 ion, and
(c) a covalently closed cryptand/crown (R/R = O(CH2 CH2 OCH2 CH2 O)2 complex.
DOI: 10.1002/9780470661345.smc007
16
Concepts
Table 7
Stability constants (log K)a for chloride salts of alkali and alkaline-earth metal ions with cryptands in H2 O.
Metal ion (ionic radius, A)
Cryptand
[2.1.1]
[2.2.1]
[2.2.2]
[3.2.2]
[3.3.2]
[3.3.3]
Cavity
c
size (A)
Li+
(0.86)
Na+
(1.12)
K+
(1.44)
Rb+
(1.58)
Cs+
(1.84)
Mg2+
(0.87)
Ca2+
(1.18)
Sr2+
(1.32)
0.8
1.15
1.4
1.8
2.1
2.4
4.30
2.50
<2
<2
<2
<2
2.80
5.40
3.90
<2
<2
<2
<2
3.95
5.40
2.2
<2
<2
<2
2.55
4.35
2.05d
< 2d
< 2d
<2
<2
<2
2.20
<2
<2
NAd
<2
<2
<2
<2
<2
2.50
6.95
4.40
2
<2
<2
<2
7.35
8.00
3.40
2
<2
Ba2+
(1.49)
<2
6.30
9.50
6.00
3.65
<2
In H2 O at 25 C.60
b Ionic radius (A)
given
in parenthesis below each cation.60

cavity radius estimated using space filling models in the endoendo form.61
d Not available.
c Cryptand
4.2.3 Cryptate effect

27, 28
The seminal papers of Lehn,

introducing the macrobicyclic polyether-containing cryptands, appeared just two
years after the original crown ether papers of Pedersen.40, 41
These totally enclosed ligands, called cryptands for the
Greek term meaning hidden or concealed ( o ), contain a three-dimensional cavity compared with the twodimensional hole of monocyclic ligands.27, 28, 59 Depending on the orientation of the lone electron pairs on the
bridgehead nitrogen atoms, the possible conformations for
cryptands are endoendo, with lone pairs pointing inward,
exoexo, with lone pairs pointing outward, and endoexo,
the mixed in, out-conformation. These three conformations
will of course have different shapes, along with potentially
different cavity sizes, which must be taken into account
when comparing the hole-size relationships between hosts
and guests in Table 7.
A consequence of the higher dimensionality is generally
an increase in complex formation constants (KML ) compared to monocyclic analogs, for cations that are able to
enter the central cryptand cavity. In addition to larger KML
values, the cryptands show more pronounced selectivity,
with the largest KML value for the cation that best matches
the internal diameter of the cavity.62, 63 Selected cryptands
are shown in Figure 21 and will be compared with their
crown and lariat ether corollaries shown in Figure 16.
Abbreviations for the simple cryptands are given by the
number of ether oxygen atoms in each of the bridging
chains enclosed in brackets. For example, [2.2.2] refers to
the cryptand with three (CH2 )2 O(CH2 )2 O(CH2 )2 chains.
In the case of polyether cryptands, the hole-size
concept of host to guest fit appears to be valid. This is
illustrated for the alkali metal ions, where the trend is Li+
being bound selectively for the [2.1.1] (log K = 4.30), Na+
for the [2.2.1] (log K = 5.40), and K+ for the [2.2.2] (log
K = 5.40)60 (Table 7). However, the maximum binding
O
O
N N
[2.1.1]
O
O
N
O
[2.2.3]
Figure 21
O
O
O
O
[2.2.1]
N N
O
O
O
N
[2.2.2]
O
O
N
O
O
[2.3.3]
O
O
O
O
[3.3.3]
Simple bicyclic cryptands of increasing size.
constants are observed for the divalent ions, (log K): 7.35
for Sr2+ in [2.2.1] and 9.50 for Ba2+ in [2.2.2]. Hence, the
cryptands bind the alkaline-earth metal ions with unusually
exceptional affinities, as Lehn noted, with the exception
of binding with the relatively small [2.1.1]. The large
enhancement of the complex formation constant, KML ,
found when comparing metal ion complexes (cryptates)
with their monocyclic or open-chain complexes (analogs)
was termed the macrobicyclic cryptate effect.62
As pointed out in discussion of the considerations pertaining to the macrocyclic effect, the complexes being compared have 1 : 1 stoichiometry, so the KML values have the
same molecularity. The values of log KML and log Kcryp
for the various ligands with alkali and alkaline-earth ions
in 95/5 methanol/water are shown in Table 8.54 The comparisons show the influence of added cooperativity (i.e.,
additional binding sites) in the series of cryptand hosts
designed to be similar in terms of the basic chemical structure. All the hosts contain an 18-membered N2 O4 ring
[2.2] with various substituents on the nitrogen atoms, where
[2.2.2]open, [2.2]BME, and [2.2]BHE have same donor
atom set as the [2.2.2]. However, the problem remains as
to choice of hydroxyl versus methyl/methoxyl end groups,
DOI: 10.1002/9780470661345.smc007

which differ in terms of steric requirements and donor atom
basicity.64 As a result, the [2.2.2]open may not exhibit the
optimal structure within the acyclic analogs. The bibrachial
[2.2]BHE brings additional complications with pendent
arms that can adopt either syn or anti orientations with
respect to the plane of the macrocycle in the metal ion
complexes. X-ray structures of the Na+ and K+ complexes
reveal that 2.2-BHE adopts the syn form for both cations
although the related host with methoxy termini has both
syn and anti conformations54 as shown in Figure 17 for
the K+ ion. The simple monocyclic derivative, [2.2]NCH3
with an N2 O4 donor atom set, has tertiary nitrogen atoms
as do the cryptands and lariat ethers in the table, and is thus
more suited for a comparison than [18]-crown-6. While the
binding constants for the lariat ethers are also provided in
Table 4, those are in methanol, and slightly different from
those determined in the mixed methanol/water solution in
Table 8.
For [2.2.2]open the only data available are for Na+ and
+
K in 95 : 5 M/W, and the cryptate effects (log Kcryp )
are 3.86 and 4.95 for Na+ and K+ , respectively, similar to
those found with the [2.2]N(CH3 )2 , but 318 times lower
than those of 2.2-BHE. It thus appears that [2.2]BHE is the
closest corollary in terms of binding affinities compared to
the cryptand [2.2.2], although in most cases, a significant
cryptate effect is seen in progressing from the macrocycle
to the cryptand. In summary, while affinities do depend
17
to some extent on the number of binding sites, as seen

throughout this chapter, maximizing cooperativity depends
on a number of other circumstances, including steric and
preorganization effects.
Large cryptate effects are also observed in water as
shown in Table 9, which provides additional thermodynamic information. The cryptate effect (log Kcryp ) is again
substantial, varying from 2.4 to 5.3. The predominant contribution to G for the complexes of [2.2.2] is the generally strikingly large, negative enthalpic term.
4.2.4 Kinetic aspects

It is of interest now to consider the kinetics of complex
formation (kf ) and dissociation (kd ) of chelate, macrocyclic,
and cryptate complexes and how these are related to
the type of ligand structure. Table 10 lists kf and kd
values for chelating (#13), macrocyclic (#4 and 5), and
cryptand (#68) ligands and the appropriate reference
compounds. For the chelate effect, the reactions of Ni2+
with py, bipy, and terpy show very little difference in
kf values. On the other hand, the values of kd decrease
by factors of 2 105 and 2 109 , for bipy and terpy,
respectively. A similar effect is seen in a comparison of
the reactions of Cu2+ ion with the thioether macrocycle
[14]aneS4 (ane denoting a saturated carbon macrocycle
and S4 the four sulfur donor atoms) and its acyclic
Table 8 Complex formation constants for reactions of Mn+ with cryptand [2.2.2] and openchain or monocyclic analogs and the cryptate effect.a
log K (log Kcryp )b
Ligand
[2.2.2]59
[2.2.2]open59
[2.2]BHE65
[2.2]N(CH3 )2 47, 59, 65
a
Na+
K+
Ca2+
Sr2+
7.21 (- - - -)
3.35 (3.86)
4.60 (2.61)
3.30 (3.91)
9.75 (- - - -)
4.80 (4.95)
5.28 (4.47)
4.47 (5.28)
7.60 (- - - -)
7.60 (0.0)
4.65 (2.95)
11.5 (- - - -)
8.44 (3.06)
6.66 (4.84)
Ba2+
12.0 (- - - -)
8.94 (3.06)
6.68 (5.32)
In 95/5 methanolwater at 25 C.
effect = log Kcryp = log K2.2.2 log Kanalog , given in parentheses.
b Cryptate
Table 9
Complex formation constants and thermodynamic parameters for cryptand [2.2.2] and [2.2] BHE.a
[2.2]BHE66
Mn+
Sr2+
Ba2+
Pb2+
Ag2+
[2.2.2]67
log K
H
TS
log K
(log K)b
H
(H )
TS
4.0
5.3
9.2
7.2
10
18
34
36
12
13
18
5
8.3
9.7
12.4
9.6
4.3
4.4
3.2
2.4
44.4
59.9
57.8
53.6
34
42
24
18
2.7
4.6
12.6
1.3
In H2 O at 25 C, H and T S are in kJ mol1 .

b Cryptate effect = log K = log K
2.2.2 log K2.2-BHE , (X)
a
= X2.2.2 X2.2-BHE .
DOI: 10.1002/9780470661345.smc007
(TS)
9
17
5
4
18
Concepts
Table 10 Rate constants for the formation and dissociation of chelate, macrocyclic, and
cryptate complexes along with the corresponding complexes of reference ligandsa .48, 6871
Complex
Solvent
log K
kf , M1 s1
Ni(pyr)2+
Ni(bipy)2+
Ni(terpy)2+
Cu((CH3 )2 -2,3,2-S4 )2+
Cu([14]aneS4 )2+
Na([2.2]BME)+
Na([2.2]BHE)+
Na[2.2.2]+
H2 O
H2 O
H2 O
H2 O
H2 O
CH3 OH
CH3 OH
CH3 OH
2.0
7.0
10.7
2.0
4.3
4.6
4.9
8.0
4.0 103
1.6 103
1.3 103
4.2 106
1.3 105
9.0 107
3.0 108
2.7 108
40
2.1 104
2.5 108
4.5 104
11.0
2.4 103
4.1 103
2.9
25 C.
[14]aneS4
(CH3)2-2,3,2-S4
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 decreases

about 30-fold, but kd decreases by a factor of 4000
for 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 that
kf varies by only a factor of 3 while kd for [2.2.2] is about
1000 times smaller than that of the lariat macrocycles. For
the chelate, macrocyclic and cryptate effects, it is clear that
the most pronounced change for each class of ligand occurs
for the dissociation rates, where decreases of 103 105 occur
for the more ordered ligands, while the formation rate
constants vary only by an order of magnitude or less.
4.3
kd , s1
Anions
Cooperativity is also seen for anion coordination chemistry

in terms of the chelate, macrocyclic and cryptate effects.
However, the area has been less extensively studied than
for the transition metals and supramolecular metal ion
hostguest chemistry. Some examples, primarily structural
with a smattering of binding constants, which illustrate the
importance of cooperativity in anion coordination chemistry
are provided below.
4.3.1 Chelate effect

The chelate effect is also seen for anion hosts. In this
case, there exists more than one class of chelate formation.
First, in anion coordination opportunities exist for chelation within a single functional group, that is, urea, thiourea,
guanidinium, and indolocarbazole (Figure 23ac). One
might say that the urea/thiourea, guanidinium, and indolocarbazole-containing ligands have preorganized minichelate cooperative binding sites. Another type of preorganization is provided by a pyridine (Figure 23d), where H
bonding tends to draw the NH groups into an appropriate
conformation for binding.
This mini-chelate effect leads to the finding that even a
single urea-containing host can form a hostguest complex
(albeit rather weak). An example is shown for the ureacontaining host linked to two nitrobenzenes (providing
additional electron withdrawing enhancement of H bonding
for the urea) (Figure 24), although as noted by the authors,
this is probably primarily an electrostatic interaction. The
acetate complex shows a 1 : 1 stoichiometry. The binding
energy for a variety of anions is really related to the basicity
of the anion, which is seen to be acetate > benzoate
> H2 PO4 > NO2 > HSO4 > NO3 . Nonetheless, it is
most probably the inherent chelation effect that even
allows for the isolation of the simple acetate structure.
An interesting and seemingly recurring phenomenon is that
the basicity of fluoride ion in organic solvents is strong
enough to result in deprotonatation of one of the urea NH
groups, activating the host for conversion of carbon dioxide
to bicarbonate in the presence of water. Thus, a bicarbonate
complex is also obtained with this simple ligand. Although
not shown in the figure, a dimeric structure is actually
formed with H bonding between two bicarbonate guests.72
Another preorganization ploy was successfully employed
by Anslyn and coworkers. The design concept behind the
tris-imidazolium cyclophane-derived tripodal ligand was to
use the ethyl groups to force the H-binding donors all in one
direction for maximized chelation.73 This would promote
the formation of an up-down-up-down-up-down pattern of
substituents. While the coordinating imidazolium groups
all did point in the same direction in the structure with
tricarballate (Figure 25), one of the ethyl groups disobeyed
DOI: 10.1002/9780470661345.smc007
H
N
H
C N
H
N
Indolocarbazole
2,6-Diamidopyridine
(b)
(c)
(d)
Examples of mini- and preorganized chelates in anion coordination.

O2N
(a)
NO2
O
N
H
(b)
Figure 24
Guanidinium
(a)
Figure 23
H
N R
H
N
N+
X
Urea (X = O)
Thiourea (X = S)
H
N
H
N
H
C N
19
N
H
(c)
(a) Chemdraw diagram of the simple urea acycle, and (b) the acetate, and (c) bicarbonate complexes.
O
O2C
H O 2 C
N+
NH
N
H
(a)
HN
+
CO2
HN
NH
H
+N
HN
N
H
NH
N
H
N
H
NH
O
HN
HN
NH
R
(b)
Figure 25 (a) Chemdraw diagram of the imidazolium host and

(b) the tricarballate complex.
common sense and also oriented in an up direction. The

host binds carballate with extremely high affinity in aqueous
conditions, Ka 7 103 .
An example of a more systematic examination of the
influence 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 ligand (Figure 26a) was designed based on the correlation with
the generally strong metal-binding tridentate terpyridine ligand. The high affinity of the tris-urea ligand in DMSO for
SO4 2 was dramatically decreased when a trace amount
of water (0.5%) was added to the solvent. As a result, the
authors decided to increase the number of binding sites to
benefit from the cumulative chelate effect of the chelate
effect and hydrophobic effects in order to circumvent the
large hydration energy of sulfate ion (Figure 26b). However, despite the complementarity observed in the crystal
N
H HN
HN
O
R
NH
(b)
(a)
N
NH H
NH
R
(c)
Figure 26 Chemdraw diagrams of (a) the tris-urea and (b) the

tetrakis-urea acycles, and (c) the sulfate complex with the tetrakisurea host.
structure (Figure 26c), 1 H NMR studies in DMDO-d6 +

0.5% H2 O indicated a lessened affinity of the tetrakis-ureas.
DOI: 10.1002/9780470661345.smc007
20
Concepts
These findings were explained by the authors as due to

a better conformational complementarity between the trisurea and the sulfate.
4.3.2 Macrocyclic effect

A number of years ago, one of the first indications that
the synthetic polyammonium macrocycles would be able
to go beyond simple recognition of anionic substrates was
published by Lehn, Mertes, and coworkers in 1983.75 The
excitement surrounding the discovery of this chemistry
was that these simple cyclic systems could mimic the
naturally occurring ATPases by catalyzing the hydrolysis of
ATP at physiological pHs in aqueous solution. The utility
of these simple macrocycles can be attributed to several
aspects: (i) they operate in water, (ii) due to their cyclic
nature the hosts are polyprotonated under physiological pH
conditions, (iii) one of the reaction pathways involves a
covalent intermediate as a result of the presence of an amine
nucleophile, and (iv) the rates of reaction are enhanced upon
the 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]N6 O2 (N6 O2 reflecting the heteroatoms in the ring)
shown in Figure 27. The reaction sequence proceeds as
depicted in the figure. This simple macrocyclic system
clearly illustrates the importance of cooperativity in binding, both by the macrocyclic ammonium sites and by the
addition of an ion capable of chelation to the ATP. At pH
7, the macrocycle is predominantly tetraprotonated, serving
to 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 suitable
binding with the host and/or by stabilizing the intermediate
phosphoramidate formation. In their polyprotonated forms,
these macrocycles also hydrolyze nucleotides and polyphosphates in the absence of metal ions, but often at slower
Table 11 Comparison of binding constants for the cyclic and

acyclic tetraamide hosts.
Anions
K(M1 ) (TAM)
K(M1 ) (TAA)
Cl
Br
AcO
H2 PO4
1930
150
3240
7410
45
160
346 (223)a
a Binding
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 the
2,6-diamidopyridine hosts of Jurczak and coworkers. In an
elegant study, the researchers compared anion binding of
the tetraamide macrocycle (TAM) with trimethylene bridges
(Figure 28b) with the corresponding tetraamide acycle
(TAA) (Figure 28a).77 They also studied macrocycles with
different chain lengths between the amide groups, but
found that the trimethylene host was superior to the others.
Binding constants were determined in DMSO-d6 by NMR
titration techniques for the macrocycle and acycle, and
the results indicated that the macrocyclic host displayed
affinities approximately 20 times higher than the acyclic
analog (Table 11). Note that in the crystal structure of
the acyclic unbound host, despite the rather zigzag shape,
for each pyridine group the two adjacent amides point
inward, exhibiting H-bonding interactions with the pyridine
nitrogen (Figure 28c). In the acyclic complex with Cl ,
the cavity is open somewhat (Figure 28d), and clearly
not as symmetrical in the binding of its guest as in the
macrocyclic case (Figure 28e). Interesting as well is the
fact that binding constants for the anions in the acycle vary
depending on which NH group is used for the measurement.
It is slightly less for the free methyl amides not connected
by the trimethylene chain, as seen for H2 PO4 .
NH2
N
N
N
N
O
HN
O
P O_
O
P O O
_
O O
OH
pH 7
H2O
NH
2
NH2
+
O
O
O
P O
O
_
P O O
_
_
O O
OH Mg2+, Ca2+, La3+
O
P
O O_
+ NH
NH2
N
N
N N
+NH2
NH2
+
O
P O
HN O
+ NH2
NH2
+
O
O
OH
OH
+ HPO42
pH 7
HN
NH2
NH2
+
H2O
ADP
HN
NH2
NH2
O
O
HN
NH2
NH2
+
Figure 27 The reaction sequence between the tetraprotonated [24]N6 O2 leading to the hydrolysis of ATP and formation of inorganic
phosphate.
DOI: 10.1002/9780470661345.smc007
N
NH
HN
NH
HN
O
NH
host that was contrary to the Hofmeister series, the latter of

which is the general trend of transport in order of decreasing
hydrophilicity.
21
HN
4.3.3 Cryptate effect

N
HN
NH
O
(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) the
uncomplexedacycle and chloride complexes of the (d) acycle and
(e) macrocycle.
A simple lariat crown ether, reported by Barboiu and

coworkers, consists of a benzo[15]crown-5 base with an
appended urea lariat (Figure 29).78 The ligand displays
a dual host binding effect that is allosteric in nature
(Figure 29a). Sodium ion brings the two crown ethers in
proximity, which also allows the lariats to be positioned
for coordination to a chloride guest. The distance between
the two binding sites, that is, the Na Cl distance, is 9.05 A

(Figure 29b). The authors observed the effective transport
of sodium salts of highly hydrophilic anions with the lariat
Lehn and coworkers provided the first evidence of encapsulated multiatomic anion binding in the hexaprotonated
aza cryptand known as bis-tren (Figure 30).79 The authors
noted that the cigar-shaped cavity provided an excellent
complementarity for the linear azide ion. The bis-tren host
displays a high affinity for N3 ion in water (log K = 4.3
for hexaprotonated form of the macrocycle) with the terminal nitrogen atoms on the N3 each interacting with the
three protonated amine hydrogen atoms. This finding led
Lehn to propose that the ligand was suitable for binding
other linear triatomic guests, such as bifluoride, although a
crystal structure was never isolated.
A number of years later, the BowmanJames group was
able to isolate an encapsulated bifluoride as well as an azide
complex in a somewhat more complex octaamide tricyclic
ligand formed by connecting two macrocycles with ethylene
linkers80, 81 (Figure 31). The two structures are essentially
isomorphous, indicating the preorganization of the tricycle
for small linear anions. While the host looks somewhat
flexible, to date only two conformations of the host have
+
+
NH2 O H2N
NH2
NH2
+
Figure 30
O
H 2N
N
N N N
O H2N+
Chemdraw diagram of the azide complex in bis-tren.
(a)
O
2
Na+
O
N
H
Cl
N
H
(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 crystal
structure of the resulting NaCl complex.
DOI: 10.1002/9780470661345.smc007
22
Concepts
N
NH
O
O NH
N
O
NH
NH
N
N
HN
HN
HN
N
HN O
N
(a)
(b)
Figure 31
(c)
(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 pseudoS4 symmetry as in the azide and bifluoride structures. A free
base form has also been characterized crystallographically,
and is isomorphous with the two anion structures. The
stability of the conformation in both structures can be
attributed to an extended H-bond network that works its
way around the inside cavity through the pyridine, amide,
and amine moieties.
Lehn and coworkers published an expanded host capable of binding dicarboxylates, such as terephthalate
(Figure 32ac).82, 83 The design was such that the host
displayed an amazing affinity for terephthalate over other
dicarboxylates (1.5 104 dm3 mol1 in aqueous solution
at pH 6 and 20 C). Binding constants for the other diacids
were in the range of 103 dm3 mol1 . This affinity brings
home the point that in addition to the number of binding sites, a complementary fit of host and guest is vitally
important.
More recently, the BowmanJames group synthesized
another multitopic host that showed selectivity for a number of dicarboxylates (Figure 32df).84 This ligand is an
expanded version of the octaamide tricycle that binds bifluoride and azide, with 12 amides potentially available for H
bonding with guests, that is, a dodecaamide tricycle. The
ligand makes use of the extra four amide linkages in the
terephthalate complex by binding two water molecules in
the side pockets of the host. Two water corks have the
appearance of holding the terephthalate in place.
A famous supramolecular host named the soccer ball
ligand in view of its similarity in terms of symmetry to
the soccerball (or in European terminology football) used
in sports (Figure 33)8588 illustrates the versatility of some
of these hosts. By virtue of its design, the soccer ball

has tetrahedral sites for H bonding, ideal for guests with
tetrahedral binding sites, either from sp3 -hybridized lone
pairs or from hydrogen atoms. In its tetraprotonated form,
the soccer ball ligand encapsulates Cl (Figure 33a). When
neutral it binds the tetrahedral ammonium ion, NH4 + . The
complementarity and cooperativity of all eight binding
sites is utilized in the NH4 + complex. The nitrogen lone
pairs, at the vertices of a tetrahedron, are perfectly matched
to H bond with the hydrogen atoms of the ammonium
ion. This leaves the oxygen atoms situated for electrostatic
interactions with the positive nitrogen center at positions
that bisect the HNH bonds. In its diprotonated form, the
soccer ball host binds H2 O internally. Here again, the host
can adapt to the guest by its degree of protonation, with H
bonding between the two lone pairs of the ligand and the
H2 O hydrogen atoms, while the other two NH groups are
poised at the other tetrahedral sites for H bonding with the
oxygen atom lone pairs.62
4.4
The chemistry beyond
Decades have now passed since the birth of supramolecular chemistry, and the field has evolved and continues
to evolve far beyond its humble beginnings. A hint of
the limitless possibilities was first expressed in the famous
1959 Caltech talk of Richard Feynman,89 Theres plenty
of room at the bottom. The lecture provided what became
a roadmap to nanotechnology. And what better source of
chemistry for this roadmap, but the supramolecular field
that began just a few short years later? For several decades
DOI: 10.1002/9780470661345.smc007
NH
N H
N
NH
(a)
O
O NH
HN
HN
N
H
N
H
N
HN
N
HN
N
NH
O NH
O
23
O
HN O
NH
N
(d)
H
N
O
H
N
HN
N
HN
(b)
(e)
(c)
(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 cryptand
and the octaaza tricycle with terephthalate, respectively. In (e), the water molecules are not shown for clarity, but to emphasize the
similar positioning of the terephthalate.
now, researchers, starting with a handful of groups, and

expanding to many, have been engaged in the development
of artificial-molecular level machineries. Supramolecular
complexes such as rotaxanes (threaded macrocycles) and
catenanes (interlinked macrocycles), which are mechanically interrelated, potentially have applications as molecular switches and machines using cooperative noncovalent
bonding interactions. The details of the chemistry and applicability of this fantastic arena is beyond the scope of this
chapter and is treated elsewhere in this compendium in
the volumes on Self-Assembly and Supramolecular Devices.
Nonetheless, the scope of cooperativity, assisted by the
chelate and macrocyclic effects, is illustrated by providing three simple examples of its extended impacts
DOI: 10.1002/9780470661345.smc007
24
Concepts
NH+
NH+
O
NH+
O
O
O
O
+HN
(a)
+HN
O
O
O
O
+HN
(b)
O
OO
(c)
Figure 33 Chemdraw views depicting the structures of the

(a) chloride, (b) water, and (c) ammonium complexes of the
versatile soccer ball ligand.
in intertwined supramolecular molecules and molecular

machines.
Sauvage and coworkers have been engaged in the study
of molecular topology, an important consideration in the
roadmap to molecular devices. Molecular knots are intriguing to chemists because of their interlinking nature, and
of the many different kinds of knots, the trefoil knot
is the simplest. Because of its intricate interwoven pattern, this beautiful knot has had a historical presence in
art as well as in scientific fields. A trefoil knot is obtained
by locking together the two ends of a regular (or overhand) knot (Figure 34a). The Sauvage group first reported
the Cu(I)-templated synthesis of molecular trefoil knots,
and the crystal structure of elegant dicopper(I) complex is
shown in Figure 34(b).90 These dicopper(I) knots are also
chiral, apparently resolving upon crystallization.
Two back-to-back reports in 1988 by Stoddart92, 93
served to catapult the field of molecular devices forward.
The two communications described the concept of using
-electron-deficient hosts, in this case a cyclobis(paraquatp-phenylene) cyclophane, to bind -electron-rich guests
such as a diphenol-derived ether. A year earlier, the
group had described the reverse, a -electron-rich host and
(a)
Figure 34
-electron deficient guest.58 The structure of the hydroquinone dimethyl ether complex with the paraquat host
(Figure 35a) indicates the threading of the cyclic quadruply charged host by the guest molecule that illustrated
the potential of the hosts as the precursors to molecular
machines.
The early electron-rich and electron poor hostguest
complexes of Stoddart and coworkers led to molecular
machines such as the mixed paraquat and crown catenane (Figure 35b and c).58, 94 In this very simple catenane, a cyclobis(paraquat-p-phenylene) is interlocked with
bis-paraphenylene-34-crown-10. The interactive forces are
mechanical and include only noncovalent, electrostatic
bonding interactions and London dispersive forces. The
rings undergo degenerate simultaneous conformational
changes due to the two identical recognition sites in each
macrocycle, and resulting in a rotation of each ring within
the cavity of the other (Figure 35b). The crystal structure
(Figure 35c) depicts the solid-state structure, confirming
the interlocked ring systems. Cooperativity is inherent in
these exquisitely dynamic intertwined systems, which can
be further modified by placing nonidentical recognition sites
in the macrocycles, resulting in further refinement of the
switching capabilities of these molecular devices.
CONCLUSIONS
All supramolecular complexes are examples of cooperativity in a sense, and there are so many very elegant ones from
which to choose, that only a few have been selected for this
chapter. When based on metal ionligand interactions, the
design of cooperative or self-assembling systems utilizes
certain properties of the ligand and metal ion. For the former, these include the number, type, and arrangement of
(b)
(a) Picture of a trefoil knot drawn using POVRAY91 and (b) a molecular trefoil knot containing two copper(I) centers.
DOI: 10.1002/9780470661345.smc007
25
(a)
O
+
+N
N+
O
(b)
(c)
Figure 35 (a) Inclusion complexes of [cyclobis(paraquat-p-phenylene)]4+ with hydroquinone dimethyl ether, (b) Chemdraw depiction
of 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 case

of metal ions, the coordination number, geometry (square
planar, tetrahedral, octahedral), and Lewis acid properties
are important. The formation of complexes (both metal ion
and supramolecular) with multidentate (chelating) ligands
plays a crucial role in a number of cooperative processes
such as template synthesis, the behavior of allosteric receptor systems, as well as the assembly of two-dimensional
grids, three-dimensional cages, nanoscale reactors (containers), molecular switches, and molecular machines. Metal
ionligand interactions may be utilized to convert a ligand from an acyclic to a macrocyclic or bi(poly)cyclic
structure.95 These multidentate chelating ligands may have
increasingly enhanced binding properties and/or selectivity
for the desired guest compared to an equivalent number of
their unidentate counterparts. The phenomena describing
this enhancement emanate from the widespread existence
of the chelate, macrocyclic and cryptate effects that are all
leveraged by cooperativity.
The concepts of the chelate, macrocyclic and cryptate
effects have come a long way since their original coinage.
Together with a better understanding of the role of cooperativity in these chemical trends and the addition of
supramolecular chemistry to the field, our understanding

of chemical processes has led and will continue to lead to
better insight to the design of a wide variety of utilizable
chemical systems at the molecular level.
ACKNOWLEDGMENTS
K.B.-J. gratefully acknowledges support from the National
Science Foundation CHE-0809736.
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Cooperativity and the Chelate, Macrocyclic and

University of Oklahoma, Norman, OK, USA

Cooperativity and the chelate, macrocyclic and cryptate

hostguest complexes. A key historical example of positive

it is evident that the same phenomena can be attributed to

In the late 1800s, the visionary Alfred Werner predicted the

Figure 2 Comparison of binding modes for transition metal

Cooperativity and chelate, macrocyclic and cryptate effects

In traditional coordination chemistry, chelates (from the

ion simultaneously. For example, ethylenediamine (en) or

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

Cu2+ + 2CH3 NH2 Cu(CH3 NH2 )2 2+

Figure 3 shows some simple chelators and their comparable

H = 100 kJ mol1 , S = 163 J mol1 K1

1018 , G = 101.8 kJ mol1 ,

Monodentate and chelating ligands and abbreviations.

ions/molecules, contributing to more disorder and an even

Cooperativity and chelate, macrocyclic and cryptate effects

Table 1 lists formation constants with selected metal ions

M(L)n + Ln M(Ln) + nL

Ni2+ + 2NH3 Ni(NH3 )2 2+

LogK1 (polydentate ligand)

Cu2+ + 4NH3 Cu(NH3 )4 2+

2.57 (5); 2.89 (6)

and n defined in (1 and 2).

where Ln is a chelating ligand with n identical donor atoms

The latter term, (n 1) log 55.5, derives from the fact

ligand (usually around 2.0 A

In addition to sequential binding effects of multiple

Figure 5 (a) Structure of the Fe(DMG)2 (Im)2 complex and

ring around the iron atom with contours at increments of 0.5 e /A

starting at 0.2 e /A.

binding of ligands to transition metals. For example, the

Macrocyclic chemistry had its beginnings in the 1960s.

Cooperativity and chelate, macrocyclic and cryptate effects

R = CH3, C2H5, C5H11

Figure 6 Final step of the reaction sequence resulting in the

Probably the most famous cryptands are those first reported

Macrocyclic and cryptand ligands.

In supramolecular chemistry, stable hostguest complexes

Figure 8 Schematic representation of multiple hostguestbinding site interactions.

Mn where n would be the number of pairwise contacts,

Ktot = (55.5)1 KH1 G1 KH2 G2 KH3 G3 KH4 G4 KH5 G5 (12)

Cooperativity and chelate, macrocyclic and cryptate effects

Perhaps the most apparent similarities with transition

4.2.1 Chelate effect

Relaxed conformation results in

Lessened solvation of lone pairs

Macrocycle (crown ether)

Limited solvation of lone pairs

In CDCl3 saturated with H2 O.35

and KML2 = 6.3 107 , respectively, and KML2 /KML1 =

often employed in the construction and/or operation of such

Cooperativity and chelate, macrocyclic and cryptate effects

4.2.2 Macrocyclic effect

followed by the type of macrocycle, crown, followed by

size from [12]crown-4 to [21]crown-7 with the ions K+ ,

the host and guest within bonding interaction (not shown).

Cooperativity and chelate, macrocyclic and cryptate effects

Chemdraw diagrams of [2.2]NCH3 and lariat ethers.

Here, the two arms are separated by the bridgehead

(log K)a (#)b

= log Kcyclic log Kacyclic .

H = 100 kJ mol1 , S = 163 J mol1 K1

1018 , G = 101.8 kJ mol1 ,

(log K)a (#)b

In H2 O at 25 C, H and T S are in kJ mol1 .