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Multidentate Acyclic Neutral Ligands and Their Complexation.

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Multidentate Acyclic Neutral Ligands and Their Complexation
By Fritz Vogtle and Edwin Weber'']
The properties of cyclic crown ethers are approximated by acyclic neutral ligands (podands),
which are compared and contrasted with open-chain bioionophores and acidic chelating agents
in this article. Variations of the endo-polarophilicity/exo-lipophilicitybalance, complex stability, ion selectivity can often be accomplished more easily, with greater versatility, and at less expense with acyclic polyethers than with their cyclic counterparts; complexation and decomplexation are generally faster in acyclic systems; and the pseudocavity usually has greater conformational flexibility. Acyclic crown ethers and open-chain cryptands stiffened by rigid "terminal groups" containing donor atoms readily form crystalline complexes of alkali and alkaline earth metals. Some open-chain neutral ligands form helical conformations in their crystalline complexes. The observed coordination numbers and geometries are of theoretical interest.
Attractive terminal group interactions lead to pseudocyclic species occupying a position intermediate between cyclic and acyclic ligands. It has recently proved possible to isolate crystalline
complexes of alkali and alkaline earth metal ions with weakly donating oligo(ethy1ene glycol
ethers) and with glycols; such complexes have also been obtained with sugars. Acyclic neutral
ligands can serve as simple models of nigericin-type bioionophores and be used analytically in
microelectrodes. The recently discovered crystalline stoichiometric complexes formed by some
acyclic neutral ligands with guest molecules such as urea, thiourea, and water provide a fresh
insight into weak interactions between neutral molecules and for the development of urea receptors
therefore inexpensive["], of versatility of ligand structure['b,"l, and of fast complex formation (see Section 4.2.5).
1. Introduction'''
Induced by formation of alkali metal ion complexes by dibenzo[1Slcrown-6
the range of available synthetic
crown ethers['] was first extended by variation of ring size
and of donor atoms in the monocyclic representative^'^' and
by the preparation of bi- [e.g. (2)] and oligocyclic cryptan&[41
1"':
~ - o n o ~ n o - ~
~ - O ~ O - ~ - O ~ - T J
(LI
(31
In order to demonstrate the importance of open-chain ligands of crown ether type (podands), we shall first consider
corresponding natural ionophores and, for purposes of demarcation, the alkali metal ion complexes of "acidic" chelate-forming ligands.
2. Acyclic Ionophoric Antibiotics
The open-chain bioionophores such as nigericin (5)I5l (see
Table 1 ) which like the cyclic bioionophores nonactin and
valinomycin[6]can complex alkali metal ions with a remarkable degree of ~electivityl'~
prompted the study of acyclic oligoethers. The exceptional properties of the cyclic crown ethers offer the only explanation for the dearth of work performed with simple acyclic neutral ligands of types (3) and
(4) (A, B, C are any structural units, vide infra). The latter
have the advantage of facile synthesis, which requires use of
neither dilution principle181nor template effect19' and is
['I
Prof. Dr. F. Vogtle, Dr. E. Weber
Institut fur Organische Chemie und Biochemie der Universitat
Gerhard-Domagk-Strasse 1, 5300 Bonn (Germany)
["I We propose the following rule in the interest of systematic use of the terms
crown ether, coronand, cryptand, and podand coronands are taken to mean medio- and macromonocyclic compounds with any heteroatoms. Cryptands are biand polycyclic compounds with any heteroatoms, podands are acyclic coronand
and cryptand analogs with any heteroatoms. The term crown ether is used for
coronands having only oxygen as heteroatom.
Angew. Chem. I n f . Ed. Engl. 18. 753-776 (1979)
Ionophoric antibiotics are lipid-soluble natural products
which form complexes with alkali or alkaline earth metal
ions and can thus influence the transport of ions through
membranes"". They can be divided into several groups on
the basis of structural feat~res[~.'.'~l:
a) Peptides"31, acyclic ionophoric antibiotics (gramicidalamethicin[15])with up to 20 amino acid units, and
also cyclic ones (antamanide[l6]);
b) Polyenes[''] and polyethers, including the open-chain nigericin antibiotics, nigericin (5jc51,grisorixin (6)Ifs1,dianemycin (7)[I9l, monensin (8)I2O1, X-206 (9)[211,
X-537 A (10)[221
(see
and cyclic macrolide esters of the actin series (nonTable I),
actin to tetrana~tin)'~~';
c) Depsipeptided"] (valinomycin, enniatin, monamycin,
beauvericin), i. e. ester amides. They usually have cyclic
structures, frequently with unusual ring sizes, which may
contain uncommon amino acids.
Most of the acyclic (or pseudocyclic, vide infra) ionophores
have a polyether structure. Of physiological[241
and clinical
imp~rtance['~lare their selectivities for various cations[7!
0 Verlag Chemie, GmbH, 6940 Weinheim, 1979
0570-0833/79/I010-0753$ 02.50/0
753
While the open-chain nigericin (5) (like most cyclic ionophores) shows a preference, e. g. for K' over Na@[261,
the order Na@> K' applies to monensin (a), also in biological sys271.
On complexation, acyclic antibiotics (e.g. nigericin) wrap
themselves around the cation like a pseudocyclic species. As
with cyclic ligands[281,this enclosure of the ions occurs in
such a way that polar regions (ether, carbonyl oxygens) of
the ligands are directed inward (endo-hydrophilic or endopolarophilic) towards the cation; the periphery of the complex therefore consists of lipophilic regions (CH2 groups, alkyl groups, aliphatic rings) making the complex exo-lipophilic and thus soluble in lipophilic media (organic solvents,
biological membranes). The generally flexible open-chain
Table 1. Important acyclic ionophoric antibiotics. Coordinated oxygen atoms are
shown in bold type.
3
H
H H
H3C0
H COOH
(5): R = OH NIGERICIN
(6): R = H GRISORIXIN
bioionophore changes its conformation on complexation; it
usually becomes less mobile. This affects, e.g. the rate of
complexation and of the dissociation of the complex into its
components[12'.In the case of monobasic acids, the pseudocyclic species are stabilized by terminal group interactions, in
the complex and in the free ligand'29,301.
In the latter case, the
pseudocavity is usually occupied by an additional water molecule@.l21.
Monensin (8Jr201,
nigericin (5)l5],grisorixin (6)I'"], X-537 A
(10)f2'1,alborixin (11)[3'1,and emericid (12)r321
(Table 1) are
well characterized carboxylic antibiotics. They all possess an
acyclic primary structure but may adopt cyclic tertiary structures as a result of hydrogen bonding. X-ray structure analyses[20b1
show the free acid monensin (8)to exist in a cyclic
arrangement with two intramolecular H bonds between the
C-0 group and a water molecule which holds the two ends
of the chain together (Fig. la). Complexation of an AgD ion
leads to differing H bonding'331;however, the C-0 does not
coordinate the central ion according to X-ray structure analyses[zoy(see Fig. Ib). In the free ligands, the water molecules bound by H bonds appear to play an important role in
complexation, in that they affect the hydration sphere of the
central
o
c
0
0
0 (coord.)
CH3
(7) DIANEMYCIN
COOH
(8) MONENSIN
a
a1
(10) X - 5 3 7 A
bl
Ill) ALBORIXIN
(12) EMERICID
154
Fig. I . a) Structure of monensin @]-monohydrate. H-bonds shown as dashed
lines. b) Fine structure of the monensin-Age complex. Metal/oxygen contacts
shown as dotted lines. Two H bonds (dashed) are responsible for the pseudocyclic ligand conformation [28].
The silver salts of the ionophoric antibiotics nigericin
(5)[5b1and grisorixin (6)['8b1
resemble the monensin-Age
except that the silver ion is coordinated by the C=O
group.
Angew.
Chew.Inr. Ed. Engl. 18, 753-776 (1979)
The Ba2@complex of X-537 A (10) crystallizes as an aggregate of two molecules of antibiotic, one Ba2a ion, and one
molecule of water of ~oIvation[~~’.
Six oxygen atoms of one
ionophore molecule and two of the other coordinate the cation. In the dimeric Ag@complex of X-537A, the Aga ions
are enclosed in almost cylindrical fashion by the ligands,
with each ion being fixed to five oxygen atoms and one phenyl
As in monensin, the C-0 groups are not joined
directly to the Age ion.
In the presence of pyridine or triphenylphosphane, 2,9bis(methoxymethyl)-2,9-dimethyl-4,7-dioxa-l
,I O-decanedioic acid (19) forms crystalline dimeric chelates with Cu2@
ions; the ether oxygen atoms play an important role in their
formation[431.Unsubstituted oligo(ethy1ene glycol) dicarboxylic acids (20) are found by pH titrimetry to show various
stability sequences with alkaline earth metal ions, depending
upon the number of ether oxygen atoms present (n=O3)1441.
3. Chelates: Alkali Metal Complexes of (Potentially)
Acidic Acyclic Ligands
In contrast to the “classical” heavy metal complexe~[~~1,
stable coordination compounds of Group I and I1 elements
with synthetic acyclic neutral ligand molecules were apparently unknown until the sixties. Crystalline products of alkali
metal hydroxides and alkoxides and 1,3-diketones, o-nitrophenol, and salicylaldehyde all have chelate
A climax was reached in the complex chemistry of protic
“chelating agents”[371on preparation of “complexones”
[ethylenediaminetetraacetic acid (EDTA) (13), nitrilotriacetic acid (NTA) (14), e t ~ . ] [ which
~ * ~ , preferentially bond to alkaline earth metal ions. Uramildiacetic acid (15) can also
form stable complexes with univalent metal ions in aqueous
solution (stability sequence: K @ < Na@ < Li@ < TI@ <
H@)I3’)I.However, MZo ions (except Be2@)are complexed
better by EDTA than by uramildiacetic acid. Complexones
having heterocyclic ether
or amine nitrogen donor
such as (16) and (17), permit further variation in
the stability sequence.
HOOCH2C,
CHpCOOH
NCHzCHpN:
HOOCHpd
CHzCOOH
,CH,COOH
N;CH,COOH
CHzCOOH
(131
11.41
i<o
CHpCOOH
o=(
CHN:
CHpCOOH
Sodium chloride and some other alkali metal halides could
be precipitated from aqueous solution as coordination compounds with rac-p,p‘-diamin0-2,3-diphenylbutane~~~).
Furthermore, the NH?, alkali metal, alkaline earth metal, and
heavy metal “salts” of oxotripyrrene-2-carboxylic acid (21)
have also been ascribed chelate character[46].
Alkali metal complexes with phosphane oxides as ligands
have been examined by X-ray structure
in the
NaBr complex of P,P’-methylenebis(dipheny1phosphaneoxide) the Na@ion is located in a trigonal-prismatic environment of six oxygen atoms of the phosphane 0xide[~*1.IR
studies suggest partly electrostatic bonding between Na@and
0.The smaller Li atom is accordingly coordinated by a tetrahedral arrangement of only four oxygen atoms in the LiI-triphenylphosphane oxide complex[491.Analogous arsenic ligands form complexes of only modest stability with alkali and
alkaline earth metal halided4’].
A roughly octahedral environment of 0 coordination sites
is found in the NaC10, complex of bis[N,N-ethylenebis(sa1icylideniminato)copper(~r)]~~~]:
two 0 donors are contributed
by the chelating ClOQion and two by each of the tetradentate ligands in the Cu complex, which are fixed in sandwich
fashion above and below the NaQ ion. Chelation of the Na@
ion is again regarded as the principal feature of the bonding
in this complex.
8-Hydroxyquinoline (22), isonitrosoacetophenone (23),
and 1-nitroso-2-naphthol (24), on the other hand, can probably form true (i. e. nonprotic) coordination compo~nds[~‘l.
QQ
‘O H
HO
Among the four-armed ligands of the same type as tetraazacycloalkane-N,N,N’,N”-tetraacetic acid (18)[421,whose
complexing properties depend on ring size, (18a), n = rn = 2,
having a pK value of 15.85, is the strongest complexing agent
known for Ca2@.In the case of (18b),n = 2, rn = 3, the stability of the Sr2@complex (pK=11.70) is very noticeable, while
(18c), n = rn = 3, is able to discriminate between Mg2@and
Ca2”.
Angeni. Chem. Inr. Ed Engl. 18, 753-776 (1979)
Another acidic complex ligand is a chiral dihydroxy compound, called “semicrown” by Wudl, which forms complex
it yields a stable
salts of type (25) with alkali metal ions[521;
crystalline salt with Lie. The optically active ligand exhibits
cation-specific ORD curves, suggesting that the Li’ and NaO
ions are probably enclosed; this appears impossible with
larger ions.
755
4. Synthetic Acyclic Neutral Ligands (Podands)
4.1. Classical Glyme Compounds (Oligoethylene Glycol Dimethyl Ethers) and Their Relatives
On going from cyclic [18]crown-6 (26) to open-chain, and
yet also hexadentate, pentaethylene glycol dimethyl ether
(“pentaglyme”) (27e) (Table 2) an approximately 104-fold
h,41) is observed
drop in stability (complexation constant Ks[’
This correfor complexation of KO ions (ca. lo3 for Na@)lS31.
sponds to a drop in the enthalpy of complexation AGO of ca.
25 kJ/mol (6 k~al/mol)[’~~.
This tendency is also observed for tert-butylammonium as
guest ion in cyclic crown ethers (28) and (29) and the corresponding glyme analogues (30)-(32)[55’.
Table 2. Comparison of some crown ethers and their acyclic analogues.
and tetrasulfide systems[s81showed that thermodynamic parameters (AH), coupled with ligand solvation effects, often
play a greater role in the origin of the macrocyclic effect[59i.
Polarographic determinations of log K,, AH, and A S for the
interaction between heavy metal ions such as PbZe with
[18]crown-6 (26) or tetraglyme (27d), n = 3 , in aqueous solution showed the cycle (26) to be some lo4 times more stable
than the open-chain ligand[601.The macrocyclic effect was attributed largely to entropy effects in this case. Measurement
of complex stability constants of some oligoethylene glycol
dimethyl ethers (27) of various chain lengths for Na@,K O ,
Cs’, T1”[6’1(potentiometric and conductometric, in CH30H)
revealed that an increase in the number of coordination sites
(ether 0 atoms) raises the stability constants and the K O /
Na@selectivity; replacement of the two methoxy chain ends
by primary carboxamide groups or ester groups impairs the
complexation properties of the ligands.
In keeping with the low stability constants-even in lowpolarity organic solvents-crystalline alkali metal complexes
of such “simple” acyclic oligoethylene glycol ethers (27), the
glymes, were unknown until very recently[621;this also applies to ligands containing polyether chains of up to ten oxygen atoms which are bent by and also partly stiffened by inclusion of ortho-substituted aryl
The stoichiometries and specific structures of the resulting
ion pair/glyme compounds were determined in tetrahydrofuran (THF) by titration of difluorenylbarium with glymes
of various chain lengths[631.Like [18]crown-6 (26) and mono~ ~ ] n = 5, and glyme-9
benzo[l8]crown-6 (33b), g l ~ m e - 7 [(278,
(27h), n = 7, give 1 :1 complexes between the ligand and difluorenylbarium. It can be shown from the optical spectra
that these complexes are mixed intimate/loose ion pairs of
The ability of
the type fluoreny18Ba20/glyme/fluorenyle[651.
glyme-5 (27d), n = 3, like monobenzo[l5]crown-5 (33a) to
form a stable 2: 1 complex with difluorenylbarium suggests
that a ligand such as glyme-10 (27i), n = 8, should have adequate bonding sites for construction of an entirely separate
1: 1 ion pair complex. Such an ion pair also results on coordination of difluorenylbarium with glyme-23 (27k); two Ba2@,
(fluorenyl):@ units may possibly be complexed to this
glyme.
Numerous publications have already appeared concerning
the synthesis and structure of crystalline glyme complexes
with transition metal ions, e.g. Fe2@,Mn”, Co2’, Ni2@,
C U ” [ ~ ~and
I , with mercury[67’and cadmium saltsi6’’, including some X-ray structure analyses[69’. While several molecules of dimethoxyethane (27a) (monoglyme) are usually required (generally three[b6,691)for complexation, dinuclear
complexes are also formed by suitably long pol yether
chains‘67‘’. X-ray structure
of the complex of
tetraethylene glycol dimethyl ether (27d) (TGM) with HgClz
(1 : 1 stoichiometry) indicates the following ligand conformation[’’!
a
*
p
?
ao mLJ3
rd‘OCH3
l
yJH3
(29) la1
/3t) [ b l
(32) Ccl
[a] &=26 (with tBuNH?CIO$’). [b] Kt=0.026 (with tBuNH?CIO?), 4.5 (with
t B u N w F 3 . [c] KE=0.0738 (with IBUNH~PF??.
The extraction constants K E (solvent CDC13/D20) show
that (29) complexes ca. lo3 more strongly with tBuNHy than
with (31) whose donor centers only partly converge. Compound (31) has complexation properties some 10’ better
than (32) with terminal naphthyl groups since there are no
longer any (mutually linked) rigid groups able to enforce
convergence of donor atoms. The difference in complex stability between the cyclic compound (28) and its acyclic analog (360:40) seems remarkably small compared with (26)/
(27e) (vide supra); apparently, the binaphthyl hinge permits
extensive perturbation of planarity (and convergence) of individual coordination sites. Thus it may be concluded that
enforced convergence of the binding sites in these simple systems, i. e. a stiffening of the ligand backbone favoring coordination, considerably increases complex stability. The modest
difference between the cyclic compound (28) and the acyclic
analogue (30) also suggests that a detailed examination of the
readily preparable open-chain neutral ligand might be a rewarding object of study.
The difference in complex stability which can result on
ring closure-retaining
the nature and geometry of donor
atoms-is denoted as the “macrocyclic effect”[4.53a,5h1.
Although this effect was originally explained in terms of entropy factors which oppose complete enclosure of cations by
acyclic polyethersls61, studies on macrocyclic tetramine’”]
’
756
Angew. Chem. Int. Ed. Engl. 18, 753-776 (1979)
ap
sc
(-)sc
up ap
ap up
ap ap
sc
(-)sc
All the H2C -0 bonds are thus antiperiplanar (ap), and the
CH2 CH2 bonds in the adjacent unit alternately synclinal
(sc) and ( - )-synclinal [(-)XI. The ligand is fixed in a circular geometry but does not form a closed circle (see Fig. 2a).
The five oxygen atoms, which are almost coplanar and all directed inward, closely embrace the Hg2B ion (2.78-2.98
New combinations of sulfur and oxygen donor centers in
oxathiapentadecanes of general type (34a) should be particularly suitable for complexation of heavy metal ions, especially Ag@,Hg2@[751.
A,.
b)
Fig. 2. Interactions between the 0 and Hg atoms in the HgCI2 complexes of (a)
TGM (27d) and (b) HGE (27/) [67a, cl.
In the corresponding tetraethylene glycol diethyl ether
(TGE)/HgCI2 c o m p I e ~ [very
~ ~ ~similar
l
Hg-0 distances and
angles are found in the interior of the chain. An sc arrangement occurs at only one end of the chain, thus avoiding steric
hindrance of the ethano groups in the ap/ap conformation.
Hexaethyiene glycol diethyi ether (27f) (HGE) can utilize
its seven coordination sites to bond two Hg2@ions at relatively short distance (Hg---0, 2.66-2.91 8);the HGE molecule exhibits the following conformation in the complex167c1:
CH,- CHz-0-
CH,-CH*--O
ap ap
sc
CH2-CH2-0
ap ap
(-)sc
CH2- CH2- 0
ap ap
sc
sc
sc
CH2- 0 CH2 CH2 -0-CHZ -CHZ-O-CH,-CH,
-CH2
sc
ap up
(-)sc
ap ap
sc
ap ap
(2 74
The adjacency of two sc/sc sequences at the central 0
atom is remarkable; it effects a separation into two coordination moieties of four coplanar oxygen atoms, each occupied
by one Hg2@ion. The central 0 atom is involved in coordination to both Hg ions (see Fig. 2b).
Similar structural units are found in the complex of tetraethylene glycol dimethyl ether (27d) (TGM) with CdC12[“].
However, owing to the smaller number of donor sites available (five per glyme molecule) additional CI bridging ligands
are required; each bridge holds together two ligands over a
total of four Cd’@ ions.
While glyme complexes of Hg2@salts are relatively easy to
obtain the preparation of corresponding coordination compounds with the softerf7’]Hg@ions runs into difficulties owing to disproportionation to Hgn and Hg2@[721.
However, a
crystalline complex of composition Hg2(diglyrne)2(N03)2has
recently been isolated; it can be kept for some time under a
protective gas but on heating (65 “C) the organic ligand (276)
is completely eliminated‘731.Corresponding Hg’ complexes
of sulfide ligands proved to be more
Angew. Chrm. Inr. Ed. Engl. 18, 753-776 (1979)
Ni’”, Co’”,
Complexation of transition metal ions (CU’~’,
Zn’@, Pd2’ and Ag2@)with the open chain sulfur-, oxygen-,
and nitrogen-containing ligand 8-oxa-5,I 1-dithia-2,14-diazapentadecane (346) has also been
Alkali metal
complexes of this “heteroglyme” appear-as expected from
the low tendency of the soft sulfur atom to coordinate the
play only a subordinate role.
hard Group I element~[~~]-to
The same applies to the many open-chain multidentate
Schiff base ligands (35) which readily form complexes with
Fe, Co, Cu, Pd, Pt, Ru, e t ~ . [ ~ ~ ] .
136)
More than 25 years ago, phenacyl kojate (36) was found to
form crystalline 2: 1 complexes with sodium halides in methan~l[’~]].
Their structures[”] (see Fig. 3) resemble those of the
[ 181crown-6 complexes of the corresponding sodium salts[”]:
six oxygen donor centers (from two phenacyl kojate units)
are grouped in planar fashion around the sodium ion; in contrast to the crown ether complex, however, four of them
come from a carbonyl group. The crystal structure is held together by H bonds between CO and OH groups and by
H...O interactions. The Na 0 distances lie between 2.56
and 2.68 A[”].
..
o
@
0
@
c
O
0 Icoord.)
Na@
Fig. 3. Crystal structure of the complex formed by phenacyl kojate (36) with
NaCI’‘”’.
Alkali metal salts have been known for some time to form
complexes with 1,4-dio~ane[~~];
however, these complexes
757
have poor thermal stability and exhibit high dioxane vapor
pressures even at 300 K. Although some of them are isolable
in crystalline form from aqueous solution they generally lose
their dioxane to the air. The coordination compounds of
NaCIO,, NaBF4, NaI with dioxane, like the AgC104 complex, possess a cubic structure with the metal ion in an octahedral environment of dioxane oxygen atoms at distances of
2.43-2.46 A. The perchlorate ion at the center of the unit
cell can undergo free rotation, and the dioxane molecules rotate about their 0--0 axes. Ions of the higher alkali metals
are too voluminous to form stable crystal structures.
Dimethyl phthalate (37) acts as a bidentate neutral ligand
towards various divalent cations such as Mg”, Ca2’, Mn2@,
Fez@,Co2@,Ni2@, and Zn20[“1. In the resulting complexes,
the metal ions are each bonded by three dimethyl phthalate
molecules via the carbonyl groups, with the coordinating carbony1 oxygens forming a regular octahedron. It is important
for these complexes to have a large counterion (e.g. InC13;
they decompose completely in the presence of water.
1371
1381
At roughly the same time, alkali metal complexes of phenanthroline and of bipyridine, including some
with potassium salts, were obtained in independent studieslsW,
The tendency of certain heterocycles to favor Li’ over
ions of the higher alkali metals is also apparent from the solubility series of the chlorides of Na’, K@,Rb@,and Cs’ in
pyridine, in which all these salts except LiCl are practically
insoluble[xyl.The situation can be modified by stepwise addition of water. This is the basis of a separation of lithium ions
from other alkali metal ions and from BaZ@which was developed as long ago as 1908””’.
4.2. Acyclic Crown Ethers and Coronands
4.2.1. Terminal Group Concept
Attachment of rigid (e.g. aromatic) terminal groups (E)
bearing donor centers (Do) [cf. (40)] to oligoethylene glycol
units (“terminal group c o n ~ e p t ” ) ~affords
~’’
neutral ligands
(41) which readily form stable crystalline complexes with alkali and alkaline earth metal ions[yz2’
in the same way as the
cyclic crown ethers. Apart from complexes of Na, K, Ca, erc.,
it is also possible to obtain such compounds of lanthanoids,
uranyl, Zn, Hg, Mg, and Ag salts, as well as ammonium ion
complexes.
r
139)
A remarkably stable 2: 1 complex is formed by 0,O‘-catecholdiacetic acid (38) and KCl[851.It has a complicated layer
structure stabilized by H bonds in which the KO ions are enclosed in sandwich fashion by ten 0 atoms (four ether and
six carbonyl oxygens) in an irregular pentagonal-antiprismatic arrangement (Fig. 4).
r
i
i
Suitable terminal groups ( E ) are 8-quinolyloxy, (42), omethoxyphenoxy (43), o-nitrophenoxy groups (44), among
many others[”~’*].
r
(42a-gl:
i
n.0-6
r
(43a-d/:
r
i
n.0-3
(440-d)
i
n=
o-3
Fig. 4. Structure of the complex of 0.0’-catecholdiacetlc acid with KCI [SS]
N o such coordination compounds can be obtained with Li,
Na, Cs, and NH, salts. The observed “precipitation selectivity” towards KO, which exceeds that of NaB(C6H5)4,is unusual since all the other known precipitation reagents for K’
also respond to Nm,Cs’, and Rborxsl.
Work by P. Pfeiffer, who isolated crystalline complexes of
1,f 0-phenanthroline (39) with, e. g. LiC104, NaC104, AgN03,
TINOs, Ca(C104)z, Sr(ClO&, and Ba(C104)2as long ago as
1938[877’,
seems to have been forgotten. The complexes are
precipitated from aqueous/alcoholic solution and can be recrystallized without decomposition. The Li complex forms
particularly readily, while the Na salts show little tendency
to undergo complexation and no corresponding K compound could be obtained at the time. The results were recently reconsidered and an interpretation based on the influence of the counterion and on protonated intermediates
758
Synthesis of unsymmetrical open-chain ligands such as
(45) permits almost any intramolecular combination of weak
and strong donor terminal groups.
The terminal groups function as anchoring points with locally fixed donor centers on which the cation can take hold; a
certain number of donor sites remains a prerequisite for complex formation. Structures such as (47) in which the terminal
groups are isolated from one another by a polymethylene
chain show only limited ability to form crystalline alkali
metal complexes although the distance between the quinolyl
units was modified by variation of n[’2.y3a1.
Apart from the terminal group donor effect, geometrical
and steric factors also play a role[”.”1: the compounds (46c),
X = C OCH3, (46d), X = C NOz, and (48) bearing an adequate number of proven donor atoms neither form crystalline complexes with alkali metal salts nor do they transfer alkali metal permanganates into organic phases. Complexation
Angew. Chem. Int. Ed. Engl.
IX, 753-776 (1979)
is apparently blocked by substituents (which in principle are
capable of coordination[y3b1)
projecting into the pseudocavitY.
Among the neutral ligands having diacetylmonoxime terminal groups (49)[941,the E configuration of the oxime appears to interfere with the formation of crystalline complexes.
tion is also retained on recrystallization of the complex (from
methanol/ethyl acetate).
The teirasubstituted ligand (53) forms not only 1 : 1 comp l e ~ e s [ ~ ~transition
"l:
from 1 : 1 stoichiometry in the (53~)LiC104 complex to 3 :2 stoichiometry (ligand: salt) in the
(53u)-sodium complex can be rationalized in terms of the
greater radius of the sodium ion, which precludes complete
R =H,OCH,.CN
( 4 5 0 - d ) : n.0-3
Id 7)
1460): x = N
Ib):
(481
X = CH
IcI: x = c-OCH,
(490- c ) :
n = 1-3
(50)
On the other hand, no steric hindrance of crystalline complex formation by the methyl groups is observed in the quinaldine compound (SO); this is easily rationalized in terms of
the helical structure of the ligand in the complex (see Section
4.2.3). The ortho-phenylene compound (51) can also form
stable complexes of the ligands (43), (52) (with positionally
isomeric methoxy terminal group), and (53), which contain
only oxygen as donor centers; only the o-methoxy derivatives
give crystalline alkali metal salt complexes under comparable conditions[""].
Terminal groups can also be attached by way of ester
groups instead of ether functions [cf. (55)]; in some cases,
transesterification was observed on attempted isolation of
crystalline alkali metal complexes in methanol as solvent1''l.
4.2.2. Stoichiometry of the Crystalline Complexes
Stable crystalline complexes are obtained not only with
Group I and 11 metals~y'~y2~y5"~
but also with transition metal
ions (ZnZ@,Cd2@,Hgzo, Ag@,CO'', Ni") and lanthanoid
and actinoid ions (Pr3@,Nd3@,UO:@) and with ammonium
salts~92~95h~:
however, many cations remain to be studied.
In spite of less strictly stipulated "cavity geometry", complexes of exactly stoichiometric composition are generally
formed-even in the presence of a large excess of one component of the complex[yzl.For example, the ligand (42d) always gives a l:l complex with KSCN regardless of whether
the molar ratio of ligand to salt is 2 :1 or 1 :2. This composiAngew. Chem. Int. Ed. Engl. 18, 753-776 (1979)
enclosure by a single ligand molecule. The fact that the
(53b)-sodium and (53b)-potassium complex also exhibit 2 : 1
stoichiometry requires a different explanation, particularly
since the ligand (43b), which bears a single o-substituent on
each side, forms a 1 : 1 sodium complex. In this case, mutual
steric hindrance in the 1,2,6-positionsrules out the availability of the methoxy groups in the optimum cation region-as
manifested, e.g., by chemical shift differences in the 'HNMR spectra of the complexes-with the result that a further ligand molecule is required for occupation of the free
coordination sites on the metal ion.
The proposed structures are also supported by features of
the IR spectra of these complexes. In general, interpretable
changes in the IR absorptions of crown ether complexes relative to the free ligands are conspicuous in the region of the
mostly strong bands of the original salt[2.'61.Above all, these
include the absorptions of inorganic anions such as NO?,
SCN', Cloy, B E , and also those of complexed ammonium
This also applies to complexes of open-chain crown
ether~I~~l.
Some of the complexes contain HZOin stoichiometric prop o r t i o n ~ ~ as
~ ' revealed
. ~ ~ ~ , by the appearance of more or less
The question whether
sharp OH bonds in the IR
the H 2 0 molecules are in coordinational contact with the
complexed cation or exist as free water of crystallization in
the crystal lattice[981will only be conclusively settled by Xray structure studies (vide infru). This also applies to the extent of participation of anions in
which has
been explained in such a way for some complexes.
159
4.2.3. X-Ray Structure Analyses of Crystalline Complexes
for N(l) and 2.96 A for N(19) are very close to the value of
2.97 calculated from the atomic and ionic radii.
The angle formed by two adjacent donor sites with Rb’ as
apex can be divided into three categories (see Fig. 5b):
0 . ..R b . . . 0 angles having values of 54-59” are determined
by the conformational arrangement, i. e. the specific geometry of the 0 C H 2 -CH2 --0fragments within the polyether
chain. The N . . . Rb.. . O angles of 52 and 53 are laid down by
the atomic arrangement in the 8-quinolyloxy group while the
angle of 77” between Rb’ and the two quinoline N atoms results from the acyclic structure of the ligand.
In the complexes of cyclic crown ethers the oxygen atoms
coordinated around the metal ion are usually coplanar; in
the ideal case, the complexed cation is located in this plane at
the center of the
If the relative sizes of cation and
cavity are less favorable then the metal ion may be displaced
somewhat from the “crown ether plane”’lo3].
In (42d) the chain bearing the oxygen and nitrogen donors
is too long to enclose the Rb@in a plane. Nevertheless, the
major part of the donor atoms is fixed in a plane in this complex (Fig. 5b). This applies to atoms N(I), 0(4), 0(7), 0(10),
and O(13). In this region of the ligand the conformational
angles at the C -C bonds are expectedly synclinal (sc) and
those at the C 0 bonds antiperiplanar (ap). In order to
avoid collision of the two terminal quinoline units, the dihe-
A
Right at the start of our investigations[921,model considerations of the structure of the ligand (42d), n = 3, equipped
with 8-quinolyloxy terminal groups, suggested that on participation of all seven heteroatoms in coordination of the metal ion a screw-shaped, and thus chiral, arrangement of the ligand skeleton should result; mutual hindrance of the a- and
P-hydrogen atoms on the quinoline ring is the reason for the
lack of coplanarity of the donor centers. The ability of ligand
(42d) to effectively wrap around a “fitting” cation in helicalchiral fashion is demonstrated by a consideration of spacefilling atomic and spherical ion modelsl’OO1.
In this respect,
(42d) is a model substance for acylic ionophores, e.g., for
open-chain gramicidins and nigericins (cf. Section 2).
An X-ray structure analysis has been performed on the
(42d)-RbI complex[lOllwhich crystallizes in beautiful platelets. It confirms the expected participation of all seven heteroatoms (50, 2N) in complexation and affords the first
proof of a helical-chiral arrangement of a synthetic open
chain ionophore around an alkali-metal ion (Fig. 5b): plus
and minus helices are present in equal amounts. However,
the iodide ions are not included in the coordination sphere of
the central ion; nor are they in direct contact with any heteroatoms of the quinolyl ether.
a1
b)
..
Fig. 5. Structures of some RbQ complexes of open-chain neutral ligands: (a) (42b)-RbI with planar wrapping around the cation; (b)
(42d)-RbI with helical wrapping of ligand around the cation; and (c) (42g)-RbI with spherical wrapping around the cation.
The bond lengths and angles between the heteroatoms (0,
N) and the Rb@ion admittedly deviate from one another but
can nevertheless be regarded as approximately symmetric
with regard to an axis shown joining the Rb@ion and the
O(10) atom in Figure 5b. Whereas the Rb’ . . . 0 distances in
the dibenzo[IS]crown-Ct-RbSCN complex (2.861-2.939 A)
largely correspond to the sum of atomic and ionic radii (2.87
.&)[‘021,
the bond lengths in the (42d)-RbI complex show
some remarkable differences: the Rb@. . . O(10) distance of
2.88 closely approaches the ideal value (2.87 A); the distances Rb@.. .0(7) and Rb’ ...O(13) of 2.99 and 2.94 A, respectively, show considerable extension. Even greater extension is observed with the bond lengths between Rb@ and
O(4) and 0(16), which have values of 3.07 and 3.09 A.The
most likely cause of such deviations in bond lengths lies in
the differing donor strengths of aliphatic or aromatic oxygen
atoms, rather than contributions by steric hindrance of the
polyether chain. In contrast, the Rb@. . . N distances of 2.91 A
A
760
dral angle at bonds C(12) O(13) C(14) --C(15) is sp instead of ap (see arrow in Fig. 5b). As a result, the heteroatoms O(16) and N(19) are displaced, together with the attached quinolyl group, from the plane formed by the other
five donor sites, and the Rb@ ion is shifted by 0.748 A towards the other quinolyl group; this imparts the particular
(helical) structure to the complex.
The helical arrangement of the (42d)-RbI complex is replaced in the RbI complex of the ligand (42b), n = 1, shorter
by two oxyethyl units, by an approximately planar arrangement (folded like a butterfly) having mirror symmetry (Fig.
5a)11@”.X-ray structure analysis of the RbI complex shows
this neutral ligand to be pentadentate. Differences in 0 -Rb
distances can also be seen here. However, the coordinative
bonds of the ether oxygen atoms to the central ion are even
longer than in (42d)-RbI and deviate considerably in the extreme case for the central 0 atom (3.18 A) from the calculated value of 2.87 A. The Rb .. N distances of 2.98 A closely
Angew Chem. In[. Ed EngL. 1X3 753-776 (1979)
approach the calculated value of 2.97 A. The coordination
sphere of the RbO which, in contrast to the case,of (42d). is
not saturated by five donor sites, is filled alternately by two
iodine atoms per ligand unit participating in complexation.
Spherical wrapping around a rubidium ion was ascertained in the RbI complex of the decadentute linear polyether
(42g), n = 6, by X-ray structure analysis (Fig. 5c)[Io5"]:All the
heteroatoms lie approximately on the surface of a sphere of
radius ca. 3 P\, whose poles are occupied by the two quinoline nitrogen atoms. Starting from one of the nitrogen donor
sites, the ligand chain runs to the equator of the sphere which
it encircles and then proceeds to the other pole. The Rb@ion
is tenfold coordinated if the Rb' . ..N and Rb@...O contacts
of 3.371 and 3.147 A are included. Similar values are known
for highly coordinated Rb@but other Rb'-polyether complexes with smaller ligands show normal values (cf. Fig. 5a,
b). The iodide ions lie in cavities between the "spheres" of
the Rb" complexes where they are held by weak van der
Waals forces. For this reason they are statistically twofold
disordered.
X-ray structure analysis of the (SO)-RbI cornplex[lw1revealed a significant difference in the ligand conformation,
compared with the (42d)-RbI complex (Fig. 5b). While a discontinuous helix having a somewhat bent but coordinated
quinoline terminal group is present in the latter, the likewise
heptadentate diquinaldine ligand (SO) is arranged as a continuous helix in its complex (see Fig. 6a). This can be explained by assuming the methyl groups of the quinaldine
units to sterically hinder planar inclusion of the cation at the
terminal group, thus inducing a helical wrapping which then
continues. In the analogous quinoline ligand (42d), on the
other hand, a planar geometry is sterically feasible at one of
the quinolyloxy termini which remains coplanar until steric
hindrance occurs on addition of the second quinolyl group so
that this latter group is kinked (see Fig. 5b).
o
c
ion chain structures (Fig. 6c)l'"''! the two carbonyl groups of
any one ligand molecule do not coordinate the potassium ion
held tightly by the five intramolecular ether oxygen donor
centers but instead the potassium ion of the preceding and
the following ligand. This observation is compatible with the
high entropy of complexation found for the sodium ion (vide
infra) which can be interpreted both as cyclization and as polymerization entropy.
As shown by the X-ray structure analysis of the complex of
phenylglycine ethyl ester-hydrotrifluoromethanesulfonate
with the double phosphane oxide O,Of-(3-oxapentamethylenedioxy)bis(triphenylphosphane oxide) (Fig. 7), the phosphane oxide moiety can be utilized both as donor terminal
group and as a structural unit enhancing the lipophilic properties of pod and^['^^'.
@ P
Fig. 7. Stereochemistry of the phenylglycine ethyl ester-hydrotrifluoromethanesulfonate complex of O,O'-(3-oxapentamethylenedioxy)bis(triphenylphosphane
oxide).
4.2.4. NMR Studies on Complexation in Solution
The line shape and position of the signals in the 'H-NMR
spectra of complexing agents are generally modified by their
In the case of acyclic ligands,
contact with metal
too, 'H-NMR spectroscopy proved extremely useful16s1for
bl
e o
Fig. 6. Geometry of the alkali metal ion complexes of the open-chain ligands (a) (SO), (b) ( 4 3 ~ )and
. (c) (S6)
The ligand also forms a continuous helix in the (43c)NaSCN complexl'"J, with a OCH3 group above or below the
other benzene ringI'O4].The central sodium ion coordinates
to all six oxygen atoms and to the SCNe ion lying above the
helix (see Fig. 6b).
X-ray structure analysis of the 1 :1 KSCN complex of the
amide Iigand (56) unexpectedly shows polymeric ligand-catAngew Chem. Int. Ed. Engl. 18, 753-776 (1979)
recognizing complexation at certain bonding sites['0xh1and
for analysis of ion pair equilibria in solution, particularly
when complexation has no effect on the optical spectraltoY1.
For example, in a 1 : 1 mixture of fluorenyllithium and
ethylene glycol dimethyl ether (DME) (27u) in deuterated
benzene, the signals of the CH2 protons are shifted upfield
by 1.22 pm and those of the CH, groups by 0.76 ppm1""]. A
762
similar situation is observed when higher glymes or crown
ethers complex with fluorenyl ion pairs[''']. Differences in
the NMR spectra are also observed when glymes form complexes with paramagnetic ion pairs('o91.
In the 'H-NMR spectra of the complexes of podands with
stiffened terminal groups, pronounced changes are observed
in the splitting pattern and in the chemical shifts of the aromatic part'92.95.I2l: the 8-quinolyloxy unit of ligand (42d) absorbs in three separate characteristic signal groups around
6=7.40, 8.10, and 8.90[921.In the KO complex the shape of
these resonance signals has changed considerably; even more
noticeable is their pronounced upfield shift (6= 0.52 ppm)
which affects mainly the pyridine protons and indicates participation of the quinoline nitrogen in coordination of the
K" ion. The absorptions of the methylene protons are generally affected much less by complexation (increasingly less towards the center of the chain); apart from further splitting of
the multiplet structure, the absorptions of methylene protons
close to the ends of the chains merely experience a slight partial upfield shift. The heptadentate helical structure of the
RbI complex of (42d) (cf. Fig. 5b) established by X-ray crystal structure analysis is in full accord with the upfield shift
found for the heterocyclic terminal groups[loO'.
The RbI complex of the quinoline ligand (42b) containing
two oxyethyl units less fails to show any sign of helicity in its
NMR spectrum["21.Containing a total of five donor atoms,
the ligand is too short to overlap in a helical fashion in solution or in its crystals (see Fig. 5aj.
The OCH3 group in the ligands (43) and (53) which possess methoxyphenyl terminal groups is even better suited as
an NMR probe for determining the structure of the complex
in s o l u t i ~ n (see
~ ~ ~Fig.
" ~ 8): while the OCH3 protons generally
exhibit an upfield shift in the Na@complexes of (43c), owing
to partial overlap of the two aromatic terminal groups, the
KO ion leads to disappearance of overlap (cf. Fig. 8a). No
upfield shift is observed since the larger KO ion is no longer
sufficiently enclosed by the inadequately long ligands in order to form a helix.
However, in the ligand (434 containing one oxyethyl unit
more, not only the Na" ion but also the larger K @ion leads
to helical overlapping of the terminal groups (see Fig. 8b).
The small ion Ca2@permit an even closer enclosure of the
cation with a helical structure showing more pronounced
overlapping than in the potassium complex.
The helical complexes of type ( 4 6 ~ having
)
central pyridine unit and aromatic or heteroaromatic terminal groups
exhibit temperature dependent 'H-NMR and I3C-NMR
spectra["'l. In the case of the NaSCN complex of the quinaldine analogue of (46u), lowering of the temperature leads to
broadening of the CH2 absorption, which can be interpreted
in terms of slowing down of the racemization (fast at room
temperature) of the plus to the minus helix and vice versa (cf.
Fig. 9). A free enthalpy of activation of AG: ~ 4 kJ/mol
1
(sz 9.8 kcal/mol) is calculated for this racemization process.
(43cl-KSCN
PIUS
IPI
minus IMI
Fig. 9. Configurational interconversion [Pj+[Mj of the complex of NaSCN with
the quinaldine analogue of (46a).
The Mg(C104)2complex of this ligand shows considerable
broadening of the OCH2 signals at room temperature as a
consequence of its tighter helical structure (small cation with
high charge density).
Measurements of "C-NMR shifts and spin-lattice relaxation times are attracting increasing interest in the study of alkali metal ion complexation by open chain neutral ligands["41.
In the future, a better understanding of complexation/decomplexation processes and their temperature dependence
should result from NMR spectroscopy of the complexed cations, e.g. with the aid of 23Na nuclear magnetic resonance['"I (vide infra).
(43d-NaSCf
4.2.5. Thermodynamics and Kinetics of Complexation in
Solution
7
6
5
4 6
a)
Fig. 8. 'H-NMR spectra (sections) of the free ligands (43c) and (434 and of some
of their complexes. The OCH, region is dashed arrows mark upfield shifts of
aromatic protons.
162
Because they have model character for the transport of
cations through biological membranes" l6l, the thermodynamics and kinetics of the complexation of Na@,KO, Rb@,
Cs2@,and Mg'" ions have been examined for various podands["7.''8'. Changes in UV absorption of the two linear
quinolyl ethers (42d), n = 3, and (46u) (in methanol) on continuous addition of metal ions reveal the existence of two
Angew. Chem. Int. Ed. Engl. 18, 753-776 (1979)
nonequivalent bonding sites for alkali metals ions, with stability constants between lo3 and lo4 1 mol-' for K , and between 10' and lo3 1 mol-' for K2[IB71.
Stepwise bonding of
Na@and KO ions induces a hypso- and hypochromic shift of
the absorption maximum of the ligands. In methanol, the
1 : 1 and 1 :2 complexes of the quinoline Iigands (42d) with
Na" and K" exhibit comparable stability. The stability constants are largely independent of ionic radius, as is apparent
from the relatively small discrimination factor K1(Na')/
K , ( K O ) = 0.5; this is a consequence of the flexibility of the
tetraethylene glycol chain which can readily adapt to the
various ions (cf. Fig. 10a). Introduction of a bridging pyridine ring into the ether chain increases the rigidity of the system, as is manifested in a greater cation selectivity
[ K ,(Na')/K, (K@)= 121 of ligand (46a) (Fig. lob).
In order to gain further information about the specific
contribution of the 8-quinolyloxy terminal groups to complexation, studies were conducted on the coordination behavior towards Mg'" since it has long been known that 8-hydroxyquinoline (22) forms stable chelates with Mg2@['I 9 l
whereas the classical oxygen-containing crown ethers show
little tendency to complex Mg2@ions['a~7"~53*'201.
Stoichiometric titrations show that (42d) has four bonding sites for
Mg2@and that (42d)-Mg2@complexes are considerably more
stable in methanol than complexes of corresponding alkali
metal ions. The four bonding sites are apparently non-equi-
dine as central units: whereas (46a) exhibits high peak selectivity for Na" ions at comparably high complex stability
(vide supra), the complexes of the two phenylene compounds
with all ions show much lower K , constants.
The fluorescence spectrum of (54) contains a pronounced
band at ca. 300 nm whose intensity can be selectively modified by cations: Rb' ions with optimum adaptation of host
and guest["'I have a strong quenching effect on this fluorescence band. Thus a n electronic interaction of the para-phenylene n-electron system can be deduced with the cation[I22l.
The changes in entropy (AS') on complexation of the openchain ligands with several cations are, e. g., - 170 for (42d)
with Li', and -59 J K - ' mol-l for Na". A S increases
sharply with increasing ionic size from Li@to Cs' while A H
decreases along the same series. The ionic radius-dependent
increase in entropy can be interpreted as being due to differing conformational changes on complexation of variously
sized ions, since the rise in the A S curve apparently opposes
expulsion of solvent molecules from the solvation sheath of
the ions-which should lead to the opposite sequence of A S
with increasing ionic size.
This finding appears all the more remarkable in view of
the decrease in A S with increasing ionic radius observed with
crown ethers such as [18]crown-6 (26) or [2.2.2]cryptand
(2)[1231.
This appears to reflect the replacement of the solvent
b)
& (42d)
R
R
R = COOH
16 l a )
R = NO2
(44 dl
R
R=H
R
14 6bi
(7961
Fig. 10. Stability constants (lo&) of various podand-alkali metal ion complexes as function of ionic radius. (a) Stepwise loss of donor terminal groups; (b) ligands with
stiffened chain; ( c ) variation of terminal group.
valent, and the conformation of the polyether molecule
changes several times on successive complexation.
Far lower K , values are found for nitro groups in (44d),
n = 3, with poor selectivity towards Na@and increasing selectivity towards Rb@ (Fig. lOc), as well as the unsymmetrical
compound (45d), n = 3, with phenyl (R = H) and quinoline at
the ends of the chains (Fig. 10a). Atypical behavior is seen
with (79b), n = 1 (see Section 4.3.3) with pronounced peak selectivity for K" and very low tendency to complex other
ions, as well as with the acidic ligand (61a) (see Section 4.2.8)
with plateau selectivity towards K @and Rb" (log&- 3) and
very low stability of the Cs' complex.
The meta- and para-phenylene system, (46b) and (S4), respectively, having 8-quinolyloxy terminal groups, was compared with the corresponding ligand (46a) containing pyriAngew. Chem. Int. Ed. Engl. 18, 753-776 (1979)
molecules by the ligand, while the increase in entropy with
open-chain ligands suggests entropy-controlled complexation.
"Na-NMR studies on the thermodynamics of complexation of the open-chain ligand (56) with Na" in pyridine as
solvent afforded A P = - 17 kcal/mol (- 71 kJ/mol),
ASo= -48 cal K-' mol-' (-201 J K - ' mol-')11241.The
strongly negative AS" value suggests an entropy of cyclization or/and polymerization (see Fig. 6c for X-ray structure
analysis). Complexation compells the ligand to adopt a particular conformation in which most or all of the oxygen donor
centers form bonds to the included Na@ion, accounting for
the relatively large change in enthalpy. Complexation of (56)
in solution is enthalpy-driven. It is seen from *'Na-NMR
studies that the interaction is best described by a successive
163
wrapping of the heptadentate ligand (56) around the sodium
ion.
Kinetic data for the complexation/decomposition equilibria of KO ions with (42d) and of NaO ions with (46a) in
methanol were obtained["'. ' 'I from temperature jump relaxation experiments['z51,which initially showed the occurrence of a simple reaction A + B e A B . The experimentally
determined rate constants k1,2 for recombination between
Na@and (46a), and of K' with (42d), of 4 x 10' and 1 x 10'
m o l '~s - I , respectively, are relatively high['2s1;nevertheless,
they are more than one power of ten lower than the value of
5 x lo9 m o l I~s expected for diffusion-controlled recombination of alkali-metal ions with uncharged monodentate ligands in methanol['26.12']. The reduced rate of complex formation can be rationalized as a consequence of stepwise displacement of solvent molecules from the inner coordination
sphere of the metal ion by coordinating oxygen atoms of the
polydentate ligand. In order to account for the high overall
rate, each individual substitution process must occur at a rate
of about 10' s-'. Values of this order have been reported for
the recombination of alkali metal ions with acidic chelating
agents such as ethylenediaminetetraacetic acid (13) and nitrilotriacetic acid (14)[12x1.
That the sum of the individual substitutions is the rate-determining step of complexation is underlined by comparison
of k l . z for (42d) and (46a): the flexible heptadentate ligand
(42d) complexes Na@ and KO four times as slowly as the
more rigid pyridine-containing ligand (46a) which has only
five coordination sites and accordingly cannot embrace a
metal ion so completely. Overall, however, complexation in
both cases is sufficiently fast to satisfy the demands formulated by Eigen et aZ.[1291
for a carrier molecule['21.
such as NaSCN, KSCN, NH4SCN, U02(N03)2 are complexed, follows from shifts and splitting of signals in the 'HNMR spectra; as with the shorter chain and more rigid ligands (cf. Section 4.2.4) this suggests helical structures. A
number of crystalline alkali and alkaline earth metal salt
complexes, including some with 1 :2 ligand/salt stoichiometry, have been i s ~ l a t e d [ ' ~an
~ l ;X-ray structure analysis has
been published for the complex of (58b) with KSCN (Fig.
1l)['nSbl:
in contrast to spherical wrapping of the decadentate
ligand (42g) around the Rb"
the polyether (586) is
wrapped in an S-shaped manner in the dinuclear KSCN
complex with a KeSCNQ ion pair located in each halfloop['osh1.The arrangement of the ligand in the complex is
stabilized by coordination to KO, with double coordination
of O(17) (cf. Hg2@-HGEcomplex, Section 4.1) and 0(1),
0(18), probably playing an important role. Interestingly, the
nitro group is rotated relative to the phenoxy group by
- 42 "C. Partial rotation through - 13" can be explained as
due to steric repulsion between an oxygen atom of the nitro
group and the ortho-situated ether oxygen atom; any twisting
in excess of this figure is possibly due to an improvement of
coordination of the nitro-oxygen atoms with K @ .Formation
of a dinuclear complex appears to be generally favored by
double coordination of the terminal nitro groups. For example, a 1 : 1 complex of K @could be isolated with the analogous ligand having 2,6-dimethoxyphenoxy in place of orthonitrophenoxy groups, while the smaller Na' ion gave a 1: 2
comple~['~~l.
4.2.6. Long-Chain Multidentate Acyclic Ligands
Long-chain multidentate podands of types (57) and
(58)[13n1
are of interest because they might be able to form helical endo-polarophilic/exo-lipophilic "ion channels". Such
multiply wound spiral structures which participate in ion
transport through
by the channel or pore
mechanism[",'31 have been detected for several biomolecules
such as g r a m i ~ i d i n [ ' Model
~ ~ ~ . studies on synthetic channelforming ionophores should provide an insight into possible
transport mechanisms.
Fig. 1 1 . Structure of the dinuclear KSCN complex of (58b)
We have no detailed knowledge about the structure of the
1 : 1 complexes of these ligands; however, it can be assumed
that helices with several turns may be
which
could comply with the pore concept of ion transport through
membranes[' 'I.
4.2.7. Neutral-Molecule Complexes of Acyclic Ligands
L
P
0
R
15 7)
(580):R = OCH,
(58b): R = N O >
All the ligands (57) and (58) qualitatively show pronounced solid/liquid phase transfer for inorganic salts;
KMn04 is readily transferred into organic phases. That salts
764
In 1970, Pedersen discovered that crown ethers not only complex metal ions but also enter into "coordinative" interaction
with neutral molecules such as urea and
Owing
to the sometimes complicated stoichiometry, the complexes
were initially regarded as adducts of the channel inclusion
Meanwhile, however, numerous substrate complexes of cyclic crown ethers have been found to have uniform stoichiometry, for example those with dimethyl acetylenedi~arboxylate['~
or~ ~CH-acid
~
compounds such as
136d1, mal~nonitrile['~~'~,
and
or with
CH3CN['36h,
or
NH-acid compounds such as benzenesulf~namide[l~~~I
phenylhydrazines['37h1
as guest molecules.
Angew. Chem. Int. Ed. Engl. 18, 753-776 (1979)
We found that open-chain ligands like (42d) and (43d) are
capable of forming stable crystalline 1:1 adducts with neutral guest molecules['381.Crystalline urea and thiourea complexes can be formed, e. g. simply by uniting methanolic solutions of the substrates and an acyclic crown ether such as
(42d). The colorless adducts can be recrystallized unchanged
from acetone. Elemental analyses confirm an exact 1:1 stoichiometry; it is also obtained when the dissolved components
are mixed in various stoichiometric ratios. It may be concluded from the stoichiometry that we are not dealing with
inclusion adducts in which the urea molecules form a crystalline host lattice with channel-like
because such
channel adducts are always found to have stoichiometries
corresponding to five to six thiourea or urea molecules for
one guest molecule (such as paraffins, e r ~ . ) [ ' ~ ~ I .
X-ray structure analysis['4o1of the crystals formed by (42d)
and thiourea establishes the presence of crown-ether type
1: 1 complexes (Fig. 12a): the NH terminal groups of the
thiourea remarkably coordinate with all seven donor sites of
the acyclic ligand, involving bifurcated H bonds.
with the N-oxide oxygen atoms, while in the resulting pseudocavity two other water molecules are linked, again by H
bonds, to each other and to the pyridine N-oxide oxygen
atoms. Both the pseudocyclization via bridging water molecules and the coordination of water in the cycle show a remarkable analogy to H 2 0 bonding in bioionophores (Fig. la)
and in cy~lodextrins['~~I.
Fig. 12b. Pseudocyclization and H bonding in the
H10
complex of the podand
(59).
Thus it has been demonstrated that podands, like the coronands, are suitable for complexation of neutral substrate molecules and therefore also have the character of receptor
modelP"; in the case of urea as guest molecule this is of
great clinical interest owing to the possibility of accelerating
dialysis. The design of improved urea receptors will utilize
the kind of bonding first observed in podand-urea complexes.
Fig. 12a. Crystal structure of the complex of (42d) with thiourea.
4.2.8. Interaction between Terminal Groups
An analogous 1 : 1 complex is formed between thiourea
and the heptadentate neutral ligand (43d); an X-ray analysis
has been performed['@".
It is characteristic that the non-crown type compound (47)
shows deviating behavior; the 1 :2 stoichiometry common for
q~inoline"~']
is found with one thiourea molecule per heteroarene. The podands (60), which contain two pyridine rings
as central unit and are therefore'fairly rigid, form crystalline
complexes of alkali, alkaline earth, and transition metal ions,
and also of urea and thiourea, with unusual
The
clearly observable, upfield shifts in the 'H-NMR spectra indicate strong face-to-face overlapping of the end groups.
In this context it was found that classical neutral transition
metal ligands such as phenanthroline (39) form crystalline
stoichiometric 1: 1 complexes with alkali metal
and
with urealescl.
(591
An interesting 1:2 complex of the double pyridine N-oxide (59) and water has also been
X-ray structure
analysis (Fig. 12b)l'041showed that two of the ligand molecules are pseudocyclized uia two H 2 0 molecules (H bonding)
Angew. Chem. Inl. Ed. Engl. 18, 753-776 (1979)
The dicarboxylic acid ( 6 1 ~ ) differs
~ ~ ' ~ from the ligands
having neutral donor terminal groups described so far in several properties: in spite of the comparatively high acidity, the
carboxy protons have not been removed in the crystalline
KSCN and Ca(SCN)2 complexes, a fact substantiated by IR
spectroscopy and interpreted with the aid of an attractive intramolecular terminal group interaction of the kind shown in
(62)19".
In this respect, (61a)can serve as a model for biotic acyclic
in which the ligand conformacarboxylic ionophores"'.
tion is enforced in pseudocyclic manner by similar strong intramolecular H bonds, partly via interposed water molec u l e ~ ~ ' ~Antibiotics
~1,
belonging to the nigericin group (see
Section 2) are very appropriate examples.
The open-chain dicarboxylic ligand (63b)['46a1behaves
analogously. It also forms a series of crystalline alkali metal
ion complexes, e.g. with KCI, KBr, KI, NaBr, RbSCN, Naand K-picrate, in which the acid acts as neutral ligand. A
crystal structure analysis is available for the K-picrate comp l e ~ [ ' ~(see
~ " ]Fig. 13).
Contrary to expectation, no head-to-tail H bonds are observed. Instead, the principal feature is the dimeric centrosymmetric structure of the complex cation. In this structure,
each individual ligand is arranged spirally and its conformation is fixed by one KO ion each. One carbonyl oxygen of the
monomer [0(17), 0(17')] serves as bridging atom and is further coordinated to a second Ke ion (see Fig. 13). In this
way, irregular eightfold coordination of potassium is
achieved, with K . . . 0 distances between 2.29 and 2.93 A; the
two KO ions are separated by 4.74 A in the dimeric complex.
765
(63b): n = I
‘OH
HO
164al: n = o
164bl: n: I
(65) COOH
0
(661
(6 71
Significantly modified torsional angles are observed at the
O(31) atom (see Fig. 13) (152 and 75”; normal values, 180
and 60°,respectively); this is responsible for the helical pitch
of the ligand. The picrate ions do not participate in coordination of KO but are bonded to one carboxy H each of the dimer via H bonds (not shown) and are also close to a benzene
ring of a second complex unit.
31
Pseudocyclization by intramolecular H bonds is postulated
for the complexes of the “acidic” ligands (65) and (66) on the
basis of their ability to transport alkali metal ions through a
liquid membrane of l-hexan01[*~~1.
That (65) permits considerably better transport than (66) is interpreted by assuming
the benzene ring to permit greater stability of the pseudocyclic conformation in the complex (cf. Section 4.1) and to lead
to better solubility of the salts in 1-hexanol. Moreover, (64a),
which does not contain a carboxy group, also transports alkali metals only poorly. The carboxy group therefore seems
to be essential for ion transport (see also Section 4.3.2).
It was recently shown that open-chain ligands having tetrahydrofuran units such as (67) effect efficient transport of
Ca2’ across lipophilic
coord.)
@
K’
Fig. 13. Crystal structure of the complex of (636) with K-picrate.
On reduction of the carboxy ligand (63a), the open-chain
polyether diol ( 6 4 ~ results
)
which forms a crystalline 1:1
complex with NaSCN and a 2 : 1 complex with KSCN1146bl.
Crystal structure analyses of the two complexes revealed
heptadentate coordination of Na” in the sodium complex
and decadentate coordination of K O on the potassium complex. In the dimeric 1 :1 NaSCN complex, one of the two hydroxy oxygen atoms of ligand (63a) bonds alternately to the
adjacent metal ion. The seventh coordination site is occupied
by the SCN’ ion. In the 2 : l KSCN complex, two ligand
units are grouped around one KQ ion in such a way that a
pseudo-twofold symmetry axis is generated. Five of the total
of six oxygen atoms of each ligand make up the tenfold coordination of the central ion. Specific H bonds are apparently
one reason for the difference in the structures. While H
bonds exist between the SCN’ ions and the two hydroxy
groups of one ligand in the NaSCN complex, two hydroxy
groups (one of which is uncoordinated) from dgferent ligands
are linked by H bonds in the KSCN complex.
766
Acyclic “neutral” ligands with “acid” phenolic terminal
groups can form several kinds of alkali and alkaline earth
(68) neutralized by inormetal salt c ~ m p l e x e s I ’complexes
~~~:
ganic counterions, such as arise from open-chain crown
ethers, and-after loss of one or both protons-acid complexes (69) and (70), in which the ligands serve as mono- and
dianions, respectively.
Special interactions between terminal groups are to be expected when nucleic bases such as adenine, thymine, etc. are
attached to the ends of oligoethylene glycol ethers[15o1.
4.3. Weakly Complexing Acyclic Neutral Ligands
There is still a lack of systematic studies in the transition
region between glymes (27) and open-chain crown ethers
(40),i. e. on those podands which bear just one strong donor
group at the end of one chain or several weaker donor terminal groups.
Angew. Chem. Int. Ed. Engl. 18, 753-776 (1979)
4.3.1. Oligoethylene Glycol Ethers Bearing only One Strong
Terminal Group
In ligand skeletons (71) having one strong donor terminal
group (E), the other end of the chain can be weakly coordinated without the complex loosing its crystallinityf15".
R'= R' = R3= R4= C6Hs['841,are suitable sensors for potentiometric activity determinations of Na', Ba", Ca", and of
other ions of Groups IA and IIA['58'.The cation selectivity is
dependent mainly upon molecular structure (nature and
number of coordination sites, nature of the chain termini,
e t ~ . ) [ ' ~ , ' ~apart
~ 1 , from the choice of measuring medium. In
R,'
(71)
r
( 7 2 ~ ~R)=: 1-Nophthyl
(726) 1 R = Phenyl
( 7 2 ~ )R: = Methyl
,R2
N
i
(730):R = I-Naphthyl
(736) 1 R =
(73C): R =
Phenyl
Methyl
Thus the tetra- to hexadentate neutral ligands (72a)a good coordinating group such as an 8( 7 2 ~ ) ~ containing
"'~
quinolyloxy group on the one side and a poor coordinating
group such as naphthoxy, phenoxy, or methoxy group on the
other still give readily crystalline complexes with various
salts. Just a single effective terminal group also permits isolation of crystalline alkali metal ion complexes of (734(73c)["'J.The short chain of the oligoethylene glycol moiety
is remarkable-as with the ligands having two strong donor
terminal gr0ups[".~~.~~1,
it need only have n > 1 and possess
four donor atoms.
The flexible chain segment attached to the rigid donor terminal group ( E ) in (71) is apparently able to wrap around the
cation after anchoring to the metal ion in a favorable planar
arrangement; a second donor terminal group is then no longer necessary for formation of crystalline complexes. However, such an additional group may well enhance its stability
and, above all, raise its complex constant.
Information about the geometry of the donor-free ends of
the chains of the complexes in solution is provided by comparison of the 'H-NMR spectra of the naphthyl ether (72a),
n = 2, and the phenyl ether (72b), n = 2[l5']:while the former
exhibits a strong upfield shift of the a- and P-quinoline protons on transition from the free ligand to the complex, only
the signal of the a-quinoline proton shows an upfield shift in
the complex of (72b). Since spatial proximity of the naphthyl/phenyl and quinolyl group can be deduced in both
cases from the chemical shift, the difference should be related to the greater anisotropic region of the naphthalene
ring; a change in the mutual orientation of the ends of the
chains might also be responsible for the differen~e"~'~.
Suitable choice of donor terminal groups (E) on the one
side and lipophilic chain termini on the other side of a ligand
skeleton should open the way to further ligand/complex topologies with almost infinitely variable lipophilic/hydrophilic balance and complex stability constants and complexation kinetics["*], which is important for some application~['~].
4.3.2. Ionophores of Dioxasuberamide Type with Lipophilic
Chain Termini
of the same
The acyclic compounds (74a) and (74b)[1531
type as dioxasuberamide and its homologue (75),
Angew. Chem. Int. Ed. Engl. 18, 753-776 (1979)
(74)
(76)
(77)
(74a), R ' = R Z= R3= R4= CHzC,H5, R' = Rh= H
(74b), R ' = R3= Propyl, R 2= R 4= Neopentyl, R' = Rb= H
(74c), R' = R2= R3= R4=C,H,, RS= R e = H
( 7 4 4 , R' = R3= CH,, R2= R4=H,CCH2OOC(CHZ), I -,
R5= R b= CH,
(74e), R ' =R2=R3=R4=Pr0pyl, R 5 = R 6 = H
(74fl, R' = R 2= R3= R4=Propyl, R5-Rh = --(CH,),--
general, divalent cations are increasingly preferred over
monovalent cations with increasing dielectric constant of the
membrane
An increase in the polarity of the ligand skeleton has a similar effect, with the result that small
cations are preferred over bulkier ones of the same
charge[7a.7b,153,1871
For example, the following selectivity sequences are found
for the ligands (74c) and (74d) by potentiometry on liquid
membrane e1ectrodes[l5'":
Comparative measurements in the dioxasuberamide series
with ligand-impregnated PVC membranes show (74a) to be a
Na@-selective i o n o p h ~ r e [ ' ~ ~(74b)
" ] , a Ca"-selective ionophoref7'1, and (75) a Ba"-selective i o n o p h ~ r e [ ' ~It~recently
].
also proved possible to tailor a ligand of similar structure for
Li@, uiz. (76), R'= R3= CH,, R2= R4 = heptyl[lS9! Paying
due attention to the coordination number/donor atom relation[1601,
the same kind of ligand could also be adapted to fit
the Na' ion by addition of another donor arm ("tripod", cf.
Section 5.2). This Na' ionophore (77), R'= R3= R S= CH,,
R2= R4 = R6= heptyl["I1 discriminates against K' ions considerably more strongly ( K E K=4.4 x lo-, in O-NPOEL'~'~)
than the Nao-selective ligand (74a) ( K E K = 2 x l o - ' , in
DBE['561,PVC matrix) and can therefore be used for intracellular studies under physiological
Ion carriers such as (78) having Cz symmetry, which possess four centers of chirality, exhibit enantiomer-selective
electromotive properties on incorporation into suitable mem767
b r a n e ~and
~ ' ~accumulate
~~
one enantiomer, e. g. of a-phenylethylammonium ions, on transport across
the 0...Mn distances in the (74j)-MgBr2 complex (Fig. 14b)
are 2.370 and 2.185 A (additive value 2.20 A). The torsional
angles show the atomic sequences C(l'), C(1), 0(1), C(2),
C(3), and O(2) of both ligands to be almost planar.
In contrast to the crystals of (74e)-CaC12 (2 : 1 stoichiometry), there are two kinds of MnZ@in different geometrical
sites in the packing of the crystals of (74j)-MnBr2(1 : 1 stoichiometry). One kind is coordinated pairwise by ligand molecules while the other is surrounded by a square plane of
bromide ions.
Although these comparatively lipophilic ligands are con4.3.3. Glyme Analogues with Donor-Free Rigid Ends
ceived as ion carriers for liquid membrane sensors[165]
and
The simplification of "open-chain crown ethers" (40)[9'.921
therefore do not have high K, values, but require fast comby
plexation kinetics in the interest of fast e q u i l i b r a t i ~ n [ l ~ ~ . ' ~ ~ ] , stepwise worsening of the donating properties of the chain
ends in (71)115']raises the question whether podands devoid
the complex stabilities nevertheless suffice for formation of
of donor terminal groups-such as (79)-might not also form
some crystalline complexes of alkali- and alkaline earth metcrystalline
complexes with alkali and alkaline earth metal
al salts[''']. The isolated complexes usually require additional
salts
(for
heavy
metal complexes, see Section 4.1).
water molecules for construction of a stable crystal lattice.
Coordinative participation of the carbonyl oxygen at0ms1'~'1,
which could be substantiated by I3C-NMR spectroscopy for
the dissolved state"
could also be established for the solid state by IR spectroscopy and by crystal structure analyses
(79U):R = 1-Nophthyl l n = l - L l
recently carried out on the CaC12 and MnBr2 complexes of
(79bl: R = Phenyl
the ligands (74e) and (74j)[I6']: in both cases the metal ion is
coordinated to four ether oxygen atoms and four carbonyl
Careful crystallization experiments with the polyethers
groups of a pair of symmetrically equivalent ligands (Fig.
(79a)
and (79b) having two donor-free but rigid aryl groups
14). In spite of differing demands of the two metal ions
as
the
chain termini and at least five ether oxygen atoms
[r(Ca'@)= 0.99 A, r(Mn'@)= 0.80 A] the coordination
(n 1) indeed afforded a series of crystalline complexes with
geometries are essentially similar. A trigonal dodecahedron
alkaline earth, and also alkali metal
is present in both cases, with the four ether oxygens and the
As with the ligands bearing donor terminal groups[921,
the
four carbonyl oxygens respectively at the corners of a disformation
of
a
pseudocycle
or
a
helix
during
complexation
in
torted square. The measured 0-metal ion distances are longsolution
can
be
deduced
from
the
upfield
shift
observed
in
er for the ether oxygens than for the carbonyl groups, with
the 'H-NMR spectra for the aromatic and aliphatic prothe latter actually shorter than the calculated ion/atom cont
o n ~ [ '(cf.
~ ~Section
]
4.2.4 and 4.3.1). Given a sufficiently long
tacts. The 0... Ca distances in the (74e)-CaC12 complex (Fig.
chain
(above
six
CH2CHz0
units), complexation can only be
14a) are 2.462 and 2.364 (sum of ionic radii 2.39 A), and
recognized from the upfield shift of the aliphatic protons. In
these cases the aryl ether oxygen atoms may possibly no
longer participate in coordination of the metal ion.
If the chain of (794 and (79b) is shortened to just four or
less CH2CHz0units, then no crystalline complexes are obtained under the experimental conditions employed, in accord with previous finding^[^.^^'. Thus the ligands (79a) and
(796) mark the limits of crystallizability of crown ether-type
complexes. These ligands (with short chains) belong to the
simplest and most inexpensive ligands available[lOl.
a)
Recently, even the long-known oligoethylene glycol dimethyl ethers (glymes) (27) (Section 4.1) without rigid terminal
groups but having a certain minimum number of chain
members, e. g. hexaglyme (27j). n = 5, heptaglyme (27g),
n = 6, have been found to form crystalline complexes with alkali/alkaline earth metal ions"691.Previous attempts to prepare such compounds had all
Thus it has been
demonstrated that glymes not only interact with solvents and
cations (solvation/association effects)[6s1but also form stoichiometric crystalline complexes whose study (X-ray structure analysis) appears of fundamental importance.
Similar stoichiometric 1 : 1 neutral complexes with alkali
and alkaline earth metal salts have meanwhile also been isoFig. 14. Geometry (a) in the complex of (74e) with CaCl, and (b) in that of (748
lated" 721 with the corresponding non-alkylated oligoethylene
with MnBrl [168].
14a7c1,
A
768
Angew. Chem. Inl. Ed. Engl. t8, 753-776 (1979)
glycols117o]
and even with ethylene glycol i t ~ e l f l ~ ~Com”.
pounds having free OH groups do not seem to require a complexing central portion in order to form crystalline complexes.
c
O
N
Sr2’
Fig. 15. Structure of the complex of heptaethylene glycol with Sr(SCN)z.
An X-ray structure analysis is available for the heptaethylene gly~ol-Sr(SCN)~
1:1 complex (Fig. 15); it reveals an interesting coordination
all eight oxygen atoms
of the glycol coordinate to the metal ion; in addition, one of
the two SCN” ions is also bonded to Sr2@via a nitrogen
atom. As in other podands having a similar number of donor
atoms (see Section 4.2.3) the ligand chain in this complex is
wrapped in helical fashion around the central ion. The
Sr . .. 0 bond lengths vary between 2.56 and 2.73 A, with the
terminal oxygen atoms showing the shortest Sr . .. 0 distances.
(a), R =n-C4H~(OCH2CH2),SCH2;(b), R = CH,(OCH2CH2),SCH2;
(c), R = CH3SCH2; (d), R = ~ - C ~ H P S C (e),
H ~R
; = ~-C,ZHZSSCHZ;
01,
R=C,HsSCH,;
(g),
R=2,6-(CH,)zC,H,SCHz;
(h),
R = C,H5CH2SCH, (0, R = 6-Naphthyl-SCH,; (k), R = C,HsOCH2;
(I), R = 0-CHO- C,H,-OCH2;
(m), R = o-CH3CO- ChH4; (n),
R = C,H~-N=N-p-C,H4--OCHz;
(o), R = 8-Quinolyl-OCH2; @),
R = 8-Quinolyl-OCH2CH2COOCH2; (41,R = C,H,S
ring by way of sulfur
These compounds, which are
reminiscent of octopi, exhibit striking phase transfer properties towards metal ions (cf. Fig. 16). (8Oa) transfers a large
proportion of alkali metal picrate (Mg, Ca, Sr, Ba) from, e. g.,
i O - 4 N aqueous solution into dichloromethane; almost all the
salt is transferred into the organic phase in the case of alkali
metal picrate solutions (Li, Na, K, Rb, C S ) ~ ’ ~ ~ ] .
R
Fig. 16. Interaction bet ween octopus-like ligands (800)and cations Me.
5. Acyclic Neutral Ligands Having Many Arms
(Oligo/Polypodands)
5.1. Ligands without Donor Terminal Groups
Many-armed neutral ligands-polypodandsf’]-are of interest for several reasons”]: the high number of donor atoms
holds promise of powerful and versatile complexation; there
is also a possibility of discovering novel stereochemical arrangements and complex geometries. Such molecular skeletons should also permit a wide range of variation of lipophilic/hydrophilic balance of both ligands and complexes.
The first compounds described were (80)-(88) which bear
several donor-containing “tentacles” attached to a benzene
~
1’1 Having already denoted podands as open-chain analogs of coronands and
crypiands (see Footnote [“I on p. 753), we classify them as di-, tri-, letru-, ...
poly-podands according to the number of donor “arms”.
Angew. Chem. Int. Ed. Engl. 18, 753-776 (1979)
Phase transfer is greatly restricted on reduction of the
number of donor sites, whether by shortening of the tentacles
as in (806) or by reduction of their number as in (81)(88).
Similar phase transfer properties are shown by the hexapodands (89)(t761
derived from cyclotriveratrylene. While (89)
can form an “octopus-like’’ complexation cavity, the conformationally more rigid (90)1176]
is unable to do so; its phase
transfer activity is therefore very modest.
The oxygen-free hexasubstituted benzenes (80c)(80g)[1771
examined for sake of comparison are naturally unable to act as ligands towards metal i o n ~ “ However,
~ ~ ~ . as was
subsequently demonstrated for various examples [(Soh),
(8Ok), (80q)[17R1;
(80r)-(80p)11791],they form a new type of
stoichiometric inclusion compound by acting as host molecules (“hexahosts”) for neutral organic molecules such as
acetone, dioxane, diglyme, trichloroethanol, dimethylformamide, dimethylacetamide, tetramethylurea, hexamethyl769
O x
with respect to their phase-transfer
(cf. Section
6). Once again, phase transfer depends upon the number of
polyether arms and upon the length of the terminal alkyl
~groups
~ ~(cf.3
Corresponding modifications have been
performed on pentaerythritol as links for polyether “tentacles” (92)[lx4I.
A n
0
3
I891
(901
phosphoric triamide, pyridine, lutidine, collidine, toluene,
styrene, cyclohexane, and other hydrocarbons[135d,
l7’]; their
precise structure has yet to be elucidated. Since decomposition of the adducts, which are stable at room temperature, is
greatly accelerated by a drop in pressure, a channel structure
would appear likely[”*~.An X-ray structure analysis has
been performed on the CCL, clathrate of the host molecule
(80q) containing fewer benzylic CH2 groups (Fig. 17)11801.
As
is typical of hexasubstituted benzenes[’“’, the SChHs side
arms point alternately upwards and downwards out of the
plane of the central benzene ring and give rise to three-dimensional intermolecular cavities in the crystal lattice which
are occupied by the CC14 guest molecules (1 :2 stoichiometry). CC13CH3 and CC13SCI can also be incorporated into
host lattice in the same ratio, whereas CC13Br and CC13N03
give 1 :1 adducts[180~1RZ1.
0
OR
‘CHO
0
OR
nn
H2,C,~-n-OYCCCH20 0 OR
nn
1
RYN,YR
N N
H,CO
CH2O
I
R
Oxygen-free polyamines of the many-armed “cascade
molecule” type (93)[1xslare of interest as chelating agents in
metalation reactions[‘R61
or as polyfunctional hydrolysis catalyst~[’”~.
Crystalline stoichiometric alkali metal salt complexes of permethylated polyamines such as (94) are
s
(941
Fig. 17. Geometry of the “hexahost” (80q) in the CCI, clathrate [ISO]
A remarkable degree of guest selectivity is found for the
hexahosts on recrystallization from solvent mixtures (e. g. oand p-xylene in equimolar amount~)[’’~~.
Which of the two
isomers is preferentially complexed depends primarily on the
structure of the h o ~ t [ l ~(80h)
~ ~ ]and
. (804 favor inclusion ofpxylene, while (80f)and (80k)take up more of the o-isomer.
An o / p ratio of 90:lO is found for hexakis(pheny1thiomethy1)benzene @Of).
Interest also attaches to adduct formation between some
“octopus molecules” bearing donor terminal groups with
crown ethers such as [12]crown-4, [15]crown-5, [I
81crown-6,
and crown ether-cation complexes (cascade c ~ m p l e x i n g ) [ ’ ~ ~ ~ .
X-ray structure analyses should reveal whether these are intramolecular compounds or whether the guest molecules are
accommodated in cavities in the crystal lattice.
Open-chain crown ether fragments without donor end
groups have been attached to the triazine system via N
atoms, and the resulting tri- and hexapodands (91) examined
770
Complexation of curbohydrutes (cyclitols, sugars) with alkali metal ions has been studied by paper electrophoresis[’”1
and by NMR s p e ~ t r o s c o p y ~the
’ ~ ~electrophoretic
~:
investigations carried on from the observation that many polyols migrate towards the cathod on paper electrophoresis in supporting electrolytes containing acetates of various
Among the polyols examined, cis-inositol (95) showed the
greatest mobility in solutions of all the metal acetates used,
the effect being most pronounced in the presence of CaZa,
Sr”, and Ba2@ion^["^]. This is not very surprising in view of
HO
$y&
* H
H
H
H
H
HO
HO
(951
(971
(961
I 98)
OH
Angew. Chem. Int. Ed. Engl. 18, 7S3-776 (1979)
the four potential complex bonding sites-three jointly acting axial OH groups and three a-e-a arrangements of 0
atoms. epi-Inositol (96) having only an a-e-a orientation of
OH groups, exhibit only about one third of the mobility of
cis-inositol under comparable conditions.
Other cyclitols and sugars, e.g. a-gulose (97) having an
OH group arrangement resembling that of (98), behave correspondingly. Worthy of note is the specificity difference between the series Ca2@,Sr2@,BaZ@,La3@,which are suitable
for both cis-(95) and epi-inositol (96), and small ions
(r=0.6-0.8 8)such as Mn", Fe3", Ni2@
, C02@,cu2",
Mg2@,which are effective only in solutions of cis-inoZnZ@,
sitol[18'"1.This suggests that the latter cations coordinate only
to the three axial OH groups of (95). Even smaller cations
(Be", AI3", Li@)have no effect at all on electrophoretic mobility.
Addition of CaC12 to a solution of epi-inositol (96) effects
significant changes in the NMR spectrar189".
'I: all signals are
shifted downfield, with that of H(3) being shifted most (0.32
ppm in 2h.1 CaC12). The diamagnetic shifts are dependent
upon the charge of the complexed cation and its bond
strength, La3@ions accordingly cause larger shifts and NaQ
smaller shifts than Ca2@ions['"'. The stability constants of
the complex formed can thus be roughly estimated from the
shift data['89",h1.
The stereochemistry was elucidated by X-ray structure
analysis of some hydrated CaBr, complexes (see Fig. 18)
which could be isolated in crystalline form by evaporation of
equimolar amounts of the components in aqueous solut i ~ n ~ in
' ~ these
~ ] ; complexes the Caz@ions are located in a
square-antiprismatic environment of eight oxygen atoms
contributed to varying extents by several ligand molecules
(three in the case of galactose, two for inositol) and by water
participating in coordination (3 to 4 molecules).
o
c
Q
OH
philic lipids" of type (99), in which the fatty acid residues are
replaced completely or partly by oligoethylene glycol ether
chains; given a sufficient number of ether oxygen atoms,
these substances become so hydrophilic that they dissolve in
~ater["~I.
5.2. Polypodands Having Donor Terminal Groups (Acyclic
Cryptands, Tetrapodands)
Although many-armed ligand skeletons with neutral coordinating terminal groups (100)11961,(101)1197]
have long been
particularly for complexation of heavy metal
ions, acyclic ligands having cryptand properties for elements
of Groups I and I1 have only recently become available['9x1
by combination of the polypodand (octopus
and terminal group concept^[^',^^].
11021
(1031 IR=H.OCH,.NO~.
CH3. NHCOCH,)
OH lcoordl
(1051
Fig. 18. Coordination sphere of the Ca"
[192a].
11041
(1061
ion in the inositol-CaBr, complex
Several bonding and torsional angles show characteristic
deviations relative to those in uncomplexed sugars. Such
changes in conformation may be involved in biological Ca"
transport['93'or in the reversible fixation of Ca'@ ions in carbohydrate compartments in membrane surfaces[1941.
1991
In this connection, there would appear to be a variety of
interesting applications for the recently synthesized "hydroAngew. Chem. I n l . Ed. Engl. 18, 753-776 (1979)
These neutral ligands (102)-(lOS), which have been designated open-chain cryptands, do indeed exhibit cryptandanalogous complexation and phase transfer behavior['9x1:
KMn04 and aqueous Na- and K-picrate are more readily
taken up in organic phases than with dibenzo[l8]crown-6 (1).
A series of crystalline complexes can be isolated with salts
such as NaSCN, KSCN, RbI, NH4SCN, Ni(C104)2,HzPtC16,
BaI,, Th(N03)3,CU(CIO~)~,
etc.[t's.'9R1.
The KSCN complex of the three-armed, decadentate neutral ligand (105), R = OCH3, which is the first alkali metal
complex of an open-chain cryptand to be examined by X-ray
structure analysis, exhibits a novel complexation geometry
(Fig. 19)f'041:
all ten donor centers including the three OCH3
terminal groups participate in coordination of the metal ion,
which is located at the center of the pseudocavity. In order to
attain this coordination, the three arms wrap around the
cation in a propeller-like fashion. Owing to the complete
screening of the cation, there is no point of attack for the anion. The SCN' ion is therefore outside the lipophilic periphery of the cation complex, as in the bicyclic cryptands.
771
Fig. 19. Structure of the KSCN complex of (105). R=OCH, ("open-chain crypland").
somewhat lower than for the analogous tripodands (1 02) and
(104)[2001.
The four large terminal groups probably offer steric hindrance to complexation of small cations.
The ethylenediamine system and the tropolone end group
in (108) appear to complement each others particularly
well120o1:
in methanol/water (88 : 12), a value of log K , = 2.5 is
found for Na' ions and 2.7, 3.0, and 3.1 for Ca", SrZe,and
Ba" ions (cf. [19R9.
Also of interest in this connection is a comparison of the
tropolone compound (108) with the corresponding dipodand
(109). Although the latter is a stronger complex ligand than
the dipodand molecule (110) with quinoline terminal group,
it is significantly weaker than the corresponding tetrapodand
(108)[ZOol.
Of all the acyclic ligands studied so farCi9*],
(102) exhibits
the highest complex constant for alkali metal ions (in methanol/water); not only its preference for Na' (logK=2.7) over
K' (logK=2.0) and Li' (logK<2) but also its high selectivity for divalent cations, especially Ba2@(log K= 3.2) and Sr2'
(logK= 2.7), warrant mention. The even higher complex
constant of the pseudocryptand (104), having three tropolone
ether terminal groups, for these divalent cations (e.g.
logK(Ba2@)=3.6, logK(Sr2')=3.3, but logK(K')
and
logK(Na0)<2) is also striking. Accordingly, we were able to
prepare a BaI, complex, but no KSCN complex, of (104). On
the other hand, the complex stabilities with the smaller ions
Lie (<2) and Ca" (<2) are significantly lower. These ligand selectivities can be rationalized with the aid of space-filling models, and apparently arise from the inability of the
pseudocavity to contrast sufficiently to ensure ubiquitous intimate contact with the small cations owing to steric constraints. Only (102) shows a logK value > 2 for Mg". Parallels between ligand cavity size and complexation strength
can also be deduced from the 'H-NMR spectra of the complexes (anisotropic upfield shift)['981.
The reaction of tris(chloroethy1)amine with salicylate ions
does not lead to the expected ether, as in the dipod system
[cf. ( 6 1 ~ ) [ ~ but
' l ] , instead, as shown by preliminary results of
X-ray structure analyses11o41,
to the tris(salicyc1ic ester) having free phenolic OH groups which forms colored neutral
complexes soluble in organic media, even with heavy metal
ions.
The benzo-annelated tripodand (106), R = OCH31i991,
has
been found to give 1:1 complexes with KI, RbI, and Ba12,
and a 1:2 complex with Ba(SCN)2; corresponding complexation experiments with (106), R = H, were unsuccessful, thus
underscoring the favorable effect of the terminal groups in
this system too. For constant chain length but different terminal groups the contribution of the terminal groups to complexation in the tripodand series (105) was found to increase
phenyl < 2-N02-phenyl s CH3
in the following
s 2-CH30-phenyl s 8-quinolyl.
The complex stabilities measured for the tetrapodands
(107) and (108) with various terminal groups were generally
(107)
772
I 108)
(1091
11101
Further studies will show whether the attachment of udditional tentacles (pentapodands . . . octapodands) gives rise to
a further (selective) enhancement of complexing ability (e.g.
towards divalent ions). It may be that a lengfhening of the
arms of the polypodands proves more favorable on account
of the less extensive steric hindrance.
The strict 1 : 1 stoichiometry recently found for the alkali/
alkaline earth metal complexes of nitrilotriethanol (111) and
of the corresponding tetra- and pentapodands (112) and
(113)1z0'1
is worthy of note: these are examples of fundamental, facile recognition and selectivity processes on a molecular l e ~ e l I ~ ~ ~ 1 .
6. Use of Open-Chain Neutral Ligands for Phase
Transfer Catalysis
While the phase transfer properties of cyclic crown ethers
and cryptands have found wide application in chemical synonly few results of this kind have so far been reported for open-chain neutral ligands.
The phase transfer efficiency of open-chain neutral ligands of type (42d) and (80a) was compared with that of cyclic and bicyclic crown ethers and cryptand~~"~"J
with the aid
of the standardized phase transfer reaction of benzyl chloride
with potassium acetate in acetonitrile as solvent. It was found
that each ligand generates a nuked anion characteristic for its
particular system. Further investigations will show to what
extent this result, obtained for KO and acetonitrile as solvent,
is valid for other systems.
Angew. Chem. Inr. Ed. Engl. 18, 753-776 (f 979)
Comparison with the noncatalyzed reaction shows that
equilibria with characteristic product yields are attained in
all cases. They vary between several percent and almost
100%. The time of equilibration also depends upon the type
of ligand, varying between a few hours and several days.
This and similar substitution reactions with other potassium salts (in acetonitrile or benzene) have also been carried
out with glymes of various chain lengths (27) and analogous
it was found that the efficiency of the oligoethylene glycol dimethyl ethers increases with concentration,
that at the same concentration (in mol/l) the longer-chain
ethylene glycol ethers are more effective than the shorter
chain ones, and that a certain minimum chain length is necessary for significant catalytic properties. Diglyme (27b) and
triglynie (27c) therefore exhibit only slight effects. At equal
concentration, the open chain ethers are somewhat inferior
to the macrocyclic crown ethers, e.g. [18]crown-6. This can
be compensated by increasing the concentration.
In the triazine series (9/), phase transfer activity peaks at
(916) and falls on shortening of the alkyl group [(9/a)] or if
the number of arms is reduced to three [(9/c), (9/d)]['x41.
Compound (91b) resembles typical trialkylphosphonium catalysts in its phase transfer
and is hardly inferior
to the alkyl-substituted cryptands['@". Whereas (91b) proved
to be a good phase transfer catalyst in all the reactions studied, the efficiency of the pentaerythritol derivatives (92) is
highly dependent upon the kind of reaction being catalyzed11x41.
During the etherification of glycols or mixtures of glycols
of various degrees of oligomerization or polymerization with
methyl chloride or dimethyl sulfate in a solid/liquid two
phase system (sodium hydroxide/benzene; light petroleum
or xylene were used in some cases), the glycol appears to initially act like a phase transfer catalyst by enclosing the sodium ion; as the reaction proceeds it is released by the resulting
ether[2051.Anion transfer from solid to solution is promoted
to a greater extent by triethylene glycol than would be expected from a potentially tetradentate ligand.
Non-linear relationships between the chain length of oligoethylene glycol ether (27) and the complex stability were
also observed on complexation of aryldiazonium ions12061:
the
complex stability increases with the number of donor atoms
up to a certain length (heptaglyme) and then falls abruptly at
octuglyme (27h). A further increase in the number of ether
oxygen atoms leads to a renewed rise in complex stability.
Since the complex constant of [18]crown-6 towards the same
diazonium ion is only about five times greater than that of
the dimethyl ether of Carbowax-100012"71,the possibility
opens up of using this less expensive glyme mixture as phase
transfer catalyst in the reaction of aryldiazonium salts12o6b1.
Aryldiazoniurn salts experience photochemical stabilization
on complexation with glymes (and crown
Interestingly, triglyme (27c) exerts a stabilizing effect comparable
with that of [15]crown-5.
7. Outlook
A new chapter of complex chemistry with neutral organic
ligands has begun. Parallel to the cyclic and polycyclic series
attempts should be made in the case of podands to create
Angew. Chem. Int. Ed. Engl. 18,7S3-776 (1979)
pseudocavities, by means of specifically interacting terminal
groups, which resemble those in bioionophores. These cavities may possibly simulate the ionic channel structure and
the bactericidal properties of the bioionophores. The incorporation of chiral structural elements into oligopodands also
appears a rewarding aim. Such molecules could also be of interest as chiral additives for enantioselective syntheses[2"x1.
Helical enclosure of metal ions such as Lie by chiral ligands
in organolithium compounds may effect a higher optical induction than the reagents examined so
The synthesis of new topologies of acyclic crown ethers
and cryptands- also for simple glycols-and their testing as
phase transfer catalysts in chemical reactions with ions is just
a matter of
There is no lack of expectation, some
rather speculative, in chemistry and other branches of
science and technology, such as photography, vulcanization
techniques, petroleum engineering, electroplating, reaction
engineering'"'? The comparatively low price of open-chain
crown compounds should further their large-scale comrnercia1 utilization1"']. Considerable progress has already been
made in the construction of multielectrode systems doped
with open-chain neutral ligands for simultaneous determination of the concentration of several cations, e. g. in blood and
~erum['~1.
Mutually comparable physico-chemical studies ( A H , AG,
AS, AK,, k ) of host-guest interactions between simple ligands
and simple guest ions or molecules could contribute much to
our understanding of passive and active ion transpOrt[ll.12.11h,1311, the mode of action of biological ionoph~resi'~],and drug/receptor, enzyme/substrate, and antigen/antibody i n t e r a c t i ~ n ~ ' ~ ~Since
. ' ' ~ ~the
. salt balance is of
vital importance for organisms (blood coagulation, sugar balance, muscle contraction, kidney function, e t ~ . ) [ " "and
~ specific modifications play an important role in pathological
concentration changes (cancer, gout, etc.) and the action of
drugs (e. g. digitalis)[z'71, further research into neutral ligand
complexation appears of general interest and practical value
in numerous fields of application.
We are indebted to the Deutsche Forschungsgerneinschaft
and the Fonds der Chernischen Industrie f o r support of our own
work. Thanks are also due to Ms. B. Jendrny f o r her assistence.
Received: May 30. 1978;
supplemented August 30, 1979 [A 291 IF.]
German version: Angew. Chem. 91, 813 (1979)
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We thank Prof. W. Saenger, Max-Planck-Institut f u r Experimentelle Medizin. Gottingen. for this investigation and for communication of the results
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[I521 Cf. data in [92].
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3.
Angew. Chem.
Inl.
Ed. Engl. 18, 753-776 (1979)
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