Cryptands and Cryptates

The following sections are included:

• Dedication
• Foreword by Jean-Marie Lehn
• About the Author
• Contents

The birth of supramolecular chemistry, the science of non-covalent interactions, is conventionally associated with the publication of a paper in 1967 by Charles J. Pedersen, a senior researcher at DuPont, Wilmington, Delaware. Pedersen, who was 63 at that time, had investigated at DuPont for many years the autoxidation of petroleum products and rubber, a complicated process catalysed by trace metals. Hence, he was interested to develop multidentate ligands aimed to suppress the catalytic activity of transition metal ions through complexation. In 1960, he started a project on the for design of ligands suitable for binding (and ‘deactivation’) of the vanadyl ion (VO²⁺, oxovanadium(IV)) and focused his attention on phenolate derivatives. In particular, he considered that bis[2- (o-hydroxyphenoxy)ethyl] ether 3 in Figure 1.1, when deprotonated, could effectively sequestrate the oxocation…

In the same year Pedersen published the papers on crown ethers, Jean- Marie Lehn, a young Professor at the Université Louis Pasteur, Strasbourg, was studying the chemical processes that occur in the nervous system. He was aware that bioelectrical stimuli originate from changes in the concentration of Na⁺ and K⁺ inside and outside the nerve cell and that the natural poly-oxa macrocycle valinomycin (6) mediates their transport across the membrane. Valinomycin shows an appealing circular formula, containing 6 ethereal oxygen atoms and 12 carbonyl oxygen atoms as potential donors. Valinomycin, in crystallographic reality (Figure 2.1(a)), shows a less fascinating, poorly symmetric structural organisation. However, on interaction with K⁺, it rearranges to provide a nice spheroidal cavity and establishes with the included cation six coordinative interactions using metal-carbonyl oxygen atoms as donors, according to an almost regular octahedral geometry (see crystal structure in Figure 2.1(b))…

Recognition, which refers to the selective interaction of a receptor with a substrate, is one of the most investigated fields of supramolecular chemistry. The substrate is a convex chemical entity whose recognition is sought, the receptor is a concave molecular system designed for establishing favourable interactions with the substrate. The selective interaction of the receptor with a substrate, in the presence of other competing substrates, is called recognition. Figure 3.1 pictorially illustrates the principle of recognition, based on shape/size matching of the receptor’s cavity and substrate…

Pedersen introduced crown ethers in 1967, thus unfolding the rich field of coordination chemistry of s block metal ions. The family of ligands containing ethereal oxygen atoms suitable for coordination of alkali and alkaline-earth cations was expanded two years later by Lehn with the synthesis of cryptands. Pedersen and Lehn were awarded with the Nobel Prize in Chemistry in 1987. The third recipient of the most prestigious award in chemistry in the same year was Donald Cram (1919–2001), Professor at the University of California at Los Angeles. Cram no wonder did extensive studies on the design of multidentate ligands for alkali metal ions. In particular, in 1985, he reported the synthesis of the cyclic molecule 14, containing a system of six linked methoxybenzene (anisyl) fragments…

NH₄⁺ is the most prominent of inorganic polyatomic cations, constituted by non-metal atoms and showing a regular tetrahedral structure. It is conventionally considered an additional alkali metal ion essentially because all its salts are soluble, a unique feature of alkali metal ions. In terms of size, the ammonium cation has an ionic radius (r = 148 pm) very close to that of K⁺ (r = 149 pm). If crown ethers and cryptands opened up the field of coordination chemistry of alkali metal ions, what about the interaction of these multidentate ligands with ammonium? Indeed, ammonium shares a tendency with alkali cations to form stable complexes with crown ethers, cryptands and other cyclic and polycyclic polyethers…

Supramolecular chemistry is the chemistry of non-covalent interactions. Non-covalent interactions are typically (but not necessarily) weak and are (necessarily) quickly reversible. They include: hydrogen bonding, electrostatic interactions, π–π donor–acceptor interactions, metal–ligand interactions. The presence of metal coordination chemistry among the sub-topics of supramolecular chemistry creates a temporal paradox. In fact, coordination chemistry was officially recognised in 1893, with the publication of the monumental paper of Alfred Werner on the amine complexes of substitutionally inert transition metal ions, and was universally recognised with the assignment to Werner of the Nobel Prize in 1913…

In 1977, Lehn synthesised a new macrobicyclic system with a molecular framework similar to that of the classical cryptands, with two bridgehead tertiary amine nitrogen atoms (22). Each linking chain contained a nitrogen, an oxygen and another nitrogen, separated by –CH₂CH_2^- spacers…

In 1987, Lehn and coworkers reported the direct and uncomplicated synthesis of the bistren cryptand 27, which is illustrated in Figure 8.1…

The most convenient way for studying the formation of dimetallic bistren cryptates in solution is based on potentiometric titration experiments. In a preliminary study, an acidic aqueous solution of the chosen octamine cryptand (e.g. 33) is titrated with standard NaOH and the protonation constants of the six secondary amine nitrogen atoms (pK_Ai) are determined through nonlinear treatment of the titration curve (potential of the glass electrode, mV, vs volume of NaOH, mL). Then, in the second experiment, a solution, e.g. 5 × 10⁻⁴ M in 33, 1 × 10⁻³ M in Cu^II(ClO₄)₂ and 10⁻² M in HClO₄, is titrated with standard NaOH. Through nonlinear least-squares processing of the titration curve, the species present at the equilibrium are identified and the corresponding complexation equilibrium constants are determined. On the basis of the values of the protonation and complexation constants, a distribution diagram (% concentration against pH) showing the species present at the equilibrium can be drawn (see Figure 9.1)…

Studies illustrated in Chapter 9 have demonstrated that dimetallic bistren cryptates do not have a ‘void’ cavity ready to include anions. The cavity is always filled with water molecules or their conjugate bases, OH⁻ or ${\text{H}}_{\text{3}}{\text{O}}_{\text{2}}^{\text{−}}$. Thus, in an aqueous solution, anion inclusion is in any case preceded by the removal of H₂O/OH⁻, a process that costs significant energy. Moreover, since studies are typically carried out in a neutral solution (pH around 7), anion inclusion involves the replacement by the anion X⁻ of OH⁻, hydrated or not. In any case, whatever the included ligand is, equilibrium studies at a given pH are expected to disclose selectivity of anion inclusion depending upon size–shape matching of receptor and substrate. A convincing example is provided by the dicopper(II) cryptate of bistren 28…

Recognition refers to the successful selective interaction of the receptor (e.g. a ‘void’ dimetallic cryptate) with a substrate (e.g. an anion), in the presence of other competing substrates. Recognition can be monitored by the operator through a variety of instrumental responses, e.g. the shift of an NMR signal or of the electrochemical potential, a modification of the UV–vis absorption spectrum (accompanied by a colour change), the quenching/revival of the fluorescence emission. In an analytical context, the receptor is called, sensor, a word borrowed from the language of the macroscopic world: ‘sensor, noun — from the Latin verb: sentĭo, sentis, sensi, sensum, sentīre, to perceive — a device that interacts with matter or energy and responds with a signal’. A glass electrode (interacts with matter) and a thermometer (with energy) are macroscopic sensors. In the molecular world, a sensor (a molecular or chemical sensor, sometimes called chemosensor) typically responds to a variation of the concentration of the substrate (or analyte). The efficiency of the sensor is expressed by the ratio of the instrumental response Δx over the variation of the concentration of the analyte Δc. The higher the Δx/Δc quotient, the more efficient the sensor. Most common chemical sensors are optical, operating either by light absorption (colorimetric sensors) or emission (fluorescent sensors). Their advantage lies in the fact that the properties investigated are visually perceived and, in addition, can be detected at very low concentration levels. Fluorescence, in particular, is a valued feature for its sensitivity and because the mechanisms for its control (quenching/revival) are known, a situation which can help the successful design of a sensor…

The FSR approach to the design of fluorescent sensors for anions is not always convenient and satisfying for many reasons: first, the covalent linking of the receptor and fluorophore is not straightforward and may require a tedious multistep synthesis. For instance, in the case of bistrenbased receptors like 34, which contains spacers of different nature, the 3 + 2 Schiff base condensation procedure cannot be employed. Moreover, the mechanism of the modification of the fluorescent emission is often unpredictable and cannot be planned with certainty. As an example, the [Zn^II ₂(L)(H₂O)₂]⁴⁺ sensor (L = 34) considered in Chapter 11 responds to ${\text{N}}_{\text{3}}^{\text{−}}$, which brings with itself the ‘signal transduction mechanism’ (in this case, the capability to transfer an electron to the photoexcited anthracene subunit, thus quenching fluorescence), but does not respond to NCO⁻, which on its own forms a very stable inclusion complex, but is reluctant to release an electron and leaves fluorescence emission undisturbed. Moreover, if the receptor must contain a metal, the choice is limited to those showing a d¹⁰ electronic configuration and not displaying redox activity (e.g. Zn^II), which excludes the numerous and hardened troops of transition metal ions. But there is another aspect which makes the FSR not too attractive. In most cases, FSR fluorescent sensors operate through an ON/OFF mechanism, like [Zn^II ₂(L)(H₂O)₂]⁴⁺ (L = 34). Among people using fluorescence as a signal, the ON/OFF response is considered less valuable than the OFF/ON response. The reason was explained to me by a friend and colleague, Fabio Grohovaz, cell physiologist at San Raffaele Hospital, Milan, according to whom ‘it is easier and more comfortable to detect an electrical torch switching on in the Black Forest, than the light of an apartment switching off in the night in Manhattan’. The aphorism is pictorially illustrated in Figure 12.1…

Nucleotides are the building blocks of nucleic acids (RNA and DNA) and are composed of a nitrogenous base (or nucleobase: adenine, guanine, citosine, thymine, uracyl), a five-carbon sugar (ribose or deoxyribose) and at least one phosphate group. The nucleobase along with the sugar gives the nucleoside, the nucleoside along with phosphate(s) gives the nucleotide. Nucleoside polyphosphates (NPPs) play a central role in many biological processes. In particular, they provide a universal source of chemical energy (adenosine triphosphate (ATP) and guanosine triphosphate), participate in cellular signalling (cyclic guanosine monophosphate (GMP) and cyclic adenosine monophosphate (AMP)) and are part of important cofactors of enzymatic reactions (coenzyme A, flavin adenine dinucleotide, flavin mononucleotide, and nicotinamide adenine dinucleotide phosphate)…

It has been mentioned in Chapter 7 that protonated bistren can include anions. In particular, the prototype of bistren cryptands, 22, in aqueous solution adjusted at pH = 5 is present at ca. 80% as the hexaprotonated form ${\text{LH}}_6^{6+}$ (the six secondary amine groups are protonated) and at ca. 20% as LH₅ ⁵⁺. A solution of cryptand 22, adjusted to pH 5, was titrated with a variety of anions and the progressive shifts of the ¹³C resonances was monitored. In any case, the formation of a complex of 1:1 stoichiometry was established. From the titration profiles (¹³C NMR shift against anion equivalents), conditional association constants were determined: the highest value was observed in the case of N₃ ^- (log K = 4.3 ± 0.3). The high stability was ascribed to the favourable fitting of the linear triatomic anion in the ellipsoidal cavity of the cryptand (see the crystal structure of the [LH₆…N₃]⁵⁺ complex in Figure 7.3). Later, the complexation equilibrium (14.1)

All the cryptands of the class 28–32, in their hexaprotonated form, offer a comfortable shelter to tetrahedral oxoanions. Hydrogen bonding complexes with ${\text{ClO}}_{\text{4}}^{\text{−}}\text{,}{\text{SO}}_{\text{4}}^{\text{2−}}\text{,}{\text{SeO}}_{\text{4}}^{\text{2−}}\text{,}{\text{CrO}}_4^{2-}\text{,}{\text{S}}_{\text{2}}{\text{O}}_{\text{3}}^{\text{2−}}$ with most of the abovementioned receptors have been isolated in the crystalline form and structurally characterised. Oxygen atoms of the oxoanions establish with the N–H fragments of the protonated secondary ammonium groups hydrogen bonding interactions of variable strength, characterised by different O…H length. At this stage, it is useful to consider the Jeffrey’s classification of hydrogen bonds summarised in Table 15.1…

A reasonable question, at this stage, is: which, among the two classes of receptors derived from bistren, whether dicopper(II) cryptates or hexaprotonated cryptands, is the most effective and selective receptor for anions? Recognition of linear dicarboxylates is a convenient playfield where to test the potential of the two approaches…

The N–H fragment of the ammonium group can donate a hydrogen bond to an anion, but the N–H fragment of the parent primary or secondary amine cannot because it is not polarised. On the other hand, an N–H fragment of a primary or a secondary amide, irrespective of whether it is carboxamide or sulphonamide, is polarised enough to behave as an H-bond donor and to form a complex with anions. In general, such an interaction is not strong enough to compete with water. Thus, the anion amide complexes typically form in aprotic solvents, even if they are of pronounced polarity (e.g. DMSO, MeCN). Figure 17.1 illustrates how primary triamides of the branched tetramine tren can coordinate a given anion X^– by donating three convergent hydrogen bonds…

Peroxide, ${\text{O}}_2^{2-}$, is an intrinsically unstable anion. Its poor stability is because of the repulsion between the 3 + 3 lone pairs present in the two oxygen atoms. Na₂O₂ is stable as a solid, but reacts violently with water to give hydrogen peroxide and sodium hydroxide:

Bistren amine cryptands have been considered in the previous Chapters as dinucleating ligands: bicyclic polyamines capable of hosting two metal centres; the length of the spacers determined the intermetallic distance and the space for a bridging anion, either monoatomic or polyatomic. We have not considered yet the ‘smallest’ bistren cryptand, 47 (bistren-C₂), in which the two tren subunit are linked by –CH₂CH_2- spacers. Bistren-C₂ can be obtained through the 2 + 3 Schiff base condensation, from tren and glyoxal. The essential element for a good yield (>50%) appears to be the slow addition of glyoxal to tren at low temperatures (0°C)…

The most valuable type of anion recognition is that related to size exclusion selectivity. Such a selectivity is observed when the receptor, providing for instance a spheroidal cavity, includes only spherical anions of radius less than or equal to a definite value. In this context, the smallest anion, fluoride, has offered a vast array of resources for exercise and investigation…

A tripodal ligand L (e.g. tren) can be converted into a cryptand by appending at each of its three arms a molecular fragment capable of behaving as a ligand towards a given metal ion M. Binding of M by these ligands generates a closed space which can host a suitable substrate. The process is pictorially illustrated in Figure 21.1. In the first reported example, three 2,2′-bipyridine fragments (bpy) were appended to the secondary amine nitrogen atoms of tren via a –CH₂– spacer in position 5, to give 52 (L). Fe^II was chosen as a ‘closing’ metal, as it forms a very stable [Fe^II(bpy)₃]²⁺ complex, of octahedral geometry, 3d⁶ low-spin. Stability is derived from the σ donation from pyridine type nitrogen atoms to the metal and from π back-donation from filled dπ orbitals of Fe^II to low energy empty π antibonding molecular orbitals delocalised over the bpy framework. In addition, the [Fe^II(bpy)₃]²⁺ complex is kinetically inert, which guarantees the function of iron(II) as a ‘glueing’ metal. This study was conducted to verify whether the [Fe^II(L)]²⁺ complex (L = 52) could be able to host in its tren cavity another transition metal, e.g. Cu^II. The stepwise process is pictorially represented in Figure 21.2…

There exists a tendency in the field of Chemistry to create molecular devices, i.e. low molecular weight systems capable of performing a desired function inspired from everyday practice. Thus, a variety of molecules or supramolecular systems of varying sophistication have been synthesised during the last two decades, which behave as (i) machines, linear and rotary motors, brakes, gears, ratchets (mechanical inspiration), and (ii) batteries, electrical wires, extendable cables, plug–socket connectors, switches (electrical inspiration). Some other molecules are addressed to hi-tech functions from electronics and computer science and behave as logic gates, adders and subtractors, calculators, and memory storage devices. The design of these systems cannot be considered as a mere academic exercise or a proud exhibition of the power of chemical synthesis. Noticeably, the Nobel Prize in Chemistry 2016 was awarded jointly to Jean-Pierre Sauvage, Fraser Stoddart and Ben Feringa ‘for the design and synthesis of molecular machines’. In particular, as Olof Ramström, Member of the Nobel Committee for Chemistry, stated: ‘we are at the dawn of a new industrial revolution of the 21st century, and the future will show how molecular machinery can become an integral part of our lives. The advances made have also led to the first steps towards creating truly programmable machines, and it can be envisaged that molecular robotics will be one of the next major scientific areas’…

The tendency of chemists to give molecular systems names borrowed from the everyday life was discussed in Chapter 22. In this perspective, cryptands rightfully belong to the family of cages. Cages are familiar objects for humankind since at least ten thousands years. Humans build and use cages, but do not love them for several reasons: (i) they are a symbol of forced spatial constriction and freedom deprivation for living beings, (ii) they exhibit private details of the imprisoned individual to the public, affirming a state of weakness and dependence, (iii) the typical guest of cages is a tender and undefended being (a canary, a parrot). Thus, humans use cages mostly for leisure, but are not proud of this practise and are reluctant to its emphasis…

The following sections are included:

• References
• Index