Molecular recognition of organic ammonium ions in solution using synthetic receptors

Abstract

Ammonium ions are ubiquitous in chemistry and molecular biology. Considerable efforts have been undertaken to develop synthetic receptors for their selective molecular recognition. The type of host compounds for organic ammonium ion binding span a wide range from crown ethers to calixarenes to metal complexes. Typical intermolecular interactions are hydrogen bonds, electrostatic and cation-π interactions, hydrophobic interactions or reversible covalent bond formation. In this review we discuss the different classes of synthetic receptors for organic ammonium ion recognition and illustrate the scope and limitations of each class with selected examples from the recent literature. The molecular recognition of ammonium ions in amino acids is included and the enantioselective binding of chiral ammonium ions by synthetic receptors is also covered. In our conclusion we compare the strengths and weaknesses of the different types of ammonium ion receptors which may help to select the best approach for specific applications.

Keywords: amino acids; ammonium ion; molecular recognition; synthetic receptors.

Figure 1

Biologically important amines and quaternary ammonium salts: histamine (1), dopamine (2) and acetylcholine (3).

Figure 2

Crown ether 18-crown-6.

Figure 3

Conformations of 18-crown-6 (4) in solvents of different polarity.

Figure 4

Binding topologies of the ammonium ion depending on the crown ring size.

Figure 5

A “pseudorotaxane” structure consisting of 24-crown-8 and a secondary ammonium ion (5); R = Ph.

Figure 6

Typical examples of azacrown ethers, cryptands and related aza macrocycles.

Figure 7

Binding of ammonium to azacrown ethers and cryptands [–113].

Figure 8

A 19-crown-6-ether with decalino blocking groups (11) and a thiazole-dibenzo-18-crown-6-ether (12).

Figure 9

1,3-Bis(6-oxopyridazin-1-yl)propane derivatives 13 and 14 by Campayo et al.

Figure 10

Fluorescent azacrown-PET-sensors based on coumarin.

Figure 11

Two different pyridino-cryptands (17 and 18) compared to a pyridino-crown (19); chiral ammonium ions as guests (20a–c).

Figure 12

Pyridino-18-crown-6 ligand (21), a similar acridino-18-crown-6 ligand (22) and a structurally related bispyridyl (bpy)-18-crown-6 receptor 23.

Figure 13

Ciral pyridine-azacrown ether receptors 24.

Figure 14

Chiral 15-crown-5 receptors 26 and an analogue 18-crown-6 ligand 27 derived from amino alcohols.

Figure 15

C₂-symmetric chiral 18-crown-6 amino alcohol derivatives 28 and related macrocycles.

Figure 16

Macrocycles with diamide-diester groups (30).

Figure 17

C₂-symmetric chiral aza-18-crown-6 ethers (31) with phenethylamine residues.

Figure 18

Chiral C-pivot p-methoxy-phenoxy-lariat ethers.

Figure 19

Chiral lariat crown ether 34.

Figure 20

Sucrose-based chiral crown ether receptors 36.

Figure 21

Permethylated fructooligosaccharide 37 showing induced-fit chiral recognition.

Figure 22

Biphenanthryl-18-crown-6 derivative 38.

Figure 23

Chiral lariat crown ethers derived from binol by Fuji et al.

Figure 24

Chiral phenolic crown ether 41 with “aryl chiral barriers” and guest amines.

Figure 25

Chiral bis-crown receptor 43 with a meso-ternaphthalene backbone.

Figure 26

Chromogenic pH-dependent bis-crown chemosensor 44 for diamines.

Figure 27

Triamine guests for binding to receptor 44.

Figure 28

Chiral bis-crown phenolphthalein chemosensors 46.

Figure 29

Crown ether amino acid 47.

Figure 30

Luminescent receptor 48 for bis-alkylammonium guests.

Figure 31

Luminescent CEAA (49a), a bis-CEAA receptor for amino acids (49b) and the structure of lysine binding.

Figure 32

Luminescent CEAA tripeptide for binding small peptides.

Figure 33

Bis crown ether 51a self assembles co-operatively with C₆₀-ammonium ion 51b.

Figure 34

Triptycene-based macrotricyclic dibenzo-[24]-crown-8 ether host 52 and guests.

Figure 35

Copper imido diacetic acid azacrown receptor 53a and the suggested His-Lys binding motif; a copper imido triacetic acid azacrown receptor 53b and the target binding area (R = COO⁻, CONHCH₂COO⁻, CONHCH₂COOCH₃, CONHCH₂CONHCH₂CONH₂; R′ = H, CH₃,CH₂-CH(CH₃)₂, CH₂CH₂CONH₂).

Figure 36

Urea (54) and thiourea (55) benzo crown receptor for transport and extraction of amino acids.

Figure 37

Crown pyryliums ion receptors 56 for amino acids.

Figure 38

Ditopic sulfonamide bridged crown ether receptor 57.

Figure 39

Luminescent peptide receptor 58.

Figure 40

Luminescent receptor 59 for the detection of D-glucosamine hydrochloride in water/ethanol and luminescent receptor 60 for ω-amino acids.

Figure 41

Guanidinium azacrown receptor 61 for simple amino acids and ditopic receptor 62 with crown ether and polyammonium macrocycle for GABA binding.

Figure 42

Chiral bicyclic guanidinium azacrown receptor 63 and similar receptor 64 for the enantioselective transport of simple amino acids into organic phases.

Figure 43

Receptors for zwitterionic species based on luminescent CEAAs.

Figure 44

1,10-Azacrown ethers with sugar podand arms and the anticancer agent busulfan.

Figure 45

Benzo-18-crown-6 modified β-cyclodextrin 69 and β-cyclodextrin functionalized with diaza-18-crown-6 at primary face (70).

Figure 46

Receptors for colorimetric detection of primary and secondary ammonium ions.

Figure 47

Porphyrine-crown-receptors 72.

Figure 48

Porphyrin-crown ether conjugate 73 and fullerene-ammonium ion guest 74.

Figure 49

Calix[4]arene (75a), homooxocalix[4]arene (75b) and resorcin[4]arene (75c) compared (R = H, alkyl chain).

Figure 50

Calix[4]arene and ammonium ion guest (R = H, alkyl, OAcyl etc.), possible binding sites; A: co-ordination of cationic or neutral guests (cation–π-interaction), B: binding site for cationic guests (ion–dipole-interaction or H-bonding).

Figure 51

Typical guests for studies with calixarenes and related molecules.

Figure 52

Lower rim modified p-tert-butylcalix[5]arenes 82.

Figure 53

The first example of a water soluble calixarene.

Figure 54

Sulfonated water soluble calix[n]arenes that bind ammonium ions.

Figure 55

Displacement assay for acetylcholine (3) with a sulfonato-calix[6]arene (84b).

Figure 56

Amino acid inclusion in p-sulfonatocalix[4]arene (84a).

Figure 57

Calixarene receptor family 86 with upper and lower rim functionalization.

Figure 58

Calix[6]arenes 87 with one carboxylic acid functionality.

Figure 59

Sulfonated calix[n]arenes with mono-substitution at the lower rim systematically studied on their response to amino acids.

Figure 60

Cyclotetrachromotropylene host (91) and its binding to lysine (81c).

Figure 61

Calixarenes 92 and 93 with phosphonic acids groups.

Figure 62

Calix[4]arene tetraphosphonic acid (94a) and a double bridged analogue (94b).

Figure 63

Calix[4]arene tetraphosphonic acid ester (92c) for surface recognition experiments.

Figure 64

Calixarene receptors 95 with α-aminophosphonate groups.

Figure 65

A bridged homocalix[3]arene 95 and a distally bridged homocalix[4]crown 96.

Figure 66

Homocalix[3]arene ammonium ion receptor 97a and the Reichardt’s dye (97b) for colorimetric assays.

Figure 67

Chromogenic diazo-bridged calix[4]arene 98.

Figure 68

Calixarene receptor 99 by Huang et al.

Figure 69

Calixarenes 100 reported by Parisi et al.

Figure 70

Guest molecules for inclusion in calixarenes 100: DAP × 2 HCl (101a), APA (101b) and Lys-OMe × 2 HCl (101c).

Figure 71

Different N-linked peptido-calixarenes open and with glycol chain bridges.

Figure 72

(S)-1,1′-Bi-2-naphthol calixarene derivative 104 published by Kubo et al.

Figure 73

A chiral ammonium-ion receptor 105 based on the calix[4]arene skeleton.

Figure 74

R-/S-phenylalaninol functionalized calix[6]arenes 106a and 106b.

Figure 75

Capped homocalix[3]arene ammonium ion receptor 107.

Figure 76

Two C₃ symmetric capped calix[6]arenes 108 and 109.

Figure 77

Phosphorous-containing rigidified calix[6]arene 110.

Figure 78

Calix[6]azacryptand 111.

Figure 79

Further substituted calix[6]azacryptands 112.

Figure 80

Resorcin[4]arene (75c) and the cavitands (113).

Figure 81

Tetrasulfonatomethylcalix[4]resorcinarene (114).

Figure 82

Resorcin[4]arenes (115a/b) and pyrogallo[4]arenes (115c, 116).

Figure 83

Displacement assay for acetylcholine (3) with tetracyanoresorcin[4]arene (117).

Figure 84

Tetramethoxy resorcinarene mono-crown-5 (118).

Figure 85

Components of a resorcinarene based displacement assay for ammonium ions.

Figure 86

Chiral basket resorcin[4]arenas 121.

Figure 87

Resorcinarenes with deeper cavitand structure (122).

Figure 88

Resorcinarene with partially open deeper cavitand structure (123).

Figure 89

Water-stabilized deep cavitands with partially structure (124, 125).

Figure 90

Charged cavitands 126 for tetralkylammonium ions.

Figure 91

Ditopic calix[4]arene receptor 127 capped with glycol chains.

Figure 92

A calix[5]arene dimer for diammonium salt recognition.

Figure 93

Calixarene parts 92c and 129 for the formation molecular capsules.

Figure 94

Encapsulation of a quaternary ammonium cation by two resorcin[4]arene molecules (NMe₄⁺@[75c]₂ × Cl⁻ × 6MeOH × H₂O; for clarity, solvent molecules and counterions have been omitted).

Figure 95

Encapsulation of a quaternary ammonium cation by six resorcin[4]arene molecules (NMe₃D⁺@[130]₆ × Cl⁻; solvent molecules, substituents and counterions are omitted for clarity; the last two resorcinarene calixes are arranged behind and in front of the scheme’s plane).

Figure 96

Structure and schematic of cucurbit[6]uril (CB[6], 131a).

Figure 97

Cyclohexanocucurbit[6]uril (CB′[6], 132) and the guest molecule spermine (133).

Figure 98

α,α,δ,δ-Tetramethylcucurbit[6]uril (134).

Figure 99

Structure of the cucurbituril-phthalhydrazide analogue 135.

Figure 100

Organic cavities for the displacement assay for amine differentiation.

Figure 101

Displacement assay methodology for diammonium- and related guests involving cucurbiturils and some guests.

Figure 102

Nor-seco-Cucurbituril (±)-bis-ns-CB[6] (140) and guest molecules.

Figure 103

The cucurbit[6]uril based complexes 141 for chiral discrimination.

Figure 104

Cucurbit[7]uril (131c) and its ferrocene guests (142) opposed.

Figure 105

Cucurbit[7]uril (131c) guest inclusion and representative guests.

Figure 106

Cucurbit[7]uril (131c) binding to succinylcholine (145) and different bis-ammonium and bis-phosphonium guests.

Figure 107

Paraquat-cucurbit[8]uril complex 149.

Figure 108

Gluconuril-based ammonium receptors 150.

Figure 109

Examples of clefts (151a), tweezers (151b, 151c, 151d) and clips (151e).

Figure 110

Kemp’s triacid (152a), on example of Rebek’s receptors (152b) and guests.

Figure 111

Amino acid receptor (154) by Rebek et al.

Figure 112

Hexagonal lattice designed hosts by Bell et al.

Figure 113

Bell’s amidinium receptor (156) and the amidinium ion (157).

Figure 114

Aromatic phosphonic acids.

Figure 115

Xylene phosphonates 159 and 160a/b for recognition of amines and amino alcohols.

Figure 116

Bisphosphonate recognition motif 161 for a colorimetric assay with alizarin complexone (163) for catechols (162).

Figure 117

Bisphosphonate/phosphate clip 164 and bisphosphonate cleft 165.

Figure 118

N-Methylpyrazine 166a, N-methylnicotinamide iodide (166b) and NAD⁺ (166c).

Figure 119

Bisphosphate cavitands.

Figure 120

Bisphosphonate 167 of Schrader and Finocchiaro.

Figure 121

Tweezer 168 for noradrenaline (80b).

Figure 122

Different tripods and heparin (170).

Figure 123

Squaramide based receptors 172.

Figure 124

Cage like NH₄⁺ receptor 173 of Kim et al.

Figure 125

Ammonium receptors 174 of Chin et al.

Figure 126

2-Oxazolin-based ammonium receptors 175a–d and 176 by Ahn et al.

Figure 127

Racemic guest molecules 177.

Figure 128

Tripods based on a imidazole containing macrocycle (178) and the guest molecules employed in the study (20a, 179a–d).

Figure 129

Ammonium ion receptor 180.

Figure 130

Tetraoxa[3.3.3.3]paracyclophanes 181 and a cyclophanic tetraester (182).

Figure 131

Peptidic bridged paraquat-cyclophane.

Figure 132

Shape-selective noradrenaline host.

Figure 133

Receptor 185 for binding of noradrenaline on surface layers from Schrader et al.

Figure 134

Tetraphosphonate receptor for binding of noradrenaline.

Figure 135

Tetraphosphonate 187 of Schrader and Finocchiaro.

Figure 136

Zinc-Porphyrin ammonium-ion receptors 188 and 189 of Mizutani et al.

Figure 137

Zinc porphyrin receptor 190.

Figure 138

Zinc porphyrin receptors 191 capable of amino acid binding.

Figure 139

Zinc-porphyrins with amino acid side chains for stereoinduction.

Figure 140

Bis-zinc-bis-porphyrin based on Tröger’s base 193.

Figure 141

BINAP-zinc-prophyrin derivative 194 and it’s guests.

Figure 142

Bisaryl-linked-zinc-porphyrin receptors.

Figure 143

Bis-zinc-porphyrin 199 for diamine recognition and guests.

Figure 144

Bis-zinc-porphyrin crown ether 201.

Figure 145

Bis-zinc-porphyrin 202 for stereodiscrimination (L = large substituent; S = small substituent).

Figure 146

Bis-zinc-porphyrin[3]rotaxane and its copper complex and guests.

Figure 147

Dien-bipyridyl ligand 206 for co-ordination of two metal atoms.

Figure 148

The ligand and corresponding tetradentate co-complex 207 serving as enantioselective receptor for amino acids.

Figure 149

Bis(oxazoline)–copper(II) complex 208 for the recognition of amino acids in aqueous solution.

Figure 150

Zinc-salen-complexes 209 for the recognition tertiary amines.

Figure 151

Bis(oxazoline)–copper(II) 211 for the recognition of amino acids in aqueous solution.

Figure 152

Zn(II)-complex of a C₂ terpyridine crown ether.

Figure 153

Displacement assay and receptor for aspartate over glutamate.

Figure 154

Chiral complex 214 for a colorimetric displacement assay for amino acids.

Figure 155

Metal complex receptor 215 with tripeptide side arms.

Figure 156

A sandwich complex 216 and its displaceable dye 217.

Figure 157

Lanthanide complexes 218–220 for amino acid recognition.

Figure 158

Nonactin (221), valinomycin (222) and vancomycin (223).

Figure 159

Monesin (224a) and a chiral analogue for enantiodiscrimination of ammonium guests (224b).

Figure 160

Chiral podands (226) compared to pentaglyme-dimethylether (225) and 18-crown-6 (4).

Figure 161

Lasalocid A (228).

Figure 162

Lasalocid derivatives (230) of Sessler et al.

Figure 163

The Coporphyrin I tetraanion (231).

Figure 164

Linear and cyclic peptides for ammonium ion recognition.

Figure 165

Cyclic and bicyclic depsipeptides for ammonium ion recognition.

Figure 166

α-Cyclodextrin (136a) and novocaine (236).

Figure 167

Helical diol receptor 237 by Reetz and Sostmann.

Figure 168

Ammonium binding spherand by Cram et al. (238a) and the cyclic[6]metaphenylacetylene 238b in comparison.

Figure 169

Receptor for peptide backbone and ammonium binding (239).

Figure 170

Anion sensor principle with 3-hydroxy-2-naphthanilide of Jiang et al.

Figure 171

7-bromo-3-hydroxy-N-(2-hydroxyphenyl)naphthalene 2-carboxamide (241) and its amine binding.

Figure 172

Naturally occurring catechins with affinity to quaternary ammonium ions.

Figure 173

Spiropyran (244) and merocyanine form (244a) of the amino acid receptors of Fuji et al.

Figure 174

Coumarin aldehyde (245) and its iminium species with amino acid bound (245a) by Glass et al.

Figure 175

Coumarin aldehyde appended with boronic acid.

Figure 176

Quinolone aldehyde dimers by Glass et al.

Figure 177

Chromogenic ammonium ion receptors with trifluoroacetophenone recognition motifs.

Figure 178

Chromogenic ammonium ion receptor with trifluoroacetophenone recognition motif bound on different matrices.