John H. Coates

Inclusion Complexes of the Cyclomalto-Oligosaccharides (Cyclodextrins)

Publisher Summary This chapter provides an overview of the inclusion complexes of cyclomalto-oligosaccharides (cyclodextrins). Inclusion complexes are chemical species consisting of two or more associated molecules in which one of the molecules—the “host”—forms or possesses a cavity into which it can admit a “guest” molecule, resulting in a stable association without formation of any covalent bonds. Secondary forces are alone responsible for the maintenance of the integrity of all inclusion complexes. One of the most important properties of the cyclodextrins is their ability to form complexes with a variety of organic and inorganic compounds. 1 H-Nuclear magnetic resonance (NMR) spectroscopy provided the first direct evidence of inclusion within the cyclodextrin cavity in solution. Using aromatic “guest” molecules, it was found that, on the addition of the guest, the resonances of the hydrogen atoms of the cyclodextrin situated on the inside of the cavity were shifted significantly upfield due to shielding by the aromatic guest. This chapter discusses determination of the structure of the cyclodextrins, and formation of the cyclodextrins from starch. It provides details about formation of inclusion complexes, detection of complex formation, and thermodynamics of complex formation. Kinetics of complex formation is also explained in the chapter.

Substituent effects and chiral discrimination in the complexation of benzoic, 4-methylbenzoic and (RS)-2-phenylpropanoic acids and their conjugate bases by β-cyclodextrin and 6A-amino-6A-deoxy-β-cyclodextrin in aqueous solution: potentiometric titration and 1H nuclear magnetic resonance spectroscopic study

A potentiometric titration study in aqueous solution (l= 0.10 mol dm–3, KCl) of the complexation of benzoic, 4-methylbenzoic and (RS)–2-phenylpropanoic acids (HA) and their conjugate bases (A–) with β-cyclodextrin, βCD, and its substituted analogue, 6A-amino-6A-deoxy-β-cyclodextrin, βCDNH2, in which a primary hydroxy group is replaced by an amino group which may be protonated to produce a singly charged species, βCDNH+3, is reported. At 298.2 K the stability constants for the complexes have the values (in dm3 mol–1) shown in parentheses: benzoic acid ·βCD (K1HA= 590 ± 60); benzoate ·βCD (K1A= 60 ± 10); benzoic acid ·βCDNH+3(K2HA= 340 ± 30); benzoate ·βCDNH+3(K2A= 120 ± 20); benzoate ·βCDNH2(K3A= 50 ± 20); 4-methylbenzoic acid ·βCD (K1HA= 1680 ± 90); 4-methylbenzoate ·βCD (K1A= 110 ± 1); 4-methylbenzoic acid ·βCDNH+3(K2HA= 910 ± 20); 4-methylbenzoate ·βCDNH+3(K2A= 330 ± 20); and 4-methylbenzoate ·βCDNH2(K3A= 100 ± 20). These data indicate that for a given cyclodextrin the guest carboxylic acids form complexes of higher stability than do their conjugate base analogues, and that βCDNH+3 forms more stable complexes with the conjugate bases than do βCD and βCDNH2. These trends are also observed for the complexation of (RS)-2-phenylpropanoic acid and (RS)-2-phenylpropanoate where the complexes indicated are characterised by the stability constants (in dm3 mol–1) shown in parentheses: (RS)-2-phenylpropanoic acid ·βCD (K1RHA= 1090 ± 30, K1SHA= 1010 ± 40); (RS)-2-phenylpropanoate ·βCD (K1RA= 63 ± 8, K1SA= 52 ± 5); (RS)-2-phenylpropanoic acid ·βCDNH+3(K2RHA= 580 ± 20, K2SHA= 480 ± 10); (RS)-2-phenylpropanoate ·βCDNH+3(K2RA= 150 ± 8, K2SA= 110 ± 10); and (RS)-2-phenylpropanoate ·βCDNH2(K3RA= 36 ± 6, K3SA= 13 ± 7). These data also show that while K1RHA and K1SHA, and K1RA and K1SA are indistinguishable for (RS)-2-phenylpropanoic acid ·βCD and (RS)-2-phenylpropanoate ·βCD, chiral discrimination is indicated by K2RHA > K2SHA for (RS)-2-phenylpropanoic acid ·βCDNH+3, K2RA > K2SA for (RS)-2-phenylpropanoate ·βCDNH+3, and K3RA > K3SA for (RS)-2-phenylpropanoate ·βCDNH2. The 1H NMR spectra of the methyl groups of the enantiomers of (RS)-2-phenylpropanoic acid appear as two separate doublets, indicating chiral discrimination when complexed by βCD or βCDNH+3, but such chiral discrimination is not observed for (RS)-2-phenylpropanoate when complexed by βCDNH+3. The implications of these observations are discussed.

Kinetic and equilibrium studies of cyclomalto-octaose (γ-cyclodextrin)-methyl orange inclusion complexes

Abstract Measurements of the equilibrium and temperature-jump u.v., visible, and induced c.d. spectra of Methyl Orange (MO) in the presence of cyclomalto-octaose (γ-cyclodextrin, γ-CD) have been carried out. Three mechanistic steps were detected through the temperature-jump data (25.0°): where K1, K2, and K3 are 45 (±7), 2.0 (±1.1) × 106, and 6.1 (±2.5) × 103 dm3.mol−1, respectively, k2 = 9.4 (±5.1) × 109 dm3.mol−1.s−1, and k−2 = 4.8 (±0.8) × 103 s−1. The equilibrium u.v./visible data are also consistent with this reaction scheme. The high stability of the dimer inclusion complex (MO)2 · γ-CD compared to that of the monomer inclusion complex MO · γ-CD appears to be related to the annular diameter of γ-CD and demonstrates a degree of selectivity in cyclodextrin inclusion complexes. The (MO)2 · (γ-CD)2 complex also contains a dimer, included by both γ-CD molecules.

Chiral molecular recognition: a 19F nuclear magnetic resonance study of the diastereoisomer inclusion complexes formed between fluorinated amino acid derivatives and α-cyclodextrin in aqueous solution

A 19F NMR spectroscopic study (282.35 MHz) of the formation of diastereoisomeric inclusion complexes by fluorinated amino acid derivatives and α-cyclodextrin (αCD) in 10% aqueous D2O solution yields the apparent stability constants KR and KS/dm3 mol–1= 7.7 ± 0.3 and 8.2 ± 0.3 for protonated α-(p-fluorophenyl)glycine (1 + H), 21.5 ± 0.4 and 22.5 ± 0.4 for deprotonated α–(p-fluorophenyl)glycine (1 – H), 14.4 ± 0.1 and 14.6 ± 0.1 for N-acetyl-α-(p-fluorophenyl)glycine (2), 13.1 ± 0.5 and 14.1 ± 0.5 for deprotonated N-acetyl-α-(p-fluorophenyl)-glycine (2– H), and 12.4 ± 0.3 and 10.6 ± 0.4 for deprotonated N-(p-fluorobenzoyl)valine (3– H), where the first and second of each pair of values refers to the diastereoisomer formed between αCD and the R and S enantiomer, respectively. The chemical shifts of the R-amino acid derivative ·αCD inclusion complexes are upfield from those of their S analogues for deprotonated N-(p-fluorobenzoyl)valine (3– H), deprotonated α-(p-fluorophenyl)glycine (1– H), and deprotonated N-acetyl-α-(p-fluorophenyl)glycine (2– H), but this relationship is reversed for protonated α-(p-fluorophenyl)glycine (1+ H) and N-acetyl-α-(p-fluorophenyl)glycine (2+ H). In the case of the N-(p-fluorobenzoyl)valine ·αCD inclusion complex (3·αCD) the chemical shift difference between the diastereo-isomers formed with the R and S enantiomers is too small for quantitative analysis and accordingly a composite KR,S/dm3 mol–1= 8.3 ± 0.3 was determined. The factors causing the variations in apparent stability constants and chemical shifts are discussed.

Metallocyclodextrins of 6A-(3-aminopropylamino)-6A-deoxy-β-cyclodextrin: their formation and enantioselective complexation of (R)- and (S)-tryptophan anions in aqueous solution

From a pH titration study, the complexation of divalent metal ions (M2+) by 6A-(3-aminopropylamino)-6A-deoxy-β-cyclodextrin (βCDpn) to form the metallocyclodextrins, [M(βCDpn)]2+, is characterized by log(K2/dm3 mol–1)= 4.22 ± 0.02, 5.2 ± 0.1, 7.35 ± 0.04 and 4.96 ± 0.08 when M2+= Co2+, Ni2+, Cu2+ and Zn2+, respectively, in aqueous solution at I= 0.10 (NaClO4) and 298.2 K. The complexation of the tryptophan anion (Trp–) by [M(βCDpn)]2+ is enantioselective for (S)-Trp– as indicated by log(K6R/dm3 mol–1) and log(K6S/dm3 mol–1)= 4.04 ± 0.03 and 4.32 ± 0.05, 4.1 ± 0.2 and 5.1 ± 0.2, and 7.85 ± 0.07 and 8.09 ± 0.05, where the first and second magnitudes refer to the stability constants for [M(βCDpn)(R)-Trp]+, and [M(βCDpn)(S)-Trp]+, respectively, when M2+= Co2+, Ni2+ and Cu2+, respectively. The corresponding magnitudes for M2+= Zn2+ are both 5.3 ± 0.1, indicating no enantioselectivity. The role of M2+ and other factors affecting complexation and enantioselectivity are discussed.

Tryptophan anion complexes of β-cyclodextrin (cyclomaltaheptaose), an aminopropylamino-β-cyclodextrin and its enantioselective nickel(II) complex

6I-(3-Aminopropylamino)-6I-deoxy-cyclomaltaheptaose (βCDpn) exhibits enhanced complexation of tryptophan anion, by comparison with βCD, while the nickel(II) complex of βCDpn complexes tryptophan anion even more strongly and exhibits a tenfold enantioselectivity in favour of the (S)-tryptophan anion.

Complexation of cobalt(II), nickel(II) and copper(II) by the pendant arm macrocyclic ligand N,N′,N″,N‴-tetrakis(2-hydroxyethyl)-l,4,8,11-tetraazacyclotetradecane

Abstract A stopped-flow spectrophotometric study of the complexation of Co2+ and Ni2+ by the pendant arm ligand, N, N′, N″, N‴-tetrakis(2-hydroxyethyl)-1,4,8,11-tetraazacyclotetradecane (L2), in aqueous solution at pH 6.80, I=1.50 (NaNO3) and 298.2 K yields the rate constants, kLH′=880 and 116 dm3 mol−1 s−1 for the complexation of Co2+ and Ni2+, respectively, by the monoprotonated ligand, L2H+. In aqueous HNO3, the decomplexation of [ML2]2+ is characterized by: kobs=k0+k1K1a[H+]/1+K1a[H+] where at 298.2 K, k0=0.21, ≈0 and ≈0 s−1, k1=151, 0.160 and 6.07 s−1, and K1a=5.2, 83 and 0.67 dm3 mol−1, respectively, when M2+=Co2+, Ni2+ and Cu2+. The effect of the pendant arms on the complexation and decomplexation processes are considered through a comparison of these data with those for 1,4,8,11-tetraazacyclotetradecane and related ligands.

The inclusion of pyronine Y by β- and γ-cyclodextrin. A Kinetic and equilibrium study

Temperature-jump spectrophotometric studies show the dye pyronine Y (PY) in its monovalent cationic form to be included by γ-cyclodextrin (γCD) in a fast step to form a 1:1 complex (PY·γCD, which is followed by the slower formation of the 2:1 complex (PY)2·γCD, in which pyronine Y dimerizes. There is also evidence for the formation of a 2:2 complex (PY)2·(γCD)2 in a third and fast step. The temperature-jump relaxation data obtained at 298.2 K from 1.0 mol dm–3 NaCl aqueous solutions at pH 6.1 yielded the apparent stability constants K1=(1.0±0.1)× 103 dm3 mol–1, K2=(1.2±1.1)× 105 dm3 mol–1 and K3= 52±22 dm3 mol–1 for these complexes, and the rate constants k2=(1.7±1.0)× 10)× 109 dm3 mol–1s–1 and k–2=(1.4±0.5)× 104s–1 for the second complex. In the presence of βCD the 1:1 PY·βCD and 1:2 PY ·(βCD)2 complexes are formed, but no complexation of PY by αCD was detected.

Chiral differentiation in the deacylation of 6A-O-{2-[4-(2-methylpropyl)phenyl]propanoyl}-β-cyclodextrin

In 0.1 mol dm–3 sodium carbonate buffer at pH 11.5 the pseudo first-order rate constants for the hydrolysis of the diastereoisomers of the title compound to give Ibuprofen {2-[4-(2-methylpropyl)phenyl]propanoic acid} and β-cyclodextrin are 2.97 × 10–5 s–1 and 3.16 × 10–4 s–1, with the diastereoisomer derived from (R)-Ibuprofen being the most susceptible to hydrolysis.

Complexation of tropaeolin 000 No. 2 by β- and γ-cyclodextrin

Measurements of the temperature-jump and equilibrium u.v.–visible and induced circular dichroic spectra of tropaeolin 000 No. 2 (TR) in the presence of α-, β- and γ-cyclodextrin (αCD, βCD and γCD) have been carried out. Three complexation steps are detected in the presence of γCD through the temperature-jump data (298.2 K): TR +γCD ⇌ TR·γCD fast (K1), [graphic omitted], γCD +(TR)2·γCD ⇌(TR)2·(γCD)2 fast (K3), where K1, K2 and K3 are (4.18 ± 1.47)× 102, (1.68 ± 0.54)× 106 and (1.77 ± 1.54)× 102 dm3 mol–1, respectively; k2=(2.27 ± 0.61)× 109 dm3 mol–1 s–1 and k–2=(1.35 ± 0.23)× 103 s–1. In the presence of βCD the third complexation was not detected and K1=(7.1 ± 0.7)× 102 and K2=(4 ± 7)× 106 dm3 mol–1; k2=(5 ± 6)× 109 dm3 mol–1 s–1 and k–2=(1.3 ± 1.5)× 103 s–1. No complexation reactions were detected in the presence of αCD. The equilibrium u.v.–visible spectra and the circular and linear dichroic spectra are consistent with these reaction schemes, but suggest different orientation and penetration for the (TR)2 dimer included in (TR)2·βCD compared with (TR)2·γCD.For the equilibrium [graphic omitted] the equilibrium constant Kd=(9.10 ± 4.28)× 102 dm3 mol–1 has been determined by u.v.–visible spectroscopy, and k–d=(2.24 ± 0.40)× 103 s–1 has been estimated from temperature-jump experiments. Hence kd=(2.0 ± 1.0)× 106 dm3 mol–1 s–1. Thus the increase in stability of (TR)2 included in (TR)2·γCD and (TR)2·βCD over that observed in the absence of cyclodextrin is a consequence of k2≈ 103kd.