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7Artificial Receptor Compounds for Chiral RecognitionThomas J. Wenzel and Ngoc H. Pham

7.1Introduction

Chiral receptor compounds have been used extensively for chiral recognition studies.This chapter describes receptor compounds that formhost–guest complexes throughnoncovalent interactions. Furthermore, only receptor compounds that have a well-defined cavity ormotif that specifically interacts with a guest throughmultiple pointsof attraction are included. Discussion is restricted to receptor compounds used forthe analysis of chiral compounds in gas or solution phase studies.

The most extensive applications of receptor compounds in chiral recognitioninvolve the use of chromatographic [1, 2] or NMR spectroscopic [3] methods.Ultraviolet–visible absorption spectroscopy is often used to determine whether areceptor compound exhibits enantiodifferentiation with substrates. Mass spectro-metric methods are increasingly being developed and used in studies of enantio-meric recognition [4].

Cyclodextrins, crown ethers, calixarenes, and calix[4]resorcinarenes are broad andwidely studied classes of receptor compounds. Studies on these systems are tooextensive to describe exhaustively, so only illustrative examples are presented.Similarly, a range of specific enantioselective receptor compounds has been de-scribed. The number of reports of such systems is so large that only examplesdesigned to illustrate the range of receptor compounds are presented.

7.2Cyclodextrins

Cyclodextrins are a series of cyclic oligosaccharides, the most common of whichcontain six (a), seven (b), or eight (c) glucose units (Figure 7.1). Cyclodextrins have abasket-shaped cavity in which the narrower opening is ringed with primary hydroxygroups at the 6-position and the wider opening is ringed with secondary hydroxygroups at the 2- and 3-positions of each glucose ring. Because the a-, b-, and

Artificial Receptors for Chemical Sensors. Edited by V.M. Mirsky and A.K. YatsimirskyCopyright � 2011 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32357-9

j191

c-cyclodextrins have different sizes, they can accommodate different guest mole-cules. Enantiomeric recognition often depends on a complementary match betweenthe size of the substrate and size of the cavity. The native, underivatized cyclodextrinsare natural compounds. However, derivatization at the 2-, 3-, and/or 6-hydroxygroups has been carried out to prepare an array of chiral cyclodextrins with differentproperties. Derivatization affects both the solubility and enantiomeric recognitionproperties of the cyclodextrins. An important factor with certain cyclodextrinderivatives involves the degree of substitution (DS). Sometimes the cyclodextrin isfully derivatized, whereas in other cases substituent groups are added in anindiscriminate fashion and a certain DS is achieved. Cyclodextrins are probably themost frequently studied family of receptor compounds and they have been widelyused in chiral recognition applications.

7.2.1Alkylated Cyclodextrins

Per-O-alkylated cyclodextrins are prepared by the reaction of a large excess of analkylhalide with cyclodextrin in the presence of a suitable base. Per-O-methylation ofcyclodextrin has been achieved using sodium hydroxide, potassium hydroxide [5], orsodium hydride [6] with methyl iodide in methyl sulfoxide. Per-O-methyl cyclodex-trins have been coated with moderately polar siloxanes as capillary gas chro-matographic phases and used for the separation of a wide range of volatile enan-tiomeric compounds, including unfunctionalized hydrocarbons [6]. Heptakis(2,3,6-tri-O-methyl)-b-cyclodextrin is now commercially available.

Hexakis(2,3,6-tri-O-methyl)-a-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-b-cy-clodextrin are water- and organic-soluble and have also been used as chiral NMRsolvating agents. For example, hexakis(2,3,6-tri-O-methyl)-a-cyclodextrin causedchiral recognition in the 1H NMR spectra of metal complexes such as Ru(bipy)3

2þ

(bipy¼ 2,20-bipyridine) and Ru(phen)32þ (phen¼ 1,10-phenanthroline) [7]. Hepta-

kis(2,3,6-tri-O-methyl)-b-cyclodextrin is an especially effective chiral NMR solvatingagent for trisubstituted allenes. The allene hydrogen resonance was a useful one toemploy in determining enantiomeric purity. The allene resonance of the (S)-isomer

O

HO OH

O

OH

123

4

5

6

Figure 7.1 Representation of cyclodextrin superimposed with one D-glucose subunit.

192j 7 Artificial Receptor Compounds for Chiral Recognition

was consistently deshielded relative to that of the (R)-isomer in the presence of thehexakis(2,3,6-tri-O-methyl)-a-cyclodextrin [8].

Hexakis(2,3,6-tri-O-pentyl)-a-cyclodextrin and heptakis(2,3,6-tri-O-pentyl)-b-cyclo-dextrinhavebeenevaluated as capillary gas chromatographic phases for the separationof enantiomers [9–11]. Reaction of the cyclodextrin with an excess of 1-bromopentaneinmethyl sulfoxide in the presence of sodiumhydroxide resulted in alkylation of the 2and 6-positions. Alkylation of the less reactive 3-position was achieved either byreaction of the 2,6-di-O-pentyl cyclodextrin with excess 1-bromopentane in tetrahy-drofuran (THF) in the presence of sodium hydride [10, 11] or by addition of moresodium hydroxide and 1-bromopentane with continuing reflux for five days [9].

Per-substituted 2,6-di-O-pentyl-a, b- or c-cyclodextrins, which are readily obtainedby alkylation using 1-bromopentane and sodiumhydroxide inmethyl sulfoxide, havealso been used as chiral gas chromatographic phases [12]. Similarly, per-substituted(2,6-di-O-methyl)-b-cyclodextrin has been prepared followed by reaction of 1-bro-mopentane and sodiumhydride to alkylate the 3-position [13]. The heptakis(2,6-di-O-methyl-3-O-pentyl)-b-cyclodextrin was employed as a capillary gas chromatographicphase.

Substitution of alkyl groups at other positions is achieved either by selectiveblockage of certain positions followed by alkylation anddeprotection or by differencesin the reactivity of the 2-, 3-, and 6-hydroxy groups in the presence of appropriatebases. For example, sodium hydride selectively reacts at the 2-position of cyclodex-trin. A reaction of one equivalent of b-cyclodextrin with seven equivalents of sodiumhydride in the presence of methyl iodide produces the heptakis(2-O-methyl)-b-cyclodextrin [14]. The heptakis(2,3-di-O-pentyl-6-O-methyl)-b-cyclodextrin has beenobtained by a multistep process. The first step involved blocking the 6-position byreaction with tert-butyldimethylsilyl chloride (TBDMS) and imidazole in dimethyl-formamide (DMF) [15]. Reaction of the blocked cyclodextrin with n-pentyl iodide andsodium hydride in DMF afforded the corresponding heptakis(2,3-di-O-pentyl)-b-cyclodextrin. After removal of the TBDMS using tetrabutylammonium fluoride(TBAF) in THF, the 6-position was methylated by reaction with methyl iodide andsodium hydride in THF.

Heptakis(2-O-methyl-3,6-di-O-pentyl)-b-cyclodextrin has been prepared using amultistep procedure. The 6- and 2-positions were first protected using TBDMS andallyl bromide, respectively. Deprotection of the 6-position enabled pentylation of the3- and 6-positions. After de-allylation, methylation of the 2-position was performed.The cyclodextrin derivative phase was then evaluated as a stationary phase for gaschromatographic separations [16].

Schemes to selectively attach permethylated b-cyclodextrin to silica gel at the 2-, 3-,or 6-positions have been described [17]. Starting with established procedures formaking the heptakis(2,3-di-O-methyl)- or heptakis(2,6-di-O-methyl)-b-cyclodextrinderivative, it was possible to prepare the correspondingmono-oct-7-enyl derivative ateither the 6- or 3-position using one equivalent of sodium hydride and 8-bromo-1-octene in DMF. The remaining hydroxy groups were then methylated usingestablished methods. The alkene group was then utilized to covalently link thecyclodextrin derivative to silica gel. Using a known 2,3,6-tri-O-methylated derivative

7.2 Cyclodextrins j193

with a single underivatized hydroxy group at the 2-position [18], the corresponding2-bound cyclodextrin was prepared by attachment of the oct-7-enyl group at theremaining 2-hydroxy group [17]. Of these, the 2-O-bonded phase was judged bestas a gas chromatographic stationary phase for the separation of enantiomericcompounds.

7.2.2Acylated and Mixed Acylated/Alkylated Cyclodextrins

Per-O-acetylated derivatives of cyclodextrins are readily prepared by reaction withexcess acetic anhydride in pyridine [19, 20]. A per-O-acetylated b-cyclodextrin im-mobilized on silica gel has been evaluated as a stationary phase in liquid chroma-tography [19]. However, mixed alkylated-acylated cyclodextrin derivatives have beenmore commonly used as chromatographic phases.

Hexakis(2,6-di-O-pentyl)-a- or heptakis(2,6-di-O-pentyl)-b-cyclodextrin has beenacetylated at the 3-position using acetic anhydride, triethylamine, and 4-N-dimethy-laminopyridine (DMAP) [10, 11]. The resulting cyclodextrins were used as stationaryphases in capillary gas chromatography. Using analogous synthetic procedures,cyclodextrin derivatives with substitution patterns such as 3-O-trifluoroacetyl-2,6-di-O-pentyl (trifluoroacetic anhydride) [12, 21], 3-O-butyryl-2,6-di-O-pentyl (butyricanhydride) [16], and 3-O-trifluoroacetyl-2,6-di-O-methyl [6] were also evaluated aschiral gas chromatographic stationary phases. A particularly interesting observationwas a temperature-dependent reversal in elution order for themethyl esters of certainphenoxypropionic acid herbicides on a gas chromatographic phase consisting ofoctakis(3-O-butyryl-2,6-di-O-pentyl)-c-cyclodextrin [16].

The 6-O-acetyl-2,3-di-O-pentyl derivatives of a-, b-, and c-cyclodextrin have beenprepared and evaluated as chiral gas chromatographic phases [15]. This compoundwas not as effective as the corresponding 3-O-acetyl-2,6-di-O-pentyl or 6-O-methyl-2,3-di-O-pentyl derivatives.

The octakis(3-O-butyryl-2,6-di-O-pentyl)-c-cyclodextrin has also been exploited forenantiorecognition using thickness shear mode resonators [22], surface acousticwave devices [23], Fourier-transform infrared reflectance spectra [23], and capacitivemicrosensors [24]. In these techniques, the cyclodextrin derivative is coated into apolymeric thin film such as poly(dimethylsiloxane) on a sensor surface. In thepresence of enantiomers, differences in signals are noted for the two enantiomers.Differences in the vibrating frequency of a quartz crystal are observed for a pair ofenantiomers when mass is deposited onto the surface. In the capacitance sensor,enantiomers of methyl propionate caused antipode signals on adsorption into thecyclodextrin layer [24].

7.2.3Carbamoylated Cyclodextrins

Various carbamoylated cyclodextrins have been used for chiral recognition inchromatographic and NMR applications. The derivatives are prepared by reacting


the cyclodextrin and appropriate isocyanate under reflux for several hours inpyridine [25, 26]. In many cases, steric hindrance created by attachment of thecarbamoyl groups limits the extent of the reaction and unreacted hydroxy groupsremain [25]. Liquid chromatographic applications include the use of a perphenylcarbamoylated derivative of b-cyclodextrin [19], an indiscriminately substituted 2,6-dimethylphenyl [25], 3,5-dimethylphenyl [26, 27], or (R)- or (S)-1-(1-naphthyl)ethyl[25] carbamoylated cyclodextrin derivatives as bonded stationary phases. Derivativesof persubstituted (2,6-di-O-pentyl)-a-, b-, or c-cyclodextrin with either a n-propyl,isopropyl, or phenyl carbamoyl group at the 3-position were used as gas chro-matographic stationary phases for free alcohols, amines, and epoxides [28].

Exhaustively 3,5-dimethylphenyl carbamoylated, partially 3,5-dimethylphenyl car-bamoylated (2,3-positions), and 6-TBDMS/3,5-dimethylphenyl carbamoylated (2,3-positions) derivatives of b-cyclodextrin have been compared for their effectiveness aschloroform-soluble chiral NMR solvating agents. The per-carbamoyl derivative wasgenerally the most effective. The 1H NMR spectra of N-(3,5-dinitrobenzoyl) deriva-tives of amino acidmethyl esters and amines exhibited enantiomeric discrimination.However, association of the substrate with the cyclodextrin involved dipole–dipoleand p–p interactions at the external carbamoyl groups instead of insertion into thecavity [29].

7.2.42-Hydroxypropylether Cyclodextrins

The reaction of either (R)- or (S)-propylene oxide with a-, b-, or c-cyclodextrin inaqueous sodium hydroxide solution produces indiscriminately substituted 2-hydro-xypropylether derivatives. The degrees of substitution range from 6.2 for a-cyclo-dextrin to 7.0 for c-cyclodextrin. The hydroxypropyl derivative was bonded to silica geland used as a liquid chromatographic phase. The permethylated derivatives of2-hydroxypropylether a-, b-, and c-cyclodextrins were evaluated as capillary gaschromatographic stationary phases. The 2-hydroxypropylether cyclodextrin phasescould be used to separate compounds with a wide variety of functional groups [30].

7.2.5Tert-butyldimethylsilyl Chloride-Substituted Cyclodextrins

The reaction of cyclodextrins with tert-butyldimethylsilyl chloride in DMF in thepresence of imidazole leads to selective derivatization at the 6-position [31, 32]. Usingestablished procedures, it is then possible to alkylate or acylate the 2- and 3-positionsof the cyclodextrin [31]. Removal of the TBDMS group using TBAF in oxolane orboron trifluoride etherate in dichloromethane opens the 6-position for furtherderivatization [31]. Alternatively, the 6-TBDMS derivative can be selectively alkylatedat the 2-position using methyl iodide in the presence of barium oxide and bariumhydroxide in DMF [32].

Heptakis(2,3-di-O-acetyl-6-O-TBDMS)-b-cyclodextrin [33], heptakis(2,3-di-O-methyl-6-O-TBDMS)-b-cyclodextrin [34], and heptakis(2,3-di-O-pentyl-6-O-


TBDMS)-b-cyclodextrin [35] have been evaluated as gas chromatographic sta-tionary phases.

7.2.6Anionic Cyclodextrins

Several negatively charged cyclodextrins have been employed in the enantiomericdiscrimination of cationic substrates. The negatively charged derivatives are espe-cially effective in capillary electrophoretic applications [36]. One example is anindiscriminately substituted sulfobutyl ether b-cyclodextrin (SBE-CD) that is pre-pared by the reaction of cyclodextrin with butane sultone in an aqueous solution ofsodium hydroxide [37]. The anionic SBE-CD derivative has been used as an eluentphase additive in reversed-phase liquid chromatography [38], capillary electropho-resis [39], and electrokinetic chromatography [40].

Indiscriminately substituted sulfated cyclodextrins are prepared by reaction withchlorosulfonic acid in pyridine or using amixture of triethylamine and sulfur trioxidein DMF [41]. It is usually possible to obtain a relatively high DS (9–14 substituentgroups) for the sulfated derivatives. Sulfated cyclodextrins have been used as eluentadditives in capillary electrophoresis [36] or as bonded phases in liquid chromatog-raphy [42]. The heptakis(2,3-di-O-acetyl-6-sulfato)-b-cyclodextrin [43] or octakis(2,3-di-O-acetyl-6-sulfato)-c-cyclodextrin [44] were used as additives in capillary electro-phoresis. Synthesis of the mixed acetyl-sulfate cyclodextrins first involved blockingthe 6-position with TBDMS, acetylation of the 2,3-positions, deprotection with borontrifluoride etherate, and reaction with pyridine and sulfur trioxide in DMF.

A commercially available sulfated b-cyclodextrin with a DS of 9 has been used as achiralNMRsolvating agent forwater-soluble cationic substrates such as pheniramine(1), carbinoxamine (2), doxylamine (3), and propranolol (4) and was more effectivethan native b-cyclodextrin [45]. The addition of paramagnetic lanthanide ions such asytterbium(III) or dysprosium(III) to mixtures of substrates and sulfated b-cyclodex-trin frequently led to enhancements in enantiomeric discrimination in the 1H NMRspectrum. The lanthanide ion bound at the sulfate groups of the cyclodextrin andcaused changes in chemical shifts in the NMR spectra of substrates that were oftendifferent for the two enantiomers.

CH CH2CH2NH(CH3)2

N

1

CH OCH2CH2NH(CH3)2

N

2

Cl


CH3C OCH2CH2NH(CH3)2

N

3

OCH2CHCH2NHCH(CH3)2

OH

4

Carboxymethylation is another common way of preparing anionic cyclodextrinderivatives. Carboxymethylated cyclodextrins have often been used to affect separa-tions in capillary electrophoresis [36]. Indiscriminate carboxymethylation is achievedby reacting sodium iodoacetate with cyclodextrin in an aqueous solution of sodiumhydroxide [46].While substitution of carboxymethyl groups occurs at the 2-, 3-, and 6-positions, addition at the 2-position predominates [46]. Procedures for the selectiveincorporation of carboxymethyl groups at the 2- (activationwith sodiumhydride) or 6-position (activation with pyridine) have been described [47].

Indiscriminately substituted carboxymethylated a-, b-, and c-cyclodextrins wereespecially effective chiral NMR solvating agents for cationic substrates [45, 47, 48].The enhanced effectiveness of the indiscriminately substituted cyclodextrins inNMRapplications relative to the 2- and 6-substituted derivatives was probably because of itsconsiderably higher degree of substitution. Enantiomeric discrimination in theNMRspectrum with the carboxymethylated cyclodextrins was much larger than observedwith the native cyclodextrins. Similar to studies with sulfated cyclodextrins describedearlier, paramagnetic praseodymium(III) or ytterbium(III) bound at the carboxy-methyl groups of the cyclodextrin derivatives and often enhanced the enantiomericdiscrimination in the 1H NMR spectra of substrates [47–49]. In several cases,resonances that did not exhibit enantiomeric discrimination in the presence of onlythe carboxymethylated cyclodextrin split into two signals when Yb(III) or Pr(III) wasadded [47, 48]. In addition, the enantiomeric discrimination with the lanthanide ionwas often so large that much lower concentrations of the carboxymethylatedcyclodextrin could be used [49].

Analogous hexakis(6-carboxymethylthio-6-deoxy)-a-cyclodextrin and heptakis(6-carboxymethylthio-6-deoxy)-b-cyclodextrin derivatives have been used to separatemetal chelate complexes (M(phen)3

þ ) [M¼Ru(III), Rh(III), Fe(II), Co(II), and Zn(II); phen¼ 1,10-phenanthroline] by capillary electrophoresis or produce enantio-meric discrimination in the 1H NMR spectra [7, 50].

7.2.7Cationic Cyclodextrins

Several cationic cyclodextrins have been prepared and used for enantiomericdiscrimination [36]. Reaction of (2,3-epoxypropyl)trimethylammoniumchloridewith


cyclodextrin in an aqueous solution of sodium hydroxide produces an indiscrimi-nately substituted O-2-hydroxypropyltrimethylammonium derivative [51]. Becauseof the quaternary amine, the O-2-hydroxypropyltrimethylammonium cyclodextrinderivative has a fixed positive charge irrespective of pH. It has been used as a mobilephase additive in capillary electrophoresis [52, 53] and reversed-phase liquid chro-matography [54] to enhance the separation of neutral and anionic compounds.

Reaction of a per-substituted 6-bromo-6-deoxy-cyclodextrin derivative with aminessuch as ethanolamine [55] or methoxyethylamine [56] produced the correspondingper-6-amino-6-deoxy derivative. The per-substituted 6-bromo-6-deoxy-cyclodextrinwas prepared by reaction of cyclodextrin with triphenylphosphine and bromine inDMF [55]. The amino cyclodextrins are positively charged at acidic pH and facilitatethe analysis of anionic species in capillary electrophoresis [55, 56]. A mono-(6-butylammonium-6-deoxy)-b-cyclodextrin was prepared by reaction of n-butylaminewithmono-(6-tosyl)-b-cyclodextrin in DMF [57]. The tosyl derivative was prepared byreaction of cyclodextrin with p-toluenesulfonyl chloride in pyridine. Protonation ofthemonobutylamine derivative at acidic pH provided a cationic cyclodextrin that wasused as a mobile phase additive in capillary electrophoresis to separate carboxylatespecies [57].

Eithermono or per-substituted 6-amino-6-deoxy cyclodextrins have been preparedby reaction of ammonia with the corresponding 6-tosyl-6-deoxy derivative [20] or byreducing the corresponding 6-azido-6-deoxy derivative with triphenylphosphine andconcentrated ammonium hydroxide in dioxane–methanol [58]. Enantiomeric dis-crimination of carboxylate species by 1H NMR spectroscopy [59], anionic species bycapillary electrophoresis [60], or various species by measured thermodynamicdata [61] shows the utility of the protonated 6-amino-6-deoxy cyclodextrin derivativesover native cyclodextrins for distinguishing anionic species.

Heptakis(6-amino-6-deoxy)-b-cyclodextrin caused non-equivalence in the1H NMR spectra of several N-acetylated amino acids. Native b-cyclodextrin did notcause enantiomeric discrimination and the heptakis(6-amino-6-deoxy)-b-cyclodex-trin was more effective than the corresponding mono(6-amino-6-deoxy)-b-cyclodextrin [62].

7.2.8Miscellaneous Cyclodextrins

Cyclodextrin derivatives with a mono-diethylenetriaminepentaacetic acid (DTPA)moiety attached at either the 2- or 6-position have been prepared and examined withparamagnetic Dy(III) as water-soluble chiral NMR shift reagents [63, 64]. Anethylenediamino [63] or amino group [64] was selectively attached at the 2- or 6-position by reaction of ethylenediamine or ammonia with the corresponding mono(O-tosyl) derivative. Reaction of the ethylenediamino or amino cyclodextrin withDTPA dianhydride afforded the corresponding cyclodextrin-DTPA amide derivative.Dysprosium(III) bound at the DTPA moiety and caused perturbations in chemicalshifts in the 1H NMR spectra of substrates bound in the cyclodextrin cavity. Theresults were much better for the 2-ethylenediamino derivative than the 6-ethylene-


diamino derivative, presumably because Dy(III) was positioned closer to the sec-ondary face, which is usually the location where enantiomeric discriminationoccurs [63]. For the amine derivative, the presence of the DTPA moiety at the 2-position seemed to block access to the cavity and it was not as effective as either the 6-amino or 2-ethylenediamino derivative [64].

Mixed cyclodextrin–crown ether systems, one example of which is 5, have beenprepared, attached to silica gel, and used as chiral liquid chromatographic stationaryphases. The cyclodextrinwas anchored to silica gel at one of theC2 positions and thenan aza crown moiety was attached to the cyclodextrin through one of the primaryhydroxy groups. Compounds associated through either the cyclodextrin or crownfunctionality, thereby increasing the versatility and selectivity of these chro-matographic phases [65].

N

O O

N

O O

NN

NH2NH

O (CH2OC(O)CH2Br)z

OCH2CHCH2O(CH2)3O

(C(O)CH2Br)y

O (C(O)CH2Br)z

Si

O

O

O

SILICA

5

(x + y + z ~ 3.2)

O

Acomprehensive review of the application of commercially available, cyclodextrin-based liquid chromatographic phases has been published [1]. In addition to the use ofnative cyclodextrins, the full range of applications of (2,3-di-O-methylated)-b-cyclo-dextrin, acetylated b-cyclodextrin, hydroxypropylether b-cyclodextrin, l-(1-naphthyl)ethylcarbamoylated b-cyclodextrin, 3,5-dimethylphenylcarbamoylated b-cyclodex-


trin, carboxymethylated b-cyclodextrin, and permethylated cyclodextrins are de-scribed. A comprehensive review of the use of cyclodextrins as chiral NMR solvatingagents was published recently [3].

7.3Crown Ethers

Crown ethers are notable for their binding to protonated primary amines. Chiralcrown ethers have been widely used for the enantiomeric recognition of chiralprimary amines. In particular, the three hydrogen atoms in the primary ammoniumion are ideally aligned to form hydrogen bonds to three of the oxygen atoms in 18-crown-6-ethers (Figure 7.2a). Secondary ammonium ions generally do not associatewell with crown ethers because they can only form two hydrogen bonds and thesecond substituent group of the ammonium salt often hinders association. Onenotable exception is (18-crown-6)-2,3,11,12-tetracarboxylic acid (6). When a neutralsecondary amine is mixed with 6, a neutralization reaction occurs to form theprotonated secondary ammonium salt and carboxylate ion of 6. Favorable associationoccurs through the formation of two hydrogen bonds and an ion pair(Figure 7.2b) [66–69].

O

O

O

OO

O

H H

N

HOOC

HOOC COOH

O

O

R R'

O

O

O

OO

O

H H

N

R

H

(a)

(b)

Figure 7.2 Interaction of a (a) primary amine and (b) secondary amine with (18-crown-6)-2,3,11,12-tetracarboxylic acid. Primary amines are studied asprotonated species. Secondary aminesare studied as neutral species and undergo a neutralization reaction with the crown ether.


O

O

O

OO

O

COOH

COOH

HOOC

HOOC

6

The preparation of crown ethers often involves the use of a chiral diol that is thenreacted with an appropriate bridging ethylene glycol unit to complete the macrocycle.Many crown ethers use two identical chiral units that are bridged by appropriateethylene glycol linkers. Several comprehensive reviews have been published thatdescribetheuseofcrownethersasbondedliquidchromatographicstationaryphases[2],chiral NMR solvating agents [3], and for the analysis of enantiomeric amines [70].

7.3.11,10-Binaphthalene-Based Crown Ethers

The 1,10-binaphthalene-2,20dihydroxy moiety has been an important chiral unit usedin the formation of crown ethers. Compound 7 was the first chiral crown etheremployed for enantiomeric recognition [71]. Initial studies explored thedistributionofracemic amine salts between aqueous and chloroform layers. Liquid chromatographicseparation of amino acid esters was achieved either by adding 7 to the mobilephase [72] or covalently bonding it to silica gel [73]. Enantiomeric discriminationwas also observed in the 1H NMR spectrum of the salt of 1-phenylethylamine [71].Among the 1,10-binaphthalene-based crown ethers, 8 was especially effective for itsenantioselectivity [74, 75]. Dynamically coated liquid chromatographic phases of 8 arecommercially available and used bymany investigators, and amethod for bonding 8 tosilica gel for liquid chromatographic applications has been described [76].

O

O

O

OO

O

7

7.3 Crown Ethers j201

O

O

O

OO

O

8

7.3.2Carbohydrate-Based Crown Ethers

Carbohydrates have been used as chiral moieties in the preparation of a large familyof crown ethers. A comprehensive review of the early work on these systems has beenpublished [77].

The crown ether with a 1,2:5,6-diisopropylidene-D-mannitol and tert-butyl-substi-tuted phenyl group (9) caused enantiomeric discrimination in extraction and liquidchromatographic studies [78]. The crown ether was coated onto a C18 silica gelbonded phase for the liquid chromatographic separations. In a subsequent study, 9was found to be more effective than 8 as an organic-soluble chiral NMR solvatingagent [79]. Enantiomeric discrimination of primary ammonium salts with 9 wasgreater in methanol-d4 and acetonitrile-d3 than in chloroform-d. It was also shownthat achiral organic-soluble paramagnetic lanthanide tetrakis-b-diketonate anions ofthe form Ln(fod)4

� (fod¼ 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedione)could be added to solutions of 9 and substrates in chloroform-d and acetonitrile-d3 to enhance the enantiomeric discrimination. The tetrakis chelate complex wasformed in solution by adding Eu(fod)3 and Ag(fod) to the sample. In the presence ofthe ammoniumchloride salt, silver chloride precipitated out of solution. Ammoniumions in the bulk solution formed an ion pair with the Ln(fod)4

�. The two substrateenantiomers have different association constants with the crown ether. Therefore,the enantiomer with the smaller association constant with 9, which has a higher


proportion in the bulk solution, exhibited larger changes in chemical shifts in theNMR spectrum.

O

O

O

OO

O

O

O

O

O

H

H

Me

Me

Me

Me

H

H

9

In a comparison with ten other glycoside-derived crown ethers, 10 was the mosteffective in causing enantiomeric discrimination in the methine resonance ofphenylglycine methyl ester hydrochloride [80]. A crown ether derived from b-ga-lactopyranoside (11) has been examined as a chloroform-soluble chiral NMRsolvating agent [80, 81]. Only modest enantiomeric discrimination was observed inthe 1H NMR spectra of amino acid ester hydrochlorides. The corresponding diolderivative (12) was soluble in acetonitrile-d3 and methanol-d4 and was far moreeffective as a chiral NMR solvating agent than 11. Of particular significance was theobservation that ytterbium(III) could be added as its nitrate salt to solutions of 12 andsubstrates in acetonitrile-d3 and often enhanced the enantiomeric discrimination inthe NMR spectrum. In this case, the Yb(III) bound to 12 in a chelatemanner throughthe two hydroxy groups and caused changes in chemical shifts in the NMR spectrumof the substrate bound to the crown ether [81].

O

O

O

OO

O

O

OMe

O O

10


O

O

O

OO

O

O

OMe

O O

11

O

O

O

OO

O

O

OMe

OH OH

12

7.3.3Tartaric Acid-Based Crown Ethers

The (18-crown-6)-2,3,11,12-tetracarboxylic acid 6, which is derived from tartaric acidandwasfirst synthesized in 1975 [82], is unquestionably themost versatile and usefulcrown ether for chiral recognition. The initial preparation of 6 involved an alkylationof the dithallium alcoholate of (N,N,N0N0-tetramethyl)tartramide in DMF by analiphatic diiodide or dibromide to produce the crown ether as a tetraamide deriv-ative [82, 83]. Heating the tetraamide in hydrochloric acid produced the tetracar-boxylic acid form of the crown. An improved preparation using (N,N,N0N0-tetra-methyl)tartramide, a glycol ditosylate, and sodium hydride has been reported [84].Both enantiomers of 6 are now commercially available.

Refluxing 6 in acetyl chloride yielded the corresponding dianhydride (13) [83].Reaction of the dianhydride with amines produced syn- and anti-diamide derivativesthat were easily separated by column chromatography [85]. However, if the reactionwas run in the presence of triethylamine, only the syn-isomer formed. Reaction of themethyl tetraamide derivative with amino acid methyl ester hydrochloride salts andtriethylamine inmethylene chloride produced the amino acid-containing tetraamide


derivatives [86]. Thermodynamic values for the association of the methyl esters ofphenylglycine and the glycine-phenylalanine dipeptide with various tetraamidederivatives of 6 have been measured and show enantiomeric discrimination [87].A membrane electrode system that incorporated tetraamides of 6 showed enantio-meric selectively toward 1-phenylethylamine and the methyl ester of phenylala-nine [88].

O

O

O

OO

O

O

O

O

O

13

OO

Of more significance has been the utilization of 6 in liquid chromatographicseparations and as a chiral NMR solvating agent. One method of immobilizing 6 onsilica gel involved reacting it with a 3-aminopropylsilanized silica gel in the presenceof 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinone (EEDQ) to form an amide link-age [89]. It was believed that a mixture of monoamide- and diamide-linked crownether occurred. A syn-diamide-linked phasewas obtained by reacting the dianhydrideof TCA with an aminopropyl silica gel [90]. A comparative study using dynamicallycoated and bonded phases of 8, the mixed monoamide/diamide phase, and the syn-diamide phase was undertaken with various amines [91]. In an effort to characterizethe separation mechanism of these stationary phases, the effect of column temper-ature, inorganic modifier, organic modifier, and acidic modifier was explored.Lipophilic and hydrophilic effects were also examined. Whereas the effect oftemperature and inorganic modifier was equivalent for all of the crown ethers, theeffect of organic and acidic modifier varied with the different crown ethers.

It has also been shown that liquid chromatographic stationary phases with 6 can beused to separate secondary amines [92]. The significance of the two hydrogen bondsand ion pairing interaction (Figure 7.2b) in explaining the unusual ability of 6 among18-crown-6 ethers to associate with secondary ammonium salts was proposed in thisstudy. A comprehensive review of the utilization of 6 in liquid chromatographicapplications has been published [93].

The utility of 6 as a chiral NMR solvating agent for primary amines has beendemonstrated [94–97]. Enantiomeric discrimination was observed in methanol-d4,acetonitrile-d3, or deuterium oxide [94, 97], although the best results were usuallyobtained in methanol-d4. The amine can be added as either a protonated salt or in itsneutral form [94, 96]. In the latter case, a neutralization reaction between the amineand 6 produces the protonated ammonium ion that is needed for association.Analysis of amino acids in deuterium oxide with the (þ )-enantiomer of 6 always


shielded the methine resonance of the D-enantiomer more than that of the L-enantiomer. Addition of ytterbium(III) as its nitrate salt to solutions of ammoniumsalts and neutral 6 caused enhancements in the enantiomeric discrimination [94, 96].The Yb(III) bound to the carboxylic acid groups of the crown and perturbed thechemical shifts of the resonances of the substrate in its bound form.

The utility of 6 as an especially effective chiral NMR solvating agent for secondaryamines has been shown [66–69]. It is necessary to add the neutral form of thesecondary amine to 6. A neutralization reaction produced the ammonium ion andmonocarboxylate of 6, thereby enabling the formation of two hydrogen bonds and anion pairing interaction needed for favorable association of the two species. The utilityof 6 as a chiral NMR solvating agent has been demonstrated for pyrrolidines [67],piperidines [68], piperazines [68], and prochiral amines [69]. A small degree ofenantiomeric discrimination was even observed in the 1H NMR spectra of tertiaryamineswith 6 [69]. Better results were obtained by examining the 13CNMRspectra ofthe tertiary amines.

7.3.4Crowns Ethers with Phenol Moieties

Awide variety of crown ethers that incorporate phenol units have been prepared (14and 15 are two examples) and evaluated for their chiral recognition properties.General procedures used to prepare these crown ethers involve coupling an appro-priate aromatic dibromide and diol [98] or ditosylate and diol [99]. Chromophoriccrown ethers are obtained by incorporation of a 2,4-dinitrophenylhydrazine unit ontoa quinone intermediate in the synthesis.

O

O

O

O

(S)(S)(S)(S)

O OMe

OMe

14

O

O

O

O

(S)(S)(R)(R)(R)(R)

(S)(S)

O

N N

OH

15

O2N

NO2

Crown ethers with the chromophoric dinitroazo aromatic unit exhibit distinctdifferences in the UV-vis absorption spectra in the presence of enantiomeric pairs,thereby providing a convenient colorimetric indicator for the analysis of chiralprimary amines [100]. Neutral primary amines can be added to the phenol-containingcrown ethers since the phenolic hydrogen atom will protonate the amine to form theammonium needed for favorable association [101].


An interesting observation with several of phenol-containing crown ethers is atemperature-dependent reversal in the enantiomeric discrimination [102], which isobserved using either UV-vis or NMR spectroscopic measurements. The tempera-ture dependence follows a van�tHoff relationship and it was subsequently shown thatchemical shifts in the NMR spectra measured as a function of temperature could beused to assign absolute configuration of the amine [103].

The phenol-containing crown ethers were also used in the development of fastatom bombardment-mass spectrometry (FAB-MS) methods designed to show theenantioselective complexation of chiral ammonium ion guests by the hosts. Onemethod involved comparing the relative peak intensities of a target host–guestcomplex ion to that of an internal standard host–guest ion. The association constantsmeasured using the FAB-MSmethodwere comparable to those obtained usingNMRspectroscopy [99]. A second method used a racemic mixture in which one of theenantiomerswas deuterium labeled [104]. Examination of the relative peak heights ofthe host–guest complexes allowed a determination of the comparative bindingpreference of the enantiomers. A comparison of FAB and electrospray ionizationmass spectrometric methods for the analysis of deuterium-labeled amino acid estersfound that FAB was more effective [105]. A procedure for determining the enantio-meric purity of amines using FAB-MS involved the use of a racemic mixture of the(R)- and (S)-isomers of the crown ether, one of which was isotopically labeled [106].Relative peak heights of the complexes were used to determine enantiomeric purity.

In some cases, the phenol-containing crown ethers also cause enantiomericdiscrimination in the 1H NMR spectra of substrates. For example, the NMRspectrum of methionine exhibited significant enantiomeric discrimination in thepresence of the adamantyl-substituted crown ether (14) [104].

Pseudo-crown ethers with larger rings, such as pseudo-24-crown-8 (16) and 27-crown-9 (17), have been shown by 1H NMR titration experiments to enantioselec-tively bind secondary amines. The larger crownmacrocycle reduced steric hindrance,thereby facilitating stronger complex formation of the secondary amine [107].

O

O O

O

O

O

O

PhPh

OH

16

O

O O

O

O

OO

O

17

OH

Ph Ph

NO2 NO2


A compound with two phenol-containing crown ethers attached to a phenolphtha-lein moiety (18) is an effective colorimetric reagent for the enantiomeric analysis ofamino acid derivatives and b-amino alcohols. The phenolphthalein-based crownether also showed an inversion of enantiomeric recognition for some substrates as afunction of temperature [108].

O

O

O

OO OH

PhPh

O

O

OO

O

OH

Ph

Ph

O

O

18

7.3.5Crown Ethers with Pyridine Moieties

Chiral crown ethers containing pyridine functionalities in the macrocycle have beenprepared and examined for their enantioselective properties. In a typical preparation(Scheme 7.1), an appropriately substituted tetraethylene glycol reacts with a 2,6-

N

O

Cl

O

Cl

+HO O O O OH

PhPh

N

O

O

O

O

O

OO

Ph Ph

19

Scheme 7.1


pyridinedicarbonyl chloride to yield the pyridine-containing crown ether [109]. Thediol with a phenyl ring was prepared from (R)- and (S)-mandelic acid and repre-sented themost challenging aspect of the synthesis. Thermodynamic datameasuredusing 1H NMR spectroscopy indicated enantiomeric discrimination of amino acidmethyl esters and 1-(1-naphthyl)ethylamine with the pyridine-containing crownethers [110]. Chiral recognition was influenced by the R-substituent group of thecrown ether and those with methyl, phenyl, or tert-butyl groups were mosteffective [111].

Compound 19was used in the development of a FAB-MSmethod for determiningassociation constants between the crown ether and ammonium ions that wasreportedly better than those described above in Section 7.3.4 on phenol-containingcrownethers. Themethoduses amixture of an achiral crownether as a referencehostwith the chiral crownether and substrate. The relative peak intensities of the differentspecies can be used to determine the association constants [112].

Utilization of a 4-allyloxy-2,6-pyridinedimethyl tosylate in the preparation of thecrown ether facilitated its attachment to silica gel and its use for liquid chro-matographic separations [113]. A similar crown ether containing a dimethylacri-dino unit (20) was attached to silica gel and used as a liquid chromatographicphase [114].

O

N

O

OO

O

MeMe

20

7.4Calixarenes

The reaction of phenol with formaldehyde in the presence of hydrochloric acidfurnishes a cavity compound in which the phenol rings are bridged by methylenegroups (21). Themost commonof the calixarenes have four phenol rings in the cavity,although varying the reaction conditions leads to analogues with higher numbers ofrings [115]. An asymmetric addition of a substituent group to the calixarene, forexample, adding a methyl substituent to only one of the phenol rings in a p-tert-butylcalix[4]arene, leads to a pair of enantiomers that are inherently chiral. Whileinherently chiral calixarenes have been the focus of many studies, they tend not to be

7.4 Calixarenes j209

especially practical for chiral recognition applications. Amore practical approach is toattach an optically pure chiral group to the calixarene. Strategies for adding chiralsubstituent groups through reaction at the phenol oxygen atoms (usually referred toas the lower rim) or the position para to the phenol group (usually referred to as theupper rim) have been described. A comprehensive review of chirality in calixarenesand calixarene assemblies has been published [116].

OH HO

OH

OH

21

Optically pure amino acids are often coupled to calixarenes. Scheme 7.2 illustratesa common scheme for upper-rim addition of amino acids [117]. The phenol group isconverted into a propoxy ether to hold the calixarene in a cone conformation. Aminoacids can then be N-terminally coupled to the carboxylic acid moiety using standardpeptide coupling reagents. An alternative means of attaching amino acids to theupper rim through the C-terminal end involves the use of the amino-substitutedcalixarene [117].

Scheme 7.3 illustrates a common strategy for lower-rim attachment of aminoacids [117]. The phenol groups are alkylated with ethyl bromoacetate and thensaponified to the carboxylic acid. Amino acids can then be added at their N-terminalend using standard peptide coupling procedures. A thorough review of the use ofpeptide calixarenes in molecular recognition has been published [117].

p-tert-Butylcalix[4]arenes with amino acids such as alanine and valine on the lowerrim have been used to separate 1,10-binaphthalene-2,20-dihydroxy, 1,10-binaphtha-lene-2,20-diamine, and binaphthyldiyl hydrogen phosphate by capillary electropho-resis [118]. Similar p-tert-butylcalix[4]arenes with alanine, valine, leucine, and proline


were also evaluated as organic-soluble chiral NMR solvating agents [49]. The calix[4]arene derivative containing the tert-butyl ester of L-alanine was the best of thosetested, but only produced a small degree of enantiomeric discrimination in the NMRspectra of 1,10-binaphthalene-2,20-dihydroxy, and for the N-(3,5-dinitrobenzoyl)

OH 4 O

O

O

O

OH

O

OHN

O

O

OMe

R

BrH2C OEt

O

KOH Me4NOH

H2N CO2Me

R

44

4

Scheme 7.3

OH 4 OH 4 O 4

O 4

HO

PhenolAlCl3

NaHnC3H7I

HexamineCF3COOH

H2N CO2Me

R

NH2SO3HNaClO2

O 4

OHO

O 4

OHN

R

OMe

O

Scheme 7.2


derivatives of 1-phenylethylamine and 1-(1-naphthyl)ethylamine. Presumably thecalix[4]arene and substrates were solvated too well by the organic solvent, therebyminimizing host–guest association needed for enantiomeric discrimination.

A synthetic procedure similar to Scheme 7.3 has been used to attach four (S)-di-2-naphthylprolinol groups to the lower rim of p-tert-butylcalix[4]arene (22). Enantio-selective recognition of substrates such as 1-phenylethylamine, norephedrine, orphenylglycinol was observed in methanol. The separation of phenylglycinol bycapillary electrophoresis was also facilitated by addition of 22 to the mobilephase [119]. The propranolol amide-derivatized p-tert-butylcalix[4]arene with an allylgroup on the upper rim (23) was prepared by a similar scheme. Enantioselectivefluorescent quenching was observed in the presence of phenylalaninol. The en-antioselectivity of 23 toward phenylalanine was enhanced considerably in thepresence of sodium or potassium ions [120].

4

O

NO

HO

O

23

4

O

NO

HO

22

Other investigators have prepared calixarene derivatives with diamide groups atthe lower rim and examined their chiral recognition properties. One example is thecoupling of two dicyclopeptides such as cyclo(pro-ser) (24), cyclo(leu-ser), and cyclo(ala-ser) to the lower rim. Discrimination of the enantiomers of methyl lactate wasobserved using these calixarenes as a gas sensing device on a quartz crystalmicrobalance [121].


OHOH O

But

But But But

O

C

R

OC

R

O

R =

24

N

HN

O

The coupling of 1-phenylethylamine and (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol to p-tert-butylcalix[4]arene (25) provided host compounds that enantio-selectively interacted with amines. Enantiomeric discrimination was observed in theUV-vis spectra with 1-phenylethylamine and 1-(cyclohexyl)ethylamine and the1H NMR spectrum of 1-phenylethylamine in chloroform-d [122].

OH OHO

RR

RR

O

C

R'

O C

R'

O

OH

NO2

HO

NH

R' =

25

Inherently chiral calix[4]arene 26 has been synthesized and resolved into its twoenantiomers by a selective crystallizationwithmandelic acid [123].Using either of thepure enantiomers of 26, enantiomeric discrimination was observed in the 1H NMRspectra ofmandelic acid. TheD- or L-phenylalaninol derivative of a p-tert-butylcalix[6]arene (27) exhibited modest selectivity in extraction studies of amino acid methylesters [124].


OPrOPr PrO

HO

OPr

NBu2

26

OMeO

HN

HO

H

4 2

27

A calix[4]arene with two 1-cyclohexylethylamino groups attached through a Schiffbase linkage (28) has been prepared. Binding constants measured by an ultraviolettitration showed discrimination of the enantiomers of 1-phenylethylamine [125]. Acalix[4]arene with a chiral L-alanine attached through a Schiff base linkage (29a)associated enantioselectively with L- and D-threonine as observed by UV-vis spec-troscopy. However, the corresponding L-alanine amide derivative prepared through acarboxylic acid intermediate (29b) did not cause any enantiomeric recognition ofthreonine [126].

OHOH OO

H

N CH3N

H

H3C

28

O

C O

OH3

O

C O

OH3

N

COOHH

CH3

CONH

COOCH2CH3

CH3H

29a 29b

Calix[5]arene 30 has been synthesized and evaluated for evidence of chiralrecognition of ethyltrimethylammonium derivatives using ultraviolet visible andNMR spectroscopy. The macrocycle in 30 provided an additional constraint that


produced a chiral space for binding of guest molecules. Large upfield shifts wereobserved for the resonances of substrates in chloroform-d, which indicates that thesubstrate is inserted deeply into the calixarene cavity and is shielded by the aromaticrings. Cation–p interactionswere likely important in explaining the association [127].

OH OH

NHHN

OH

OHOH

NH

HN

HN

NH

O

OO

O

HN

O

O

NH

O

O

30

Anoptically pure tris(aminoethyl)amine ligandwas bound to alternate phenol sitesin a p-tert-butylcalix[6]arene to form 31. The tris(aminoethyl)amino group locked thecalix[6]arene into a cone conformation. Enantiomeric discrimination in the 1H NMRspectrum of 4-methylimidazolidin-2-one and propane-1,2-diol was observed with 31in chloroform-d [128].

OMeO O

RN

OOMe

NR RN

N

MeO

31


The reaction of p-tert-butylphenol with elemental sulfur and sodium hydroxide intetraethylene glycol dimethyl ether leads to the formation of thiacalixarenes (32) withsulfur bridges between four, five, or six phenolic rings [129]. Using reactionscomparable to those shown in Scheme 7.3 for regular calixarenes, 1-phenylethyl-amine or 1-(1-naphthyl)ethylamine was coupled to the bottom rim through amidelinkages [130]. The calixarenes were used as gas chromatographic stationary phasesto separate volatile derivatives of enantiomeric alcohols, amines, and amino acids.Whereas the thiacalixarenes exhibited enantioselective interactions with certainsubstrates, the corresponding calixarenes with methylene bridges between thephenol rings were ineffective at causing enantiomeric discrimination.

OH

32

S

4

A series of homoazacalixarenes that incorporate amino acids as part of themacrocyclic framework have been prepared and examined for their enantioselectiveproperties. The compounds are prepared using a bis(chloromethyl)phenol-formalde-hyde tetrameror trimer that is thencyclizedwithanaminoacidmethyl esterofvalineorcysteine. These systems demonstrated enantiomeric discrimination towarda-methyl-benzyltrimethylammonium iodide. Association involved an interaction of the cationicnitrogen group with the p-basic aromatic rings in the calixarene cavity [131].

A rigid cone-shaped calixarene has been prepared from syn-dihydroxy[2.5]meta-cyclophane (Scheme 7.4) [132]. Chiral substituent groups such as themethyl esters ofphenylalanine or phenylglycinewere added at theN-terminal end through the phenoloxygen atoms using a procedure similar to that in Scheme 7.3 [133]. The phenylgly-cine derivative exhibited enantioselectivity toward amino acids, as evidenced byextraction studies and transport properties across a liquid membrane. A crown ethermoiety has also been coupled to two alternate hydroxyl groups of the rigid calixareneframework [134]. Enantioselective recognition of 1-phenylethylamine was observedin extraction studies with the calixarene-crown couple.

Several other mixed calixarene–crown ether systems have been synthesized andevaluated for their chiral recognition properties. Each of these employs a crown oraza-crown unit that bridges two of the phenol hydroxy groups of the calixarene. Thebinaphthyl-based crown of calix[4]arene 33 has two indophenol-type units andfunctioned as a chromogenic solid phase receptor for phenylglycinols that adsorbed


OHOH

OHOH

OHOH

(CH2O)n, LiOH

diglyme

OO O O

EtOOCEtOOC

COOEtCOOEt

BrCH2CO2Et,

NaH, THF/DMF

Scheme 7.4

from solution [135]. Compound 34, which has a crown ether and naphthoic acidfunctionality attached through the phenol hydroxy groups, isfluorescent and showedenantioselective recognition toward leucinol [136]. The calixarene–crown couplewitha 1,2-diphenyl-1,2-oxyamino residue (35) produced enantiomeric discrimination inthe 1H NMR spectrum ofmandelic acid [137]. Calix[4](aza)crown couple 36 containsvaline units and produced enantiomeric recognition in the dibenzoate derivatives oftartaric and amygdalic acid, as evidenced by 1H and 13C NMR and ultravioletspectroscopy in chloroform-d [138].

OH HOX

N ONO

X =O

O

OO

OO

33


O OHO O

O O

n

O COOH

34

OHOH OO

H2CCH2

O NH

H2CCH2

HHPhPh

35

OHOH OO

HN

N

HN

RR

O O

36

R'

Certain calixarene compounds such as 37a and 37b exhibit the ability to formdimers in solution. A mixture of achiral 37a and chiral 37b has the possibility offorming homo- and heterodimers. The heterodimer of 37a and 37b did produce asmall degree of enantiomeric discrimination in the 1H NMR spectrum of racemicnopinone. Similarly, the heterodimer formed from the corresponding L-isoleucineand p-methylphenyl-substituted calixarenes produced enantiomeric splitting of themethyl signal in the NMR spectrum of 3-methylcyclopentanone [139].

O

C10H21

HN

HN

O

R

4

a -C6H4-p-C7H15

37

R

b -SO2C6H4-p-CH3

c -C(C4H9)C(O)OCH3

7.5Calix[4]resorcinarenes

Calix[4]resorcinarenes are prepared by the reaction of resorcinol and an aldehyde,leading exclusively to a tetrameric calix[4]resorcinarene (38). Unlike calixarenes –

which are restricted to the use of formaldehyde, which results in a methylene bridgebetween the phenol rings – essentially any aldehyde can be used in the preparation ofcalix[4]resorcinarenes. Altering the nature of the bridge between the resorcinol rings


readily facilitates the preparation of calix[4]resorcinarenes with a wide range ofsolubilities.

RR

R R

HO OH

HO

HO

HO OH

OH

OH

38

Chirality in calix[4]resorcinarenes is achieved either through inherently chiralsystems or by attachment of optically pure chiral substituent groups. While manyexamples of inherently chiral calix[4]resorcinarenes have been prepared and stud-ied [140], they have rarely been used for the purpose of chiral recognition. Anexception involves the inherently chiral calix[4]resorcinarenes 39–41 [141]. These arechiral because of the alternate substitution pattern at the hydroxy groups. Enantio-meric discrimination of various N-trimethylammonium salts was observed byelectrospray ionization mass spectrometry.

OMeHO

4

39

OHO

4

40

(S)(S)

OMeO

4

41

NH

(S)(S)Ph

O

A common strategy for obtaining chiral calix[4]resorcinarenes is to attach anoptically pure secondary amine between the two resorcinol hydroxyl groups using

7.5 Calix[4]resorcinarenes j219

Mannich conditions. Attachment of groups such as N-a-dimethylbenzylamine, N-methyl-1-(1-naphthyl)ethylamine, N-methyl-a-methylbenzylamine, and N-benzyl-a-methylbenzylamine to calix[4]resorcinarenes prepared using either acetaldehydeor octylaldehyde provided a set of organic-soluble compounds that were examinedas chiral NMR solvating agents. No evidence for association between thesecalixresorcinarenes and a wide range of substrates compounds was observed inchloroform-d [49].

Attachment of a primary amine such as 1-phenylethylamine in the presence of twoequivalents of formaldehyde leads to a cyclic product with oxazine rings (42) [142,143]. Studies have, generally, found that the formation of one oxazine ring directs theformation of the remaining three oxazine rings in the same orientation so that onlyone geometric isomer forms. The 1-phenylethylamine derivative was shown by UV-vis spectroscopy [143] or surface tension isotherms in Langmuir monolayers on awater surface [142] to enantioselectively discriminate 1-phenylethylamine, 1-(cyclo-hexyl)ethylamine [143], or amino acids [142]. Calix[4]resorcinarene derivatives withnorephedrine (43) [142, 143] and 1-phenylethylamine hydrochloride (44) [143] werealso examined for their chiral recognition properties. In every case, only modestdegrees of enantiomeric discrimination were observed. Presumably, this is becausethe organic solvent effectively solvates the substrate and calix[4]resorcinarene andreduces the extent of the association.

O

N

Y

R

HO

4

Y = PhCHCH3

R = C11H23

42

OH

N

HO

4

43

O

Ph

OH

NH2

HO

4

44

Ph CH3

Cl-

In contrast, quite substantial host–guest complexation is observed with water-soluble calix[4]resorcinarenes containing a sulfonated bridge between the resorcinolrings and prolinylmethyl chiral moieties (45a–e) [144–149]. These calix[4]resorcinar-enes have a hydrophobic cavity and the hydrophobic portion of water-soluble organicsalts favorably associate by insertion into the cavity.


R

OHHO

SO3-Na+

4

N

CH2

COOHN

CH2

COOH

HO

N

CH2

COOH

HO

N

CH2

COOH

HO

N

CH2

COOH

OH

(a) (b) (c) (d) (e)

45 R = λ

The L-prolinylmethyl derivative (45a) is an effective water-soluble chiral NMRsolvating agent. In initial work, 45a was shown to be more effective for water-solublesubstrates containing a phenyl ring than those with only aliphatic groups. Largeshielding of the phenyl ring of the substrate indicated that association involvedinsertion of the hydrophobic aromatic ring of the substrate into the calix[4]resorcinar-ene cavity with the para-proton deepest in the cavity. The aliphatic substituent group ofthe substratewas thenpositioned to interactwith the chiral prolinylmethylmoiety. Theresonances of the ortho-hydrogen in the 1H NMR spectrum generally showed largerenantiomeric discrimination than those of the meta- or para-hydrogen atoms, whichwas consistent with their relative proximities to the prolinylmethyl moieties [144].

Subsequent studies showed that even greater association, larger changes inchemical shifts, and often greater enantiomeric discrimination occurred in the1H NMRspectra of bicyclic substrates such as 1-(1-naphthyl)ethylamine, propranololhydrochloride (4), and tryptophanmethyl ester hydrochloridewith 45a [145, 146]. For1-(1-naphthyl)ethylamine, propranolol, and tryptophan, the relative changes inchemical shifts for hydrogen atoms of the substrates indicated geometries as shownin Figure 7.3a–c, respectively. It was postulated that 45a could accommodate anaromatic ring as shown in Figure 7.3b if it adopted a flattened cone conformation.Substrates such as carbinoxamine (2), doxylamine (3), pheniramine (1), chlorphen-iramine, and brompheniramine also associate with 45a. Steric hindrance from thepara-substituted halide atom on 2, chlorpheniramine, and brompheniramine blocks


insertion of the phenyl ring into the resorcinarene cavity. The magnitude of theperturbations in chemical shifts indicated that the pyridyl ring inserts into the cavityas shown in Figure 7.3d [146]. For pheniramine and doxylamine, the magnitude ofthe changes in chemical shifts indicated that both rings associated to some degreewithin the cavity.

The association of substrates with 45a requires an aromatic ring relatively free ofsteric hindrances. Studies have shown that mono- and ortho-substituted phenylrings, and naphthyl rings that are mono-substituted, 1,2-, 1,8-, or 2,3-disubstituted,readily form host–guest complexes with 45a by insertion of the aromatic ring into thecavity [147]. Compounds with indole, dihydroindole, and indane ring systems inwhich there are no other substituents on the six-membered ring also formhost–guestcomplexes with 45a.

More recent work has shown that calix[4]resorcinarenes with 3- and 4-hydroxy-proline substituent groups (45b–d) are oftenmore effectivewater-soluble chiralNMRsolvating agents than 45a [147–149]. Presumably the hydroxy groups on the prolinemoiety are involved in dipole–dipole interactionswith the substrates that enhance theenantiomeric discrimination.

Another strategy for preparing chiral calix[4]resorcinarenes is to attach opticallypure moieties through the hydroxy groups of the resorcinol rings. For example, L-valine-tert-butylamide substituent groups have been attached through the hydroxyl

RR

NHR

N

R

(a)

(c)

(b)

(d)

Figure 7.3 Model geometries of association of (a) 1-(1-naphthyl)ethylamine, (b) propranolol,(c) tryptophan and (d) chlorpheniramine with 45a.


groups of a calix[4]resorcinarene prepared using 1-undecanal. The resulting calix[4]resorcinarene (46) was used as either a coated or bonded capillary gas chro-matographic stationary phase to separate N(O,S)-trifluoroacetylmethyl esters ofamino acids [150]. Octamide derivatives of calix[4]resorcinarenes (47) have beenprepared by heating the corresponding octaethoxy methylated calix[4]resorcinarenein the liquid amine. Amberlite XAD resins were impregnatedwith the octamide calix[4]resorcinarenes and modest enantiomeric discrimination of sodium salts oftryptophan and phenylglycine was observed [151].

O O

NH

O

HN

O

HN

O

HN

4

46

OO

R

NH

OH

NH

HO

4

Ra CH3

b Ph

47

The hydroxy groups on adjacent resorcinol rings can be bridged with suitablereagents. One example is the bridged phosphamide derivatives 48. These formLangmuir monolayer films on water and a pH-dependent enantiomeric discrimina-tionwas observed either throughsurfacepotential or surfacepressure isotherms [152].


R R

RR

O

O

P

O

O

P

PP

O

OO

O

HNCH3

HNH3C

NH CH3HNH3C

R = C11H23

48

Two hydroxy bridged calix[4]resorcinarenes have been coupled into an elaboratehemicarciplex structure with binaphthyl [153–155] and (S,S)-1,4-di-O-tosyl-2,3-iso-propylidene-L-threitol linkages [154]. The hemicarciplexes exhibited stereoselectiveencapsulation properties toward 1-bromo-2-methylbutane, 1,3-dibromobutane [153],and 2-butanol [154], and produced enantiomeric discrimination in the 1H NMRspectra of aryl alkyl alcohols, sulfoxides, alkyl halides, and alkyl alcohols [155].

An alternative strategy for preparing calix[4]resorcinarenes involves the tetramer-ization of 2,4-dimethoxycinnamic acid amides with boron trifluoride etherate(Scheme 7.5) [156]. The valine amide derivative exhibited gas phase enantiomericdiscrimination toward amino acids in studies using electrospray ionization massspectrometry. Optically pure 2-aminobutanewas used to displace the amino acid fromthe calix[4]resorcinarene to examine the extent of enantioselectivity. Both thermody-namic and kinetic factors were important in the displacement process [157].

OMeMeO

COR

4

OMeMeO

COR

BF3Et2O

Scheme 7.5


7.6Miscellaneous Receptor Compounds

A wide variety of specialized receptor compounds have been developed. Oftentimesthese are designed for a single class of compounds or to accommodate a specificmolecule. Ionic groups such as the guanidiniummoiety or polar functionalities suchas amides, ureas, thioureas, and carbamates are frequently incorporated into clip-shaped, cleft-shaped, or macrocyclic cavity compounds. The following sectionexemplifies the wide range of chiral receptor compounds that have been reported.A comprehensive review of the use of receptor compounds for the chiral recognitionof anions has been published [158].

The cationic guanidinium group has been used in designing receptor moleculesfor carboxylate species. Compound 49, which contains naphthyl substituent groups,produced a small degree of enantiomeric discrimination in the 1H NMR spectra ofmandelate, naproxenate, andN-acetyl tryptophan [159]. Compounds with lasalocid Aor crown ether appendages (50), have been employed as zwitterionic amino acidcarriers in membranes [160] or in extraction or NMR discrimination studies [161].The ammonium ion associated with the crownmoiety of 50while the carboxylate ionassociated with the guanidinium group.

NH

N

NH

OOO

O

Cl

49

O

N O

O

O O

NH

N

NH

OSO

NHO

50

Cl

The axial chiral p-electron deficient tetracationic receptor 51 contains a 1,10-binaphthyl unit and two cyclophane units. It was effective at enantiodifferentiatingaromatic amino acids such as phenylalanine, tyrosine, and tryptophan in water andtheir N-acetylated derivatives in organic solvents [162]. The bisbinaphthyl macrocy-clic species 52 exhibited enantioselective recognition of mandelic acid that could bemonitored by fluorescence spectroscopy [163]. Macrocyclic receptor 53 with onebinaphthyl and two xanthone units permitted the enantioselective extraction ofamino acids in water in the presence of an 18-crown-6 ether. The ammonium groupof the amino acid associatedwith the crown ether while the carboxylate ion associatedwith the macrocycle [164].

7.6 Miscellaneous Receptor Compounds j225

OHHO

N N

HOOH

NN

51

HOO

HN

O HO

52

S

S

HN

NH

O O

OO

BuO

BuO

O

O

HN

HN

Et2N(O)C

Et2N(O)C O

O

t-Bu

t-Bu

O

53


Macrocycle 54 contains an N,N0-bis(6-acylamino-2-pyridinyl)isophthalamide unitand was found to function as an effective chiral NMR solvating agent for carboxylicacids, oxazolidinones, lactones, alcohols, sulfoxides, sulfoximines, isocyanates, andepoxides [165]. The presence of the nitro group strengthened the hydrogen bondingproperties of the amide groups of the macrocycle. In a subsequent report, 54 wasbound to silica gel and used as a liquid chromatographic stationary phase to separatevarious compounds [166].

O

O

HN

HN

O

O

N

N

HN

NH

O

O

NO2

54

Compound 55 is an example of an acyclic thiourea receptor that exhibited chiralrecognition toward amino acids [167]. The compoundhas a cleft with four hydrogenbond donors suitable for chiral recognition of carboxylate ions. Compounds56 [168] and 57 [169] are examples of macrocyclic compounds that show selectivebinding toward certain amino acid enantiomers such as N-protected glutamate andaspartate. Binding of amino acids to 56 and several similar analogues was strongerin relatively polar solvents such as acetonitrile and methyl sulfoxide, whereas nobinding occurred in chloroform [168]. This is opposite of the common behavior inwhich polar solvents effectively solvate the polar groups of the substrates andmacrocycle to reduce binding. The unusual behavior was ascribed to a solvent-induced change in conformation that inhibited binding in chloroform. In con-trast, 57 showed strong binding of monocarboxylates in chloroform but not methylsulfoxide [169].


NH

NH

S

NH HN OO

PhPh NH2 NH2

OO

55

N

O NH

NH

N

Ph

Ph

O

N

OHN

HN

N

Ph

Ph

O

NH

NH

S

HN

HN

S

56

N

O

NH HN

O

N

NH

NH

S

PhPh

57

Compound 58 is a bischromenylurea macrocyclic compound with diphenyl-p-xylylenediamine spacers that has a cavity of suitable geometry to distinguish theenantiomers of naproxen [170]. Diphenylglycoluril-based receptors with appendedamino acid groups, one of which is compound 59, have been shown to exhibitenantioselective binding of catechol amines and amino acids. The compounds arewater-soluble and enantiorecognition was monitored using UV-vis spectrosco-py [171].


O

NHO

R

R

O

O

HN O

R

R

ONH

NH

O

R = HR = Me

58

N

N

Ph

O

O N

O

O N

N

N

Ph

O

O

O

O

O

O

COOH

NH

O

O

COOH

HN

O

O

4

4

59

The cleft-shaped molecule N-(3,5-dinitrobenzoyl)-4-amino-3-methyl-1,2,3,4-tetra-hydrophenanthrene (60) has been bound to silica gel and used as a highly versatileliquid chromatographic stationary phase [172]. The cleft geometry, amide function-ality, and dinitrobenzoyl ring provide sites that facilitate association and enantio-meric recognition of substrates. The organic-soluble analog of 60 is effective as achiral NMR solvating agent for various substrates, including epoxides, amides,lactones, lactams, alcohols, sulfoxides, and primary amines [173].

CH3

N O

O2N NO2

H

60


Compound 61 is a C3-symmetric receptor that was attached to silica gel and usedfor the liquid chromatographic separation of neutral compounds having diversestructural features, including N-boc and N-3,5-dinitrobenzoyl protected aminoacids [174]. A macrocycle assembled from chiral 1,2-diphenyl-1,2-diamine and 5-allyloxyisophthalic acid groups (62) was immobilized onto silica gel and found topreferentially bind the L-enantiomers of amino acids [175].

S

S

S

NH

O

O

NH

O

HN

HN

O

O

O

O

HN

NH

O

O

61

O

HNNH

O O

O

HNNH

O O

62

Compound 63 and similar analogs are patterned after chiral liquid chro-matographic stationary phases. The 1H NMR spectra of dinitrobenzoyl derivativesof aryl amides and carboxylic acid esters in chloroform-d exhibited enantiomericdiscrimination in the presence of 63 [176]. Receptor 64 in which the R group isphenyl, naphthyl, or cyclohexyl forms three hydrogen bonds with carboxylic acids.Naproxen and other chiral carboxylic acids exhibited enantiomeric discrimination inthe 1H NMR spectrum in the presence of 64. The naphthyl derivative was the mosteffective of the three receptor compounds [177].


O

O

N

H

O

N

H

N

H

O

N

H

O

O

63

N

O

HR

O

N

H

N

64

The acyclic receptor 65, which is based on chiral deoxycholic acid, forms amolecular tweezer that is capable of enantiomerically discriminating amino acidmethyl esters. The association was monitored using UV-vis spectroscopy [178].Similarly, acyclic anthryl-containing receptors, one example of which is 66, exhibitedenantiomeric discrimination toward tetrabutylammonium mandelate. Enantiodif-ferentiation was observed using fluorescence and NMR spectroscopy [179]. Macro-cyclic dioxopolyamines derived from one or two L-proline units showed chiraldiscrimination in the 1H NMR spectra of mandelic acid and some of its derivativesaswell as naproxen. The compoundwith two prolinemoieties (67) wasmore effectiveat causing enantiorecognition [180].

COOCH3

O

O

NH

O2N

O

HN

NO2

O

65

N

C

O

NH

HN

C

HN

O

NH

66


N N

NH HN

HN

OO

67

Carbamate derivatives of the cinchona alkaloids quinine, quinidine, cinchoni-dine, cinchonine, and the C9 epimers have been exploited for chiral recognition inliquid chromatography, capillary electrophoresis, extractions, and membranes. Insome cases, the enantiomeric discriminating ability is unparalleled in magnituderelative to other enantioselective reagents. Geometric considerations show thatthese compounds have a distinct, pre-organized binding cleft into which thesubstrate molecules fits, which explains the remarkable selectivity for certaincompounds [181].

The tripodal oxazoline 68 was effective in extraction experiments at enantiodis-criminating b-chiral aliphatic and aromatic primary ammonium ions. The threeoxazoline rings tip up to hydrogen bond and secure ammonium ions in thecavity [182]. Compound 69, which has two oxazoline rings attached to a pyridylring, binds effectively to secondary amines and is an effective chiral NMR solvatingagent. The amines are analyzed as protonated cations and form hydrogen bonds tothe nitrogen atoms of 69 [183].

NO

Ph

N

O

N

O

Ph

Ph

68

N

N

OO

N

R1 R2

R1 = Ph, R2 = PhR1 = Ph, R2 = H

69

The phosphorylated macrocycle 70 caused enantiomeric discrimination of thediammonium ions of lysine and arginine. The host molecule is effective because ithas both anionic groups and a hydrophobic binding site. Lysine and arginine ionshave sufficiently long spacing between the two ammonium ions to associatesimultaneously at both anionic phosphate groups. Mono cations or compoundswith shorter distances between the two ammonium ions do not show enantiodiffer-entiation with 70 [184].


O

P

EtO

O

O

Me

Me

O

P

OEt

O

O

Me

Me

Me

MeMe

70

The azamacrocycle 71 is an effective chiral discriminating agent for dicarboxylatessuch as malate, tartrate, aspartate, and glutamate. Potentiometric titrations andelectrospray ionization-mass spectrometry were used to examine the presence ofenantiomeric differentiation [185].

N

NH HN

NH HN

N

71

The anti-configuration of 72 is a clip-shaped molecule. The indole ring oftryptophan has a similar size and shape to the cavity of the compound. Circulardichroism titrationdata showed that tryptophanmethyl ester hydrochloride exhibitedenantioselective insertion into the clip [186].

OAc

OAc

ROOC

COOR

72


The water-soluble cyclophane 73, which is derived from tartaric acid, causesenantiodifferentiation of carboxylic acids, 1-arylethanols, and aryl amines. Enantio-meric discrimination was observed in the 1H NMR spectra and the aromatic rings ofthe cyclophane caused shielding of the guest substrate [187]. Compound 74 is awater-soluble cyclophane with a hydrophobic cavity. Enantiorecognition of substrates suchasmenthol and citronellol was observed in the 1H NMR spectrum. The hydrophobicportion of the substrate associated in the cyclophane cavity [188]. Cryptophane 75wasspecifically designed to accommodate and enantiomerically discriminate bromo-chlorofluoromethane. The 1H resonance exhibited enantiodifferentiation in chloro-form-d [189].

HN NH

OMe

H

H

OMe

NHHNOMe

H

H

OMe

73

RO2C

RO2C

SO

ONH

SO

OHN

CO2R

CO2R

NN

74

OO O O O

O

CH3

CH3CH3

O O O

75


7.7Metal-Containing Receptor Compounds

Metal complexes have been used extensively for chiral recognition, although few aredesigned in such a way that the metal site can be considered a true receptor cavity.Examples of metal complexes suitable for the analysis of chiral anions have beenreviewed [158].

One interesting set of compounds are so-called zinc tweezer porphyrins, 76 beingone example [190, 191]. Diamine substrates of suitable dimensions bind simulta-neously at the two zinc ions and characteristic circular dichroism exciton spectra canbe used for configurational assignments. Alternatively, mono amines can be deri-vatized with 4-N-Boc-aminomethyl-2-pyridine-carboxylic acid to create a diaminefunctionality of appropriate dimensions to bridge the zinc ions [190]. A zinc tweezerwith biphenyl or naphthyl spacers showed excellent enantioselectivity towardlysine [192].

Zn

NN

N N

Zn

NN

N NO

O

O

O

76

Zinc tweezer compounds have also been used as chiral NMR shift reagents. Theseare effective for compounds such as 1,2-diaminocyclohexane, aziridine, and isoxazo-line, all of which can bind simultaneously to both zinc ions. The resonances of thesubstrates shift to exceptionally low frequencies (e.g., chemical shifts at �7 ppm)because of the large shielding of the porphyrin ring [191].

Compound 77 is a porphyrin dimeric ligand that when complexed with cobaltexists in a tweezer configuration. Differences in the circular dichroism spectra oflimonene and trans-1,2-diaminocyclohexane were observed in the presence of 77.The enantiodiscrimination of limonene was especially noteworthy. The porphyrincomplex was also coated onto a quartz crystal microbalance and used for enantio-selective gas-phase sensing of limonene [193].

7.7 Metal-Containing Receptor Compounds j235

N

NH

N

HN

S S

C

O

O

N

NH

NH

N

C

O

O

77

The bimetallic barium–zinc crown-salen complex (78) forms a folded geometry.The compound binds rigid bidentate guests such as amino acid esters in a sandwich-like conformation. Enantiodifferentiation was noted using UV-vis and circulardichroism spectra [194].

O

Zn

N

O

N

O O

O OBa2+

2ClO4

-

78

HH

O

Zn

N

O

N

O O

HH


The rhodium complex [Cp�Rh(20-deoxyadenosine)]3(OTf)3 (Cp� ¼g5-C5Me5;OTf¼CF3SO3

�) has a triangular dome-like cavity and can associate with suitablesubstrates through noncovalent p–p and hydrophobic interactions. The compoundwas a useful chiral NMR shift reagent for aromatic carboxylic acids, cyclohexyl aceticacids, and dipeptides and tripeptides [195].

Ruthenium receptor 79 contains a bipyridine-diamide moiety with two attachedmacrocyclic groups. Based on phosphorescence and 1H NMR titrations, the complexshows selective binding of DD-dipeptides over the corresponding LD-, DL-, and LL-isomers. The system has also been used to screen 3375 different tripeptides in a15� 15� 15 library. The tripeptides were bound on polystyrene beads and thosewithstrong binding to the receptor could be identified colorimetrically. Stereoselectiverecognition occurred primarily for tripeptides with alanine residues [196].

N N

Ru

O

HN

O

NH

NH

HN

HN

NH

O

O

O

O

NH

HN

HN

NH

O

O

O

O

79

(bpy)2

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