DOI: 10.1002/chem.201200247 Calix[4]tubes: An Approach to Functionalization Kirill Puchnin, [a] Pavel Zaikin, [a] Dmitry Cheshkov, [b] Ivan Vatsouro,* [a] and Vladimir Kovalev* [a] Introduction Progress in calixarene chemistry, explored intensively for the last 30 years, proves that this macrocyclic core is very suitable for building highly complicated supramolecular sys- tems targeted to molecular recognition, self-assembly, catal- ysis, biomimicking, and so on. This has become possible mainly due to the versatility of methods for selective and ex- haustive functionalization and conformational control, which have been most studied for calix[4]arenes. [1] More than 10 years ago the calix[4]tube family (Figure 1) was introduced by Beer and co-workers, and high potassi- um-uptake selectivity has been established for these unique quadruple-bridged bis-macrocycles. [2] Further investiga- tions [3] revealed the potassium template effect which governs calixtube formation from calix[4]arene tetratosylates and calix[4]arenes with free narrow rim. Full-thia calixtube [4] and hybrid heterotubes in which the “classical” and thiacalix[4]- arene cores are grafted within one molecule [5] have been also prepared by this method. The high specificity of potas- sium binding by classical calixtubes has been attributed to geometrical fit between potassium ion and the cryptand-like internal cavity of calixtubes, which is reached by the guest through one of the calix[4]arene “gates”. [6, 7] This channel- like behavior allowed one to expect calixtubes to mimic the action of cellular potassium ion channels, [2, 3] but appropriate functionalization is required to investigate these properties of calixtubes. Also, derivatization of calixtube wide rim(s) with an anion-binding site may lead to heteroditopic hosts for ion-pair recognition. [8] Until now, the only published derivatization of calixtubes was achieved by halogenation. While the reaction of halo- Abstract: Adamantylcalix[4]arenes decorated with ester groups and cal- ix[4]arene tetratosylates were used to prepare a series of calix[4]tubes bear- ing 3-methoxycarbonyl- and 3-me- thoxycarbonylmethyl-1-adamantyl units (up to eight) in good yield. These com- pounds were subjected to further chemical transformations giving a wide set of novel ester-, acid-, hydroxy-, amine-, and urea-functionalized cal- ix[4]tubes. Introduction of urea groups into the calixtube core led not only to anion-targeted receptors, but also pro- vided heteroditopic behavior of the hosts, which enriches the well-estab- lished potassium-uptake ability of cal- ix[4]tubes. Keywords: anion recognition · cal- ixarenes · calixtubes · host–guest systems · synthetic methods [a] K. Puchnin, P. Zaikin, Dr. I. Vatsouro, Prof. V. Kovalev Department of Chemistry M. V. Lomonosov Moscow State University Lenin)s Hills, Moscow, 119991 (Russia) Fax: (+ 7) 495-932-8846 E-mail : [email protected][email protected][b] D. Cheshkov State Research Institute for Chemistry and Technology of Organoelement Compounds 38, Sh. Entuziastov, Moscow, 111123 (Russia) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201200247. Figure 1. Known classical, thia-, hybrid, and halogenated calixtubes. # 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2012, 18, 10954 – 10968 10954
Transcript
DOI: 10.1002/chem.201200247
Calix[4]tubes: An Approach to Functionalization
Kirill Puchnin,[a] Pavel Zaikin,[a] Dmitry Cheshkov,[b] Ivan Vatsouro,*[a] andVladimir Kovalev*[a]
Introduction
Progress in calixarene chemistry, explored intensively forthe last 30 years, proves that this macrocyclic core is verysuitable for building highly complicated supramolecular sys-tems targeted to molecular recognition, self-assembly, catal-ysis, biomimicking, and so on. This has become possiblemainly due to the versatility of methods for selective and ex-haustive functionalization and conformational control,which have been most studied for calix[4]arenes.[1]
More than 10 years ago the calix[4]tube family (Figure 1)was introduced by Beer and co-workers, and high potassi-um-uptake selectivity has been established for these uniquequadruple-bridged bis-macrocycles.[2] Further investiga-tions[3] revealed the potassium template effect which governscalixtube formation from calix[4]arene tetratosylates andcalix[4]arenes with free narrow rim. Full-thia calixtube[4] andhybrid heterotubes in which the “classical” and thiacalix[4]-arene cores are grafted within one molecule[5] have beenalso prepared by this method. The high specificity of potas-sium binding by classical calixtubes has been attributed togeometrical fit between potassium ion and the cryptand-likeinternal cavity of calixtubes, which is reached by the guestthrough one of the calix[4]arene “gates”.[6,7] This channel-
like behavior allowed one to expect calixtubes to mimic theaction of cellular potassium ion channels,[2,3] but appropriatefunctionalization is required to investigate these propertiesof calixtubes. Also, derivatization of calixtube wide rim(s)with an anion-binding site may lead to heteroditopic hostsfor ion-pair recognition.[8]
Until now, the only published derivatization of calixtubeswas achieved by halogenation. While the reaction of halo-
Abstract: Adamantylcalix[4]arenesdecorated with ester groups and cal-ix[4]arene tetratosylates were used toprepare a series of calix[4]tubes bear-ing 3-methoxycarbonyl- and 3-me-thoxycarbonylmethyl-1-adamantyl units(up to eight) in good yield. These com-pounds were subjected to further
chemical transformations giving a wideset of novel ester-, acid-, hydroxy-,amine-, and urea-functionalized cal-
ix[4]tubes. Introduction of urea groupsinto the calixtube core led not only toanion-targeted receptors, but also pro-vided heteroditopic behavior of thehosts, which enriches the well-estab-lished potassium-uptake ability of cal-ix[4]tubes.
[a] K. Puchnin, P. Zaikin, Dr. I. Vatsouro, Prof. V. KovalevDepartment of ChemistryM. V. Lomonosov Moscow State UniversityLenin�s Hills, Moscow, 119991 (Russia)Fax: (+7) 495-932-8846E-mail : [email protected]
genated calixarenes with tetratosylates was unsuccessful,direct bromination or iodination of calixtubes with unsubsti-tuted wide rim led to the desired halogenated calix[4]tubesin moderate to high yield.[7] Nevertheless, further conver-sions of the bromo- and iodotubes (Figure 1) have neverbeen published and were also unsuccessful in our hands,most likely due to steric hindrance within the tube molecule.
In recent years we have shown that carboxylated adaman-tyl units are useful building blocks for the construction ofhost molecules, as they can be easily introduced into calixar-enes by trifluoroacetic acid (TFA)-promoted adamantyla-tion. The carboxyl groups can be converted to a wide rangeof functional groups by convenient chemical transforma-tions.[9] In this work prefunctionalized adamantylcalix[4]ar-ene derivatives were used for the synthesis of calixtubesbearing up to eight ester groups, which were converted fur-ther to alcohols, acids, amides, amines, and ureas to givefunctionalized calixtubes including fluorescent anion recep-tors and heteroditopic hosts.
Results and Discussion
Synthesis : Template-assisted synthesis of calixtubes requirestetraphenolic calix[4]arenes and calix[4]arene tetratosylates.Ester groups were introduced to calix[4]arenes of both typesthrough adamantane linkers. Wide rim unsubstituted cal-ix[4]arene 1 was exhaustively adamantylated with 3-hy-droxy-1-adamantanecarboxylic acid (in TFA/C2H4Cl2/CF3SO3H) or 3-hydroxy-1-adamantylacetic acid (in TFA/C2H4Cl2) and further subjected to acid-catalyzed esterifica-tion to give tetraesters 2 and 3 according to published proce-dures[9d] with slight modifications (Scheme 1).
For selective adamantylation, partially substituted cal-ix[4]arene 4[10] with two distal 3,5-dinitrobenzoyl groups atthe narrow rim was used. These groups were found earlierto provide a good difference in nucleophilicity of para posi-tions of substituted and unsubstituted calixarene aromaticmoieties and also to tolerate the general adamantylationconditions.[11] When treated with a slight excess (2.1 equiv)of 3-hydroxy-1-adamantanecarboxylic acid or 3-hydroxy-1-adamantylacetic acid in TFA in the presence of CF3SO3H,calixarene 4 was converted predominantly to distally diada-mantylated derivatives which, however, could not be sepa-rated easily from reaction mixtures. Thus, after removal ofthe solvent mixture, crude adamantylation products werehydrolyzed and then esterified to give, by chromatographicseparation, the corresponding bis- (5, 6) and mono-adaman-tylated (7, 8) calix[4]arenes (Scheme 1). The yield of calixar-enes 7 and 8 can be increased a little bit by using only oneequivalent of adamantylating reactant, but more complicat-ed mixtures of unsubstituted calixarene 1, bis-adamantylatedcalixarenes, and target compounds 7 or 8 were obtained inthis case.
The convenient procedure for synthesis of tetratosylate 9(alkylation of the parent p-tert-butylcalix[4]arene with ethylbromoacetate[12] followed by ester reduction[13] and tosyla-
tion[14]) is obviously not applicable for narrow-rim modifica-tion of ester-functionalized calixarenes. To obtain the de-sired compound, 2-bromoethyl acetate was used for alkyla-tion of ester 2. Despite wide variation of reaction conditions(solvent, temperature, reaction time, excess of reagents, ad-dition sequence of reactants), in all cases a mixture of tri-and tetraalkylated calixarenes was obtained, from which thetarget tetraether could not be separated. Nevertheless, mildhydrolysis of acetate groups, which did not affect the steri-cally hindered 3-methoxycarbonyl-1-adamantyl moieties,furnished a mixture of tri- and tetrols, from which the de-sired calixarene 10 was successfully isolated and then trans-formed into target tetratosylate 11 (Scheme 2).
Nine functionalized calix[4]tubes 12–20 with one, two,four, six, or eight ester groups in one or both calixarenemacrocycles (Scheme 3) were isolated in good yield for thefirst time. To this end, phenolic calixarenes 2, 3, and 5–8were mixed with 1.05–1.10 equivalents of tetratosylate 9 or11 and 5 equivalents of K2CO3 and heated in boiling o-xylene for 60–70 h. o-Xylene was selected (instead of aceto-nitrile) as it provides better yield of calixtubes due to higherboiling point[3] and lower polarity, which probably can leadto greater development of the potassium template effect.Purification of tetrafunctionalized tubes 12 and 13 was rela-tively simple and did not require any “hard” chromatogra-phy, so the workup was performed very fast to give thetarget bis-macrocycles on multigram scale. The same tech-nique was efficient also in the case of octafunctionalizedtubes 18 and 19, while purification of selectively adamant-ylated calixtubes required full-length column separation.
Scheme 1. Synthesis of phenolic calix[4]arenes. a) 3-HOOC ACHTUNGTRENNUNG(CH2)n-1-ada-mantanol/TFA/C2H4Cl2 (+CF3SO3H); b) KOH/EtOH/H2O; c) HCl; d)MeOH/H2SO4/THF.
All new calixtubes were characterized by NMR and massspectra. Due to a flattened cone-to-flattened cone confor-mational exchange (Figure 2), which is slow on the NMRtimescale, the time-averaged symmetry of the calixtube coreis C2v.
[2,3] This feature produces the characteristic doublingof signals in NMR spectra. Such clear signal splitting wasobserved in spectra of calixtubes 12, 13, 18, and 19, in whicheach calixarene macrocycle forming the tube is equally widerim substituted. As representative examples, 1H NMR spec-tra of tetra- and octafunctionalized calixtubes 12 and 19(Figure 3) contain two sets of signals from trans- andgauche-OCH2CH2O moieties[3] as well as an appropriatenumber of ArH and OMe resonances.
When one of the calix[4]arene macrocycles of a tube wasselectively substituted, a much more complicated pattern ap-peared in NMR spectra. This phenomenon has been ob-served earlier for partially substituted tubes and has been at-tributed to unequal distribution of two flattened cone con-formers of calixtubes with different inclinations of bulkygroups at a wide rim.[3,7] 2D EXSY NMR can be applied toanalyze the conformational distribution in these cases, andexact structures of each conformer of partially adamantylat-ed calixtubes can be accessed by using other NMR tech-niques, as will be published elsewhere. In the present study,another approach was used to prove the tubular structure ofcompounds 14–17 and 20. It has been well documented thatbinding of potassium ions by the cryptand-like cavity ofa calixtube freezes the conformational mobility of calixtubecore and brings it to C4v symmetry (Figure 4),[2,3] so the totalmolecular symmetry must be imposed by only the substitu-tion pattern at wide rims.
Adding an excess of KI to solutions of compounds 14–17and 20 in CDCl3/CD3OD (4/1) led to drastically simplifiedspectra showing the expected formal molecular symmetry ineach case. For instance, clear C2v symmetry with all-gaucheOCH2CH2O groups can be easily concluded from the1H NMR spectrum of 14·K+ (Figure 5).
The most readily available tetraester calixtubes 12 and 13were subjected to further chemical transformations(Scheme 4). The ester groups were hydrolyzed under alka-
Scheme 2. Tetratosylates used in calixtube syntheses. a) 2-Bromoethylacetate/NaH/DMF; b) K2CO3/MeOH/THF/H2O; c) TsCl/Py.
Scheme 3. Synthesis of functionalized calixtubes. a) K2CO3/o-xylene.
Figure 2. Conformational exchange in calixtube core.
Figure 3. 1H NMR spectra of calixtubes 12 (a) and 19 (b), 400 MHz,CDCl3, 25 8C;N residual solvent peaks.
line conditions or with phase-transfer catalysis, which wasmore efficient in the case of acetic ester 13, and the result-ing acids 21 and 22 were shown to be easily convertible toamides (e.g., 23, 24) by a standard SOCl2-activation route.However, the main purpose was to introduce an anion-bind-ing site into calixtube molecules to extend their ionophoreproperties from simple cation binders to ion-pair heterodi-topic hosts, and the urea moiety was selected as one of themost efficient anionophore groups.[15] The appropriate ami-nated calixtube precursors were synthesized by well-devel-oped methods of adamantylcalixarene chemistry.[9a,b,16] Acid21 was converted to the azide and then to isocyanate 25(Curtius rearrangement), which was then hydrolyzed to tet-rakis(3-amino-1-adamantyl)-substituted calixtube 26. Reduc-tion of tetraester 13 led to alcohol 27, which was treatedwith phthalimide under Mitsunobu conditions. Cleavage ofphthalimide groups by hydrazine hydrate gave calixtube 29bearing four amino groups attached to adamantane nucleithrough flexible ethylene linkers and therefore less stericallyhindered than those in calixtube 26.
Further reaction of amines 26 and 29 with p-tolyl isocya-nate or fluorescent 1-isocyanatopyrene (generated from 1-aminopyrene and triphosgene) gave calixtubes decoratedwith anion-binding sites. Notably, no reaction was observedbetween amine 26 and 1-isocyanatopyrene or between isocy-anate 25 and 1-aminopyrene even after prolonged heating inboiling toluene or xylene, most likely due to steric repulsionof bulky reactants.
For comparative purposes, calixtubes 36 and 37 bearingonly two distal urea groups were obtained from diester 15
by the same synthetic pathwayas for tubes 31 and 32(Scheme 4). To evaluate the in-fluence of the calixtube core onanion-binding properties of thereceptors, fluorescent tetrakis-and bis-urea adamantylcalix[4]-arenes 46 and 47 were also syn-thesized from correspondingcone tetra- and bis-acids 38 and39, which were obtained fromesters 3 and 6 by exhaustivenarrow-rim butylation followedby hydrolysis (Scheme 5).[9d]
For none of the ureas withflexible ethylene linkers be-tween adamantane and ureagroups were the expected pat-terns obtained in NMR spectrain neat CDCl3. Thus, for tetra-kis-urea derivatives 31, 32 and46 a set of broad signals ap-peared, while the 1H NMRspectra of bis-ureas 36, 37 and47 showed splitting of most ofthe resonances. Most probably,intra- and/or intermolecular hy-
Figure 4. Symmetry changes in calixtubes on potassium-ion complexa-tion.
Figure 5. 400 MHz 1H NMR spectra of pure 14 (a, CDCl3) and its potassi-um complex (b, CDCl3/CD3OD, 4/1), 25 8C;N residual solvent peaks.
Scheme 4. Chemical transformations of calixtubes. a) KOH/EtOH/H2O, then HCl; b) nBu4NOH/THF/H2O,then HCl; c) SOCl2/benzene, then Et2NH/THF; d) SOCl2/benzene, then NaN3/acetone/H2O, then benzene/heating; e) HCl/dioxane; f) LiAlH4/THF; g) PhtH/Ph3P/DIAD/THF; h) N2H4·H2O/EtOH; i) Isocyanate/tolu-ene.
drogen bonds between the urea groups are responsible forthese complications of the spectra.[17] This phenomenon(particularly in calixtubes in which it can compete with theinternal mobility of the core) deserves special attention. Forthe purpose of this research, to characterize these com-pounds several drops of CF3CO2D were added to CDCl3 sol-utions of bis- and tetrakis-urea calixarenes 31, 32, 46, and47, and clear 1H and 13C NMR spectra were acquired andfully interpreted. Notably, for tube 30 with more rigid ureamoieties an adequate 1H NMR spectrum was collected evenfrom CDCl3 solution, but for solubility reasons this com-pound was also characterized by NMR spectroscopy inCDCl3/CF3CO2D. As expected, the hydrogen bond breakingsolvent changed but did not simplify the 1H NMR spectra ofbis-urea tubes 36 and 37, so these compounds (as well astheir precursors 33–35) were characterized as C2v-symmetri-cal potassium complexes by 1H NMR spectroscopy inCDCl3/CD3OD.
Complexation study : As cation-binding properties of calix-tubes have already been well studied, and also in the presentwork the ability of functionalized calixtubes to bind potassi-um ions was demonstrated, further investigations focused onanion and ion-pair recognition by calixtubes enriched withurea groups. First, 1H NMR titration was tried in[D6]DMSO to avoid line broadening and signal overlap inspectra of tetrakis-urea calixarenes. However, in this highlycompetitive medium, addition of small amount of tetra-n-butylammonium chloride or bromide did not cause anymeasurable change in chemical shifts, while at higher guestconcentrations a strong salt effect masked the chemical-shiftchanges.
As the NMR experiment failed, the receptor activity to-wards anions was measured by fluorescence titration forpyrene-containing calixtubes 32, 37 and model calixarenes46, 47 in chloroform. All compounds showed strong pyrenefluorescence, but the monomer/eximer emission ratio wasdrastically different for tetrakis- and bis-ureas. While for tet-
rakis-ureas 32 and 46 an excimer emission (�490 nm) wasdominant (Figure 6 a, c), almost no excimer emission wasobserved for bis-ureas 37 and 47 (Figure 6 b, d). Clearly, ex-cimer formation occurred between pairs of pyrene groupsfrom proximal (in tetrakis-ureas) but not distal (in bis-ureas) wide-rim substituents of free ligands.
In most cases, gradual addition of titrants resulted in clearand ratiometric changes in fluorescence spectra, from whichcomplex composition (mainly 1:1) and binding constants(Table 1) were successfully extracted by nonlinear curve fit-ting. In Figure 6 (left column) typical spectral changes onaddition of halides, hydrogensulfate, and nitrate anions tothe calixarene solutions are shown for chloride titrations.For tetrakis-urea calixtube 32 and tetrakis-urea model calix-arene 46 a rise of both monomer and excimer emissions oc-curred. Towards these ions calixtube 32 and calixarene 46showed quite similar receptor behavior, and Cl� was boundmost strongly by both ligands. The small spectral changesobserved in several cases (see Table 1) should not be inter-preted just as weak complexation, but could also be due to
Scheme 5. Synthesis of model tetra- and bis-ureas. a) nBuI/NaH/DMF,then KOH/EtOH/H2O; b) LiAlH4/THF; c) PhtH/Ph3P/DIAD/THF; d)N2H4·H2O/EtOH; e) Isocyanate/toluene.
Figure 6. Changes of fluorescence spectra of compounds 32 (a), 37 (b), 46(c), and 47 (d) on addition of nBu4N
specific anion coordination that does not affect the HOMO/LUMO population of the fluorophore.
In contrast, in bis-ureas 37 and 47 the calixtube core influ-ences crucially the anion complexation mode: more rigidcalixtube 37 formed 1:1 complexes (except for I�), whileflexible calixarene 47 bound two halide, hydrogensulfate, ornitrate anions per ligand molecule (Table 1). Qualitativeanalysis of spectral changes also supports the differences incomplexation behavior of bis-ureas: a rise of excimer emis-sion was observed only in the case of calixtube 37 (Fig-ure 6 b), but not for model compound 47 (Figure 6 d), whilethe clear changes in the “monomeric” parts of fluorescencespectra occurred for both calixarenes.
Binding of H2PO4� by all of the bis- and tetrakis-urea cal-
ixarenes proceeded more efficiently than that of other stud-ied anions (Table 1). Moreover, in the case of tetrakis-ureacalixarenes 32 and 46 selective fluorescent-sensor behaviortowards H2PO4
� was clearly demonstrated (Figure 6, rightcolumn): a significant increase of monomer emission atabout 410 nm with quenching (for 32) or no change (for 46)of excimer emission was unique to dihydrogenphosphateamong all studied anions.
Possible molecular structures of tetrakis-urea calixtubeand its anion complexes were obtained by quantum-chemi-cal calculations. Geometry optimization was performed fortetrakis-urea calixtube 31, 31·Cl�, and 31·H2PO4
�at the DFTlevel of theory (PBE[18]/L1,[19] quantum-chemical programPRIRODA[20]). In the free ligand, four intramolecular hy-drogen bonds of type NH···CO···NH graft adjacent ureagroups into two pairs, and two other hydrogen bonds of typeNH···CO connect these pairs (Figure 7 a). Slow exchange inthis cyclic hydrogen-bond array (directional or between thetwo types of bonds) may be responsible for the line broad-ening in 1H NMR spectra of 31 in noncompeting solvents.
In complex 31·Cl� (Figure 7 b) all of the urea moieties areturned inward with their NH groups forming the cavitywhich accommodates Cl� through multiple NH···Cl bonds.The energy-minimized structure of 31·H2PO4
� (Figure 7 c)shows quite a different mutual orientation of the urea sub-stituents and also some more complicated interactions be-tween the host molecule and the anionic guest: in additionto P=O···HN and P�O···HN contacts with urea moieties do-nating protons into hydrogen bonds, there are also two P�
OH···NH bonds with urea groups serving as acceptors. De-spite rearrangement of urea groups on complex formation,both in chloride and dihydrogenphosphate complexes thecalixtube core remains almost undisturbed and keeps itsoriginal flattened cone conformation.
These conclusions are consistent with the changes ob-served in 1H NMR spectra after addition of about ten equiv-alents of anions to solutions of 31 in CDCl3. Anion complex-ation resulted in simplification of the aromatic parts of thespectra (Figure 8), with two sets of tolyl resonances becom-ing clearly visible. Low-field broad signals (marked), whichcan be attributed to urea NH groups involved in complexa-tion, also appeared. At the same time, singlets from the cal-ixtube aromatic system and tert-butyl groups (not shown) re-mained unchanged.
It is not clear if it would be correct to transfer the calcu-lated binding site structures in 31·Cl� and 31·H2PO4
� to theanion complexes of pyrene-containing tetrakis-urea 32, assome weak interactions between pyrene units (for instance,p–p stacking) may influence the complexation. Much moretime and resource consuming higher level calculations arerequired to consider all these features and, in particular, toexplain the H2PO4
�-sensing selectivity of 32, but the theoret-ical observations made in this study still provide some gen-eral understanding of the anionophoric action of urea-sub-stituted calixtubes from the structural point of view.
Table 1. Binding constants lg K for 1:1 complexes of calixtubes 32, 37and model compounds 46, 47 (cL =5 � 10�6
m) with anions (as nBu4Nsalts), as determined by fluorescence titration in CHCl3 at 25 8C (lex =
360 nm).
Anion 32 37 46 47
Cl� 4.2�0.1 3.2�0.1 3.9�0.1 –[b]
Br� –[a] 2.7�0.1 3.8�0.1 –[b]
I� –[a] –[b] –[a] –[b]
HSO4� –[a] 2.8�0.1 2.8�0.1 –[b]
NO3� 3.1�0.1 2.7�0.1 3.1�0.1 –[b]
H2PO4� 4.5�0.1 4.0�0.1 4.7�0.1 4.2�0.1
[a] Small changes in fluorescence spectra. [b] Nonlinear fit converged forsingle 1:2 (calixarene:anion) complex with lg b12�6.
Figure 7. Energy-minimized structures of free 31 (a) and its Cl� (b),H2PO4
To check whether the embedded anion-binding site turnscalixtubes from selective potassium binders to ditopic hostsfor ion-pair recognition, solid–liquid KI extraction kineticswas studied for ester- (13, 14) and urea-functionalized (30,31, 36) calixtubes. Potassium iodide was selected as it hasbeen shown to be best extracted by calixtubes[3] and also hasbetter solubility in organic solvents among common inorgan-ic potassium salts. The experiments were carried out directlyin NMR tubes with 20-fold excess of solid KI. Potassiumuptake was followed by integration of well-resolved1H NMR signals from tert-butyl groups and/or calixtube aro-matic protons of a free ligand (C2v-symmetrical core) and itsK+-complex (C4v-symmetrical core, see Figure 4).
First, extraction into CDCl3/CD3OD (4/1) was measured.In this medium (which has been used to measure potassiumuptake by unfunctionalized calixtubes) all compounds stud-ied showed fast extraction kinetics, and no rational differ-ence in potassium uptake by ester- and urea-functionalizedcalixtubes was found. Obviously, the H-bond-breaking sol-vent disfavored anion recognition by urea groups, so thatthe binding process was controlled mainly by cation com-plexation. In contrast, when neat CDCl3 was used, which istolerant of hydrogen bonds and, on the other hand, is a lessfavorable solvent for KI, urea-enriched tubes 30, 31 and 36were much better extractants than esters 13 and 14(Figure 9). Nevertheless, the extraction rates for all thetubes were much lower than those in CDCl3/CD3OD.
Along with the expected simplification of 1H NMR spec-tra due to C2v!C4v symmetry change of the calixtube coreon K+ binding, a low-field shift of NH resonances was ob-served for urea-functionalized calixtubes. These changes,which were most clearly visible for bis-urea calixtube 36(Figure 10) appeared, reasonably, to be due to anion com-plexation by urea groups.
Among the ureas, the most efficient extractant was 31,which most likely can better solvate the K+I� ion pair and
therefore accelerate disruption of the salt�s crystalline lat-tice. Quantum-chemical calculations provided a possible ge-ometry of the extracted complex (Figure 7 d). In this energy-minimized structure the calixtube core has clear C4v symme-try, while the anion is stabilized by four urea groups ina manner resembling that of complex 31·Cl�.
Finally, to get insight to thermodynamics of ion-pair com-plexation, tetra-ester calixtube 13 and tetrakis-urea calix-tube 31 (cL =1.5 � 10�3
m) were each equilibrated for 24 hwith exactly one equivalent of KI in CDCl3/CD3OD (4/1) at25 8C. The clear solutions were then analyzed by 1H NMR,and from complex/ligand ratios binding constants were cal-culated. For ester-functionalized calixtube 13 the value of2.4 � 104
m�1, which is consistent with the published data for
the full-tert-butylcalixtube (4 �104m�1),[2] was obtained. At
the same time, for tetrakis-urea calixtube 31 an eight timeshigher complexation constant of 1.9 �105
m�1 was found. It is
not clear if this difference in complexation constants wasprovided by iodide-ion binding in the urea site (which canbe not completely suppressed in competing CDCl3/CD3OD
Figure 8. Parts of the 1H NMR spectra of pure 31 (a), and after additionof ten equivalents of nBu4N
+Cl� (b) and nBu4N+H2PO4
� (c) in CDCl3 at25 8C. N Residual solvent peaks, * proposed NH signals.
Figure 9. Kinetics of solid–liquid extraction (solubilization) of KI byester- (13, 14) and urea-calixtubes (30, 31, 36) in CDCl3, cL�1�10�3
m.
Figure 10. Parts of the 1H NMR spectra (scaled nonproportionally) of 36on solubilization of KI in CDCl3 at 25 8C. a) 50 min, b) 168 h, c) 672 h(55 % uptake).N Residual solvent peaks, * proposed NH signals.
medium) or just by different abilities of calixtube cores in13 and 31 to form mononuclear potassium complexes. (NoNH resonances were visible in CDCl3/CD3OD mixture, andthus a complexation-induced shift, if any, could not be mea-sured.) When KPF6 (noncoordinating anion) was used in-stead of KI, the apparent complexation constant with tetra-kis-urea 31 was calculated to be only 2.7 � 103
m�1. Still, this
could not be regarded as an independent proof for anion co-ordination in 31/KI/CDCl3/CD3OD system, for this salt wasshown earlier not to fill completely all of the available calix-tube molecules even at 20-fold excess of KPF6.
[3] Compari-son of the signals from C4v-symmetrical species in 1H NMRspectra of 31/KI and 31/KPF6 mixtures (Figure 11) did not
show any difference, within the accuracy of the experiment,for resonances of the complexes in these two cases, soiodide complexation in competing CDCl3/CD3OD mediumremained unproved.
The possible cooperative effect of potassium/anion bind-ing by urea-substituted calixtube 32 was probed in noncom-peting chloroform solutions by fluorometry. As titration ofan anionic complex with potassium species was not possibledue to very slow potassium complexation kinetics, the studywas planned as a titration of 32·K+ with nBu4N
+H2PO4�.
Preparation of 32·K+ was first tried in neat chloroform byaddition of exactly one equivalent of KPF6, KBPh4, or KI(weakly or noncoordinating anions), but even after twoweeks of stirring at room temperature the conversion offree ligand to potassium complex was negligible in all cases,as probed by NMR spectroscopy (in contrast to kineticmeasurements mentioned above, in which a 20-fold excessof KI was used). Hence, the complex 32·K+ was prepared inCHCl3/CH3OH (4/1) and, after removal of the solvents anddrying, redissolved in neat chloroform. NMR spectra fromCDCl3 solutions of the species showed about 70–80 % ofcomplexed calixtubes in all cases. The samples were titratedwith nBu4N
+H2PO4� in CHCl3 under exactly the same con-
ditions as for free 32. Surprisingly, during the first titration
steps almost no changes were observed in fluorescence spec-tra, while after addition of about one equivalent of theanion titrations followed qualitatively that of free 32, andthe calculated binding constants were the same as presentedin Table 1 for 32·H2PO4
�. Reasonably, potassium decom-plexation took place in a chloroform solution of 32·K+ onaddition of dihydrogenphosphate anions. This was unambig-uously confirmed by 1H NMR: addition of an excess ofnBu4N
+H2PO4� to CDCl3 solutions of 32·K+PF6
�, 32·K+
BPh4�, or 32·K+I� turned the characteristic spectral pattern
of C4v-symmetrical potassium complexes into that of C2v-symmetrical empty calixtube core.
Thus, the ion-pair recognition ability of calixtubes en-riched with urea groups was successfully demonstrated onlyby solid–liquid extraction in chloroform. Unfortunately, be-cause of solubility reasons, other potassium salts with bettercomplexed anions (e.g., chloride or dihydrogenphosphate),which could probably provide more impressive results, cannot be studied in this way.
Conclusion
A series of functionalized calix[4]tubes were synthesized,not by chemical transformation of unfunctionalized calix-tubes, but by calixtube preparation from ester-substitutedadamantylcalix[4]arene counterparts. Bis-macrocycles withup to eight ester groups were obtained in moderate to goodyield and were demonstrated to be easily converted to nu-merous functional derivatives, including acids, amides, alco-hols, and amines. In particular, calixtubes enriched with ureagroups were prepared and studied as anion hosts, fluores-cent sensors, and ditopic receptors for potassium iodide. Thefunctionalized calixtubes maintained the potassium uptakeability which was established for unfunctionalized ones. Thisability was extended in urea-functionalized calixtubes, as fol-lows from potassium iodide uptake/solubilization experi-ments.
In future, this research will be continued as functionalgroups have increased the solubility and thus the potentialto utilize the potassium channel-like behavior and unprece-dented conformational properties of the calixtubes. At themoment, only functionalized calixtubes bearing adamantaneunits as linkers between the core and functional groups havebeen prepared, but we hope that calixtubes with directly at-tached functional groups will become available by using theapproaches and methods developed in this study.
Experimental Section
General experimental methods : NMR spectra were acquired at 25 8C ona Bruker Avance 400 instrument and chemical shifts are reported in ppmreferenced to solvent signals. In 13C NMR spectra, signal assignment wasassisted by APT and DEPT135 experiments. Signals labeled with an as-terisk are close to one another and could not be attributed more definite-ly without additional experiments. Selectively wide rim substituted calix-tubes were characterized as potassium complexes, which were obtained
Figure 11. 1H NMR spectra of free 31 (a) and its equilibrated mixtureswith one equivalent of KI (b) and KPF6 (c) in CDCl3/CD3OD (4/1) at25 8C. N Residual solvent peaks.
by addition of an excess of solid KI to NMR tubes containing CDCl3/CD3OD (4/1) solutions of calixtubes and keeping the solutions until equi-librated (2–4 d). MALDI-TOF mass spectra were run on a Bruker Auto-Flex II apparatus, and ESI and APPI mass spectra were obtained froman Agilent 1100 LC/MS system. Fluorescence measurements were per-formed on a Fluorat-02-Panorama spectrofluorometer. Chemicals re-ceived from commercial sources were used without further purification.Solvents were purified and dried according to standard procedures. p-H-calix[4]arene (1),[21] 25,27-bis(3,5-dinitrobenzoyloxy)calix[4]arene (4),[10]
and tetratosylate 9[14] were synthesized according to published proce-dures.
Tetraester 2 : A mixture of calixarene 1 (6.36 g, 15.0 mmol), 3-hydroxy-1-adamantanecarboxylic acid (17.64 g, 90.0 mmol), a 2% solution ofCF3SO3H in TFA (90 mL), and dichloroethane (90 mL) was heated at60–658C (oil bath) with stirring for 10 h. The solvent mixture was re-moved in vacuo and the resultant sticky mass treated with water over-night. The solid formed was collected, washed with water and methanol,and then dissolved in THF (250 mL). Methanol (150 mL), H2SO4 (96 %,4.7 mL, 84.0 mmol), and water (5 mL) were added and the mixture wasstirred at reflux for 20 h. The solvents were removed in vacuo and theresidue was washed with water and methanol, and dried. Purification bycolumn chromatography (silica gel, CHCl3/hexane 1/1) followed by crys-tallization from CH2Cl2/hexane afforded pure 2 as colorless needles(12.25 g, 69%). Analytical data were the same as published previously.[9d]
Tetraester 3 : A mixture of calixarene 1 (3.56 g, 8.4 mmol), 3-hydroxy-1-adamantylacetic acid (10.6 g, 50.4 mmol), neat TFA (50 mL), and di-chloroethane (34 mL) was heated at 70–75 8C with stirring for 20 h. Thesolvent mixture was removed in vacuo and the resultant sticky mass wastreated with water overnight. The solid formed was collected, washedwith water and methanol, dried, and then dissolved in dry THF(140 mL). Dry methanol (84 mL) and H2SO4 (96 %, 2.6 mL, 46.0 mmol)were added and the mixture was stirred at reflux for 20 h. The solventswere removed in vacuo and the residue washed with water and methanoland dried. Purification by column chromatography (gradient fromhexane to hexane/CHCl3 1/3) followed by crystallization from CH2Cl2/hexane afforded pure 3 as colorless needles (7.52 g, 72 %). Analyticaldata were the same as published previously.[9d]
Diesters 5, 6 and monoesters 7, 8 : A mixture of calixarene 4 (3.25 g,4.0 mmol), 3-hydroxy-1-adamantanecarboxylic acid (1.65 g, 8.4 mmol) or3-hydroxy-1-adamantylacetic acid (1.76 g, 8.4 mmol), a 2% solution ofCF3SO3H in TFA (15 mL), and dichloroethane (15 mL) was heated at60–658C with stirring for 2 h. The solvent mixture was removed in vacuo.The residue was washed with water and methanol, dried, and added toa stirred solution of KOH (2.02 g, 36.0 mmol) in ethanol (100 mL). Themixture was stirred at reflux for 8 h and then concentrated almost to dry-ness. HCl (5 m, 50 mL) was added and the dark-brown solid was collect-ed, washed with water, dried, and then subjected to flash chromatogra-phy (CH2Cl2/ethanol 10/1) to remove the main part of the 3,5-dinitroben-zoic acid (remained on the column). The eluted solution was evaporatedin vacuo and the residue dissolved in dry THF (40 mL). Methanol(20 mL) and H2SO4 (96 %, 0.64 mL, 12.0 mmol) were added and the mix-ture was heated to refluxed with stirring for 20 h. The solvents were re-moved and the residue washed with water and methanol and dried.Column chromatography (gradient from hexane to hexane/CHCl3 1/3) af-forded pure mono- (7, 8) and diesters (5, 6).
Tetraalcohol 10 : NaH (60 % suspension in oil, 1.44 g, 36.0 mmol) wasadded portionwise to a stirred solution of tetraester 2 (1.79 g, 1.5 mmol)in dry DMF (30 mL). The mixture was stirred under a dry atmospherefor 30 min and 2-bromoethyl acetate (5.29 mL, 48.0 mmol) was added.The reaction mixture was stirred at room temperature for 7 d and thenquenched with 2m HCl (100 mL), and the products were extracted withCH2Cl2. The organic solution was washed with water and brine and thesolvent evaporated. The resultant oil was briefly heated to reflux withmethanol, cooled, and the solution carefully decanted. The residue wasdissolved in THF (25 mL) and methanol (25 mL), and a solution ofK2CO3 (0.91 g, 6.6 mmol) in water (5 mL) was added. The mixture wasstirred at reflux for 4 h and allowed to stand overnight at room tempera-ture. The solvents were removed and the residue was taken up inCH2Cl2, washed with 2m HCl and water, and dried with MgSO4. The sol-vent was evaporated in vacuo and the residue was treated by columnchromatography (gradient from CH2Cl2 to CH2Cl2/ethanol 30/1) to affordcompound 10 as a white solid (0.59 g, 29%); m.p. 172–174 8C; 1H NMR(400 MHz, CDCl3): d= 6.85 (s, 8 H; ArH), 4.35 (d, 2J ACHTUNGTRENNUNG(H,H) =12.6 Hz,4H; ArCH2Ar), 4.01 (m, 8H; OCH2), 3.96 (m, 8 H; OCH2), 3.64 (s, 12 H;OCH3), 3.23 (d, 2J ACHTUNGTRENNUNG(H,H) = 12.6 Hz, 4H; ArCH2Ar), 2.09 (br s, 8H;CHAd), 1.93–1.42 (m, 48H; CH2Ad); 13C NMR (100 MHz, CDCl3): d=
Tetratosylate 11: TsCl (0.46 g, 2.4 mmol) was added to a cooled (0–5 8C)solution of calixarene 10 (0.28 g, 0.20 mmol) in dry pyridine (5 mL). Themixture was kept at �18 8C for 3 d and filtered. The filtrate was added toice-cold water, and the mixture was allowed to warm to room tempera-ture. The solid formed was separated, washed with water, dried and thenwashed with ethanol to afford pure 11 as a white solid (0.34 g, 84%);m.p. 113–115 8C; 1H NMR (400 MHz, CDCl3): d=7.79 (m, 8H; ArHTs),7.33 (m, 8H; ArHTs), 6.69 (s, 8 H; ArH), 4.38 (m, 8H; OCH2), 4.21 (d, 2J-ACHTUNGTRENNUNG(H,H) =12.6 Hz, 4H; ArCH2Ar), 4.07 (m, 8H; OCH2), 3.63 (s, 12H;OCH3), 3.00 (d, 2J ACHTUNGTRENNUNG(H,H) =12.6 Hz, 4H; ArCH2Ar), 2.43 (s, 12H; CH3),2.08 (br s, 8H; CHAd), 1.89–1.48 (m, 48H; CH2Ad); 13C NMR (100 MHz,CDCl3): d=177.64 (C=O), 152.25, 144.77 (CAr), 144.16 (CArTs), 133.61(CAr), 133.04 (CArTs), 129.93, 127.97 (CHArTs), 124.65 (CHAr), 71.70(OCH2), 69.40 (CH2OTs), 51.57 (OCH3), 44.01, 42.43, 41.72, 38.10, 35.69,35.60 (CAd, CH2Ad), 30.83 (ArCH2Ar), 28.65 (CHAd), 21.64 (CH3);MALDI-MS: m/z : 2008.1 [M+Na]+ for C112H128NaO24S4 (2008.8).
Ester-functionalized calixtubes 12–20 : A mixture of phenolic calixarene(2, 3, 5–8), tetratosylate (9, 11), anhydrous K2CO3, and o-xylene wasstirred at reflux under dry atmosphere for 60–70 h. After cooling, the re-action mixture was filtered, the solid was washed with CH2Cl2, and com-bined organic solution evaporated in vacuo. The residue was dissolved inCH2Cl2, washed with 2m HCl and water, and the solution dried with
MgSO4. The residue after solvent removal was subjected to flash chroma-tography (chloroform) followed by crystallization from CH2Cl2/hexane orto full-length column chromatography (gradient from hexane to hexane/CHCl3 1/3).
Tetraacid 21: A mixture of calixtube 12 (0.97 g, 0.50 mmol), KOH (90 %,0.56 g, 9.0 mmol), and ethanol (30 mL) was stirred at reflux for 8 h. Thesolvent was removed in vacuo, and the residue treated with 2m HCl(50 mL). The solid formed was separated, washed with water, and driedto yield compound 21 as a white solid (0.92 g, 97%); m.p. >300 8C;1H NMR (400 MHz, CDCl3/CF3CO2D): d=7.14 (s, 4H; ArH), 7.10 (s,4H; ArH), 6.54 (s, 4H; ArH), 6.52 (s, 4 H; ArH), 5.20 (br s, 8H; OCH2),4.62 (d, 2J ACHTUNGTRENNUNG(H,H) =12.5 Hz, 4 H; ArCH2Ar), 4.60 (d, 2J ACHTUNGTRENNUNG(H,H) =12.5 Hz,4H; ArCH2Ar), 4.41 (br s, 8H; OCH2), 3.31 (d, 2J ACHTUNGTRENNUNG(H,H) =12.5 Hz, 4H;ArCH2Ar), 3.30 (d, 2J ACHTUNGTRENNUNG(H,H) =12.5 Hz, 4 H; ArCH2Ar), 2.33–1.20 (m,56H; HAd), 1.34 (s, 18 H; C ACHTUNGTRENNUNG(CH3)3), 0.84 (s, 18H; C ACHTUNGTRENNUNG(CH3)3); 13C NMR(100 MHz, CDCl3/CF3CO2D): d =156.39, 155.87, 153.41, 152.91, 144.93,144.68, 143.37, 142.79, 135.45, 135.14, 132.19, 131.96 (CAr), 125.64, 125.00,124.96, 124.29 (CHAr), 73.05, 72.96, 72.76, 72.56 (OCH2), 44.58, 42.72,42.34, 42.05, 37.77, 37.57, 36.82, 35.37, 35.23 (CAd, CH2Ad), 34.00, 33.60 (C-ACHTUNGTRENNUNG(CH3)3), 32.44, 32.35 (ArCH2Ar), 31.65, 30.96 (C ACHTUNGTRENNUNG(CH3)3), 28.57, 28.36(CHAd); ESI-MS: m/z : 1888.7 [M]� for C124H144O16 (1889.0).
Tetraacid 22 : A mixture of calixtube 13 (1.00 g, 0.50 mmol), aqueousnBu4NOH (20 %, 5.05 mL, 4.0 mmol), and THF was stirred at reflux for6 h. The solvent was removed in vacuo, and the residue treated with 5 m
Tetraamides 23 and 24 : A solution of calixarene 21 (0.094 g, 0.05 mmol)or calixarene 22 (0.097 g, 0.05 mmol) in a mixture of dry benzene (2 mL)and SOCl2 (4 mL) was gently heated to reflux with stirring for 4 h. Theexcess SOCl2 was removed in vacuo, and the residue was repeatedly re-evaporated with fresh benzene. The solid obtained was dissolved in dryTHF (10 mL), cooled (0–5 8C), and a solution of Et2NH (0.206 mL,2.0 mmol) in dry THF (5 mL) was added dropwise with stirring. The stir-ring was continued for 1 h, and the mixture was allowed to stand over-night at room temperature. After removal of the solvent, CH2Cl2
(20 mL) was added, and the solution was washed with 1m HCl (10 mL)
and water and dried with MgSO4. The solvent was removed and the resi-due reprecipitated from CH2Cl2/hexane.
Tetraisocyanate 25 : The chloroanhydride prepared from calixtube 21(0.38 g, 0.20 mmol), SOCl2 (8 mL), and dry benzene (8 mL) was dissolvedin dry acetone (20 mL) and cooled (0–5 8C). A solution of NaN3 (0.52 g,8.0 mmol) in water (1 mL) was added dropwise with stirring. Stirring wascontinued for 1.5 h and then the mixture was kept at +4 8C overnight.Water was added and the products were repeatedly extracted withCH2Cl2. Combined organic layers were washed with water, dried withMgSO4, and evaporated in vacuo. The residue was dissolved in dry ben-zene and the solution was heated to reflux for 1.5 h. The solvent was re-moved in vacuo to give pure 25 as a white solid (0.33 g, 88%); 1H NMR(400 MHz, CDCl3): d=7.11 (s, 4H; ArH), 7.07 (s, 4H; ArH), 6.50 (s, 4H;ArH), 6.45 (s, 4 H; ArH), 5.17 (br s, 8 H; OCH2), 4.59 (d, 2J ACHTUNGTRENNUNG(H,H) =
Tetraamine hydrochloride 26 : HCl (2 m, 10 mL) was added to a solutionof calixtube 25 (0.33 g, 0.176 mmol) in dioxane (10 mL). The resultingmixture was heated at reflux for 8 h and cooled. The solid formed wascollected, washed with Et2O, and dried to give pure 26 as a white solid(0.32 g, 95 %); m.p. >300 8C; 1H NMR (400 MHz, [D6]DMSO): d =8.31(br s, 6H; NH3), 8.24 (br s, 6H; NH3), 7.17 (s, 4H; ArH), 7.08 (s, 4 H;ArH), 6.48 (s, 4H; ArH), 6.44 (s, 4H; ArH), 5.06 (br s, 8 H; OCH2), 4.52(d, 2J ACHTUNGTRENNUNG(H,H) =12.6 Hz, 4H; ArCH2Ar), 4.49 (d, 2J ACHTUNGTRENNUNG(H,H) =12.6 Hz, 4H;ArCH2Ar), 4.32 (br s, 8 H; OCH2), 3.30 (d, 2J ACHTUNGTRENNUNG(H,H) = 12.6 Hz, 4H;ArCH2Ar), 3.29 (d, 2J ACHTUNGTRENNUNG(H,H) =12.6 Hz, 4 H; ArCH2Ar), 2.27 (s, 4 H;CHAd), 2.19–1.18 (m, 52 H; CHAd +CH2Ad), 1.29 (s, 18 H; C ACHTUNGTRENNUNG(CH3)3), 0.79(s, 18 H; C ACHTUNGTRENNUNG(CH3)3); ESI-MS: m/z : 1773.9 [M+H]+ for C120H148N4O8·H(1774.1).
Carboxymethyladamantylcalix[4]arene tetrabutyl ethers 38 and 39 : Anoil suspension of NaH was added to a stirred solution of tetraester 3 ordiester 6 in dry DMF. After 30 min 1-iodobutane was added and the mix-ture was stirred at room temperature for 24 h. After quenching with 2 m
HCl, products were repeatedly extracted with CH2Cl2. Combined organiclayers were evaporated in vacuo, and a solution of KOH in ethanol wasadded to the residue. The mixture was stirred at reflux for 8 h, cooled,and then triturated as described below.
Tetrakis(carboxymethyladamantyl)calix[4]arene tetrabutyl ether 38 : Thecompound was obtained from tetraester 3 (1.00 g, 0.80 mmol), NaH(60 %, 1.28 g, 32.0 mmol), 1-iodobutane (3.64 mL, 32.0 mmol), DMF(30 mL), KOH (90 %, 0.81 g, 13.0 mmol), and ethanol (48 mL). After thehydrolysis step was completed, the mixture was cooled to �18 8C and thesolid formed was separated, washed with cold ethanol, suspended in 5 m
HCl (40 mL), and allowed to stand overnight at room temperature. Thesolid was collected, washed with water and methanol, and dried to affordpure 38 as a white solid (0.78 g, 69 %). Analytical data were the same aspublished previously.[9d]
Bis(carboxymethyladamantyl)calix[4]arene tetrabutyl ether 39 : The com-pound was obtained from diester 6 (0.42 g, 0.50 mmol), NaH (60 %,0.80 g, 20.0 mmol), 1-iodobutane (2.28 mL, 20.0 mmol), DMF (20 mL),KOH (90 %, 0.25 g, 4.5 mmol), and ethanol (15 mL). After the hydrolysisstep was completed, the mixture was concentrated almost to dryness, 5m
HCl (25 mL) was added, and the solid was separated, washed with water,dried, and reprecipitated from CH2Cl2/hexane and CH2Cl2/methanol togive pure 39 as a white solid (0.39 g, 76%); m.p. >300 8C; 1H NMR(400 MHz, CDCl3/CF3CO2D): d=7.06 (s, 4 H; ArH), 6.29 (t, 3J ACHTUNGTRENNUNG(H,H) =
Alcohols 27, 33, 40, and 41: A solution of ester or acid in dry THF (2/3of total volume) was added dropwise to stirred suspension of LiAlH4 inTHF (1/3 of total volume). The mixture was stirred at reflux for 3 h andallowed to stand overnight at room temperature. Water (1 mL per 1 g ofLiAlH4 loaded), 3 m NaOH (1 mL per 1 g of LiAlH4 loaded), and water(3 mL per 1 g of LiAlH4 loaded) were added with stirring and the solidformed was filtered off. The filtrate was evaporated in vacuo and the resi-due washed with methanol (for 27, 33) or acetonitrile (for 40, 41) anddried to afford an alcohol.
Phthalimides 28, 34, 42, and 43 : Diisopropylazodicarboxylate (DIAD)was added to a cooled (0–5 8C) solution of Ph3P in THF (1/3 of totalvolume) with stirring. After about 15 min the mixture became heteroge-neous, and phthalimide was added. After an additional 15 min of stirring,a solution of an alcohol in THF (2/3 of total volume) was added drop-wise. Stirring and cooling were continued for 2 h and the mixture was al-lowed to stand at room temperature for 3 d. The clear solution was con-centrated in vacuo and the residue was washed repeatedly with methanolto afford a phthalimide-substituted calixarene.
Amines 29, 35, 44, and 45 : A mixture of a phthalimide, hydrazine hy-drate, and ethanol was stirred at reflux for 7 h. After cooling, the solutionwas concentrated to almost dryness, water was added and products wereextracted with CH2Cl2. The organic solution was washed with aqueousNa2CO3 (5 %), water and evaporated in vacuo to give a pure amine.
Tolylureas 30, 31, and 36 : A mixture of an amine, p-tolyl isocyanate, andtriethylamine in dry toluene was heated at 60 8C for 4 h (only for 30) andwas stirred at room temperature overnight. The solvent was removed invacuo and the residue heated with methanol. The solid formed was sepa-rated, washed with methanol, dried, and subjected to column chromatog-raphy (CH2Cl2, only for 30) or reprecipitated from CH2Cl2/hexane toafford a urea.
Pyrene-containing ureas 32, 37, 46, and 47: A solution of 1-aminopyrenein toluene (20 mL per 0.1 g) was added to a stirred solution of triphos-gene in dry toluene (10 mL per 0.1 g). The mixture was gradually heatedand was kept at reflux for 1 h. The solvent was removed in vacuo withstrong heating (>90 8C). The residue was dissolved in dry toluene (1/3 oftotal volume), and a solution of calixarene amine in dry toluene (2/3 oftotal volume) was added. The mixture was heated in an oil bath at 110 8Cfor 20 h, the solvent removed in vacuo, and the residue washed withmethanol, dried, and subjected to column chromatography (gradientfrom CH2Cl2 to CH2Cl2/ethanol 20/1) to afford a urea.
Tetrakis-urea 32 : Pure compound was obtained as a pale beige solid(0.125 g, 56%) from 1-aminopyrene (0.098 g, 0.45 mmol), triphosgene(0.134 g, 0.45 mmol), and amine 29 (0.142 g, 0.075 mmol) in toluene(90 mL); m.p. >300 8C; 1H NMR (400 MHz, CDCl3/CF3CO2D): d=8.35–7.61 (m, 36H; ArHPyr), 7.14 (s, 4 H; ArH), 6.97 (s, 4 H; ArH), 6.55 (s,4H; ArH), 6.40 (s, 4H; ArH), 5.17 (m, 8H; OCH2), 4.59 (d, 2J ACHTUNGTRENNUNG(H,H) =
This work was supported by Russian Foundation for Basic Research(projects 09-03-00971, 11-03-92006-HHC).
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