The novel cryptand in/out-3, containing two tripyrrolemethane units briged by three 1,3- diisopropylidenbenzene arms was readily synthesized by a convergent three-step synthesis. It binds fluoride by inclusion with excellent selectivity with respect to a number of other tested anions. The structure of the free receptor and that of its fluoride complex were investigated in solution by NMR spectroscopy. The solid state X-ray structure of the free cryptand 3 was also determined

Cafeo, Grazia

Colquhoun, Howard M.

Cuzzola, Angela

Gattuso, Mario

Kohnke, Franz H.

Valenti, Luca

White, Andrew J. P.

The Journal of Organic Chemistry

English

Grazia Cafeo

Howard M. Colquhoun

Angela Cuzzola

Mario Gattuso

Franz H. Kohnke

Luca Valenti

Andrew J. P. White

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Synthesis, X-ray Structure, and Anion-Binding Properties of a Cryptand-Like Hybrid Calixpyrrole

Central Archive at the University of Reading

1Synthesis, X-ray Structure and AnionBinding Properties of a Cryptand-LikeHybrid CalixpyrroleGrazia Cafeo§, Howard M. Colquhoun◊, Angela Cuzzola†, MarioGattuso§, Franz H. Kohnke§*, Luca Valenti§, and Andrew J. P.White‡§Dipartimento di Chimica Organica e Biologica, Università diMessina, viale Ferdinando Stagno D’Alcontres 31, 98166Messina (Italy), ◊ Department of Chemistry, University ofReading, Whiteknights, Reading, RG6 6AD (UK),†Dipartimento di Chimica e Chimica Industriale, Universitàdi Pisa, via Risorgimento 35, 56126 Pisa (Italy) and‡Chemical Crystallography Laboratory, Department ofChemistry, Imperial College London, South Kensington,London, SW72AZ (UK)franz@unime.itThe novel cryptand i n /o u t - 3 , containing twotripyrrolemethane units briged by three 1,3-diisopropylidenbenzene arms was readily synthesized by aconvergent three-step synthesis. It binds fluoride byinclusion with excellent selectivity with respect to anumber of other tested anions. The structure of the freereceptor and that of its fluoride complex were investigatedin solution by NMR spectroscopy. The solid state X-Raystructure of the free cryptand 3 was also determined.Calixpyrroles are macrocycles containing pyrrole unitslinked to each other through quaternary carbon atoms (mesoposition). Since the discovery that calix[4]pyrrole is able tobind anions and small neutral molecules through theformation of hydrogen bonds,1 these receptors have been thesubject of intense study.2 A large number of derivatives havebeen reported in which the anion-binding properties weremodulated by varying the size of the macrocycle (i.e. bychanging the number of pyrrole units or by the inclusion ofother aromatic rings);3-4 by changing the nature ofsubstituents at the β-positions of the pyrrole rings,5 by theuse of substituents other than methyl at the meso-positions,6or connecting two meso positions with an appropriate bridge(strapped calixpyrroles).7 Cryptand-like calixpyrrole can beconsidered a special case of strapped calixpyrrole in which thestrap is the same as half of the macroring. To date, only a fewexamples of such structures have been reported.8,9 The host-guest chemistry of the tripyrrolemethane moiety, that can befound at the poles of these cryptands, has also recently beeninvestigated.10Recen t ly ,  we  r epor t ed  the  syn thes i s  ofcalix[2]benzo[4]pyrrole containing m-phenylene units4a fromthe acid-catalysed condensation of 1  and acetone. As adevelopment of this work, here we report the synthesis of abicyclic[3.3.3]tribenzoesapyrrole (Scheme 1) inspired by thebicyclic[3.3.3]nonapyrrole described previously by Sessler.9Scheme 1 Synthesis of in/out-bicyclic[3.3.3]tribenzoesapyrrole cryptand3. Stereoisomers out/out-4 and in/in-4 could not be found in the crudemixture.Treatment of bis-pyrrole derivative 111 with triethyl-o-formate/TFA gave the bis-formyl building block 2 in excellentyield. The acid-catalyzed condensation of 1  and 2 ,(stoichiometric ratio 2:1 respectively, in EtOH-TFA) can inprinciple yield two compounds: in /out -3  and the twoconformers o u t /o u t -4  and i n / i n - 4  which might beconformationally stable, i.e. incapable of interconversion by,for example, passage of one 'strap' into the cavity of themacroring defined by the other two bridges. However, onlyone cryptand-like compound was isolated from this reaction.The 1H and 13C NMR spectra were consistent with the in/outconfiguration of the methyne meso-like hydrogen atoms and aC3v time-averaged symmetry. In fact, the proton spectrumcontained two different signals for the pyrrole-NH groups (δ7.64 and 7.66 ppm respectively), and two AB systems for thepyrroles β-CH (δ 4.98, 5.65, and 5.40, 5.86 ppm). The meso-like methyne protons appeared as two singlets (δ 4.82 and5.22 ppm). These chemical shifts are analogous to thoseobserved for the in-proton in the bicyclo[3.3.3]nonapyrrolederivative9 and for the methyne proton of the ‘free’tripyrrolemethane unit10 respectively. Finally, the m-phenylene CH protons appear as four (and not three) differentresonances because the molecule does not contain an‘equatorial’ plane of symmetry. These features rule outcompounds 4 in which only one type of meso-like methyneprotons are present and in which the pyrrole unis at the two‘polar caps’ are equivalent.2Crystals of bicyclic macrocycle in/out-3 were obtained fromacetone. The X-ray crystal structure (Figure 1) confirmed thein-out configuration assigned on the basis of NMR data. The‘in’ methine CH [C(24)] points towards the cavity of thediametrically positioned cup-like tripyrrolemethane unitbased around C(1). The structure is partly self-filling, with adistance of 4.5124(16) Å between C(1) and C(24). Themolecule has approximate C3 symmetry about the C(1)···C(24)vector, and as each of the three m-phenylene arms is folded inthe same sense the molecule has conformational chirality. It i simportant to note however, that the molecule crystallised in acentrosymmetric space group and so there are equal numbersof both enantiomers present. Around each of the methinecarbon atoms the three pyrrole rings are canted in the samesense such that the N–H groups are next to the methine proton,and the C(1)- and C(24)-based tripyrrolemethane moieties arestaggered with respect to each other by ca. 41°.The three included acetone molecules (two of which aredisordered—see supporting information) are hydrogenbonded to the N–H atoms of the pyrrole units linked to C(1).The N···O, H···O distances (Å) and N–H···O angles (°) for the fullor major occupancy orientations of the acetone molecules are2.9303(16), 2.13 and 148 for the N(3)–H···O interaction,2.894(5), 2.08 and 151 for the N(43)–H···O interaction, and2.967(2), 2.18 and 146 for the N(48)–H···O interactionrespectively. The other three N–H units are oriented towardsthe inside of the macrocycle and so are not available for anynoteworthy intermolecular interactions.Two of the pyrrole rings and one of the m-phenylene ringsare involved in intermolecular C–H···" interactions withmethyl groups.12 One of the methyl hydrogen atoms of theordered acetone molecule approaches the N(20)-based pyrrolering with an H···" separation of ca. 2.87 Å, and a C–H···" angleof ca. 154°, the H···" vector being inclined by ca. 70° to thering plane. The N(65)-based pyrrole ring is approached by ahydrogen atom on C(40) in a neighbouring macrocycle [H···"2.97 Å, C–H···" 141°, H···" vector inclined by 82°], and theC(56)-based m-phenylene ring is approached by a hydrogenatom on C(32) in a different adjacent macrocycle [H···" 3.04 Å,C–H···" 115°, H···" vector inclined by 77°].Figure 1. The molecular structure of in/out-3.Cryptand in/out-3 was tested as a molecular receptor forseveral anions (F-, Cl-, NO3-, HSO4-, CH3COO-, H2PO4-) as theirTBA salts by 1H-NMR titration experiments in CD2Cl2.Significant complexation induced shift (CIS) of the NHprotons, that is typical for the formation of host-guestcomplexes with anions in the case of calixpyrroles,2c,4a,7a,7dwas observed only for the binding of fluoride.Figure 2. Partial 1H NMR (CD2Cl2, 500 MHz) spectra of: A) the freereceptor in/out-3, and B) of TBA[in/out-3.F-] complex including the mostsignificant assignments and CISs.This complex was found to be kinetically slow on the NMRtime scale and its spectrum (see Figure 2) was consistent witha 1:1 stochiometry. The association constant (K 1562 ± 163M-1) could easily be determined by integration of theresonances of free and complexed cryptand.13 In the complex,the NH protons appear as two signals of equal intensity, one asa doublet (δ 11.9 ppm, JHF 40 Hz)2c and one as a singlet (δ 9.00ppm) respectively. Only the pyrrole AB system that in freein/out-3 resonates at higher chemical shifts (δ 4.82 and 5.22ppm) is dramatically affected by the complexation and it i sshifted to low field. We believe that this is caused by aconformational rearrangement upon binding of fluoride, bywhich the tripyrrolemethane component having the ‘out’methyne configuration adopts a perching conformation withall of the three NH protons pointing towards the center of thecryptand containing the fluoride ion. Consequently, the β-pyrrole CH units that were partly filling the cryptand in thefree receptor and hence shielded and resonating at unusuallyhigh fields (see also X-Ray structure, Figure 1), are ejectedfrom the cavity and resonate at the usual δ  values in thecomplex. Moreover, in the complex the three ‘isolated’phenylene protons resonate as a singlet and are shifted tolower field (Δδ 0.35 ppm). These spectral features demonstratethat in/out-3 is capable of forming an inclusion complex withfluoride.3The formation of a 1:1 inclusion complex is also consistentwith the observed high selectivity towards fluoride. Thebinding constant is surprisingly small, especially comparedto the 1:1 binding constants reported previously for thetripyrrolemethane group with TBAF in more polar solvents(41000 and 5000 M-1 in CD3CN and DMSO-d6 respectively).10Unfortunately our attempts to obtain crystals of the n-TBA[in/out-3.F-] complex have not been successful to-date.However, further evidence for the above described mode ofbinding of fluoride by cryptand in/out-3 was provided by ac o m p u t a t i o n a l  m o d e l i n g  e x p e r i m e n t .  Thecrystallographically-determined structure of the in-outcryptand 3 was imported into Cerius2 (v.3.5, Accelrys Inc.,San Diego), and the three pyrrole rings of the "out" unit werere-oriented to bring their NH groups inside the cavity. Afluoride ion was inserted into the cryptand and charge-equilibration was used to redistribute atomic charges withinthe complex. The system was then minimised (molecularmechanics, Dreiding II14 force field), resulting in a structurewith an almost perfect 3-fold rotation axis through thefluoride ion. In the minimised structure, the cryptand formsthree strong hydrogen bonds to fluoride via the re-orientedpyrrole NH groups. The H-bond parameters are very close tothose reported in a previous paper,4a averaging ca. 2.97 Å(N···F), 2.01 Å (H···F) and 169° (N-H···F), with the fluoride ionperching symmetrically on the three NH groups. The "in"methyne CH unit also points directly at the fluoride ion,though making a somewhat longer contact, with parameters3.44 Å (C···F), 2.36 Å (H···F) and 178° (C-H···F). This completesa "tetrahedral" coordination of the fluoride ion, with 3 closeNH and one more distant CH unit forming the anion-bindingpocket. The three remaining NH hydrogens, although orientedinwards, lie too far from the fluoride ion to form hydrogenbonds (average H···F = 3.06 Å, N–H–F = 137°). The final model,with three bound and three non-bound NH hydrogens, is thusin excellent agreement with the 1H NMR data.Figure 3. The Dreiding II force field minimized molecular model of thecomplex [in/out-3.F-], showing a geometry consistent with that assignedon the basis of its 1H NMR spectrum.Encouraged by these results we attempted alternativesyntheses of the cryptands 4 which could be prepared togetherwith in/out-3 , by the acid-promoted condensation of 1,3-bis(1',1'-dimethylhydroxymethyl) benzene with tripyrrolyl-methane. However, these reactions were fruitless, and in spiteof our efforts, cryptand(s) 4 remain elusive.Experimental Section1,3-Bis[1’-(pyrrol-2-yl)-1’,1’-(dimethyl)methyl]benzene 1was prepared as described in ref. 11.1,3-Bis[1’-(pyrrol-2-carboxaldehyde-5-yl)-1’,1’-(dimethyl)methyl]benzene 2.Triethylorthoformate (2 mL) was added to a mixture of 1 (1g, 3.4 mmol) and TFA (5 mL) at -10°C under Ar. The redmixture was stirred at this temperature for 5 min, then pouredonto ice (600 mL) and EtOAc (300 mL). The organic phase wasseparated, washed with aq. NaHCO3 (3 x 200 mL), dried(MgSO4) and concentrated. The resulting red oil was subjectedto column chromatography (SiO2, hexane:EtOAc 3:1) to give ayellow solid as the main fraction which was characterizedwithout further purification as 2: 72 % yield (0.85 g). mp 155-6 °C. 1H NMR (500 MHz, CDCl3): δ 1.65 (s, 12H, CH3), 6.18 (m,2H, CH-Py), 6.88 (m, 2H, CH-Py), 6.99 (m, 1H, CH-Ar), 7.08 (m,2H, CH-Ar), 7.23 (m, 1H, CH-Ar), 8.85 (sbr, 2H, NH), 9.37 (s,2H, CHO); 13C NMR (125 MHz, CDCl3): δ 29.6 (CH3), 39.9[C(CH3)2], 108.5, 121.7 (CH-Py), 123.8, 124.4, 128.6 (CH-Ar),132.0, 147.5, 149.6 (Cq), 178.5 (CHO). Calculated forC22H24N2O2 M = 348.2; found ESI-MS (+): [M+H]+, 349.2 m/z.A good match between measured (accurate MS-ESI) andcalculated isotopic pattern was obtained (see SI).Cryptand in/out-3.A mixture of 1  (0.60 g, 2.05 mmol) and 2  (0.36 g, 1.02mmol) in EtOH dry (250 mL) was degassed by bubbling withAr for 5 min., and TFA (1.57 ml, 20.5 mmol) was added underAr at 0 °C. The mixture was stirred for 4h at RT, quenched byaddition of aqueous NaHCO3 (50 mL), concentrated anddiluted with CH2Cl2 (50 mL). The organic layer was separated,washed with aq. NaHCO3 (3 x 50 mL), dried (MgSO4) andconcentrated. The resulting brown oil was subjected to columnchromatography (SiO2, hexane:EtOAc 95:5) to give a orangesolid as the main fraction which was crystallized from acetoneto give in/out-3: 0.14 g, 15 %, mp 168 °C. 1H NMR (500 MHz,CDCl3): δ 1.52 (s, 18H, CH3), 1.66 (s, 18H, CH3), 4.83 (m, 1H,CH-in), 4.98 and 5.65 (2 x m, 6H, CH-Py), 5.22 (m, 1H, CH-out), 5.40 and 5.86 (2 x m, 6H, CH-Py), 6.22 (m, 3H, CH-Ar),7.20 (m, 3H, CH-Ar), 7.27 (m, 3H, CH-Ar), 7.35 (m, 3H, CH-Ar),7.64 (sb, 3H NH), 7.66 (sb, 3H, NH); 13C NMR (125 MHz,CDCl3): δ 28.9, 30.1 (CH3), 36.6 (CH-in), 36.8 (CH-out), 39.0,39.6 (C(CH3)2), 101.8, 104.2, 104.7, 105.0 (CH-Py), 120.9,123.2, 126.6, 127.9 (CH-Ar), 130.0, 131.8, 137.2, 142.1, 148.3,151.5 (Cq). Calculated for C62H68N6 M = 896.5; found ESI-MS(+): [M+H]+, 896.8 m/z. Elemental analysis gave inconsistentresults because variable amounts of residual acetone solventwere retained after prolonged drying (see X-Ray structure).Crystal data for in/out-3: C62H68N6·3C3H6O M = 1071.46,monoclinic, P21/n (no. 14), a = 13.3422(2), b = 22.6427(4), c =421.7077(3) Å, α = 102.5717(16)°, V = 6400.74(18) Å3, Z = 4,Dc = 1.112 g cm–3, µ(Mo-Kα) = 0.068 mm–1, T = 173 K, yellowprisms, Oxford Diffraction Xcalibur 3 diffractometer; 20074independent measured reflections (R int = 0.0218), F2refinement, R1(obs) = 0.0511, wR2(all) = 0.1328, 11778independent observed absorption-corrected reflections [|Fo| >4σ(|Fo|), 2θmax = 66°], 789 parameters. CCDC 7687441H NMR Complexation studies and titrations:The n-TBA salts were dried in a vacuum oven for at least 24h. Solvents were used as supplied in sealed ampoules, and carewas taken to minimize exposure to moisture. The anions wereadded as measured volumes of solution (ca  0.035 M) inCD2Cl2 to a solution of in/out-3  (0.0025 M) in the samesolvent (0.7 mL), the total volume was kept constant byevaporation with anhydrous nitrogen. After each addition, thestoichiometric ratios  between salts and in/out-3 were also re-determined from the resonance intensities of the host protontowards those of the TBA cation. Quantitative 1H NMRintegrations were obtained by the use of appropriate pulsedelays in all cases. Slow exchange was observed in thetitration of in/out-3 with F- anion and the K values weredetermined from the ratios of the intensities of bound and freespecies for solutions having different ratios of cryptand andsalt.13 Measurements were averaged and found reproducible towithin 15%.Acknowledgement. We thank the University of Messina for financialsupport.Supporting Information Available:Details of experimental procedures, 1H and 1 3C NMR spectra forcompounds 2 and 3 and 1H NMR spectra used for determination of theassociation constant for the TBA[in/out-3.F-] complex, MS spectra forthe new compounds, X-Ray crystallographic file (CIF) for  in/out-3,atomic coordinates for the Dreiding II force field minimized molecularmodel of the complex [in/out-3.F-]. This material is available free ofcharge via the Internet at    http://pubs.acs.org   The CIF files are alsoavailable from the Cambridge Crystallographic Data Centre, 12 UnionRoad, Cambridge CB2 1EZ, U.K. [fax: _44(0) 1223 336033 or e-maildeposit@ccdc.cam.ac.uk], under CCDC reference 768744References1 (a) Gale, P. A.; Sessler, J. L.; Kràl, V.; Lynch, V. J. Am. Chem. Soc. 1996,118, 5140-5141; (b) Allen, W. E.; Gale, P. A.; Brown, C. T.; Lynch, V. M.;Sessler, J. L. J. Am. Chem. Soc. 1996, 118, 12471-12472.2 (a) Sessler, J. 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Synthesis, x-ray structure and anion binding properties of a cryptand-like hybrid calixpyrrole

Synthesis, x-ray structure and anion binding properties of a cryptand-like hybrid calixpyrrole

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