202 J.C.S. Perkin ILigands for the Alkali Metals. Part 3.t Further Examples of Nitrogen-containing ' Crown ' CompoundsBy Joyce C. Lockhart and Maurice E. Thompson, Department of Inorganic Chemistry, The University,Newcastle upon Tyne NEI 7RUAn unambigous route from o-aminophenol to dibenzo-crowns with two secondary amine links is reported.' Somenew mono- and di-nitrogen-containing monobenzo-crowns have also been prepared. The simple mononitrogen-containing crowns can be modified by N-substitution, with, for example, a pendant donor group, sufficientlyflexible to co-ordinate to metals held in a polyether ring.FURTHER work on the synthesis and modification of mono-and di-nitrogen-containing crowns is reported. Adinitrogen pentaoxygen dibenzo-crown (VI) has beenprepared by an unambiguous route.Its spectral charac-teristics enable confirmation of the structures assigned( I l a ; R = H (Ills; R = Hb ; R = CO*CHCHiC02Hc ; R = C0.CHjCH2Brd ; R = Pr"e ; R = CHiCHiCHiOEtf ; R = CHiCHiCHZBrb ; R = Mepreviously to related monobenzo-crowns ,l e.g. (Ia) and(IIa) . The possibility of adding ancillary groups to cyc-lic polyethers was explored by studying the N-substitu-tion of the monobenzo-crown (Ia). It was hoped there-by to marry some of the characteristics of EDTA-typeligands with those of the cyclic polyethers. The effectof the pendant substituent on the alkali-cation-com-plexing power of the polyethers is being investigated.EXPERIMENTALPreparation of the Dinitrogen Crow% (VI) .-This compoundwas synthesised by the route shown in the Scheme.Theintermediate diamine (IV) was made by adapting the methodof Cannon et aZ.2Bis-( 2-o-nitro$henoxyethyE) ether. Bis- (2-chloroethyl)ether (75 g) was treated with o-nitrophenol (95.6 g) indimethylformamide (250 ml) containing potassium carbon-ate (28 g ) . The yellow product contained some o-nitro-phenol and was recrystallised from methanol to give thedinitro-compound (111) (72 g, ca. 64.4%), n1.p. 68", M+ 348(Found: C, 53.1; H, 4.4; N, 8.0. C,,H,,N,O, requires C,52.7; H, 4.4; N, 7.7%).Bis-( 2-o-aminofihenoxyethy2) ether. The dinitro-com-pound (111) (58 g) was reduced in a stirred refluxing solutionofitin(I1) chloride dihydrate (250 g) in concentrated hydro-chloric acid (750 ml).Tin was removed as tin(rr) sulphideand the filtrate was extracted with ether (3 x 250 ml) . Thet Refs. 1 and 3 are considered as Parts 1 and 2, respectively.J. C. Lockhart, A. C. Robson, M. E. Thompson, D. Furtado,C. K. Kaura, and A. R. Allan, J.C.S. Pc.rkin I, 1973, 577.extracts gave an oily residue (38 g). A portion of the oil(10 g) was adsorbed onto Celite,3 which was then placed ona neutral alumina (200 g ; grade IV) column. The columnwas eluted with 9 : 1 light petroleum-ether ( 2 1). The sol-vent was removed to give the diamine (IV) (8.5 g ) a paleyellow oil (Found: C, 66.3; H, 6.8; N, 9.6. C1,H,,,N2O3requires C, 66.7; H, 7.0; N, 9.7%), M+ 288, vmX 3 350 and3 480 cm-l (NH,); hydrochtloride (solid) (Found: C, 51.9;Sn, HCI 1SCHEMEH, 5.6; C1, 18.2; N, 7.3.C,,H,,N,O,Cl requires C, 53.3;H, 6.1; C1, 19.6; N, 7.7%).R. D. Cannon, B. Chiswell, and L. M. Venanzi, J. Chem.J. R. Blackborow, J. C. Lockhart, D. E. Minnikin, A. C.A. C. Linsdell, Ph.D. Thesis, Newcastle upon Tvne. 1971.SOC. (A), 1967, 1277.Robson, and M. E. Thompson, J. Chromatog., 1975,107, 3801977 203The diamide (V). Solutions of the diamine (IV) (7.08 g,0.025 mol) and ethylenedioxybis(acety1 chloride) (2.7 g,0.0125 mol), each in anhydrous benzene (500 ml), wereadded simultaneously to anhydrous benzene (1 1) (modific-ation of the cryptand synthesis ,) stirred under nitrogenduring 5 h. The mixture was stirred under nitrogen for afurther 5 days, then filtered, and the solvent was removed togive a yellow solid (4 g, ca. 88%) (Found: C, 60.8; H, 5.9;N, 6.3.C,,H,,N,O, requires C, 61.4; H, 6.05; N, 6.51%),M+ 430.The diamide (V) (3.8 g) was dissolved inanhydrous tetrahydrofuran (100 ml) and slowly added to asuspension of lithium aluminium hydride (2 g) in anhydroustetrahydrofuran (250 ml). The mixture was refluxed undernitrogen for a further 8 h. The solution was cooled, theexcess of hydride destroyed by addition of 2 : 1 tetrahydro-furan-water, and the mixture filtered. Solvent was re-moved under reduced pressure to give a brown solid, whichwas purified by chromatography on a neutral alumina (1 00 g ;grade IV) column, eluted with benzene. Removal of thesolvent left the product (2.2 g), which was recrystallisedfrom methanol to yield 5,6,7,9,10,12,13,14,20,21,23,24-dodecahydrodibenzo[h,t][ lJ4,7,13,16,1O,19]~entaoxadiaza-cycloheneicosine, a white crystalline solid, m.p.117 "C(Found: C, 65.6; H, 7.4; N, 7.0. C22H,oN20, requires C,65.7; H, 7.5; N, 7.0%), T (CDC1,) 6.75 (NCH,), 6.40(OCH,), 5.90 (ArOCH,), 5.13 (NH), and 3.30 (ArH), v h ~3 400 cm-l, M+ 402.The following new monobenzo-crowns were made byroutes described previously; 193 they had appropriate n.m.r.and i.r. spectra : 1,2,3,5,6,8,9,11,12,13-decahydro-l5-methyZ-4,7,1OJl,13-benzotrioxadiazacyclo~entadecine ( IIb) , a paleyellow oil (Found: C, 64.6; H, 8.5; N, 9.9%; M+, 280.The crown (VI).C,,H2,N,0, requires C, 64.8; H, 8.6; N, 10.Oyo; M , 280);2,3,5,6,8,9,11 , 12,14,15-decahydro- 16H- lJ4,7,10,13,16-benzo-pentaoxa-azacyclo-octadecine (IX), a pale yellow oil (Found :C , 60.0; H, 8.8; N, 4.1%; M+, 311.C,,H,,NO, requires15,l7,18-dodecahydro-19H-lJ4, 7,10J13,16,19-benzohexaoxa-azacycloheneicosine (X), a pale yellow oil (Found: C, 61.6;C, 61.7; H, 8.1; N, 4.5%; M, 311); 2,3,5,6,8,9,11,12,14,-€3. Dietrich, J. M. Lehn, and J. P. Sauvage, TetrahedronLettevs, 1969, 2885.H, 8.2; N, 3.95% ; M+, 355. C,,H,,NO, requires C, 60.8;H, 8.2; N, 3.9%; M, 355); 2,3,5,6,8,9,11,12,14,15,17,18,-20J21-tetradecahydro-22H- 1,4,7,10,13,16,19,22-benzohe~ta-oxa-azacyclotetracosine (XI) , a pale yellow oil (Found : C,59.9; H, 8.1; N, 2.9%; M+, 399. C,,H,,NO, requires C,60.1; H, 8.3; N, 3.5%; M, 399).N-Substituted Derivatives of the Monobenzo-crown (Ia) .-3-Carboxypropionyl derivative (Ib) .3-Carboxypropionylchloride (0.46 g 2.92 mmol) was added to the crown (Ia)(0.78 g, 2.92 mmol) in anhydrous benzene (50 ml.). A vis-cous liquid (0.95 g) obtained from this benzene layer afterhydrolysis showed m/e 366 as the highest mass fragment inits mass spectrum [(Ib) would give m/e 3671. The liquid waspurified by column chromatography (adsorbed on Celiteand then placed on neutral alumina grade IV, and elutedwith benzene and 9 : 1 light petroleum-ether). The productwas detected as a brown spot on t.1.c. (RF 0.56) and re-covered as a solid (0.63 g) (Found: C, 58.8; H, 7.1; N, 4.0.C1,H,,NO, requires C, 58.9; €3, 6.9; N, 3.8%), uco 1655and 1735 cm-l.N-3-Bromo~ropionyZ derivative (Ic) . 3-Bromopropionylchloride (0.95 g, 5.5 mmol) was added to a stirred solution ofthe crown (Ia) (1.47 g, 5.5 mmol) and potassium carbonate(3.04 g, 11 mmol) in benzene (250 ml).The mixture wasstirred overnight, filtered, and evaporated to leave a brownliquid (2.1 g) (Found: C, 51.5; H, 5.8; N, 3.6%; M+, 403/401. C,,H24BrN0, requires C, 50.8; H, 6.0; N, 3.5%; M,401/403), uco 1 650 cm-l.(i) With lithium aluminiumhydride. The amide (Ic) (0.44 g, 2.2 mmol) was added tolithium aluminium hydride (168 mg, 4.4 mmol) a treflux in anhydrous tetrahydrofuran under nitrogen.After 3 h the mixture was cooled and the excess hydrideremoved. A viscous brown liquid (0.2 g) was recovered,m/e 309, i.r. and n.m.r. data consistent with N-propyl struc-ture (Id) (Found: C, 64.2; H, 8.3; N, 4.3.C,,H,,NO,requires C, 66.0; H, 8.7; N, 4.5%; M, 309).(ii) By the Borch method., The amide (Ic) (0.8 g, 2mmol) was treated in dry dichloromethane (50 ml) undernitrogen with 1M-triethyloxonium tetrafluoroborate (2.5ml). Evaporation left a solid residue which was stirred inethanol (100 ml) (cooled in an ice-bath) while sodium boro-hydride (0.1 g, 2.6 mmol) was added. The solution waswarmed slowly to room temperature and stirred for afurther 18 h. Ethanol was removed under vacuum andwater (40 ml) added to the residue, then solid potassiumhydroxide to adjust the pH to 14. Ethereal extracts ofthe alkaline solution (3 x 50 ml) gave a brown liquid(0.53 g), the N-3-ethoxypropyl derivative (Ie) (Found: C,61.8; H, 8.4; N, 3.8%; M+, 353.C1,H,lNO, requiresC, 64.6; H, 8.8; N, 4.0%; M , 353).(iii) With diborane. Diborane was passed in a stream ofnitrogen into tetrahydrofuran (100 ml) containing the amide(Ic) (0.8 g, 2 mmol) for 1 h. The solution was stirred over-night, hydrochloric acid added to destroy the excess of di-borane, and the solvent evaporated off. The residue wastreated with water (25 ml) and alkali and extracted withether. The extracts (3 x 50 ml) afforded a viscous liquid(0.67 g) which was purified by adsorption on Celite 3 andcolumn chromatography on alumina (25 g) to give the N-3-bromopropyl derivative (If) as a solid (Found : C, 51.8 ; H,6.5; N, 3.5%; M+, 387/389. C,,H,,BrNO, requires C,Reduction of the amide (Ic).R. F. Borch, Tetrahedron Letters, 1968, 61, 65.H.C. Brown, J . Amer. Chem. Sac., 1960, 82. 4233204 J.C.S. Perkin I52.6; H, 6.7; N, 3.6%; M , 3871389). Attempts t o con-dense (Ia) directly with chloroacetic acid as in a typicalEDTA synthesis were unsuccessful.Diethyl 1,4,10,13-Tetraoxa-7,16-diazacyclo-octadecane-7,16-diacetate.-n-Butyl-lithium (28 g of 15% solution in hexane;6.6 mmol) was treated with a solution of 1,4,10,13-tetra-0xa-7,16-diazacyclo-octadecane (VII) 5 (0.576 g, 2.2 mmol)in bis-(2-methoxyethyl) ether (50 ml) under nitrogen. After1 h ethyl bromoacetate (0.715 g, 4.4 mmol) was added, andstirring was continued for 48 h. The solution was filteredand evaporated t o leave a brown liquid ester (0.58 g) (Found:C, 52.1; H, 8.2; N, 6.0%; M+, 434. C,,H,,N,O, requiresC, 55.4; H, 8.75; N, 6.45y0 ; N, 434) vmx.(Nujol) 1 652 and1 730 cm-l (CO), T (CDC1,) 8.77 (6 H, t , CH,), 7.1 (8 H, t , ringNCH,), 6.4 (16 H, m, ring OCH,), 5.97 (4 H, q, CH,Me), and5.47 (4 H, s, NCH,CO,). Several attempts at the corres-ponding alkylation of the crown (Ia) were unsuccessful.N-Substitution of 1,2,3,5,6,8,9,10-0ctahydro-4,7,1,10-benzodioxadiazacyclododecine (VIII) .-The reaction of 3-carboxypropionyl chloride (0.789 g, 5.0 mmol) with thecrown (VIII) was carried out as for (Ia) t o give, on hydro-lysis, a red viscous liquid (0.62 g), the di-N-(3-carboxy-propionyl) derivative (cf. ref. 9) (Found: C, 61.5; H, 6.8;N, 10.1%; M+, 526. Calc. for C,,H,,N,O,: C, 63.8; H,7.2; N, 10.6%; M , 526); vco (Nujol) I 660 cm-l.G.1.c.-Mononitrogen crowns, like oxygen crowns,lo*llcould be characterized by g.1.c.OC,H,~NH*[CH2*CH,*O1,.CH2*~H2, injected in ethanolicsolution into a 5 f t x 318 in' SE30 (3%) on Chromosorb Wcolumn, had characteristic retention times (e.g.n = 3, tR0.93min; n = 4, 2.24 min; n = 5, 4.86 min; n = 6, 10.86min, with helium as carrier gas, flow rate 50 ml min-l at237 "C). A plot of log tR versws n was a straight line forn = 3-6 (column at 237 "C) and for n = 4-8 (column at267 "C). Exceptions were the morpholinophenol and thephenolic crown [(la) and (4) , respectively in ref. 11, alreadyshown t o have different types of structure.The crownsI---------- --______RESULTS AND DISCUSSIONWe have shown that the NH group of a simple mono-nitrogen crown (Ia) provides a convenient location forsubstituents which can modify the properties of the mole-cule. We did not succeed in alkylating nitrogen benzo-crowns such as (Ia) with n-butyl-lithium, nor in cross-linking the NH, groups of the diamine (IV) with bis-(2-chloroethyl) ether.The product of the latter reactionhad the required mle value (388) for the.dibenzo-crownbut gave a positive result in an azo dye test, and wasprobably a morpholine.* Condensation of (IV) withbis-acid chlorides followed by reduction of the amidelinks was satisfactory.* R. Smith, J . L. Bullock, F. C. Bersworth, and A. E. Martell,J . Org. Chem.. 1949, 14, 355.R. J . Hayward and 0. Meth-Cohn, J.C.S. Perkin I , 1975,212.In studies of crown ethers designed to discover andexploit the reasons for complexing of alkali and alkalineearth metal cations, considerable emphasis has beenplaced on thermodynamic descriptions of complex form-ation. Interest in the simple 1 : 1 type of complex form-ation [equation (i)] centres on attaining two effects: (a)the greatest overall equilibrium constants K for equation(i) and (b) the greatest differential between stability con-stants of the complexes as M+ is varied.In the explan-ation of complexing, (a) is intrinsically important, butKcrown + M+ =+= [crown, M+] (9in its exploitation the differential effect (b) is more im-portant , and highest complexing power may be sacrificedto obtain (b). The sodium-potassium differentials are ofthe greatest interest in biological, medical, and industrialapplications. The relative affinity of particular crownsfor particular cations is , of course, strongly dependenton the conditions of measurement.For example, Frensdorff 12 measured a series of log Kvalues in methanol which indicated 18-crown-6 to havethe highest log K value for potassium, whereas selectivitybetween potassium and sodium was greatest for dibenzo-30-crown-10. Considering the simple effect of replacingone oxygen donor of a crown by a nitrogen, we note thatthe nitrogen crown does not compete as a complexingagent. Frensdorff's log K value for the mononitrogenanalogue of 18-crown-6 shows that the cornplexing powerfor potassium is reduced (one hundred-fold difference inK ) .12 Moreover, spectrophotometric comparison of Kin methanol for ligands (Ia) and benzo-15-crown-5 com-plexing with sodium shows a hundred-fold reduction inK for the nitrogen compound.Yet the selectivity[effect (b)] of the nitrogen ligands is in some applicationsgreater. In solvent extraction studies l3 the absoluteamount of alkali metal ion extracted by nitrogen crownswas less, but the selectivity for potassium over sodiumwas improved in comparison with analogous crowns withonly oxygen donors. When we added a pendant donorgroup (carboxylic acid) to the nitrogen function, itimproved overall extraction [effect (a)] but not selectivity.A more extensive physical evaluation of nitrogen crownsis proceeding.We thank Drs. J. R. Blackborow and H. C. Kelly fordiscussions, and the S.R.C. and Albright and Wilson forfinancial support (CASE Studentship to M. E. T.).[6/1104 Received, 10th June, 19761lo K. Madan and D. J. Cram, J.C.S. Chem. Comm., 1975, 427.l1 D. A. Jaeger and R. R. Whitney, J . Org. Chem., 1975,40.92. ** H. K. Frensdorff, J . Amer. Chem. SOG., 1972, 95, 600.C. J . Pedersen, Fed. Proc., 1968, 27, 1305
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