SYNTHESIS OF NOVEL CROWN ETHER COMPOUNDS AND lONOMER MODIFICATION OF NAFION
by JONG CHAN LEE, B.S., M.S. A DISSERTATION IN CHEMISTRY Submitted to the Graduate Faculty of Texas Tech University in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Approved
August, 1992 L3
ACKNOWLEDGEMENTS
I am deeply indebted to Dr. Richard A. Bartsch for his constant encouragement and patience throughout my graduate career. His diligent pursuit of excellence in science inspired me to perform research for the love of it. I would like to thank Drs. Robert D. Walkup, Allan D. Headley, Dennis C. Shelly, Bruce R. Whittlesey. John N. Marx for their willingness to provide help and advice. I would also like to thank friendly co-workers. Dr. T. Hayashita, Marty Utterback, John Knobeloch, Zuan Cong Lu, J. S. Kim, and Dr. Joe McDonough for the wonderful times in the laboratory. I would like to thank Dow Chemical Company U. S. A. and Texas Advanced Technology Program for much of the funding of this research project. I would like to extend gratitude to my wonderful parents and sisters for their support throughout the years that I have spent abroad. Most importantly, I thank my wife Sun Yong without whose endless love and patience none of this would have been possible.
11 TABLE OF CONTENTS
ACKNOWLEDGEMENS ii LIST OF TABLES xi LISTOFHGURES xii I. INTRODUCnON 1 Crown Ether Background 1 Cation Complexation by Crown Ethers 2 Synthesis of Monobenzo and Dibenzocrown Ethers 4 Lariat Ethers 1 0 Chromogenic Crown Ethers 1 3 Acyclic Polyether Compounds 1 5 Nafion® lonomer Membrane 1 7 Statement of Research Goal 2 0 II. RESULTS AND DISCUSSION 2 2 Crown Ethers with Aromatic Rings as Part of the Polyether Ring 2 2 Benzo and Dibenzocrown Ethers-Cesium Effect 2 2 1.3-Xylyl Crown Ethers 4 1 Crown Ethers with Pendant Groups 4 3 Pyridyl Crown Ethers 4 3 Crown Ether Xanthates 5 4 Methoxy Crown Ethers 5 7 Chromogenic Crown Ethers 5 9 Acyclic Polyether Carboxylic Acids 6 0
111 Chemical ModiHcaiton of Nafion® lonomer Membrane.. 65 Summary 8 3 III. EXPERIMENTAL PROCEDURES 8 5 Instrumentation and Reagents 8 5 General Procedure for the Preparation of Benzo- and Dibenzocrown Ethers 8 6 Monobenzo-12-crown-4 (30) 8 7 Monobenzo-14-crown-4 (39)..... 8 7 Monobenzo-15-crown-5 (6) 8 7 Monobenzo-18-crown-6 (7) 8 7 Monobenzo-21-crown-7 (8) 8 7 Mono[4(5)-tert-butylbenzo]- 21-crown-7 (41) 8 8 Dibenzo-12-crown-4 (54) 8 8 Dibenzo-13-crown-4 (52) 8 8 Dibenzo-14-crown-4 (51) 8 8 Dibenzo-15-crown-5 (44) 8 8 Dibenzo-16-crown-5 (46) 8 9 unsvm-Dibenzo-18-crown-6 (45) 8 9 Dibenzo-19-crown-6 (47) 8 9 Dibenzo-21-crown-7 (48) 8 9 svm-Dir4(5)-tert-buttvlbenzol- 21 -crown-7 (49) ~ 8 9 l,8-Naphtho-16-crown-5 {S6) 9 0 l,8-Naphtho-19-crown-5 (57) 9 0 l,8-Naphtho-22-crown-7 (58) 9 0
IV o,o'-Biphenyl-17-crown-5 (59) 9 0 o,o'-Biphenyl-20-crown-6 (60) 90 o,o'-Biphenyl-23-crown-7 (61) 91 2,2'-Binaphtho-17-crown-5 (62) 91 2,2'-Binaphtho-20-crown-6 (63) 91 2,2'-Binaphtho-23-crown-7 (64) 91 N,N'-Ditosyl-4,I3-diazadibenzo- 18-crown-6 (69) 9 1 N-Tosylmonoazadibenzo-18-crown-6 (70) 9 2 2,3 -Pyridino-15 -crown-5 (71) 9 2 2,3-Pyridino-18-crown-6 (72) 9 2 2,3-Pyridino-21-crown-7 (73) 9 2 General Procedure for Preparation of 1,3-Xylyl Crown Ethers 76-78 9 2 l,3-Xylyl-18-crown-5 (76) 93 l,3-Xylyl-21-crown-6 (77) 93 l,3-Xylyl-24-crown-7 (78) 9 3 l,3-Bis(bromomethyl)benzene (74) 9 3 General Procedure for the Preparation of sym- (Hydroxy)(methyl)dibenzocrown Ethers 87 and 95 94 Procedure A 9 5 Procedure B 9 6 sym-(Hydroxv)(methvl)dibenzo-16-crown-5 (87) 95 svm-(Hydroxv)(methyl)dibenzo-14-crown-4 (95) 9 5 General Procedures for the Preparation of Pyridyl Substituted Crown Ethers Using Sodium Hydride 9 5 Syin-(2-Picolyloxy)dibenzo- 13-crown-4 (82) 9 6 5^III-(2-Picolyloxy)dibenzo- 14-crown-4 (83) 9 6 &XIIl-(Methyl)(2-picolyloxy)dibenzo- 14-crown-4 (98) 9 7 SXni-(2-Picolyloxy)dibenzo- 16-crown-5 (84) 9 7 fiyni-(Propyl)(2-picolyloxy)dibenzo- 16-crown-5 (91) 97 2-Picolyl dodecyl ether (104) 9 8 General Procedure for the Preparation of Pyridyl Substituted Crown Ethers Using Potassium Hydride 9 8 sym-(Methyn(2-piclyloxy)dibenzo- 16-crown-5 (90) 9 9 sym-(Decyn(2-picoyloxy)dibenzo- 16-crown-5 (92) 9 9 sym-(Propyn(benzvloxv)dibenzo- 16-crown-5 (103) 9 9 Sodium sym-Dibenzo-16- crown-5-oxyxanthate (105) 100 Methyl sym-Dibenzo-16- crown-5-oxyxanthate (107) 101 Methyl sym-Dir3(4)-tert-butvlbenzo1- 16-crown-5-oxyxanthate (108) 101 General Procedure for Preparation of svm (Alkyl)(methoxy)dibenzocrown Ethers 111-113 102 sym-(Methvn(methoxv)dibenzo- 16-crown-5 (111) 10 2
VI SXIII-(Propyl)(methoxy)dibenzo- 16-crown-5 (112) 102 &yiTi-(Decyl)(methoxy)dibenzo- 16-crown-5 (113) 103 General Procedure for Preparation of N-(2-Trifluoro-4,6-dinitrophenyl)-4'- Aminobenzocrown Ethers 114 and 116 103 N-(2-Trifluoro-4,6-dinitrophenyl)-4'- aminobenzo-14-crown-4 (116) 103 N-(2-Trifluoro-4,6-dinitrophenyl)-4'- aminobenzo-15-crown-5 (114) 104 N-(2-Trifluoro-4,6-dinitrophenyl)-5'- nitro-4'-aminobenzo-15-crown-5 (115) 104 General Procedure for the Preparation of Acyclic Polyether Secondary Alcohols 117, 119 and 120 1 05 1,3-Bis(ii-niethoyphenoxy)-2- propanol (117) 105 l,3-Bis(2.-methoxyphenoxy)-2- propanol (119) 105 l,3-Bis(a-methoxyphenoxy)-2- propanone (120) 106 General Procedure for the Preparation of Acyclic Polyether Tertiary Alcohols 121 and 122. 1 06 2-[(Q.-Methoxyphenoxy)methyl]-l- (fi.-methoxyphenoxy)-2-pentanol (121) 107 2-[(fi.-Methoxyphenoxy)methyl] -1 - (fl.-methoxyphenoxy)-2-dodecanol (122) 107 General Procedure for the Preparation of Acyclic Polyether Carboxylic Acids 123-127 108
Vll 1,3-Di(fi.-methoxyphenoxy)-2- (oxyacetoxy)propane (123) 1 0 8 1,3-Di(iTj.-methoxyphenoxy)-2- (oxyacetoxy)propane (126) 10 8 1,3-Di(p.-methoxyphenoxy)-2- (oxyacetoxy)propane (127) 109 4,4'-Bis[(ii-methoxyphenoxy)methyl]- 3-oxaheptanoic acid (124) 109 4,4'-Bis[(ii-methoxyphenoxy)methyl]- 3-oxatridecanoic acid (125) 1 09 3,9-Dioxa-6-(N-tosylaza)- undecane-l,ll-diol (146) 109 1,11 -Dimethoxy-3,9-dioxa-6- (N-tosylaza)undecane (147) 1 10 l,ll-Dimethoxy-3,9-dioxa-6- azaundecane (148) 1 10 N-Tosyldiethanolamine (137) 1 11 N-Tosylmonoaza-15-crown-5 (138) 1 11 Monoaza-15-crown-5 (130) 1 13 General Procedure for the Preparation of 4'-Nitrobenzocrown Ethers 139-144 113 4'-Nitrobenzo-12-crown-4 (139) 1 14 4',5'-Dinitrobenzo-14-crown-4 (143) 114 4'-Nitrobenzo-14-crown-4 (144) 1 14 4'-Nitrobenzo-15-crown-5 (140) 114 4'-Nitrobenzo-18-crown-6 (141) 115 4'-Nitrobenzo-21-crown-7 (142) 115
Vlll General Procedures for the Preparation of 4'-Aminobenzocrown Ethers 132-135 and 145 1 15 Procedure A 1 15 Procedure B 115 4'-Aminobenzo-12-crown-4 (132) 116 4'-Aminobenzo-14-crown-4 (145) 116 4'-Aminobenzo-15-crown-5 (133) 116 4'-Aminobenzo-18-crown-6 (134) 1 1 6 4'-Aminobenzo-21-crown-7 (135) 117 General Procedures for Modification of Nafion® 117 Membrane 1 1 7 Method A 1 17 Method B 117 Hydrolysis of Nafion® Sulfonyl Chloride Membranes 11 8 General Procedure for the Preparation ofDimesylates 118 Triethleneglycol dimesylate (34) 1 19 Tetraethyleneglycol dimesylate (36) 1 19 1,2-Bis[3-(mesyloxy)propyloxy] ethyleneglycol dimesylate (35) 119 Pentaethyleneglycol dimesylate (37) 119 Hexaethyleneglycol dimesylate (38) 1 20 Ethyleneglycol dimesylate (42) 1 20
IX Propyleneglycol dimesylate (43) 1 20 N-Tosyl-diethanolamine dimesylate (68) 1 20 REFERENCES 1 21 LIST OF TABLES
1. Cation Diameters and Cavity Sizes of Crown Ethers 3 2. Yields of the Benzo-18-crown-6 in Ring Closure Reactions with Different Alkali Metal Fluorides 1 0 3. Comparison of Yields for Benzo-12-crown-4 from Alternative Methods 27 4. Comparison of Yields for Monobenzocrown Ethers from Alternative Methods 2 9 5. Cyclization Yields for Dibenzocrown Ethers 3 2 6. Comparison of Cyclization Yields from Different Reaction Conditions 3 6 7. Comparison of Cyclization Yields for 54-56 from Differrent Reagent 3 8 8. Yields of Compounds 82-84 4 5 9. Yields of Compounds 90-92 and 98-100 4 9 10. Chemical Modification of Nafion® Membrane by Method 1 7 4 11. Conversion of Nafion® Membrane to the Sulfonyl Chloride Form Followed by Hydrolysis 7 5 12. Effect of Chlorination Time Upon Alkali-metal Cation Permeation 7 6 13. Chemical Modification of Nafion® Membrane with Monoaza-15- crown-5 by Method II 7 9 14. Influence of Coupling Agents upon Alkali-Metal Cation Permeation 8 1
XI LISTOFHGURES
1. The First Crown Ethers with Cyclic Hexaethers 1 2. Log Ks versus the Ratio of Cation Diameter to Cavity Size for Alkali Metal Complexed Dicyclohexano-18-crown-6 4 3. Synthetic Approaches for Cyclization Reactions 5 4. The Template Effect in the Synthesis of 18-crown-6 7 5. Complexation of Metal Ion by Lariat Ether 1 1 6. Carbon-pivot and Nitrogen-pivot Lariat Ethers 11 7. Double Armed Diaza-18-crown-6 Compounds 12 8. Typical Chromogenic Crown Ethers 14 9. Cation Complexation Mode of lonizable Crown Ether 21 14 10. The First Acyclic Polyether Compound which Shows Potassium Ion Slectivity 1 5 11. Bartsch's Acyclic Polyether Ligands 1 6 12. Structure of Nafion® Sulfonate Membrane 17 13. Ion-Cluster Structure of Nafion® Membrane 18 14. Schematical View of Cesium-Assisted Cyclization 3 0 15. Structure of the 2 + 2 Adduct of Dibenzo-13-crown-4 3 4 16. Proposed Complexation of Silver Cation by Pyridyl Pendant Crown Ether 98 5 2 17. X-ray Crystal Structure of Pyridyl Pendant Crown Ether 82 5 3 18. X-ray Crystal Structure of Pyridyl Pendant Crown Ether 83 5 3 19. X-ray Crystal Structure of Pyridyl Pendant Crown Ether 84 5 4 20. THF-Insoluble Complex of Methoxy Crown Ether with Nal 5 8
Xll 21. Model of Acyclic Polyether Carboxylate Complexation with a Lithium Cation 6 1 22. Structures of Nafion® 117 and Crown Ethers to be Attached to the Membranes 65 23. IR Spectrum of Nafion® 117 (*), Nafion®-monoaza-12- crown-4 (**) and Nafion®-monoaza-15-crown-5 (#) 83
Xlll CHAPTER I INTRODUCnON
Crown Ether Background The systematic synthetic method of crown ether synthesis was reported by Pedersen in 1967.HI Various kinds of crown ethers with different ring sizes and rigidity were prepared by an adaptation of the Williamson ether synthesis. Crown ethers 1 and 2 exhibit good selectivity for potassium cation in extraction from aqueous solution into organic solvents in the presence of the other alkali metal cations. The hydrocarbon portion of the macrocyclic ring orients itself
o o
1 2 Figure 1. The First Crown Ethers with Cyclic Hexaethers.
outwards from the cation which provides lipophilicity to solubilize the cation in the organic solvent. The metal ion selectivity of the macrocyclic ring is related to the size of the cavity formed by the ether oxygen atoms. A convenient nomenclature for crown ethers was proposed by Pedersenni in which macrocyclic ring 1 and 2 are designated 18- crown-6 and dibenzo-18-crown-6, respectively. The specific
1 designation "crown" is preceded by the kind and number of substituents on the polyether ring, and the total number of atoms which constitute the polyether ring and is followed by the number of heteroatoms in the ring. The term dibenzo refers to the two benzene rings connected on the ring.
Cation Complexation by Crown Ethers Pedersen first discovered the complexation of crown ethers with alkali metal ions.t^l The formation of complexes by binding of metal cations is caused by electrostatic ion-dipole interaction between cations and electron-rich oxygen donor atoms. The stability of these complexes depends on the relative sizes of the cation and the cavity size of the polyether ring. Pedersen proposedt^^ the factors which influence the stability of crown ether-metal cation complexes are: the relative sizes of the crown ether cavity and the metal ion; the number of oxygen atoms in the crown ether ring (the more the better); the coplanarity of the crown ether ring; the symmetrical placement of the oxygen atoms; the basicity of the oxygen donor atoms (the stability of the complex increases with increasing basicity); steric hindrance in the crown ether ring (the less steric hindrance, the more stable is the complex formed); the tendency of the ion to associate with the solvent (complexation of the metal ion requires desolvation); and, the electrical charge on the cation. The stability of a crown ether complex is measured by the stability constant Kg which is defined by the law of mass equilibrium.[3] A high stability constant can be obtained when the size of metal ion matches well the cavity size of crown ether ring. In other words the relationship between cavity size of crown ether ring and cation diameter is very important in determining the stability of the complex. The cavity sizes of several crown ether rings and alkali metal ion diameters are summarized in Table 1.^4] As shown in the table, Li+and 14-crown-4, Na+ and 15-crown-5, K"*" and 18-crown-6, Cs"*" and 21-crown-7 fit best in size.
Table 1. Cation Diameters and Cavity Sizes of Crown Ethers.
Cation Cation Diameter [A]t5,6] Crown Ether Cavity Diameter [A]
Li 1.36 14-crown-4 1.2a . 1.5b Na 1.90 15-crown-5 1.7 - 2.2 K 2.66 18-crown-6 2.6 - 3.2 Rb 2.98 19-crown-6 3.0 - 3.5 Cs 3.38 21-crown-7 3.4 - 4.3 a Lower values estimated from Corey-Pauling-Koltun (CPK) models, b Higher values from Fisher-Hirschfelder-Taylor (FHT) models. The stability constant versus the ratio of cation diameter to cavity size for dicyclohexano-18-crown-6 complexes with alkali metal ions is plotted in Figure 2.t7] As expected by the cavity size and metal ion size relationship, dicyclohexano-18-crown-6 complexes best with potassium ion and shows highest stability constant. The other alkali metal ions have lower stability in complexation due to the difference of cavity size and ion diameter.
LogK
0.6 0.2 1.0 1.2 cation diameter/cavity size Figure 2. Log Ks vs. the Ratio of Cation Diameter to Cavity Size for Alkali Metal Complexed Dicyclohexano-18-crown-6.
Synthesis of Monobenzo- and Dibenzocrown Ethers The synthesis of macrocyclic ring compound usually gave low yields and oligomers. These problems can be avoided by use of high dilution conditionf^l which facilitates the cyclization reaction by use of very low concentrations of reactants. The presence of one or more rigid groups also enhances of cyclization yields by reducing the conformational possibilities of the reactants.[2] The most widely used approaches for cyclization are shown in Figure 3.t9] Approaches 2 and 3 provide the most efficient one-pot
Approach 1. -X I mol base /'"^n C-Y
Approach 2.
-X Y- j^ mol base C-X * Y- ) ^X Y-^
Approach 3. ^^^^
1 C + 2 ^ 4 mol base ^ /^ ^\ X . , z
Approach 4.
C ^^-^ 2 mol base. ^^ ^ ^\ f^ ^
Approach 5. C ^ "\ 1 mol base, ^ Dimerization ^ /'^ ^^ X X-^ ^Z Y ^7 Z-^
Figure 3. Synthetic Approaches for Cyclization Reactions. synthesis of monobenzocrown ethers. The stepwise Approach 4 provides the most versatile synthesis of dibenzocrown ethers. In an adaptation of Approach 1, Pedersen first synthesized 18-crown-6 by cyclization of hexaethyleneglycol monochloride using tert-BuOK as a base under high dilution conditions (Scheme 1).^! The yield was only 2%. Cram et al. prepared 12-crown-4, 15-crown-5 and 18 Scheme 1
o o-^^ci tert-BuOK CH3OCH2CH2OCH3 cO OH
-crown-6 by the reactions of dichlorides and diols using lithium, sodium and potassium hydroxides, respectively (Scheme 2).HO]
Scheme 2 ^O-N, o o
Yield 13 %
OI CI U<0. + ^n NaOH o o O CI H-O-^ 1,4-Dioxanc Yield 14 % 4^3 KOT" o o^ THF-H2O o o k,o^ 1 Yield 40-60 % The relatively high yields of cyclic crown ethers 1, 3 and 4 were obtained without use of high dilution conditions. The striking increase in yield for 18-crown-6 can be rationalized by a template effect of the potassium cation which keeps the chains together during reaction (Figure 4).ni]
CI r u^ (ci
Figure 4. The Template Effect in the Synthesis of 18-crown-6.
In consideration of the results shown in Scheme 2, the optimal template effect is achieved when the diameter of cation fits best to the cavity of the crown ether being formed. Dibenzo-18-crown-6 (2) was synthesized by utilizing Approaches 3 and 4 in 45% and 80% yields, respectively (Scheme 3).[2] Scheme 3 OH , , ^ , _ P 0^,^^. I„! X, ^ CI/ \ o/ \ CI tcrt-BuOK rjtf^^Sr / xV{[j OH ^^^O O
2) CI O CI ^ rr^TT^i^ tClt-BuOK ^. OTHP THPO
THP = tetrahydropyranyl
The reaction of partially protected catechol with bis(2-chloroethyl) ether via Approach 4 gave a higher yield than the condensation reaction of catechol and bis(2-chloroethyl)ether which utilized Approach 3. The template effect of potassium cation is important to obtain a good yield. For preparation of monobenzocrown ethers the reaction of catechol salts with polyethylene glycol derivatives such as halides,[2] p-toluenesulfonates,n2] ©r methanesulfonatesHS] have been used most frequently. Luis et al. evaluated several synthetic routes to benzocrown ethers with different ring sizes and found that the most
8 convenient synthetic method was the reaction of o-bis(2- hydroxyethoxy)benzene 5 and oligoethyleneglycol-p-tosylates (Scheme 4).n4] xhe yields for monobenzocrown ethers 6-8 ranged from 30-64%. In addition to the high dilution method and template effect for macrocyclization reactions, cesium assisted ring closure reactions have been used for synthesis of medium and large
Scheme 4
I f 5 n Yield 6 2 53 % 7 3 64 % 8 4 30 %
macrocyclic compounds.[15] Benzo-18-crown-6 was prepared by the reaction of pentaethylene glycol tosylate with catechol (Scheme 5).[16]
Scheme 5 aDH MF/CH3(J^ OH TsO O OTs Among the alkali metal cations used in the reaction cesium exhibited the highest yield and shortest reaction time. Yields and reaction times for benzo-18-crown-6 forming cyclization reactions are summarized in Table 2.
Table 2. Yields of the Benzo-18-crown-6 in Ring Closure Reactions with Different Alkali Metal Fluorides.
Base Isolated Yields (%) Reaction Time (h) LiF, NaF no reaction 140 KF 52 69 CsF 60 12
The cesium assisted synthesis of benzocrown ethers often provides higher yields of cyclization reaction products without the use of the high dilution method.^V]
Lariat Ethers A simple crown ether complex lacks the ability to envelop a cation and thereby enhance the binding strength. To overcome this drawback crown ethers with a side arm which provides an additional binding site have been synthesized and named as "lariat" ethers.t^^] Their complexes with metal ions usually show additional stability relative to those of the simple crown ethers.
10 The lariat ether concept is represented schematically in Figure 5. At first the crown ether ring would complex with the metal ion
M ^
D: Additional donor atom M: Metal Ion Figure 5. Complexation of Metal Ion by a Lariat Ether. in the way normally associated with crown ether binding and then the donor group attached to the side arm further solvates the cation in the crown ether ring. Lariat ethers can be separated into two classes by the identity of the pivot atom which attaches the side arm to the polyether ring. Typical lariat ethers are shown in Figure 6. The carbon-pivot lariat
CH2OR /_^ . R ^ o^ r ^^ ^o^ o o' R_ 9^ 9 CH2OH 10 CH2OCH3 ^ 1 1 CH2C6H4OCH3-0 1 3 OH 12 CH2OC6H4OCH3-P 14 OCH3 Figure 6. Carbon-pivot and Nitrogen-pivot Lariat Ethers.
1 1 ethers can be prepared by synthetic manipulation of glycerol (HOCH2CHOHCH2OH). The nitrogen-pivot lariat ether are normally prepared by N-alkylation of azacrown ethers and are easier to synthesize than their carbon-pivot counterparts. The carbon-pivot lariat ethers are more chemically stable but less dynamic than the nitrogen-pivot analogues because of the facile inversion of the nitrogen atom. Lariat ether 11 showed better extractability for sodium cation than the para substituted one 12.n8] xhe former is able to complex the metal cation with the methoxy group, but the latter cannot utilize the additional binding site of the side arm due to the an unfavorable alignment of the donor group. Tsukube et al. has prepared pyridino- and quinolino- incorporating diaza-18-crown-6 compounds (Figure 7).tl9]
D 15 -Q
16
17
D--' 18
D = Donor Group 1 9
Figure 7. Double Armed Diaza-18-crown-6 Compounds.
12 These new series of double-armed diazacrown ethers provided excellent transport ability toward transition metal cations, such as Cu, Co and Zn cations, which is rarely seen with simple crown ethers. The cooperative action of the crown ether ring and additional cation ligating donor groups provide three-dimensional complexation of metal ions. The lariat ethers 15 and 17 with pyridine and quinoline rings as secondary donor groups exhibited good transport ability toward Cu, Zn, Ba and Pb cations. However related compounds 16, 18, and 19 showed very low transport ability for transition metals because of an inappropriate orientation of the donor group in the complex or a lack of electron donating ability of the side arm.
Chromogenic Crown Ethers A series of crown ether derivatives have been prepared which have color-inducing functional groups.t20] These compounds are designed to become colored when complexed with alkali and alkaline earth metal ions which are normally colorless. This type of compound has been developed for use as spectrophotometric analytical reagents for specific cations. The selectivity for cation complexation can be controlled by choosing a suitable cavity size in the crown ether portion. The color changes of these compounds are related to the charge transfer transitions of their dye moieties. Chromogenic crown ethers may be either non-ionizable or ionizable compounds as shown in Figure 8.
13 2 0 ^ ' 21 ^O^O-^
Non-ionizable Compound lonizable Compound
Figure 8. Typical Chromogenic Crown Ethers.
Non-ionizable crown ether 20 showed that the modified rings retain the metal ion discriminating ability which is present in the corresponding simple crown ethers.t^l] The color change of ionizable compound 21 is associated with ionization of the proton which is assisted by complexation of the metal cation in the crown ether ring. The chromogenic crown ether 21 selectively extracts specific alkali metal ions from water into organic solvents via the structure shown in Figure 9.t22] The chromogenic crown ether 21 has been demonstrated to be suitable for the extraction and spectrophotometric determination of sodium in human blood.[22]
-N—M---0
Figure 9. Cation Complexation Mode of lonizable Crown Ether 21
14 Acyclic Polvether Compounds Open chain analogues of crown ethers have attracted considerable attention because of the advantage of facile synthesis, versatile variation of structures, inexpensive starting materials and their rapid complexation of metal cations.[23] Their use as phase transfer catalysts[24] and extractants[25] is well documented. An acyclic polyether compound which complexes with alkali and alkali earth metals is the bis(quinoline) oligoether 22 which has an 8-hydroxyquinoIine residue at the end of chain structure (Figure 10).[26] This compound showed potassium ion selectivity in the presence of other alkali metal ions. The introduction of aromatic substituents carrying electron-donating centers at the ends of the oligoethyleneglycol chain enhances the rigidity of the ligands and considerably increases complexation ability. The 8-quinolinole, o- hydroxy, o-methoxy, o-carboxylic acid and tropolone units can be used as rigid end groups.[27,28] Also the flexible ethylene glycol units in ligand molecules can be replaced by rigid aromatic group.[29]
o o
22 Figure 10. The First Acyclic Polyether Compound which Shows Potassium Ion Selectivity.
15 The creation of lithium selective acyclic compounds is difficult because the lithium ion has the smallest radius among alkali metals and exhibits a very high hydration energy. However, a lithium- selective acyclic ligand 23 was prepared which has four oxygen atoms and a 8-quinolinol moiety as donor groups.[301 Bartsch and co-workers prepared various kind of lipophilic acyclic diioniazble polyethers.[3I] Some of these acyclic ligands are shown in Figure 11. Acyclic ligands 24 and 25 showed barium ion
\_0 OH ^jj COJHHOJC
n -ta 24 2 25 3 26 4
HiiCio'^ CO2H HO2C C10H21 n 27 1 28 2 29 3
Figure 11. Bartsch's Acyclic Polyether Ligands.
16 selectivity in the presence of magnesium, calcium and strontium cations. The highest barium selectivity was observed for compound 25. Acyclic polyether dicarboxylic acid 28 with lipophilic groups exhibited excellent selectivity for barium ion in competitive solvent extraction. Compounds 27 and 29 which have one less or one more ethylenoxy unit than compound 28 showed decreased barium selectivity. Examination of Corey-Pauling-Koltun (CPK) space filling model showed a pseudocyclic conformation when ligand molecule 28 was complexed with a barium cation.
Nafion® lonomer Membrane The perfluorosulfonate ionomers marked by Dupont as Nafion® products exhibit remarkable chemical and thermal stability and have been used as ion exchange resins,[32] as a membrane separator in electrochemical applications[32] and as an acid catalyst in synthetic organic chemistry.[34] Nafion® perfluorinated membranes are constructed from a perfluorinated resin which has the general chemical structure shown in Figure 12 where the value of m can be as low as 1. The pendant ionic groups interact to form ion-rich
-K3'2CF2-i5-CF2CF-
(OCF2CF)„OCF2CF2S03Na* CF3 Figure 12. Structure of Nafion® Membrane.
17 aggregates contained in a nonpolar matrix which strongly influences polymer properties and applications. Although Nafion® is not covalently crosslinked, it has a highly ordered structure. The ionizable sulfonate groups form clusters, which cause the production of water containing pockets in a hydrophobic matrix. At low temperature, the Nafion® membrane containing water molecules possesses the rigidity of a crosslinked polymer.[34] The molecular organization of a cluster of Nafion® membrane is shown in Figure 13.[35] Counterions are largely concentrated in high-charge
^''^'^'-y/y y yy / y y yy - ' .y .y j:i—^yy y y >-r^yy y
Figure 13. Ion-Cluster Structure of Nafion® Membrane.
shaded regions which provide continuous diffusion channels. The first surface modification of Nafion membrane was conducted by Lowry et al.[36] in the study, Nafion® 117 perfluorosulfonic acid membrane was converted to the reactive
18 sulfonyl chloride form by refluxing in a 33 weight % solution of PCI5 in POCI3 for 96 hours. The sulfonyl chloride intermediate was converted to a sulfonamide form by contacting the polymer with a 95% ethylenediamine solution (5% water) at room temperature for up to 250 hours. The quantitative conversion of the sulfonic acid polymer to its sulfonyl chloride form was verified by the disappearance of the S-0 symmetric stretch (1060 cm-1) in the infrared spectrum. This diamine-modified Nafion® membrane showed improved cation selectivity over the original Nafion® membrane. A Japanese patent[37] also describes the conversion of Nafion® perfluorosulfonic acid resin to the sulfonyl chloride form by refluxing in a mixture of PCI5 and POCI3 for 24 hours. Nearly 100% efficiency was achieved if the membrane was converted into the ammonium form before transformation to the sulfonyl chloride form. Hayashita conducted dialysis experiment with Nafion® perfluorinated acid membrane by utilizing proton-coupled transport.[39] The mechanism for the proton-driven permeation system involves transport of alkali metal cations from the source solution (aqueous solution containing 1 mM alkali metal chlorides, pH=11.0) to the receiving solution (0.1 M HCl solution) accompanied by back transport of protons from the receiving phase to the source phase. The result showed the permeation selectivity ordering of K+>Rb+>Cs+>Na+>Li+ after 7 hours.
19 Statement of Research nnal During the past two decades, much attention has been given to the design and synthesis of macrocyclic compounds capable of selective recognition for ionic species. Among them, crown ethers are finding many practical applications due to their unique metal ion complexation and transport ability. The major portion of this dissertation encompasses the development of new efficient cyclization methods for monobenzo- or dibenzocrown ethers as well as the synthesis of lariat ethers and the preparation of acyclic polyether compounds. A new cyclization method for aromatic ring containing crown ethers with various ring sizes is to be developed and evaluated by comparison with reported methods. Lariat ethers possessing high potential for complexation of either alkali or transition metal ions are to be synthesized by introduction of carefully chosen pendant side arm groups. Acyclic polyether carboxylic acids with methoxy donor groups which are useful for preparation of metal ion selective condensation polymers are to be prepared. The second portion of this dissertation is the chemical modification of Nafion® ionomer membrane which may be used to separate one ionic species from the others. The goal is to provide barrier layers on each side of the membrane through which metal ion permeation will be controlled by the identify of the ionic species.
20 To achieve this goal, the feasibility of attaching ionophore molecules onto the surface of Nafion® perfluorosulfonic acid will be examined.
21 CHAPTER n RESULTS AND DISCUSSION
Crown Ethers with Aromatic Rings as Part of the Polvether Ring Benzo- and Dibenzocrown Ethers-Cesium Effect After discovery and first synthesis of crown ethers by Pedersen, numerous attempts have been made to find more efficient synthetic methods. Among the many different kinds of crown ether compounds, some of the most popular and fundamental types are monobenzo and dibenzocrown ethers. By introduction of various kinds of functionalities on the aromatic unit of such crown ethers through electrophilic substitution reactions, the properties of crown ethers may be altered to give improved metal ion complexation and transport ability. Initially, Pedersen prepared monobenzo crown ethers by the reaction of catechol and a dihalide in the presence of NaOH in 1-butanol (Scheme 6).[2]
Scheme 6
^°\ci-R-Cl -4^0H^ rY°)R .2Naa.2H20 ^^OH 1-butanol "V^Q R = A divalent organic group.
The yields of cyclization products were found to be highly dependent on the size of the polyether rings. Crown ethers with five or six oxygen atoms were always formed in higher yields than their
22 smaller-ring analogues. The synthetic strategy for this method is utilization of the SN2 substitution reaction of catechol anions with polyethyleneoxy compounds which have suitable leaving groups, such as halide. However, the overall yield which could be obtained by this method were only modest. With increasing demand for a variety of crown ether compounds, the development of higher yielding synthetic methods was sought. Several groups have reported improved synthetic methods for the preparation of benzo- and dibenzocrown ethers. Cesium-assisted synthesis of crown ethers with aromatic subunits was found to provide superior yields compared with other alternative synthetic routes.[39] Macrocyclization of catechol either with a polyethyleneglycol dihalide and CS2CO3 or with a polyethyleneglycol ditosylate[40] and CsF gave good yields.[39] The former combination was used by Kellogg and coworkers who obtained very good yields of monobenzo- 15-crown-5 and monobenzo-21-crown-7 (Scheme 7). Although this
Scheme 7
1) CS2CO3
•v^OH 2) Br Br ^-^Oj^n n Yield(%) DMF 6 3 50 4 days 7 4 74 8 5 78
23 procedure utilized some laborious steps and less accessible starting materials (dihalides of polyethylene glycols) the yields were remarkable. The latter method which was developed by Bartsch and coworkers also gave high yields for the synthesis of crown ethers with benzo group substituents. Benzo-12-crown-4 30 was obtained 29% yield by this method (Scheme 8).
Scheme 8
^xN^OH I 1 01 + CsF + ^ jryryi-r CH3CN ^r^s^o o-i K^nu TsO O O OTs —^ H T OH 80 °C "^^^^^O O-I 1-3 days ' ' 3 0 Ts= p-Toluenesulfonate ^^^
It was clearly established that the presence of cesium cations was necessary to promote the enhanced yields of crown ether product during the macrocyclization step. Although these methods showed high efficiency for benzocrown ether synthesis, they also have certain disadvantages. Kellogg's method has serious shortcomings for the preparation of benzocrown ethers with ring sizes smaller than 18-crown-6. Thus, the 50% yield of benzo-15- crown-5 6 is low compared with yields obtained through alternative routes.[14] Bartsch's approach used CsF which is more expensive than CS2CO3. Also fluoride anion can act as a nucleophilie and produce competitive displacement reactions on polyethylene glycol
24 ditosylates.[4l] Therefore, optimization of reaction conditions becomes very important. In the current research, a new combination of reagents for the cesium-assisted cyclization was discovered and evaluated for the preparation of monobenzo or dibenzocrown ethers with varying ring sizes. Cesium carbonate was chosen as the base due to its cheaper price than cesium fluoride, availability and a proven effectiveness for macrocyclization. Mesylate was selected as the leaving group because of its higher reactivity than tosylate. Acetonitrile was used as the reaction solvent because its appropriate boiling point as well as high dielectric constant and polar aprotic nature which should provide good solubility for the reactants and possible rate enhancement of reaction. The first evaluation of this system (Cs2C03/polyethyleneglycol dimesylate/CH3CN) was attempted for the preparation of monobenzo-12-crown-4. Cyclization of catechol 33 with the dimesylate of triethyleneglycol (34) induced by CS2CO3 in CH3CN at reflux was performed to produce monobenzo-12-crown-4 (30) (Scheme 9). An acetonitrile solution of dimesylate 34 (1 equiv) was added dropwise with a syringe pump to a reaction mixture of catechol 33 (1 equiv) and CS2CO3 (2-3 equiv) at reflux. Under these reaction conditions, the 1 + 1 adduct 30 was obtained in 45% yield which is far superior to yields reported for other methods. Although high dilution techniques usually are advantageous for macrocyclization, in this reaction a high yield of cyclized product was obtained without the use of such kind of methods.
25 Scheme 9
OH
l!^^^ MsO O O CMS CH3CN 'i^^o o-J 33 34 80°C ' ' 3 0
(trace)
A trace amount of 2 + 2 product 31 was detected by TLC, but was easily removed from the crude product by recrystallization from heptane. Table 3 compares the yields for monobenzo-12-crown-4 obtained by alternative synthetic method. This comparison clearly demonstrates that the Cs2C03/dimesylate combination is the most efficient for the cyclization reaction to produce monobenzo-12- crown-4.
26 Table 3. Comparison of Yields for Benzo-12-crown-4 from Alternative Methods.
Reactants and Solvent Yield (%) Reference catechol, dichloride, NaOH, 1-BuOH 4 1 catechol, ditosylate, CsF, CH3CN 2 9 3 9 catechol, dimesylate, CS2CO3, CH3CN 4 5
Encouraged by this result, the synthesis of previously unreported monobenzo-14-crown-4 was undertaken. Reaction of catechol and polyethyleneglycol dimesylate (35) in the presence of CS2CO3 in CH3CN gave desired product 39 in 76% yield (Scheme 10).
Scheme 10
OH .. ^ l^ * MsO O O CMS CH3CN "isAo O-I 3 8 80°C k^ 39
c? o ( trace )
27 The very high yield of this small ring crown ether illustrates the advantage of the new synthetic method. A trace amount of the 2 + 2 product 40 was detected by TLC. It was easily separated from 3 9 by column chromatography and was identified by mass spectrometry. Benzo-14-crown-4 has been found to exhibit excellent complexation selectivity toward lithium cation.[42] For further evaluation of the Cs2C03/dimesylate/CH3CN combination, several already reported monobenzocrown ethers with varying ring sizes (15, 18 and 21 members) were synthesized (Scheme 11).
Scheme 11
r>
MsO O O CMS cHjQJ '^ Kf^O ^ > A V " XL 34 1 6 H 1 ^^2 7 H 2 37 3 8 H 3 ^* "^ 4 1 t-Bu 3
All reactions gave only the 1 + 1 adduct with no detectable 2 + 2 adduct (TLC). The cyclization yields are summarized in Table 4 and compared with yields reported for other preparative methods. As
28 can be seen the new method always produced higher or comparable yields than those which have been reported previously.
Table 4. Comparison of Yields for Monobenzocrown ethers from Alternative Methods.
Compound Leaving Group Base Solvent Yields(%) Reference 6 a NaOH 1-BuOH 62 2 6 OTs CsF CH3CN 61 16
6 OMs Cs2CC>3 CH3CN 71 7 a NaOH 1-BuOH 60 2 7 OTs CsF CH3CN 60 16 7 OMs CS2CO3 CH3CN 75 8 a NaOH 1-BuOH 50 43 8 OTs CsF CH3CN 65 16 8 OMs Cs2CC>3 CH3CN 81 4 1 OMs CS2CO3 CH3CN 77
It has been proposed that the large surface area of the cesium cation can coordinate both the negatively charged phenolate anion and a partial negative charge on the leaving group to promote intramolecular cyclization.[44] This proposal for the new synthetic method is depicted in Figure 14.
29 Figure 14. Schematical View of Cesium-Assisted Cyclization.
In addition to monobenzocrown ethers, dibenzocrown ethers have received a great deal of attention due to their selectivity in metal ion complexation ability as well as their versatility for functionalization on the aromatic rings. Furthermore many kinds of crown ether polymers could be made by utilizing dibenzocrown ethers as monomers. In consideration of their importance to crown ether chemistry, the limited number of synthetic methods for their synthesis is surprising. The most popular method for the preparation of dibenzocrown ethers was developed by Pedersen (Scheme 12).[1]
Scheme 12. ar ":o ™ ^^ ocf^o + 2 NaCl + 2 H2O
30 However, this method gave only modest or low yields for most dibenzocrown ethers and the procedure is somewhat tedious. A simpler and more efficient synthetic method would be beneficial. Therefore, the potential of the new cyclization method was also evaluated for preparation of dibenzocrown ethers. Initially dibenzocrown ethers with relatively large ring sizes (15- 21 members) were prepared (Scheme 13). Bis(hydroxyaromatic)
Scheme 13 a:O H HO„X. )
A 43 44 I" MsO CMS 45 2
^O O;"^ 2 47
^0 0. aoHHo.,***^ ^J3-RMSOOOCM^ r\r~\r\. S ,0;r^-v-^ ^ °v^)^^ ,
4 8 R=H 4 9 R= t-butyl
31 compounds were reacted with polyethyleneglycol dimesylates in the presence of CS2CO3 in CH3CN at reflux to give the desired dibenzocrown ethers. The yields obtained by this method are summarized in Table 5 and compared with those reported by Pedersen. As illustrated in Table 5 the Cs2C03/dimesylate/CH3CN
Table 5. Cyclization Yields for Dibenzocrown Ethers
Yield (%) for Synthesis with Compound Ring Size Cs2C03/dimesylate KOH/dichloride^
44 15C5 57 43 45 18C6 75 25 4 6 16C5 83 18 47 19C6 61 16 48 21C7 78 36 4 9 21C7 67
^Reference [1].
system gave much higher yields than the KOH/dichloride/1-butanol combination. Apparently cesium cations assist dibenzocrown ether formation. To investigate the applicability of the new synthetic method to the preparation of small-ring dibenzocrown ethers, the reaction of bis-l,3-(2-hydroxyphenoxy)propane with 1,3-propanediol
32 dimesylate (50) in die presence of CS2CO3 in refluxing CH3CN was performed (Scheme 14). After work up and purification by column
Scheme 14
^^ .OH HO^^ y\ 0 0
51 chromatography dibenzo-14-crown-4 (51) was obtained in 92% yield. This is a dramatic yield improvement from the 27% reported by Pedersen.[ll No 2 + 2 adduct was detected by TLC. In view of the smaller ring size, the absence of 2 + 2 adduct is remarkable. Buchanan reported the first synthesis of dibenzo-13-crown-4 in 33% yield by the reaction of 1,2-bis(o-hydroxyphenoxy)ethane with 1,3-dibromopropane and LiOHH20 in l-butanol.[45] The synthesis of dibenzo-13-crown-4 by the reaction of a bisphenol with a glycol dimesylate and CS2CO3 in CH3CN was attempted. Two different pathways to dibenzo-13-crown-4 are possible (Scheme 15). Dibenzo- 13-crown-4 (52) was obtained in 72% yield by Pathway A and 52% by Pathway B. For Pathway A a trace of 2 + 2 product 53 was
33 Scheme 15
.OOH HO ^
*-^0 0-^ '*° °* C3%CII \ /\ 1—1 '' 0 O
Pathway B formed but was readily separated from 52 by recrystallization from CH2Cl2-MeOH. A larger amount of 2 + 2 adduct (Figure 15) was obtained for Pathway B so its removal was more difficult than in the
[ ]
53 Figure 15. Structure of the 2 + 2 Adduct of Dibenzo-13- crown-4.
34 case of Pathway A. Therefore Pathway A is the route of choice for the preparation of dibenzo-13-crown-4. Preparation of dibenzo-12-crown-4 was also attempted by the use of the Cs2C03/dimesylate/CH3CN system (Scheme 16). Unfortunately, the amount of cyclization product formed was too small to allow complete separation of the 2 + 2 adduct 55 and the 1 + 1 adduct. The major product was the 2 + 2 adduct and the 1 + 1 adduct was obtained in a 12% crude yield. Although the melting point (208 oC) of the crude 1 + 1 adduct was identical with the reported value (208-209 oC),[ll the presence of the 2 + 2 adduct was detectable in the mass spectrum. Thus the Cs2C03/dimesylate/CH3CN
Scheme 16
OH HO I' OH HO,^^ ^ Cs,C03 ^ O O I I 80°C ? ? 54
a;•0 X)O" a[ X)] 55
35 system was found to be ineffective for the synthesis of dibenzo-12- crown-4. In Table 6, the yields of dibenzocrown ethers 51, 52 and
Table 6. Comparison of Cyclization Yields for Different Reaction Conditions.
Yield r%^ for Svnthesis with Compound Ring Size CS2CO3/ MOH/ Reference dimesvlate dihalide 5 1 14C4 92 27 1 5 2 13C4 74 33 45 5 4 12C4 12a 1 1 1
^Crude yield.
54 obtained with the new synthetic method are compared with those reported for reactions in which MOH and dihalides were involved. For further evaluation of the new synthetic method, crown ethers were synthesized which have aromatic units derived from 1,8- dihydroxynaphthalene, 2,2'-biphenol and 2,2'-binapthol in their molecular structures. These dihydroxyaromatic compounds were reacted with glycol dimesylates to give the corresponding crown ethers (Scheme 17).
36 Scheme 17
HO OH n. 56 1 57 2 58 3
rAr^/H/n ^^^^^^ MsO 0 0 0 OMs CUgCN n=l,2,3 80°C
n. 62 1 63 2 64 3
The yields of crown ethers 56-64 are shown in Table 7 and compared to yields from alternative synthetic methods. The yields from the new reaction procedure are comparable to those from reported ring closure reactions.
37 Table 7. Comparison of Cyclization Yields for 56-64 for Different Reagents
Ring CS2CO3/ Alternative routes Compound Size dimesylate reagents yield(%) reference
5 6 16C5 77% CsF/Tosylate 63 39 57 19C6 80% CsF/Tosylate 53 39 58 22C7 54%
5 9 17C5 64% Okahara method^ 64 46 6 0 20C6 75% CsF/Tosylate 23 16 6 1 23C7 73% Okahara method^ 73 46
6 2 17C5 52% Okahara method* 54 46 63 20C6 80% t-BuOK/Tosylate 60 47 64 23C7 85% Okahara method* 59 46
^Reaction of diol with tosylchloride and alkali metal hydoxide.[48]
N,N'-Ditosyl-4,13-diazadibenzo-18-crown-6 (69) is a precursor for the preparation of 4,13-diazadibenzo-18-crown-6, which is widely used as a starting material for the synthesis of various types of cryptands. Macrocycle 69 has been prepared by reported procedure which used the reaction of N-tosyl-bis-[2-(2-hydroxyphenoxy)-ethyl] amine and tritosyl diethanolamine in the presence of potassium tert- butoxide.[49] However, the procedure is tiresome and time
38 consuming (5 days). A more efficient and simpler synthetic method would be highly beneficial for large scale synthesis. The new cyclization method of Cs2C03/dimesylate/CH3CN was used for the synthesis of 69. The reaction of N-tosyl-bis-[2-(2- hydroxyphenoxy)ethyl]amine (67) with N-tosyl diethanolamine dimesylate (68) and CS2CO3 in CH3CN at reflux for 24 h gave the desired compound 69 in 74% yield (Scheme 18).
Scheme 18
^ 66 Ts r\i/-i
OH ^^^OH
65 I Ts 67
CS2C03,CH3CN K^Q Q-K^
Ts 69
39 The synthetic precursors mono-THP-protected catechol (65), tritosyl diethanolamine (66) and N-tosyldiethanolamine ditosylate were prepared by literature methods.[49] it is interesting to note that when granular CS2CO3 was used for conversion of 67 into 69, the yield dropped to around 50%. When powdered CS2CO3 was used, the yield increased to 74%. This indicates that powered CS2CO3 should be used for the cyclization reaction to obtain the highest yield. The cyclization yield for N-tosyl monoazadibenzo-18-crown-6 (70) synthesis was also enhanced by use of the new method. Previously 70 was prepared by Hogberg and Cram in 34% yield by reaction of bis[2-(o-hydroxyphenoxy)ethyl]ether with N-tritosyl diethanolamine and K2CO3 in DMF.[50] By use of the new method compound 70 was obtained in 72% yield (Scheme 19).
Scheme 19
Ts rT''""''n+ nln cs,co3, fyQ o^ K^Q O^^ MsO N OMs -^^^p I^A^ ^XJ
70
Kellogg and co-workers have synthesized crown ethers which contain a pyridine unit.[40] Reaction of 2,3-dihydroxypyridine with CS2CO3 in MeOH was followed by addition of the polyethyleneglycol dibromide in DMF. However, cyclization yields were only modest
40 (14-31%) due to the formation of 2-pyridone. Three different ring- sized crown ethers 71-73 were prepared by the reaction of 2,3- dihydroxypyridine with polyethyleneglycol dimesylates and CS2CO3 in CH3CN (Scheme 20). Yields for the cyclization reactions shown
Scheme 20
\ O"^ i X ^ MsO O O OMs ^^' 11 S N^OH ™3CN N O ojSn A ^ Yieldr%^ This method Reported method n 71 1 14 14^ 72 2 3 7 23^ 73 3 22 31^ a: Kellogg's yields (ref. 40)
in Scheme 18 are very similar to those obtained by Kellogg and co-workers.
1.3-Xvlyl Crown Ethers For comparison of alkali metal binding properties by calorimetry with analogous compounds which have intraanular - CO2H, -OCH3 and -OCH2CO2H groups 1,3-xylyl crown ethers were prepared. Reinhoudt and co-workers reported the first synthesis of 1,3-xylyl crown ethers by the reaction of l,3-bis(bromomethyl)- benzene with polyethyleneglycol and potassium tert-butoxide in
41 toluene.[5II The driving force for the reaction was thought to be a template effect of the potassium cation. In this study potassium hydride in THF was utilized as the base-solvent combination. The approach used to synthesize the 1,3-xylyl crown ethers is illustrated in Scheme 21. Precursor dibromide[52] 74 was prepared by
Scheme 21
Br CH. I + cH3-r yo ecu CH O^N hv A Ac„ Br 7 4 Br Br B r\n/i HOOO(H Hoo oai t-BuOK KH Toluene THF
A n A' O O. 76 2 Vo oJ^ II 3 VO o-y 78 4 I—I 75
irradiation (500 W lamp) of m-xylene in the presence of 1,3- dibromo-5,5-dimethylhydantoin in 38% yield after recrystallization of the crude product from absolute methanol. A condensation reaction of compound 74 with the polyethylene glycols having various sizes in dry THF containing potassium hydride produced compounds 76,77 and 78 in 53, 30 and 20% yields, respectively.
42 after column chromatography. The polyethyleneglycol reactants were carefully dried before use with a benzene azeotrope and a Soxhlet apparatus. The yields of 76, 77 and 78 obtained from the present cyclizations are comparable to those of Reinhoudt and co workers. However, the attempt to prepare the 15-membered (n=l) 1,3-xylyl crown ether by use of this method gave a complicated product mixture. A change of the base to NaH did not help to complete the reaction. Probably the poor solubility of the dialkoxide in THF is responsible for the poor reaction. By use of the procedure of Reinhoudt and co-workers, l,3-xylyl-15-crown-4 (75) was prepared in 11% yield after vacuum distillation. The highest yield was obtained for compound 76 which would be expected for a template effect of the potassium ion. Apparently for smaller (75) or larger (78) ring sized crown ethers the template effect is less effective due to their inappropriate geometry when complexed with potassium ion.
Crown Ethers with Pendant Groups Pyridyl Crown Ethers It is well-known that the incorporation of nitrogen atoms into a crown ether ring usually improves the complexation ability for transition metals since it is a soft donor atom.[53] Introduction of a nitrogen atom to replace an oxygen atom in a crown ether also alters the complexation behavior toward alkali metal cations.[54]
43 For study of the influence of attaching a pendant pyridyl unit to a crown ether ring, a series of new ligands has been prepared. From such crown ethers cooperative action of the crown ether ring and pendant pyridyl unit might be expected to enhance the complexation ability toward certain metal cations. The initial synthetic approach toward pyridyl pendant crown ethers involved two different routes (Scheme 22). In Method A
Scheme 22
Method A
79-CH2CH2- 82-CH2CH2- 8 0 -CH2CH2CH2- 8 3 -CH2CH2CH2- 8 1 -CH2CH20C:H2CH2— 8 4 -CH2CH2OCH2CH2-
44 MeUiod B
H .OH
KXQ QAJ V2 NaH
H, yOa\^^
HQ O O
crown ether alcohols 79-81 were reacted with picoylcholoride hydrochloride and two equivalents of NaH in DMF. Method B used THF as a reaction medium, the crown ether alkoxide, and free picoylchloride. Yields of ligands 82-84 obtained by Methods A and B are shown in Table 8.
Table 8. Yields of Compounds 82-84.
Compound Method A Method B 82 18% 36% 83 33% 63% 8 4 35% 56% 45 The results demonstrate that Method B is superior to Method A. Therefore, Method B was adopted as the synthetic method for attachment of pyridyl unit to crown ethers.
The synthetic routes to pyridyl-pendant lipophilic dibenzo-16 crown-5 derivatives are summarized in Scheme 23. Crown ether
Scheme 23
H^.O H O
Tone's oxidation voy 85 CHsMgl C3H7MgBr ^vX)H C3H7^H CioH2fS CSHT^OIN OClp OClp 90 voy voy 91 92 46 alcohol 85 was treated with Jones reagent[55] to produce sym- ketodibenzo-16-crown-5 (86) in 65% yield. Reaction of crown ether ketone 86 witii CsU-jMgBT and CioH2iMgBr in THF gave 88 and 89, respectively, after quenching with a saturated aqueous solution of NH4CI. In the case of crown ether alcohol 87, a mixed solvent system of THF-Et20 (1:1) was used as a reaction medium for the Grignard reaction due to the poor solubility of CHsMgl in THF. Magnesium turnings were added to a solution of methyl iodide in Et20 at room temperature to make a white emulsion of the Grignard reagent (CHsMgl) followed by addition of keto crown ether 86 in THF. In this way crown ether alcohol 87 was obtained in 72% yield. This procedure gave much higher yield than that for the reported procedure[56] which used THF-Et20 (2:1) as solvent for the preparation of CHsMgl. Crown ether alcohols 87-89 were then converted into the corresponding pyridyl pendant crown ether compounds 90-92. The first attempts to make pyridyl pendant lipophilic crown ethers used NaH as the base and gave only poor yields, probably due to the steric bulkness of the lipophilic groups. When the stronger base KH was substituted for NaH, novel ligands 90, 91 and 92 were obtained in 17, 22 and 36% yields, respectively. To investigate the ring size effect on metal ion complexation, pyridyl pendant dibenzo-14-crown-4 derivatives were also synthesized (Scheme 24). The ixiIl-hydroxybenzo-14-crown-4 (93) was prepared by the reported method.[57] By treatment of 93 with Jones reagent, sym-ketodibenzo-14-crown-4 (94) was obtained in 34% yield. Thorough drying under vacuum was necessary before 47 further use to eliminate facile reaction of 94 with moisture in die atmosphere. Reaction of Grignard reagents witii keto crown ether 94 gave crown ethers 95-97. For the preparation of 95, CHsMgl was Scheme 24 CioHzjMgBr CH^^H CiAivOH NaH u 97 THF HQ NaH KH THF THF HCl HQ CH-^OCHr-N'-' u 98 aVoX) lj«9 U 100 produced first by the reaction of CH3I and Mg turnings in Et20 and then 94 was added to obtain the product. Pyridyl-pendant dibenzo- 14-crown-4 compounds 98, 99 and 100 were prepared by Method B (Scheme 20). For the preparation of decyl group containing crown 48 ether 100, KH was used as a base. Crown ether 98 was the only solid compound among the pyridyl-pendant crown ethers with a general alkyl group and pyridyl-containing side arm. Yields for the preparation of the lipophilic pyridyl pendant dibenzo-16-crown-5 and dibenzo-14-crown-4 compounds are given in Table 9. Attachment of a pyridyl unit to sym-(methylhydrQxy)dibenzo- 14-crown-4 (102) was also attempted. By use of the reported method of Tomoi[58] and co-workers, sym-vinylidenedibenzo-14- crown-4 (101) was prepared. Reaction of bis-l,3-(2- hydroxyphenoxy)propane, methallyl dichloride and NaOH in aqueous 1-BuOH gave a cyclization yield of 66%. Reduction of vinylidene crown compound 101 with BH3-THF followed by treatment of Table 9. Yields of Compounds 90-92 and 98-100. Compound Base Yield (%) 9 0 KH 17 9 1 KH 22 92 KH 36 9 8 NaH 3 0 9 9 NaH 5 9 100 KH 66 49 H202-NaOH gave crown ether alchol 102 in 20% yield.[59] The reaction of crown ether alcohol 102 with picoyl chloride hydrochloride by Methods A and B was attempted (Scheme 25). Neither of the methods gave the desired product. Scheme 25 .OH HO, ^*^0 O-"^^ NaOH, 1-BuOH ^^*^o O 101 H^^^CHgOH 11 NalJ.^ No reaction ,0 o, 2)H202, NaOH 'O O' NaH DMhX Decomposition A products 102 No reaction occurred with NaH in THF and decomposition products were obtained when the reaction was conducted in DMF at reflux. To investigate how the pyridyl-pendant crown ethers would compare with either a benzyl-pendant crown ether or a pyridyl compound without a crown ether ring, model compounds 103 and 104 were prepared (Scheme 26). 50 Scheme 26 C3H7V ^OH C3H7. .OCHB 88 103 CH3(CH,),oCH,OH + Q^c, ^ • |QLOCH,(CH,),„CH3 HCl A 104 The benzyl pendant crown ether 103 was synthesized in 80% yield by the reaction of crown ether 88 with benzyl bromide in the presence of KH. Pyridyl dodecyl ether 104 was obtained in 8% yield. This poor yield may result from the high basicity of the alkoxide from dodecyl alcohol which could react with pyridyl unit of compound 104. Extractions of metal picrates into chloroform were conducted by Mark Eley of the Bartsch Research Group. The pyridyl crown ethers showed poor extractability of alkali metal picrates in general. Crown ethers 98-100 which possess the dibenzo-14-crown-4 unit exhibited selectivity for lithium picrate over other alkali metal picrates. On the other hand, the crown ethers which have an 16- crown-5 unit exhibited extraction selectivity for sodium picrate as would be predicted from their size. The dibenzo-16-crown-5 103 which has benzyl side arm group showed very poor extractability for 51 alkali metal picrates. However, these crown ethers with pendant pyridyl groups exhibited outstanding extraction ability for silver picrate. Among the pyridine containing crown ethers, 98 showed highest extractability for silver picrate. For 98 which has a methyl group and a pyridyl pendant dibenzo-14-crown-4 unit, the percent extraction of silver picrate was 15 times greater than that for lithium picrate, the best extracted alkali metal picrate. Presumably this exceptionally high extractability arises from preorganization of binding site as illustrated in Figure 16. The affinity of nitrogen c^^X^ Figure 16. Proposed Complexation of Silver Cation by Pyridyl Pendant Crown Ether 98. toward silver cation is well known.[60] Therefore cooperative binding of the silver cation by both the pyridyl side arm and the dibenzo-14- crown-4 ring is postulated. The X-ray crystal structures for 82-84[61] which have no alkyl groups geminal to the pendant pyridyl unit shows that the pendant pyridine rings point away from the crown ether ring in the solid state (Figures 17-19). 52 Figure 17. X-ray Crystal Structure of Pyridyl-Pendant Crown Ether 82. Nl C24 C23 Figure 18. X-ray Crystal Structure of Pyridyl-Pendant Crown Ether 83. 53 ClI 04 C12 013 ^^5 Figure 19. X-ray Crystal Structure of Pyridyl-Pendant Crown Ether 84, Crown Ether Xanthates Dibenzo-16-crown-5 xanthates were prepared for evaluation of their alkali metal cation binding properties. Scheme 27 illustrates the synthesis of the crown ether xanthates by reaction of crown ether alcohols with NaH and then carbon disulfide. In the case of crown ether xanthate 105, the pure product was isolated in 56% yield as a yellow solid by recrystallization. Purification of the crude 54 product from the reaction to form 106 was unsuccessful because of the instability of the bright yellow solid product which decomposed Scheme 27 H. ^OH § HxDCS-Na* r^s^N^O O 105 R=H 106 R=t-butyl on prolonged exposure to air. Differentiation of crown ether xanthates 105 and 106 from their precursor alcohols by ^H and l^c NMR and IR spectroscopy was difficult. Formation of crown ether xanthates was verified by treatment with methyl iodide to produce the corresponding xanthanthate methyl esters (Scheme 28). The reactions were followed by TLC and 55 Scheme 28 R-f-oc: :x>^ * CH3. w- «cx: :i>^ ^"'•"•>' III Kbutyl newly formed products were isolated by column chromatography. ^H NMR spectra of both products 107 and 108 clearly showed -SCH3 peak in the region of 2.5-2.6 ppm. Also elemental analysis confirmed formation of the xanthate methyl esters. Attempts to prepare the xanthate from sym-(decyl)hydroxydibenzo-16-crown-5 (109) by reaction of crown alcohol 89 with NaH or KH then carbon disulfide were unsuccessful (Scheme 29). Probably steric bulkness of decyl group prevented the suitable approach of the crown alcohol anion to the carbon disulfide. Scheme 29 S CioH2iv^OH CioHjiv^O-C-SM-^ 56 Methoxy Crown Ethers Major disadvantages of crown ethers for practical use are their high cost and some toxic properties.[62] An attractive method of circumvent both problems is to incorporate the crown ethers in a polymer backbone. The resultant polymer resin can be used as stationary phases for the chromatographic separation of alkali metal and alkaline earth metal cations and their counter anions. Methoxy crown ethers were prepared for use in preparation of ion-exchange resins by condensation polymerization with formaldehyde in formic acid.[63] The synthetic route to methoxy crown ethers is presented in Scheme 30. The straight forward nucleophilie substitution reaction of crown ether alkoxide with methyl iodide was utilized to produce methoxy crown ethers which was previously employed for preparation of compound 110.[64] Crown ether alcohols were reacted Scheme 30 R OCH3 CHJ .0 O, NaH a )0 THF R 110 H 111 CH3 112 C3H7 113 C10H21 57 with two equivalents of methyl iodide and three equivalents of NaH in THF to give corresponding methoxy crown ethers 110-113. In all cases, THF-insoluble precipitates were formed which were thought to be the complex of crown ether with Nal and were unique among the crown ether synthesis. Probably the poor solubility of methoxycrown ethers complexes with the sodium cation in organic solvents is caused by formation of stable complexes with the rather soft counter anion of I" (Figure 20). To circumvent this problem, the crude products were washed with 1 N-NaOH aqueous solution. After evaporation of the reaction solvent, CH2CI2 was added to the crude R ^OCH, .Q ,0, I Figure 20. THF-insoluble Complex of Methoxy Crown Ether with Nal. solid product followed by washing with 1 N-NaOH solution several times to make a homogeneous solution of salt-free methoxy crown ethers. Further purification of the crude product by recrystallization from hexane-THF or column chromatography on alumina with EtOAc- hexane (1:2) solvent mixture gave compounds 110-113 in 56-90% yield. 58 Chromogenic Crown Ethers For the extractive photometric determination of alkali metal ions, two new chromogenic crown ethers were prepared. A trifluoromethyphenylamino functionality was selected as an appropriate chromogenic group to be incorporated into the benzocrown ether ligands. Enhancement of acidity and improved solubility in aqueous media are expected to result from attachment of a trifluoromethylphenyl group to an amino benzocrown ether. Synthetic attempts were made to also introduce a nitro group onto the benzene ring of the crown ether to further enhance the acidity of the chromogenic crown ethers. Scheme 31 shows the synthetic route to a potentially Na-selective chromogenic crown ether 115. Compound 114 prepared by the reaction of 4'-aminobenzo-15- crown-5 with l-chloro-4,6-dinitro-2-trifluoromethylbenzene, according to the literature method.[65] Treatment of 114 with a Scheme 31 CI CF, NaHCO. """Ccf 3 * "X> MeOH 133 Lv°-^ CHCI3 N0/^k/°^ 115 59 solution of equal amount of acetic acid, fuming HNO3 and chloroform gave the desired chromogenic crown ether 115 in 22% yield as a reddish solid after purification of the crude product by column chromatography. For the potential application in selective photometric extraction of lithium ion, chromogenic crown ether 116 which is based on benzo-14-crown-4 was synthesized (Scheme 32). The aminobenzo Scheme 32 145 ^ '^0^ 116 ^ crown ether was reacted with l-chloro-4,6-dinitro-2- trifluoromethylbenzene and sodium bicarbonate in MeOH to give 116 in 22% yield. The introduction of a nitro group onto the benzene ring of 116 was attempted by treatment with AcOH, fuming HNO3 and chloroform. However none of the desired product could be isolated from the complex reaction mixture. Acyclic Polvether Carboxvlic Acids Although cyclic ligand systems generally exhibit better complexation ability for metal ions than their acyclic counterparts, metal ion complexation by acyclic ligands is a topic of considerable 60 interest. It is well-known that the complexation and decomplexation of metal ions by acyclic ligands are more rapid than for closely related cyclic systems.[66] In a few cases acyclic ligands showed better complexation ability than their cyclic analogues.[67] Inspired by these results acyclic ligand systems were designed and synthesized in the present work. Examination of CPK models indicates that an acyclic system with four oxygens and a carboxylic acid side arm should provide a suitable complexation site for a lithium cation. Also positioning of the carboxylic acid group might be influenced by attachment of an alkyl group to the same carbon which bears the side arm (Figure 21). Figure 21. Model of Acyclic Polyether Carboxylate Complexation with a Lithium Cation. Acyclic polyether carboxylic acids with four ethereal oxygens were prepared for investigation of their complexation behavior toward alkali metal cations. Precursor alcohols 117-119 were synthesized by reaction of epichlorohydrin with corresponding methoxyphenoxide in aqueous THF (Scheme 33). The reaction was 61 Scheme 33 H OH A a HpmiF p 1^] CH30 0CH3 -OCH3:0- m -OCHs.O- 117 p- m- 118 P- 119 carried out under high dilution conditions and progress of the reaction was followed by TLC. Initially 0.5 equivalent of epichlorohydrin was used. Subsequently, it was found that the addition of another portion (0.5 equiv) of epichlorohydrin enhanced the yield. The yields acyclic polyether alcohols ranged from 42% to 66%. Acyclic polyether alcohol 117 was oxidized to ketone 120 by Jones reagent in 65% yield. Acyclic polyether compounds with alkyl groups (-C3H7, -C10H21) were prepared by the reaction of ketone 120 with corresponding Grignard reagents in THF to give acyclic polyether alcohols 121 and 122 in 69% and 47% yields, respectively (Scheme 34). 62 Scheme 34 H_OH o o / o o\ u CH/ CH, 12 0 CH/ CH CsHvMgBr / \C10H21MgBr CaHv^OH / \ Cio"2i wOH 0 0 o 0 / CH3/ CH3 C^3 CH3 121 122 Acyclic polyether alcohols 117-119 and 121-122 were converted into the corresponding acyclic polyether carboxylic acids 123-127 by reaction with KH (6 equivalents of 35% dispersion in mineral oil) in THF followed by addition of bromoacetic acid (Scheme 35). The crude products were purified either by recrystallization or column chromatography to give acyclic polyether carboxylic acids 123-127 in 67-90% yields. 63 Scheme 35 R^OH R^OCHjCOOH .0 O KH + BrCHnCOOH THF a. 0 O p a p CH / CH, o q 3 CH/ CH3 J, H 123 H C3H7 12 4 C3H7 ^10^21 ^10^21 ^^^ R^OH R^OCHjCOOH .0 O .0 o (^ IQ) + BrCH2C00H KH THF CH O OCH, 0 Q CH30 -OCH;^ -0CH2 m 118 m 126 p 119 P 127 The alkali metal cation binding property of acyclic polyether ligands prepared in this study will be tested by titration calorimetry. Recently, Dr. Hayashita of the Bartsch Research Group prepared the condensation polymers of acyclic monomers 123 and 124 and the resultant resin showed lithium selective sorption ability.[68] 64 Chemical Modification of Nafion® lonomer Membrane The goal of this phase of the research was to prepare new synthetic polymeric ionomer membrane materials by attachment of alkali metal ion chelating reagents to the surface of a commercially available membrane to produce a metal ion recognition site or ion channel gate. As the commercially available membrane Nafion® 117 128 (0.007 inch Uiick, equivalent weight 1100)[69] was selected because of its cation exchange properties and chemical inertness. Monoazacrown ethers and 4'-aminobenzo-crown-ethers which have specific interactions with alkali metal cations were chosen as the chelating agents to be attached to the surface of the Nafion® 117 membrane. The structure of Nafion® 117 and the crown ether compounds are shown in Figure 22. OCFj-CF-O-CFj-CFj-SOjH 128 CF3 s RfSOsH (Nafion® 117) (^O^ H2N, '^ 129 1 132 1 130 2 133 2 131 3 134 3 135 4 Figure 22. Structures of Nafion® 117 and Crown Ethers to be Attached to the Membranes. 65 Preparation of the known monoaza crown ether compounds was attempted by three different synthetic routes. The first route was reaction of diethanolamine with sodium metal in t-BuOH to produce dianion 136 followed by addition of polyethyleneglycol ditosylate in dioxane (Scheme 36).[70] Purification of the crude Scheme 36 H H I ^v'r^n ^ XT t-BuOH . I—^'^—I HO N OH + Na Na -O N CTNa H TsO 0 O OTs a p-Dioxane 1 130 n= 1, 2 '^O 0^° 2 131 products by high vacuum (1 X 10-3 mm Hg) distillation only gave modest yields because the products were thermally decomposing during the distillation process. The second route utilized N-tosyl protected diethanolamine 137 followed by removal of the tosyl group (Scheme 37). Reaction of diethanolamine with p.-toluene sulfonyl chloride in the presence of potassium carbonate gave N- tosyl diethanolamine 137 in 70% yield.[71] N-Tosylmonoaza-15- crown-5 (138) was obtained by the reaction of 137 and triethyleneglycol ditosylate in 31% yield. 66 Scheme 37 w Ts HO^N^H ^ CH3-Q^S02a^|j0^ HO N QH 137 Ts H I ' 1) 2 NaH /-N-\ y^N"\ THF-DMF (1:4) ^ ,-<0 o--> , 6% Na(Hgr—) ^ r<^ o-> ^ r^r\r-\ r^ ^1 Na2HP04 L ^J 2)TsO O O OTs ^O^^ MeOH O^J^ 138 Removal of the tosyl group was carried out by treatment with 6% sodium amalgam to give monoaza-15-crown-5 (130). The third route followed a procedure reported by Gokel,[72] which provided rather clean and high yield syntheses of the monoazacrown ethers. In this route, a benzyl group was used as the protecting group of the amine function of diethanolamine. Almost quantitative deprotection was accomplished by catalytic hydrogenation. By use of this route, large amounts of monoaza-15-crown-5 (130) and monoaza-18- crown-6 (131) were prepared. Preparation of the 4'-aminobenzo crown ethers with various ring sizes was carried out by nitration and reduction of the appropriate benzocrown ethers. The synthetic route for the 4'- aminobenzocrown ethers is summarized in Scheme 38. Nitration of the benzocrown ethers was achieved by treatment with a solution of 67 Scheme 38 fY^'^? O) ' HNO"^^3 > 0,N.^^O.N^^^^O'^ ^>^ 139 J "iv:^ O. AcOH OJL^ ^S 140 3 142 5 10% Pd/C n 133 J3 ml y^™^NH. 134 4 5% Pd/C n. 132 2 --al 135 5 glacial acetic acid, fuming nitric acid and chloroform.[73] Compounds 139-142 were obtained in 68-86% yield. Reduction of the nitro group was performed by two different methods. For compounds 133 and 134, catalytic hydrogenation with 10% Pd on carbon at 40 psi of hydrogen in DMF was used to give desired products in 84- 100% yields.[74] Reaction of 132 and 135 with anhydrous hydrazine and 5% Pd on carbon in THF-EtOH at reflux provided the reduced products 132 and 135 in 92% and 100% yields, respectively. There was no substantial difference in effectiveness between these two hydrogenation methods. Preparation of 4'-aminobenzo-14-crown-4 was also attempted (Scheme 39). Initial reaction of benzo-14-crown-4 with fuming nitric acid, AcOH and chloroform for 24 h gave only dinitrated compound 143 in 62% yield. However, by use of a shorter reaction 68 Scheme 39 n HNO3 ^^v^*=^0 o AcOH CHCI3 24 h 143 HN03 AcOH CHCI3 12 h t NH2NH2 HzN^^^^cfi U^OO^ 5% Pd/C XAO O^ 14 4 \^ 145 time (1 h) only the mononitrated product 144 was obtained in 79% yield. Reduction of 144 by use of anhydrous hydrazine and 5% Pd on carbon provided 4'-aminobenzo-14-crown-4 (145) in quantitative yield. To investigate potential structural effects of the coupling reagent when bonded to Nafion®, an acyclic polyether compound 148 with a secondary amine group was prepared. Scheme 40 shows the synthetic route to 8-aza-2,5,ll,14-tetraoxapentadecane. Reaction of p.-toluenesulfonamide with 2-(2-chloroethoxy)ethanol in the presence of anhydrous potassium carbonate gave tosyl-protected diol 146 in 68% yield.['73] Subsequent treatment with sodium hydride and methyl iodide produced dimethoxy compound 147 in 81% yield. 69 Scheme 40 r-TT_/=\ o^ / v/—V K2CO3 / \/ \ ™3-A /~S02NH2 + n''^ U Viu • Ts-N O OH ^^_J^ ^ 2 CI O OH DMF Y O OH 146 CH3l,NaH / yOorH 6%Na(Hg) O/^ OCH3 THF V_/ \_J^^ Na2HP04 ^O^0CH 3 147 148 The desired acyclic polyether compound 148 was obtained by removal of the tosyl group in 60% yield with 6% sodium amalgam in dioxane-methanol. For attachment of crown ethers with secondary or primary amine groups to the Nafion®-H, the sulfonic acid groups must be transformed into reactive sulfonyl chloride functions. Based upon the literature precedent,[74] it should be possible to convert Nafion® perfluorosulfonic acid membrane 128 into the sulfonyl chloride form 149 followed by reaction with monoazacrown ethers or 4'- aminobenzo crown ethers to provide different types of ionophoric sulfonamides (Scheme 41). 70 Scheme 41 ^<^o^ p C M O Monoazacrown ethers ^i f. , \ / " o k^o^ RfSOsH —<- RfS02a n=1 - 3 149 \ O H y—, 4'-Aminobenzocrown ethers *^f \) V^^V^ I ^^O 0^" ^^ n = l-4 For the first attempted chlorination of Nafion® 117 membrane, the procedure reported in a Japanese patent was employed (Method I).[37] Thus, a 2" X 2" piece of Nafion® 117 membrane was immersed in 0.5 N-NH4OH aqueous solution for 48 h then washed with water to neutral pH and dried to give the ammonium sulfonate form 150. It was noted that this pre-treatment stiffened the membrane and made it difficult to stretch. Compared with the original Nafion®-H membrane, a weight loss of about 3.5% was noted for the ammonium sulfonate form. The membrane piece 150 was refluxed in the mixture of PCI5-POCI3 (1:2 w/w) for 24 h to make sulfonyl chloride form 151 (Scheme 42). 71 Scheme 42 (Method I) 0 O P " ^„ 1)0.5 NNH4OH n . + Rf-S-OH :i ^ R S-ONH4 O 2) Washed with H2O ^ 3) Dried 150 1) PCl5-POCl3(l:2 w/w) A, 24 h II ^ Rf-S—a 2) Washed with CCI4 6 3) Dried 1^1 The sulfonyl chloride form of the membrane 151 was flexible and white in color. Compared with the original Nafion®-H membrane piece, the sulfonyl chloride forms usually showed a very modest weight gain (Table 10). Another four sulfonyl chloride membranes (152-155) were prepared by the same procedure and reacted with monoaza crown ethers 129-131 and 4'-aminobenzo-15-crown-5 (133) in the presence of triethylamine (Scheme 43). Scheme 43 Et3N,THF 151+ Monoaza-15-crown-5 •Membrane 156 A ,^-, w ic if Et3N,DMF 15 2 + Monoaza-15-crown-5 L_ »• Membrane 157 O Dc^ic^^w 10 A Et3N,DMF Rf~S—a 153 + Monoaza-18-crown-6 £: • Membrane 158 O ^ , Et3N, DMF 154+ Monoaza-12-crown-4 fl- »• Membrane 159 ^ Et3N, DMF 155 + 4'-Aminobenzo-15-crown-5 »-Membrane 160 72 The first coupling reaction of monoaza-15-crown-5 (130) with the sulfonyl chloride membrane 151 in refluxing THF for 12 h produced an inhomogeneous membrane 156 with a bubbled surface. This problem disappeared when the solvent was changed to DMF (membrane 157). Membranes 158 and 159 which were obtained in DMF had good physical appearance. However, the 4'-aminobenzo- 15-crown-5 coupled membrane 160 appeared to be very inhomogeneous. In view of these initial results, the synthetic efforts for modification of Nafion®-H membrane were mainly made with monoazacrown ethers. The results of chemical modification of Nafion®-H by Method I are summarized on Table 10. Permeation testing[38] of membranes 156-159 showed no transportation of alkali metal ions under conditions for which unmodified Nafion® gave good transport. Thus, it appeared that the chemical procedures which were utilized for covalent attachment of the crown ethers were highly disruptive to the membrane properties. To determine if the problem was in the sulfonyl chloride-forming step, a series of experiments was conducted in which Nafion®-H membrane was converted into the sulfonyl chloride form and then hydrolyzed back to the sulfonic acid form. Three different Nafion®-H (2" X 2" size) were refluxed with PCI5-POCI3 (1:2 w/w) for varying periods of time to give sulfonyl chloride forms 73 Table 10. Chemical Modification of Nafion® Membrane by Method I. Weight change Coupling product for RfSOiCl Coupling Weight form, % Agent^ Solvent Shape change^, % 156 +7.5 130 THpd bad -9.0 157 -0.3 130 DMFd OK -5.6 158 +2.0 131 DMFd OK -9.4 159 +0.1 129 DMpd OK -9.6 160 +3.5 133 DMFe OK -14.6 ^With 2.0 equiv of the crown ether compound and 1.0 equiv of triethylamine. ^Relative to the weight of the original RfSOsH form. ^Relative to the weight of the RfS02Cl form. ^Refluxed for 12 hours. ^Refluxed for 24 hours. 161-163 and which were then hydrolyzed to sulfonic acid forms 164-166 by refluxing in 5% NaOH aqueous solution followed by acidic treatment with 5% HCl aqueous solution. Also Nafion®-H membrane was refluxed in 5% NaOH for 24 hours and then acidified with 5% HCl (membrane 167) for comparison with untreated Nafion®-H (Scheme 44). The results are summarized in Table 11. The membrane from the shorter chlorination time showed a weight increase. When membranes 164-167 were subjected to permeation 74 Scheme 44 PCI5-POCI3 1)5% NaOH, 24 h, A RfS03H ^^'^ ^^^)> RfS02a —^ RfSOsH* 2)5% HCl, 1 h 1)5% NaOH Chlorination time 24 h, A 24 h 161 164 2)5% HQ 4h 162 165 1 h 1 h 163 166 * Regenerated Nafion®-H Table 11. Conversion of Nafion® Membrane to the Sulfonyl Chloride Form Followed by Hydrolysis. Reflux with RfSOiCl form Membrane PCI5-POCI3, h weight change^ % Appearance 164 24 -2.4 flexible with white color 165 +3.2 flexible with white color 166 1 +5.2 stiffened 167 0 ^Relative to the weight of original RfSOsH form. 75 testing, membranes 166 and 167 gave very good metal cation permeation with a selectivity order which is very similar to diat of unmodified Nafion® membrane. On the other hand, membranes 164 and 165 gave very low alkali metal cation permeation (Table 12).[38] Table 12. Effect of Chlorination Time upon Alkali-metal Cation Permeation.[38] Reaction Permeation Cone in Receiving Phase (mM) Membrane time, h time, h Li+ Na+ K+ Rb+ Cs"*- fion 117 7 3.19 3.78 4.44 4.22 3.90 164 24 24 0.03 0.11 0.09 0.00 0.00 165 4 15 0.00 0.34 0.16 0.00 0.00 166 1 15 4.65 6.27 6.46 6.45 6.35 167 0 15 5.89 7.71 8.40 8.50 8.30 These results indicate the use of longer chlorination times is detrimental to the permeation properties of the membranes. To investigate the dependence of time and temperature on the coupling reaction of the sulfonyl chloride membrane with monoazacrown ethers, a set of experiments was conducted. For these experiments, monoaza-15-crown-5 was chosen as a model coupling agent. Five pieces of Nafion®-H membranes were converted into the sulfonyl chloride forms 168-172 with reaction times varying from 1 to 3 hours. After the reaction, the membranes were washed several 76 times with brief refluxing in CCI4 and then dried for one day under vacuum. The sulfonyl chloride forms 168-171 were then reacted with two equivalents of monoaza-15-crown-5 and one equivalent of triethylamine in DMF at reflux or 50^0 to produce membranes 173- 176. In addition one sulfonyl chloride membrane 172 was heated for 48 h in DMF in the absence of the monoazacrown ether to give membrane 177. The procedures are summarized in Scheme 45. There was a 3-5% weight increase for sulfonyl chloride membranes Scheme 45 (Method II) PCI5-POCI3 f^O 0, (1:2 w/w) _ -_. ^ Monoaza-15-crown-5 „ gQ ^ J RfSOsH -RfSOaQ ^^^^ f mj Chlorination time (h) Reflux ^ ^ ^ 1 168 ^ 173 Reflux 2 169 ^ 174 Reflux 3 170 ^ 175 50°C 3 171 ^ 176 3 172 RfS02a ^^ ^ RfSOiQ* 17 2 50 °C.48 h 17 7 168-172 compared to corresponding original Nafion®-H membranes. Membranes 173-175 which were formed by coupling at reflux were swollen and remained so even after drying. When the temperature 77 for coupling was reduced to 50 ^C, membrane 176 was produced which was initially swollen, but returned nearly to its original size after drying. Contrary to membranes 173-175 for which the coupling was performed at reflux and a significant weight increase with membrane 176 for which the coupling was conducted at 50 °C. For membrane 177, a swollen membrane was produced which returned nearly to the original size after drying. However, a significant weight loss was experienced instead of the weight gain which was found with membrane 176. The results are summarized in Table 13. Based upon these results, a coupling reaction of the sulfonyl chloride membrane obtained from a 3 hour chlorination reaction with a monoazacrown ether for 48 hour at 50 ^C was selected as the optimum reaction conditions. Having determined the best chlorination time and coupling reaction condition, membranes modified with monoazacrown ethers and other secondary amines were prepared. Membranes modified with diethylamine, dibutylamine, morpholine bis(2- methoxyethyl)amine, and 8-aza-2,5,ll,14-tetraoxapentadecane (148) were also prepared to compare their permeation properties with those for monoazacrown ether modified membranes (Scheme 46). After the coupling reactions the resultant membranes were washed with CH2CI2 and then immersed in water. Modified membranes 178-185 had good physical appearance (transparent yellowish film). The modified membranes were subjected to 78 Table 13. Chemical Modification of Nafion® Membrane with Monoaza-15-crown-5 by Method II. RfS02Cl form Membrane Weight Appearance Coupling Coupling product change^ Time Temp. Weight Appearance % h change,^% 173 +5.0 stiffened 12 reflux -24.0 swollen 174 +3.2 stiffened 20 reflux -8.2 swollen 175 +4.8 flexible 24 reflux -7.2 badly distorted 176 +4.1 flexible 48 50 oc +6.2 c 177d +3.5 flexible 48 50 oc -6.4 c ^Relative to weight of original RfSOsH form. ^Relative to the weight of the RfS02Cl form. cSwollen but returned nearly to the original size after drying. ^Obtained without use of coupling agent. 79 Scheme 46 j^ Et^, DMF /\ RfS02Cl*+H-N RfSOrN \y 48 h, 50°C \y 178 H-N RfSOrN^^^ 179 H-N O •^— RfSOr-N^o^gQ .As^OCH. ^^s^0CH3 H-N V^, OCH, ^^^0CH3 r-^ 181 (^O OCH3 H-N -^ OCH, '^^^°-l^0j)CH3 ^ 182 H-N O RfSOrN o Co O. f^O o RfSOrN H-N J k.oj). 184 Co o^ H-N ^ O RfSOrN ^ o, \J V7 185 * Made from 3 h chlorination time permeation testing toward alkali metal cationst^S] with a dialysis experiment. The results are recorded in Table 14. When diethylamine, dibutylamine, and morpholine were coupled with the sulfonyl chloride form, little permeation of the 80 alkali metal cations was observed in the resultant membranes. When the oxygen number of the secondary amine was increased, however, the permeation efficiency was improved. The membranes which had been coupled with acyclic amine 182 or cyclic polyether amine 183-185 having more than three oxygen atoms gave efficient permeation that was comparable with that for the original Nafion®-H membrane. Membrane 182 exhibited intermediate permeation. Table 14. Influence of Coupling Agents upon Alkali-Metal Cation Permeationt38] Membrai ne Permeation Concentration in receiving Dhase Cmmol/L) Time (h) Li+ Na+ K+ Rb+ Cs+ Nafion® 117 7 3.19 3.78 4.44 4.22 3.90 178 7 0.00 0.04 0.12 0.13 0.00 179 7 0.00 0.00 0.00 0.00 0.00 180 7 0.00 0.02 0.19 0.00 0.00 181 7 0.11 0.23 0.47 0.58 0.76 182 7 1.98 2.95 4.10 4.17 4.59 183 7 0.53 1.40 3.03 3.65 4.25 184 7 1.40 2.47 4.28 4.63 5.08 185 7 0.51 0.91 1.47 1.58 1.95 aThe source solution was 1.0 mM in each of the five alkali metal cations at pH=ll. 81 These results suggests that the hydrophilicity of the channel site of the membrane plays an important role in metal ion permeation. These results indicate that the polyether units can behave as a channel gate for metal permeation. The permeation selectivity order for the monoazacrown ether-modified Nafion® membrane was Cs+>Rb+>K+>Na+>Li+ which differs from the ordering of K+>Rb''">Cs+>Na+>Li+ observed for unmodified Nafion® membrane. In addition, the overall range of selectivities for the modified Nafion® membranes is greater than that for unmodified Nafion® membrane. These results verify that the covalent attachment of the monoazacrown ethers onto the surface of Nafion®-H membrane was successful. To further confirm the presence of monoazacrown ethers in the modified membrane, FT-IR spectra of Nafion®-117, Nafion®- monoaza-12-crown-4 (183) and Nafion®-monoaza-15-crown-5 (184) membranes were investigated by attenuated total reflectance (ATR) analysis.['^'7] Figure 23 shows the ATR spectra for the three membranes. For the crown ether-modified membranes, there are significant decreases in the strength of the 1057 cm-1 absorption due to the symmetric S-0 stretching vibration for sulfonic acid. This would be expected if sulfonamide groups were present in the Nafion®-H membrane. This result again verifies the covalent attachment of monoazacrown ethers onto the Nafion®-H membrane. 82 O.OB- 0.06- 0.04- 1* « 0.02- M ^^ »^-^^ 0.00- i 1 1 1 1 1 1 1 i 1350 1300 1250 1200 1150 1100 1050 1000 950 Hdventisibers Figure 23. IR Spectrum of Nafion® 117 (*), Nafion®-monoaza-12- crown-4 (**) and Nafion®-monoaza-15-crown-5 (#). Summary The highly efficient cyclization method for aromatic group containing crown ethers utilizing cesium carbonate, polyethyleneglycol dimesylate and CH3CN has been discovered. A series of 1,3-xylyl crown ethers has been prepared to study their alkali metal binding properties by calorimetry. Various kinds of pyridyl crown ethers with different size of the macrorings and sizes of alkyl group have been synthesized. Among them 83 sym-(methyl)picolyoxy-dibenzo-14-crown-4 exhibited outstanding extraction ability toward silver picrate. Acyclic polyether carboxylic acids and methoxy crown ethers have been prepared to make ion- exchange polymer resins by condensation polymerization of crown ether carboxylic acids with formaldehyde in formic acid. Two new chromogenic crown ethers which have potential for selective extraction of lithium and sodium cations have been prepared. The optimum reaction time for surface chlorination of Nafion®- H membrane was found. The best coupling reaction condition between Nafion® sulfonyl chloride form and monoazacrown ethers were established. By use of these results, ionophore molecules have been successfully introduced at or near the two surfaces of Nafion® membrane. 84 CHAPTER m EXPERIMENTAL PROCEDURES Instrumentation and Reagents Melting points were determined with a Fisher Johns melting point apparatus and are uncorrected. iH NMR spectra were taken with an IBM AF-200 nuclear magnetic resonance spectrometer. The chemical shifts are expressed in parts per million (ppm) downfield from tetramethylsilane. Infrared spectra were taken with a Nicolet MS-X FT-IR or Perkin-Elmer 1600 Series FT-IR spectrophotometer on NaCl plates and are given in wavenumbers (cm^l). Mass spectra were obtained with Hewlett Packard 5995 GC/MS spectrometer. Unless specified otherwise starting materials and solvents were reagent grade and used as received from chemical suppliers. Dry solvents were prepared as follows: pyridine and pentane were dried over KOH pellets, N,N-dimethylformamide (DMF) was dried over 4A molecular sieves or MgS04; tetrahydrofuran (THF) was distilled from Na and benzophenone; tert-butyl alcohol was distilled from CaH2; MeOH was distilled from magnesium turnings to which a crystal of iodine had been added; and EtOH was dried by azeotropic distillation in the presence of benzene. Thin layer chromatography (TLC) was performed with either Analtech Alumina OF or Silica GF prepared plates. The glass plates were precoated with 250 mm thicknesses of silica gel and alumina. 85 Column chromotography was performed using either alumina (80- 200 mesh) or silica gel (60-200 mesh) from Fisher Scientific. Elemental analysis was performed by Desert Analytics (Tucson, AZ) and Galbraith Laboratories (Knoxville, TN). l,3-Bis(m-methoxyphenoxy)-2-propanol (118) and monoaza- 12-crown-4 (129) were available from other studies.^78.79] sym- (Hydroxy)(propyl)dibenzocrown ethers 88 and 96 were prepared by reported procedures.t68,80] Nafion® 117 membrane was purchased from Aldrich Chemical Company. General Procedure for the Preparation of Benzo- and Dibenzocrown Ethers Under nitrogen, the diol or bisphenol (2.09 g, 19.0 mmol) was dissolved in 100 mL of MeCN and powdered CS2CO3 (15.48 g, 47.50 mmol) was added. The resulting mixture was refluxed for 3 h. To the mixture, the appropriate dimesylate (6.48 g, 19.0 mmol) in 50 mL of MeCN was added during an 8-h period with a syringe pump. After an additional 24 h at reflux, the reaction mixture was cooled to room temperature and filtered through a pad of Celite on a sintered glass funnel. The collected solid was washed with CH2CI2 (20 mL). The combined filtrate and washing were evaporated in vacuo and the residue was dissolved in CH2CI2 (100 mL). The solution was washed with water (50 mL) and dried over MgS04. After evaporation of solvent in vacuo, the residue was chromatographed on alumina with EtOAc as eluent. 86 Monobenzo-12-crown-4 (30). A white solid with mp 44-46 OC (lit[2] mp 45-46 oC ) was obtained in 45% yield. IR (deposit from chloroform on NaCl plate): 1060 (C-0) cm-l. iH NMR (CDCI3): 5 3.32- 4.35 (m, 12H), 6.48-7.12 (m, 4H). Monobenzo-14-crown-4 (39). After chromotography the 2 + 2 cyclization product was separated by recrystallization from benzene to provide monobenzo-14-crown-4 as a colorless oil in 76% yield. IR (neat): 1120 (C-0) cm-l. 1H NMR (CDCI3): 6 1.96-2.07 (m, 4H), 3.61-3.85 (m, 8H), 4.01-4.35 (m, 4H), 6.88-7.11 (m, 4H). Anal. Calcd for C14H20O4: C, 66.64; H, 7.99. Found; C, 66.66; H, 7.88. The 2 + 2 cyclization product, dibenzo-28-crown-8, had mp 98-99 ^C. IR (deposit from chloroform on a NaCl plate): 1124 (C-0) cm-l. 1H NMR (CDCI3): 5 1.98-2.11 (m, 8H), 3.46-3.70 (m, 16H), 4.03-4.08 (m, 8H), 6.89-7.06 (m,8H). Anal. Calcd. for C28H40O8: C, 66.64; H, 7.99. Found: C, 67.00; H, 8.16. Monobenzo-15-crown-5 (6). A white solid with mp (litt^l mp 79-79.5 ^C) was obtained in 71% yield. IR (deposit from chloroform on a NaCl plate): 1121 (C-0) cm-l. 1H NMR (CDCI3): 5 3.78 (S, 8H), 3.69-3.93 (m, 4H), 4.11-4.16 (m, 4H), 6.84-6.94 (m, 4H). Monobenzo-18-crown-6 (7).t2] A yellowish oil was obtained in 65% yield. IR (neat): 1128 (C-0) cm-l. IR NMR (CDCI3): 5 3.55- 3.94 (m, 16H), 4.13-4.18 (m, 4H), 6.80 (s, 4H). Monobenzo-21-crown-7 (8).t43] A colorless oil was obtained in 81% yield. IR (neat): 1113 (C-0) cm-l. IR NMR (CDCI3): 5 3.64- 4.42 (m, 24H), 6.89-7.12 (m, 4H). 87 Mono[4(5)-tert-butylbenzo]-21-crown-7 (41).[58] A colorless oil was obtained in 77% yield. IR (neat): 1121 (C-0) cm-l- IH NMR (CDCI3): 5 1.3 (S.9H) 3.4-4.3 (m, 24H) 6.64-7.18 (m,3H). Dibenzo-12-crown-4 (54). The crude product was chromatographed on silica gel with EtOAc-hexane (1:2) as eluent and then recrystallized from CH2Cl2-hexane to give a white solid with mp 208 OC (lit[2] mp 208-209 oC) in a 12% crude yield. MS: m/z 272 (M+). IR (deposit from chloroform on a NaCl plate): 1129 (C-0) cm-l. IH NMR (CDCI3): 5 4.33 (s, 8H), 6.97-7.05 (m, 8H). Dibenzo-13-crown-4 (52). The crude product was chromatographed on alumina with EtOAc-hexane (1:2) as eluent and recrystallized from CH2CI2-CH3OH to give a white solid with mp 134- 135 oc (lit[45] mp 134-136 oQ in a 74% yield. MS m/z 286 (M+). IR (deposit from chloroform on a NaCl plate): 1116 (C-0) cm-l. in NMR (CDCI3): 5 2.10-2.21 (m, 2H), 4.08-4.34 (m, 8H), 6.86-7.07 (m, 8H). Dibenzo-14-crown-4 (51). The crude product was chromatographed on alumina with EtOAc-hexane (1:3) as eluent to give a white solid with mp 149-151 oc (lit[2] mp 150-152 oQ in 92% yield. IR (deposit from chloroform on a NaCl plate): 1126 (C-0) cm-l. IH NMR (CDCI3): 5 2.28 (m, 4H), 4.25 (t, 8H), 6.92 (m, 8H). Dibenzo-15-crown-5 (44). The crude product was chromatographed on alumina with EtOAc-hexane (1:4) as eluent to give a white solid with mplll-114 oc (lit[2] mp 113-115 oQ in a 57% yield. IR (deposit from chloroform on a NaCl plate): 1123 (C-0) cm-l. 88 IH NMR (CDCI3): 5 3.95 (t, 4H), 4.19 (t, 4H), 4.38 (s, 4H), 6.92-6.94 (m, 8H). Dibenzo-16-crown-5 (46). A white solid with mp 115-117 oc (lit[2] mp 117-118 oQ was obtained in a 83% yield. IR (deposit from chloroform on a NaCl plate) 1123 (C-0) cm-l. IR NMR (CDCI3): 5 2.15-2.34 (m, 2H), 3.62-4.29 (m, 12H), 6.83-7.04 (m, 8H). lLILSXm.-Dibenzo-18-crown-6 (45). A white solid with mp 117-119 oc (lit[2] mp 117-118 oQ was obtained in a 75% yield. IR (deposit from chloroform on a NaCl plate): 1128 (C-0) cm-l. ijj NMR (CDCI3): 5 3.82-3.93 (m, 8H), 4.16-4.20 (m, 4H), 4.42-4.57 (m, 4H), 6.89-6.99 (m, 8H). Dlbenzo-19-crown-6 (47). The crude product was chromatographed on silica gel with EtOAc-hexane (1:2) as eluent to give a white solid with mp 84-86 oC (lit[2] mp 85-86 oQ in a 61% yield. IR (deposit from chloroform on a NaCl plate): 1124 (C-0) cm-l. IH NMR (CDCI3): 5 2.20 (m, 2H), 3.74-3.82 (m, 8H), 3.99-4.19 (m, 8H), 6.76-6.91 (m, 8H). Dibenzo-21-crown-7 (48). A white solid with mp 104-106 oc (lit[2] mp 106.5-107.5 oC) was obtained in 78% yield. IR (deposit from chloroform on a NaCl plate): 1125 (C-0) cm-l. 1H NMR (CDCI3): 5 3.87-4.21 (m, 20H), 6.86-6.94 (m, 8H). svm-Dir4(5)-tert-butvlbenzo1-2l-crown-7 (49) The crude product was chromatographed on alumina with EtOAc-hexane (1:2) as eluent and then recrystallized from Et20 to give white solid with mp 87-89 oc (lit[58] mp 86-88 oC) in 67% yield. IR (deposit 89 from chloroform on a NaCl plate): 1146 (C-0) cm-l. 1H NMR (CDCI3): 5 1.28 (s, 18H), 3.84-4.23 (m, 20H), 6.77-7.26 (m, 6H). l,8-Naphtho-16-crown-5 (56). A white solid with mp 112- 114 oc (lit[39] mp 110-112 oc) was obtained in 77% yield. IR (deposit from dichloromethane on a NaCl plate): 1281, 1114 (C-0) cm-l. 1H NMR (CDCI3): 5 3.65-3.85 (m, 8H), 3.99-4.26 (m, 8H), 6.77-6.81 (m, 2H), 7.26-7.39 (m, 4H). l,8-Naphtho-19-crown-5 (57).[39] A yellow oil was obtained in 80% yield. IR (deposit from dichloromethane on a NaCl plate): 1281, 1111 (C-0) cm-l. 1H NMR (CDCI3): 5 3.64-3.87 (m, 12H), 4.02-4.27 (m, 8H), 6.79-6.86 (q, 2H), 7.26-7.42 (m, 4H). l,8-Naphtho-22-crown-7 (58). A colorless oil was obtained in 54% yield. IR (deposit from dichloromethane on a NaCl plate): 1280, 1112 (C-0) cm-l. 1H NMR (CDCI3): 5 3.68-3.85 (m, 16H), 3.99- 4.14 (m, 4H), 4.23-4.28 (m, 4H), 6.83-6.87 (q, 2H), 7.26-7.42 (m, 4H). Anal. Calcd for C22H30O7: C, 65.01; H, 7.44. Found: C, 65.07; H, 7.26. o,o'-Biphenyl-17-crown-5 (59). A white solid with mp 105-108 oc (lit[46] mp 105-107 oC) was obtained in 64% yield. IR (deposit from dichloromethane on a NaCl plate): 1264, 1130 (C-0) cm-l. IH NMR (CDCI3): 5 3.47-3.61 (m, 12H), 3.98-4.22 (m, 4H), 6.92- 7.34 (m, 8H). o,o'-BiphenyI-20-crown-6 (60).[46] A colorless, sticky oil was obtained in 75% yield. IR (deposit from dichloromethane on a NaCl plate): 1263, 1126 (C-0) cm-l. 1H NMR (CDCI3): 5 3.55-3.76 (m, 16H), 3.98-4.22 (m, 4H), 6.94-7.34 (m, 8H). 90 o,o*-Biphenyl-23-crown-7 (61).[46] A colorless oil was obtained in 73% yield. IR (deposit from dichloromethane on a NaCl plate): 1263, 1125 (C-0) cm-l. IR NMR (CDCI3): 5 3.51-3.75 (m, 20H), 4.06-4.26 (m, 4H), 6.95-7.33 (m, 8H). 2,2'-Binaphtho-17-crown-5 (62).[46] A white solid with mp 112-113 oc (lit[46]ii4-115 oC) was prepared in 52% yield. IR (deposit from dichloromethane on a NaCl plate): 1262, 1133 (C-0) cm-l. IH NMR (CDCI3): 5 3.20-3.68 (m, 12H), 3.97-4.26 (m, 4H), 7.13- 7.34 (m, 6H), 7.41-7.50 (d, 2H), 7.83-7.95 (m, 4H). 2,2*-Binaptho-20-crown-6 (63). A colorless solid with mp 129-131 oc was obtained in 80% yield. IR (deposit from dichloromethane on a NaCl plate): 1271, 1132 (C-0) cm-l. 1H NMR (CDCI3): 5 3.35-3.67 (m, 16H), 4.00-4.20 (m, 4H), 7.14-7.35 (m, 6H) 7.44-7.48 (d, 2H), 7.83-7.95 (m, 4H). 2,2*-Binaptho-23-crown-7 (64).[46] A colorless oil was obtained in 85% yield. IR (deposit from dichloromethane on a NaCl plate): 1265, 1133 (C-0) cm-l. IR NMR (CDCI3): 5 3.31-3.66 (m, 20H), 4.02-4.17 (m, 4H), 7.06-7.35 (d, 2H), 7.83-7.95 (m, 4H). N,N'-Ditosyl-4,13-diazadibenzo-18-crown-6 (69). A white solid with mp 218-219 oc (lit[48] 219-220 oC) was obtained in 74% yield. IR (nujol): 1461, 1328 (S=0); 1115 (C-0) cm-l . in NMR (CDCI3): 5 2.41 (s, 6H), 3.71-3.77 (m, 8H), 4.09-4.15 (m, 8H), 7.30 (d, 4H), 7.72 (d, 4H). 91 N-Tosylmonoazadibenzo-18-crown-6 (70). A white solid with mp 159-160 oc (lit[49] mp 159-160 oC) was obtained in 72% yield. IR (deposit from dichloromethane on a NaCl plate): 1332,1255 (S=0); 1124 (C-0) cm-l . IH NMR ( CDCI3): 5 2.37 (s, 3H), 3.75-4.21 (m, 16H), 6.71-6.91 (m, 8H), 7.26 (s, 2H), 7.74 (s, 2H). 2,3-Pyridino-15-crown-5 (71).[40] A white solid with mp 63-65 oc (lit[40] mp 64.5-65.5oC) was obtained in 14% yield. IR (deposit from dichloromethane on a NaCl plate): 1204, 1124 (C-0) cm-l. IH NMR (CDCI3): 5 3.69-3.94 (m, 12H), 3.87-3.94 (t, 2H), 4.47- 4.51 (t, 2H), 6.77-6.98 (q, IH), 7.04-7.09 (d, IH), 7.70-7.74 (d, IH). 2,3-Pyridino-18-crown-6 (72).[40] A yellow solid with mp 76-78 oc was obtained in 37% yield. IR (deposit from dichloromethane on a NaCl plate): 1204, 1125 (C-0) cm-l. IH NMR (CDCI3): 5 3.63-3.95 (m, 16H), 4.13-4.17 (m, 2H), 4.50-4.54 (m, 2H), 6.77-6.84 (q, IH), 7.0-7.07 (d, IH), 7.69-7.72 (d, IH). 2,3-Pyridino-21-crown-7 (73).[40] A colorless oil was obtained in 22% yield. IR (deposit from dichloromethane on a NaCl plate): 1257, 1123 (C-0) cm-l. IH NMR (CDCI3): S 3.63-3.96 (m, 20H), 4.14-4.18(m, 2H), 4.50-4.54 (m, 2H), 6.78-6.84 (q, IH), 7.05- 7.09 (d, IH), 7.70-7.73 (d, IH). General Procedure for Preparation of 1.3-Xvlvl Crown Ethers 76-78 Potassium hydride (3.43 g, 30.0 mmol, 35% dispersion in mineral oil) was washed with pentane (2 X 20 mL) and suspended in 50 mL of THF. With stirring under nitrogen, a solution of 92 polyethylene glycol (10.0 mmol) in 50 mL of THF was added dropwise during 30 min. After 1 h a solution of 1,3- bis(bromomethyl)benzene (2.64 g, 10.0 mmol) in 60 mL of THF was added dropwise during a period of 30 min. The reaction mixture was stirred at room temperature for 24 h. Water (10 mL) was added and the solvent was evaporated in vacuo. The aqueous mixture was extracted with CH2CI2 (2 X 50 mL). The combined extracts were washed with water (30 mL), dried over MgS04 and evaporated in vacuo. The residue was purified by chromatography on alumina with ethyl acetate as eluent. l,3-Xylyl-18-crown-5 (76).[50] A colorless oil was obtained in 53% yield. IR (neat): 1353, 1102 (C-0) cm-l. IH NMR (CDCI3): 5 3.65-3.72 (m, 16H), 4.65 (s, 4H), 7.11-7.30 (m, 3H), 7.72 (s, IH). l,3-Xylyl-21-crown-6 (77).[50] A colorless oil was obtained in 30% yield. IR (neat): 1352, 1111 (C-0) cm-l. in NMR (CDCI3): 5 3.69-4.04 (m, 20H), 4.60 (s, 4H), 7.11-7.33 (m, 3H), 7.72 (s, IH). l,3-Xylyl-24-crown-7 (78).[50] A colorless oil was obtained in 20% yield after precipitation of a side product from diethyl ether- hexane. IR (neat): 1351, 1113 (C-0) cm-l. IH NMR (CDCI3): 5 3.28- 4.23 (m, 24H), 4.63 (s, 4H), 7.19-7.43 (m, 3H), 7.46 (s, IH). l,3-Bis(bromomethyl)benzene (74). To a suspension of l,3-dibromo-5.5-dimethylhydantoin (68.62 g, 0.24 mol) in 300 mL of CCI4 was added nL-xylene (21.23 g, 0.20 mol) and 1.50 g of benzoyl peroxide. The suspension was irradiated with a 500 W lamp for a 4 h period. The reaction was followed by TLC. The reaction mixture 93 was cooled to room temperature after a light yellowish suspension was obtained. The reaction mixture was washed with water (4 X 200 mL) and dried over MgS04. The solvent was evaporated in vacuo to give a yellowish liquid. A large amount (300 mL) of absolute methanol was added to the liquid residue and the resulting solution place in a refrigerator to precipitate a white solid. The solid was collected and dried to give 20.10 g (38%) of the product as a white solid with mp 73-74 oc (lit[51] mp 74-76 oC). IR (deposit): 1211, 1163 (C-0) cm-l. IH NMR (CDCI3): 5 4.47-(s, 4H), 7.20-7.36 (m, 4H), 7.50 (s, IH). General Procedure for the Preparation of svm-(Hvdroxv)(methyn dibenzocrown Ethers 87 and 9 5 To 0.39 g (16,2 mmol) of magnesium turnings in 140 mL of anhydrous Et20 under nitrogen was added dropwise 4.59 g (32.4 mmol) of methyl iodide. The reaction mixture was stirred in an ice bath until the magnesium disappeared and white emulsion formed. A solution of the sym-ketocrown ether (32.4 mmol) in 210 mL of THF was added dropwise at 0 oc. Reaction was continued for 10 hr at room temperature. To the reaction mixture, 80 mL of 5% aqueous ammonium chloride solution was added, and the mixture was stirred for 5 hr. The solvent was evaporated and extracted with CH2CI2 (2 x 100 mL). The CH2CI2 solution was washed with water, dried over magnesium sulfate and evaporated in vacuo. The crude product was chromatographed on alumina with EtOAc as eluent. 94 sym-(Hydroxy)(methyI)dibenzo-16-crown-5 (87). A white solid with mp 109-111 oc (lit[55] mp 110-111 oc) was obtained in 72% yield. IR (deposit from dichloromethane on a NaCl plate): 3410 (OH), 1130 (C-0) cm-l . IH NMR(CDCl3): 5 1.43 (s, 3H), 4.17-3.69 (m, 12H), 6.93 (s, 8H). sym-(Hydroxy)(methyl)dibenzo-14-crown.4 (95). A white solid with mp 140-142 oc (lit[57] mp 142.5-143 oC) was obtained in 61% yield. IR (deposit from dichloromethane on a NaCl plate): 3490 (OH), 1124 (C-0) cm-l . IH NMR (CDCI3): 5 1.34 (s, 3H), 2.49 (m, 2H), 3.72 (s, OH), 4,45-4.83 (m, 8H), 6.91 (s, 8H). General Procedure for the Preparation of Pvridvl-Subsntuted Crown Ethers Using Sodium Hvdride Procedure A. Under nitrogen, svm-hydroxydibenzo-16- crown-5 (4.00 g, 11.0 mmol) and 0.48 g (11.0 mmol) of a 60% dispersion of NaH in mineral oil were added to 120 mL of dry DMF. The reaction mixture was stirred for 1 h at room temperature. A solution of 2-picolyl chloride hydrochloride (0.95 g, 5.8 mmol) dissolved in 50 mL of dry DMF was added dropwise during a 10-min period and the reaction mixture was stirred for 24 h and quenched with 20 mL of H2O. The DMF was removed in vacuo and the remaining aqueous mixture was extracted with CH2CI2 (2 X 50 mL). The combined CH2CI2 extracts were dried over MgS04 and evaporated in vacuo. The residue was chromatographed on alumina with EtOAc as a eluent. 95 Procedure B. Under nitrogen, 2-picolyl chloride hydrochloride (0.26 g, 1.58 mmol) and 0.06 g (1.58 mmol) of a 60% dispersion of NaH in mineral oil were added to 80 mL of dry THF. The reaction mixture was stirred for 2 h at room temperature. The precipitate was removed by filtration through a bed of Celite on a sintered glass funnel. The filtrate was added dropwise to a solution of sxi!l-hydroxydibenzo-16-crown-5 (0.55 g, 1.58 mmol) and 60% dispersion of NaH ( 0.12 g, 3.16 mmol) in 60 mL of dry THF. The reaction mixture was stirred for 24 h at room temperature and quenched with 20 mL of water. The THF was removed in vacuo and the remaining aqueous mixture was extracted with CH2CI2 (2 X 50 mL) and dried over MgS04. After evaporation of the solvent in, vacuo, the crude product was chromatographed on alumina with EtOAc as a eluent. svm-(2-Picolvloxv)dibenzo-13-crown-4 (82). A white solid with mp 72-73 oC was obtained in a 18% yield by procedure A and in a 36% yield by procedure B. IR (deposit from chloroform on a NaCl plate): 1114 (C-0) cm-l. IH NMR (CDCI3): 5 3.78-3.83 (m, IH), 4.01-4,45 (m, 8H), 4.84 (s, 2H), 6.85-7.25 (m, 8H), 7.49-7.52 (m, IH), 7.62-7.69 (m, 2H), 8.51-8.53 (d, IH). Anal. Calcd. for C23H23NO5: C, 70.21; H, 5.89. Found: C, 70.06; H, 5.83. sym-(2-Picolvloxv)dibenzo-14-crown-4 (83). A white solid with mp 97-98 oC was obtained in a 33% yield by procedure A and in a 63% yield by procedure B. IR (deposit from chloroform on a NaCl plate): 1107 (C-0) cm-l. IH NMR (CDCI3): 5 1.94-2.54 (m, 2H), 96 3.90-4.46 (m, 4H), 4.86 (s, 2H), 6.68-7.05 (m, 8H), 7.10-7.35 (m, IH), 7.52-7.80 (m, 2H), 8.48-8.72 (m, IH). Anal. Calcd for C24H25NO5: C, 70.74; H, 6.18. Found: C; 70.76; H, 6.14. SXin.-(Methyl)(2-picoIyloxy)dibenzo-14-crown-4 (98). A yellowish oil was chromatographed on alumina with EtOAc-hexane (1:2) as a eluent to give a white solid with mp 130-132 oc in a 30% yield by procedure B. IR (deposit from chloroform on a NaCl plate): 1118 (C-0) cm-l. IH NMR (CDCI3): 5 4.12-4.38 (m,8H), 4.91 (d, 2H), 6.84-6.99 (m, 8H), 7.14-7.26 (t, IH), 7.55-7.74 (m, 2H), 8.53-8.55 (d, IH). Anal. Calcd. for C24H25O5NO.5 H2O: C, 69.75; H, 6.56. Found: C; 69.77; H, 6.60. &XIlL-(2-Picolyloxy)dibenzo-16-crown-5 (84). A white solid with mp 41-43 oC was obtained in a 35% yield by procedure A and in a 56% yield by procedure B. IR (deposit from chloroform on a NaCl plate): 1111 (C-0) cm-l. IH NMR (CDCI3): 5 3.91-4.43 (m, 13H), 5.03 (s, 2H), 6.82-7.00 (m, 8H), 7.18-7.26 (m, IH), 7.71-7.75 (q, 2H), 8.56-8.58 (d, IH). Anal. Calcd for C25H28NO6O.ICH2CI2: C, 67.43; H, 6.34. Found: C, 67.66; H, 6.00. svm-(Prop vn(2-picolyloxv)dibenzo-16-crown-5 (91) A reddish-colored oil was chromatographed on alumina with EtOAc- hexane (1:2) as eluent to give a yellow sticky oil in a 22% yield by procerue B. IR (neat): 1122 (C-0) cm-l. IH NMR (CDCI3): 5 0.91-1.04 (m, 3H), 1.50-1.62 (m, 2H), 2.00-2.08 (m, 8H), 7.11-7.17 (m, IH), 7.63-7.68 (m, 2H), 8.50-8,54 (m, IH), Anal. Calcd for C28H33NO6O.ICH2CI2: C, 68.90; H, 6.86, Found: C, 69.10; H, 6.92. 97 2-Picolyl Dodecyl Ether (104). A colorless oil was obtained in an 8% yield by procedure B. IR (neat): 1122 (C-0) cm-l. IH NMR (CDCI3): 5 0.77-0.83 (m, 3H), 1.18-1.34 (m, 18H), 1.51-1.65 (m, 2H), 3.44-3.51 (t, 2H), 7.05-7.12 (m, IH), 7.34-7.39 (d, IH), 7.56-7.64 (m, IH), 8.45-8.48 (m, IH). Anal. Calcd for C18H31NO: C, 77.92; H, 11.26. Found: C, 78.01; H; 11.35. General Procedure for the Preparation of Pvridvl-Substituted Crown Ethers Using Potassium Hydride Under nitrogen, KH (3.03 g, 26.4 mmol, of a 35% dispersion in mineral oil) was washed with pentane (2 X 20 mL) to remove the protecting oil and 80 mL of THF was added. To the suspension, picolyl chloride hydrochloride (1.09 g, 6.6 mmol) was added. After stirring at room temperature for 2 h, the solid was removed by filtration through a bed of Celite on a sintered glass funnel. The filtrate was added dropwise to the mixture of the crown alcohol (1.20 g, 3.3 mmol) and KH (1.51 g, 13.2 mmol) in 80 mL of THF and the mixture was stirred for 24 h at room temperature. Water (20 mL) was added, and the reaction mixture was extracted with CH2CI2 (2 X 50 mL). The combined CH2CI2 extracts were washed with water (30 mL), dried over MgS04 and evaporated in vacuo. The crude product was chromatographed on alumina with EtOAc-hexane (1:2) as eluent. 5jJlL-(I^ecyl)(2-picolyloxy)dibenzo-14-crown-4 (100). Chromatography of the crude product gave a colorless oil in a 66% yield. IR (neat): 1118 cm-l. IH NMR (CDCI3): 5 0.84-0.90 (t, 3H), 98 1.24-2.04 (m, 18H), 2.29 (m, 2H), 4.14-4.34 (m, 8H), 4.88 (s, 2H), 6.86-6.99 (m, 8H), 7.17-7.26 (m, IH), 7.61-7.70 (m, 2H), 8.53-8.55 (m, IH). Anal. Calcd for C34H45NO5: C, 74.55; H, 8.28. Found: C, 74.66; H, 8.29. aXIIL-(Methyl)(2-picolyloxy)dibenzo-16-crown-5 (90). A sticky oil was obtained in 17% yield. IR (neat): 1123 (C-0) cm-l. IH NMR (CDCI3): 5 1.66 (s, 3H), 3.81-4.46 (m, 12H), 5.04 (s, 2H), 6.81- 6.98 (m, 8H), 7.14-7.26 (m, IH) 7.62-7.68 (m, 2H), 8.50-8.54 (m, IH). Anal. Calcd. for C26H29NO6: C, 69.16; H, 6.47. Found: C, 69.65; H, 6.45. iXJIL-(Decyl)(2-picoIyloxy)dibenzo-16-crown-5 (92). A colorless oil was obtained in 36% yield. IR (neat): 1123 cm-l. IH NMR (CDCI3): 5 0.84-0.90 (t, 3H), 1.00-1.68 (m, 16H), 2.00-2.08 (q, 2H), 3.91-4.47 (m, 12H), 5.08 (s, 2H), 6.79-6.97 (m, 8H), 7.10-7.17 (m, IH), 7.60-7.67 (m, 2H), 8.50-8.52 (d, IH). Anal. Calcd for C35H47NO6: C, 72.76; H, 8.20. Found: C, 72.56; H, 8.19. iXI!L-(Propyl)(benzyloxy)dibenzo-16-crown-5 (103). Under nitrogen, KH (1.75 g, 15.3 mmol, of a 35% dispersion in mineral oil) was washed with pentane (2 X 20 mL) to remove the protecting mineral oil and 100 mL of dry THF was added. To the suspension, crown ether alcohol 88 (2.0 g, 5.1 mmol) in 30 mL of THF was added slowly. After stirring at room temperature for 1 h, a solution of benzyl bromide (0.87 g, 5.1 mmol) in 50 mL of THF was added dropwise and the mixture was stirred for 15 h at room temperature and quenched with 10 mL of H2O. The THF was removed in vacuo and the remaining aqueous mixture was extracted 99 with CH2CI2 (2 X 50 mL). The combined CH2CI2 extracts were washed with water (50 mL), dried over MgS04 and evaporated in vacuo. The residue was chromatographed on alumina with EtOAc-hexane (1:3) as eluent to give 1.96 g (80%) of a white solid with mp 97-98 oC. IR (deposit from chloroform on a NaCl plate): 1139 (C-0) cm-l. IH NMR (CDCI3): 5 0.96-1.03 (t, 3H), 1.49-1.61 (m, 2H), 1.97-2.05 (m, 2H), 3.86-4.45 (m, 12H), 4.92 (s, 2H), 6.80-6.91 (m, 8H), 7.23-7.44 (m, 4H). Anal. Calcd for C29H34O6: C, 72.78; H, 7.16. Found: C, 72.99; H, 7.21. Sodium svm-Dibenzo-16-crown-5-oxy xanthate (105). The protecting mineral oil from NaH (2.16 g , 54.0 mmol of 60% dispersion in mineral oil) was removed by washing with 50 mL of pentane under nitrogen and 180 mL of THF was added. To the mixture, svm-hydroxydibenzo-16-crown-5 (6.0 g, 17.4 mmol) in 50 mL of THF was added dropwise and the mixture was stirred for 1 h at room temperature. Carbon disulfide (2.90 g, 37.5 mmol) in 40 mL of THF was added dropwise during a 30-min. period. The reaction mixture was stirred for 10 h at room temperature and was filtered. To the filtrate 20 mL of water was added and the THF was evaporated in vacuo. The remaining aqueous mixture was extracted with CH2CI2 (2 X 50 mL). Evaporation of the CH2CI2 in vacuo gave a yellow solid which was purified by recrystallization from absolute ethanol to give 4.30 g (56%) of a yellow solid with mp 148-152 oc. IR (deposit from dichloromethane on a NaCl plate): 1238 (C=S) cm-l. 100 IH NMR (CDCI3): 5 3.72-4.58 (m, 13H), 6.70-7.17 (s, 8H). Anal. Calcd for C20H2iO6S2NaH2O: C, 51.89; H, 4.97. Found C, 52.04; H, 4.48. Methyl ixnL-Dibenzo-16-crown-5-oxyxanthate (107). Xanthate 105 (1.33 g, 3.0 mmol) was dissolved in 50 mL of absolute ethanol at room temperature and a solution of CH3I (0.86 g, 60 mmol) in 10 mL of EtOH was added under nitrogen. The reaction mixture was stirred for 3 h at 50 oc. After evaporation of the solvent in vacuo. 50 mL of water was added and the mixture was extracted with CH2CI2 (2 X 50 mL). The organic layer was dried over anhydrous MgS04 and the solvent was evaporated in vacuo, the residue was chromatographed on silica gel with EtOAc as eluent to give 0.86 g (66%) of a white solid with mp 97-100 oC. IR (deposit): 1255 (C=S) cm-l. IH NMR (CDCI3): 5 2.52 (s, 3H), 3.80-4.78 (m, 13H), 6.74-7.24 (m, 8H). Anal. Calcd for C21H24O6S2: C, 57.78; H, 5.54. Found: C, 58.04; H, 5.64. Methyl svm-Dir3(4)-tert-butylbenzol-16-crowD-5-oxy xanthate (108). Following the synthetic procedure given for 107, sodium xanthate 106 (0.40 g, 0.75 mmol) and CH3I (0.22 g, 1.50 mmol) in 50 mL of absolute ethanol were stirred for 3 h at 50 oc. After addition of water (20 mL), the mixture was extracted with CH2CI2 (2 X 30 mL). The organic layer was dried over MgS04 and chromatographed on silica gel with EtOAc as eluent to give 0.11 g (27%) of a red solid with mp 65-67 oC. IR (deposit from dichloromethane on a NaCl plate): 1121 (C=S) cm-l. IH NMR (CDCI3): 5 1.27 (s, 25H), 2.54 (s, 3H), 3.93-4.61 (m, 13H), 6.87-7.06 (m, 6H). 101 Anal. Calcd for C29H40O6S2I.5H2O: C, 60.50; H, 7.61. Found: C, 60.68; H, 7.36. General Procedure for Preparation of svm-(Alkvn(methoxy)dibenzocrown Ethers 111-113 To a solution of NaH (0.60 g, 15.0 mmol), 60% dispersion in mineral oil) in dry THF (120 mL) was added the appropriate dibenzocrown ether alcohol (5.15 mmol) in 30 mL of THF. The reaction mixture was stirred for 2 h at room temperature. A solution of CH3I (1.46 g, 10.30 mmol) in 50 mL of THF was added dropwise, and the mixture was stirred for 24 h at room temperature. Water (50 mL) and CH2CI2 (200 mL) were added. To the inhomogeneous solution 1 N-NaOH aqueous solution (80 mL X 2) was added and the mixture was shaked vigorously. The organic layer was separated and washed with brine (50 mL), water and dried over MgS04. The residue was purified by column chromatography on alumina with EtOAc as eluent to give the desired product. svm-(Methvl)(methoxy)dibenzo-16-crown-5 (111). A white solid with mp 115-117 oC was obtained in 80% yield. IR (deposit from chloroform on a NaCl plate): 1122 (C-0) cm-l. IH NMR (CDCI3): 5 1.51 (s, 3H), 3.53 (s, 3H), 3.85-4.27 (m, 12H), 6.81-7.26 (m, 8H). Anal. Calcd for C21H26O6: C, 67.36; H, 7.00. Found: C, 67.60; H, 7.09. svm-(Propyn(methoxv)dibenzo-16-crown-5 (112). A white solid with mp 91-920C was obtained in 90% yield. IR (deposit 102 from chloroform on a NaCl plate): 1122 (C-0) cm-l. IH NMR (CDCI3): 5 1.02 (t, 3H), 1.38-1.57 (m, 2H), 1.85-1.93 (m, 2H), 3.55 (s, 3H), 3.64- 4.35 (m, 12H), 6.81-7.06 (m, 8H). Anal. Calcd for C23H30O6: C, 68.63; H, 7.51. Found: C, 68.32; H, 7.60. SXm.-(Decyl)(methoxy)dibenzo-16-crown-5 (113). After chromatography the crude product was recrystallized from hexane- THF to give a white solid with mp 59-60 oc in 56% yield. IR (deposit from chloroform on a NaCl plate): 1123 (C-0) cm-l. IH NMR (CDCI3): 5 0.88 (t, 3H), 1.26 (m, 16H), 1.89 (m, 2H), 3.55 (s, 3H), 3.83-3.95 (m, 4H), 4.13-4.18 (m, 6H), 4.33 (d, 2H), 6.81-6.98 (m, 8H). Anal. Calcd. for C30H44O6: C, 71.97; H, 8.86. Found: C, 72.04; H, 8.77. General Procedure for the Preparation of N-(2-Trifluoro-4.6-dinitrophenvn-4'- aminobenzocrown Ethers 114 and 116 To a solution of the 4'-aminobenzocrown ether (5.78 g, 20.4 mmol) in 250 mL of absolute methanol was added 2-chloro-3,5- dinitrobenzotrifluoride (5.68 g, 21.0 mmol) then sodium bicarbonate (2.3 g, 27.4 mmol). The mixture was refluxed for 24 h. The precipitate was filtered and solvent was removed from the filtrate in vacuo. The crude residue was chromatographed on alumina with EtOAc as a eluent to give the desired product. N-(2-Trifluoro-4,6-dinitrophenyI)-4'-aminobenzo-14- crown-4 (116). A red solid with mp 121-123 oC was obtained in 22% yield. IR (deposit from chloroform on a NaCl plate): 3415 (Nil); 1511 (NO2); 1132 (C-O) cm-l. IH NMR (CDCI3): 5 1.75-2.04 (m, 4H), 103 3.40-3.81 (m, 8H), 4.09-4.18 (m, 4H), 6.46-6.63 (m, 2H), 6.80-7.10 (d, IH), 7.64 (s, NH), 8.65 (d, IH), 8.87 (d, IH). Anal. Calcd for C21H22N3O8F3: C, 50.30; H, 4.42. Found: C, 50.73; H, 4.54. N-(2-Tr if luor 0-4,6-dinitrophenyl)-4'-aminobenzo-15- crown-5 (114). A red solid with mp 135 oC was obtained in 54% yield. IR (deposit from chloroform on a NaCl plate): 3416 (NH); 1597 (NO2); 1133 (C-0) cm-l. IH NMR (CDCI3): 5 3.71-3.93 (m, 12H), 4.06- 4.17 (m, 4H), 6.55-6.60 (q, 2H), 6.77-6.81 (d, IH), 7.64 (s, NH), 8.66 (d, IH), 8.85 (d, IH). Anal. Calcd. for C21 H22N3O9F3: C, 48.74; H, 4.29. Found : C, 49.15; H, 4.26. N-(2-Trifluoro-5,6-dinitrophenyl)-5'-nitro-4*- aminobenzo-15-crown-5 (115). To a solution of aminobenzo crown ether 114 (1.50 g, 1.9 mmol) was added acetic acid and fuming nitric acid (2.5 mL of each). The reaction mixture was stirred for 10 min at room temperature. The organic layer was separated and washed with water (4 X 50 mL) and dried over MgS04. After evaporation of the solvent in vauo. the residue was chromatographed on silica gel with EtOAc as eluent to give 0.34 g (21%) of a sticky reddish oil. IR (neat): 3462 (NH); 1583 (NO2); 1130 (C-0) cm-l. in NMR (CDCI3): 5 3.59-3.71 (m, 12H), 3.82-3.87 (m, 2H), 4.01-4.05 (m, 2H), 5.86 (d, NH), 6.65-6.70 (d, IH), 6.98-7.05 (q, IH), 8.79-8.80 (d, IH), 9.09-9.10 (d, IH). Anal. Calcd for C14H21NO4.O.9 EtOAc: C, 46.04; H, 4.43. Found: C, 46.38; H, 3.92. 104 General Procedure for the Preparation of Acvclic Polvether Secondary Alcohols 117 119 and 120 To 16.39 g (132 mmol) of the appropriate methoxyphenol in 1.8 L of water-THF (1: 1), 5.28 g (132 mmol) of NaOH was slowly added. The mixture was stirred and heated for 2 h at 80 oc under nitrogen and then cooled to 50 oc. Epichlorohydrin (6.11 g, 66 mmol) was added during an 8-h period with a syringe pump and stirring was continued at 50 oc for 2 days. After evaporation of the THF in vacuo, the residue was extracted with CH2CI2 (2 X 100 mL). The CH2CI2 extracts were washed with brine, dried over MgS04, and evaporated in vacuo. Chromatography of the residue on alumina with EtOAc as eluent gave the desired product. l,3-Bis(o-methoxyphenoxy)-2-propanol (117). A white solid with mp 69-71 oC was obtained in 66% yield. IR (deposit from chloroform on a NaCl plate): 3428 (OH); 1253; 1124 (C-0) cm-l. IH NMR (CDCI3): 5 3.72 (s, IH), 3.80 (s, 6H), 4.15-4.25 (m, 4H), 4.42 (pen, IH), 6.80-7.00 (m, 8H). Anal. Calcd for C17H20O5: C, 67.09; H, 6.62. Found: C, 67.24; H, 6.73. l,3-Bis(p-methoxyphenoxy)-2-propanol (119). After chromatography the crude product was recrystallized from Et20 to give white solid with mp 99-101 oC in 54% yield. IR (deposit from chloroform on a NaCl plate): 3417 (OH); 1233; 1046 (C-0) cm-l. IH NMR (CDCI3): 5 2.83 (s, OH), 3.58-3.86 (m, 6H), 3.96-4.24 (m, 4H), 105 4.28-4.36 (m, IH), 6.82-6.89 (m, 8H). Anal. Calcd for C17H20O5: C, 67.09; H,6.62. Found: C, 67.28; H, 6.70. l,3-Bis(o-methoxyphenoxy)-2-propanone (120). To 1.8 L of acetone was added 20.0 g (65.7 mmol) of 1.3-bis(ii- methoxyphenoxy)-2-propanol (117). The solution was stirred for 2 h in an ice bath and 120 mL of Jones reagent was added during a 2 h period. (The Jones reagent was prepared by addition of 27.6 mL of cone H2SO4 to 32.0 g of Cr03 in 40 mL of water followed by enough water to make 120 mL.) Stirring was continued for an additional 24 h at room temperature. The green precipitate was filtered and the solvent was removed from the filtrate in vacuo. Water (500 mL) was added and the mixture was extracted with CH2CI2 (2 X 100 mL). The combined CH2CI2 extracts were washed with water (2 X 100 mL), dried over MgS04, and evaporated in vacuo to give a brownish oil. Recrystallization from EtOAc-hexane gave 13.0 g (65%) of a white solid with mp 69-71 oC. IR (deposit from chloroform on a NaCl plate): 1742 (C-0) cm-l. IH NMR (CDCI3): 5 3.86 (s, 6H), 4.96 (s,4H), 6.83-6.97 (m, 8H). Anal. Calcd. for C17H18O5; 67.54; H, 6.00. Found: C, 67.67; H. 6.05. General Procedure for the Preparation of Acvclic Polvether Tertiary Alcohols }2^ and 122 To 0.13 g (12.6 mmol) of magnesium turnings in 100 mL of THF under nitrogen was added 1.55 g (12.6 mmol) of l-bromopropane, and the mixture was refluxed until the magnesium turnings 106 disappeared. The solution was cooled to 0 oc and 1.91 g (6.3 mmol) of ketone 120 in 20 mL of THF was added. The reaction mixture was refluxed for 5 h and cooled to 0 oc. After slow addition of 30 mL of 5% aqueous NH4CI, the THF was evaporated in vacuo. The resulting oil was extracted with Et20 (100 mL). The ether extract washed with water (2 X 50 mL) and dried over MgS04. After evaporation in vacuo the residue was chromatographed on alumina with EtOAc as eluent to give the desired product. 2 - [ (fi.-M e t h o X y p h e n o x y) m e t h y I ] -1 - (iL- methoxyphenoxy)-2-pentanol (121). A colorless oil was obtained in 68% yield. IR (neat): 3482 (OH) cm-l. IH NMR (CDCI3): 5 0.92-0.99 (t, 3H), 1.42-1.63 (m, 2H), 1.71-1.80 (m, 2H), 3.17 (s, IH), 3.75-3.86 (m, 6H), 3.98-4.12 (q, 4H), 6.82-7.06 (m, 8H). Anal. Calcd for C20H26O5O.25H2O: C, 68.49; H, 7.55. Found: C, 68.72; H, 7.83. 2-[(fi.-Methoxyphenoxy)methyIl-l-(iL- methoxyphenoxy)-2-dodecanol (122). A colorless oil was obtained in 47% yield. IR (neat): 3482 (OH) cm-l. IH NMR (CDCI3): 5 0.84-0.90 (t, 3H), 1.22-1.29 (t, 16H), 1.72-1.60 (q, 2H), 3.79-3.84 (d, 6H), 3.98-4.16 (m, 4H), 6.82-7.05 (m, 8H). Anal. Calcd for C27H40O5: C, 72.94; H, 9.07. Found: C, 72.36; H, 9.45. General Procedure for the Preparation of Acvclic Polvether Carboxylic Acids 123-127 After removal of the mineral oil from 27.43 g (0.24 mol) of KH (35% dispersion in mineral oil) with pentane under nitrogen, 0.039 mol of the acyclic polyether alcohol in 100 ml of THF was added 107 during a 1 h period. The mixture was stirred for 1 h at room temperature and 5.42 g (0.078 mol) of bromoacetic acid in 125 mL of THF was added during a 3-h period. The mixture was stirred for 24 h and water (5 mL) was carefully added to consume the excess KH. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in water (200 mL) and acidified to pH 108 l,3-Di(]2.-methoxyphenoxy)-2-(oxyacetoxy)propane (127). A yellow liquid was obtained in 84% yield. IR (neat): 3213 (OH), 1760 (C=0), 1226, 1038 (CO) cm-l. 1H NMR (CDCI3): 5 3.68 (s, 6H), 4.06 (s, 5H), 4.34 (s, 2H), 6.76-6.77 (m, 8H). Anal. Calcd for C19H22O7: C, 62.97; H, 6.12. Found: C, 62.87; H, 6.15. 4,4-Bis[(fi.-methoxyphenoxy)methyl]-3-oxaheptanoic acid (124). A pale yellow oil was obtained in 81% yield. IR (neat): 3354 (OH); 1733 (C=0) cm-l. IH NMR (CDCI3): 5 1.01 (m, 3H), 1.39- 1.51 (m, 2H), 1.80-1.88 (mn, 2H), 3.64 (s, 6H), 4.02-4.22 (q, 4H), 4.40 (s, 2H), 6.82-7.01 (m, 8H). Anal. Calcd for C22H28O7: C, 65.33; H, 6.98. Found: C, 65.04; H, 7.00. 4,4-Bis[(2.-methoxyphenoxy)methyll-3-oxatridecanoic acid (125). A colorless oil was obtained in 77% yield. IR (neat): 3354 (OH); 1772 (C=0) cm-l. IH NMR (CDCI3): 5 0.84-0.90 (t, 3H), 1.25-1.61 (m, 16H), 1.82-1.89 (m, 2H), 3.77-3.88 (m, 6H), 4.08-4.34 (m, 4H), 4.42 (s, 2H), 6.82-7.00 (m, 8H). Anal. Calcd for C30H42O7O.5H2O: C, 68.81; H, 8.28. Found: C, 68.72; H, 8.49. 3,9-Dioxa-6-(N-tosylaza)-undecane-l,ll-diol (146).t73] To a mixture of 32.25 g (0.26 mol) of 2-(2-chloroethoxy)ethanol and 69.10 g (0.50 mol) of anhydrous K2CO3 in 200 mL of dry DMF was added 17.1 g (0.1 mol) of p-toluene-sulfonamide in 50 mL of DMF. The reaction mixture was refluxed for 4 d with vigorous stirring. The insoluble material was filtered and the filtrate was evaporated in vacuo. The oily residue was chromatographed on alumina with EtOAc as eluent to give 24.0 g (68%) of yellow oil. IR (neat): 3385 109 (OH); 1333, 1159 (SO2); 1159 (C-0) cm-l. IH NMR (CDCI3): 5 2.38 (s, 3H), 2.87 (s, IH), 3.08-3.21 (m, 2H), 3.28-3.92 (m, 6H), 6.06-6.24 (t, IH), 7.18-7.62 (m, 4H). l,ll-Dimethoxy-3,9-dioxa-6-(N-tosylaza)undecane (147). Under nitrogen, a solution of diol 146 (2.77 g, 8.0 mmol) dissolved in 20 mL of dry THF was added to a suspension of 1.28 g (32.0 mmol) of NaH (60% dispersion in mineral oil) in 20 mL of THF. After stirring for 1 h at room temperature, a solution of methyl iodide (4.54 g, 32.0 mmol) dissolved in 50 mL of THF was added slowly. After 24 h, the solvent was removed and the residue was taken up in CH2CI2 (100 mL), washed with 1 N-NaOH aqueous solution, then water and dried over MgS04. Evaporation of the solvent in vacuo gave 2.44 g(81%) of yellow oil. IR (neat): 1340, 1158 (SO2); 1158 (C-0) cm-l. IH NMR (CDCI3): 5 2.42 (s, 3H), 3.21- 3.67 (m, 22H), 7.27-7.33 (m, 2H), 7.65-7.73 (m, 2H). Anal. Calcd for C17H29NO6S: C, 54.38; H, 7.78. Found: C, 54.37; H, 7.59. l,ll-Dimethoxy-3,9-dioxa-6-azaundecane (148). Under nitrogen at room temperature. Na2HP04 (1-87 g, 13.2 mmol) and 6% sodium amalgam (14.40 g) were added to tosylate 147 (2.27 g, 6.0 mmol) dissolved in 200 mL of anhydrous dioxane-methanol (1:1). The reaction mixture was refluxed for 2 d. The precipitate was filtered and washed with methanol (50 mL). After evaporation of the combined filtrate and washing, CHCI3 (100 mL) was added to the residue. The mixture was filtered and the filtrate was evaporated in vacuo. The crude product was chromatographed on silica gel with 110 EtOAc and then MeOH as eluents to give 0.80 g (60%) of yellow liquid. IR (neat): 3504 (NH); 1199 (C-0) cm-l. IH NMR (CDCI3): 5 2.18 (s, NH), 3.41 (s, 6H), 3.52-3.67 (m, 16H). Anal. Calcd. for C10H23NO4: C, 54.27; H, 10.47. Found: C, 53.88; H, 10.25. N-Tosyldiethanolamine (137). Under nitrogen, diethanolamine (28.0 g, 0.27 mol) and K2CO3 (21.0 g, 0.15 mol) were added to 150 mL of water. The reaction mixture was stirred for 1 h at 70 oc. p.-Toluenesulfonyl chloride (50.0 g* 0.25 mol) was added slowly over a 30-min period. The reaction mixture was refluxed for 1 h, cooled to 50 oc, and filtered. The filtrate was placed in ice bath and white crystals precipitated. The crystals were filtered and washed with water. Recrystalization from water gave a white solid. The solid was dissolved in acetone and dried over MgS04. Evaporation of the solvent gave 45.8 g (70%) of white solid with mp 100-101 oc. IH NMR (CDCI3): S 2.56 (s, 3H), 3.11-3.47 (t, 4H), 3.65- 3.98 (t, 4H), 4.20 (s, 2H), 7.18-7.80 (q, 4H). N-TosyImonoaza-15-crown-5 (138). Method A: N-Tosyl diethanolamine was added to a 60% dispersion of NaH in mineral oil (2.60 g, 0.01 mol) suspended in 100 mL of DMF-THF (4:1). After 1 h triethyleneglycol ditosylate (4.58 g, 0.01 mol) in 25 mL of DMF-THF (4:1) was added at room temperature during a 5-h period. After 2 d, the precipitate was filtered and 20 mL of water was added to the filtrate. The THF was evaporated in vacuo and CH2CI2 (300 mL) was added to the residual liquid. The solution was extracted repeatedly 111 with brine to remove the DMF. The organic layer was washed with water (100 mL) and dried over MgS04. The solvent was removed in vacVTQ. Residual DMF was removed under vacuum at 40 oc/0.04 mm. Column chromatography of the residue on silica gel with EtOAc as eluent gave 1.10 g (31%) of white crystals, with mp 27-290C (lit[69] mp 29-320C). IR (deposit from dichloromethane on a NaCl plate): 1350, 1295 (SO2), 1127 (C-0) cm-l. INMR (CDC13); 5 1.62-1.88 (m, 3H), 3.68-4.50 (m, 20H), 7.72-8.02 (d, 2H),8.18-8.42 (d, 2H). Method B: Under nitrogen, small pieces of freshly cut sodium metal (4.10 g, 0.180 mol) were added to a solution of diethanolamine (6.30 g, 0.60 mol) in 480 mL of dry t-butyl alcohol. The mixture was heated (70 oC) to dissolve the sodium metal. To the reaction mixture, a solution of triethylene glycol ditosylate (27.40 g, 0.060 mol) in p- dioxane (300 mL) was added dropwise during a 6-h period. The reaction was continued for 24 h at 70 oC. After cooling and filtration of the solid material, the filtrate was evaporated in vacuo. The oily residue was dissolved in water (100 mL) and extracted once with hexane to remove hexane-soluble by products. The aqueous layer was extracted with CH2CI2 (2 X 100 mL). The combined organic layers were dried over MgS04 and evaporated in vacuo to give 14.65 g of crude oily product. To the solution of crude monoaza-15-crown- 5 (4.0 g, 18.0 mmol) in CH2CI2 (80 mL), 25% NaOH ( 20 mL) was added dropwise during a 1 h period. To the reaction mixture, p- toluenesulfonyl chloride was added and the mixture was refluxed for 5 h. The reaction mixture was cooled to room temperature and 30 112 mL of water was added. The CH2CI2 layer was separated, washed with water (20 mL), and dried over MgS04. After evaporation of the solvent in vacuo, the residue was chromatographed on alumina with CH2CI2 as eluent to give 1.00 g (15%) of white solid. Monoaza-15-crown-5 (130).[70] Under nitrogen, tosyl- protected monoaza-15-crown-5 (0.72 g, 2.00 mmol) was added to 100 mL of dry MeOH-dioxane (1:1) containing Na2HP04 (0.62 g, 4.34 mmol) and 4.80 g of 6% sodium amalgam. The mixture was stirred at reflux for 24 h and filtered. The solvent was removed from the filtrate in vacuo and the residue was dissolved in 50 mL of CH2CI2. The resulting solution was washed with H2O (30 mL X 2) and dried over MgS04. Evaporation of solvent in vacuo gave 0.14 g (32%) of colorless oil. IR (deposit from a dichloromethane on a NaCl plate): 3413 (NH), 1116 (C-0) cm-l. IH NMR (CDCI3): 5 2.54-2.95 (q, 4H), 3.02 (s, NH), 3.48-3.88 (m, 16H). General Procedure for the Preparation of 4'-Nitrobenzocrown Ethers 139-144 Under nitrogen, benzo-12-crown-4 (2.62 g, 11.7 mmol) was dissolved in 80 mL of CHCI3 and glacial acetic acid (50 mL) was added. To the reaction mixture, a solution of fuming nitric acid (15 mL) in 30 mL of CHCI3 was added dropwise during a 30-min. period. Reaction was continued for 24 h at room temperature. The organic layer was separated and washed with saturated aqueous Na2C03 and then with water (2 X 100 mL) and dried over MgS04. After evaporation of the solvent in vacuo, the residue was 113 chromatographed on alumina with EtOAc as eluent to give the desired product. 4'-Nitrobenzo-12-crown-4 (139). A yellow solid with mp 98-100 oc (litfSl] mp 96-97 oC ) was obtained in 74% yield. IR (deposit): 1588 (NO2): 1124 (C-0) cm-l. 1H NMR (CDCI3): 5 3.74-3.93 (m, 8H). 4.25-4.30 (m, 4H), 6.98-7.02 (d, IH). 7.88-7.97 (m, 2H). 4*,5'-Dinitrobenzo-14-crown-4 (143). After chromatography the yellowish residue was recrystallized from EtOAc-hexane to give a yellow crystalline solid with mp 86-88 oc in a 72% yield. IR (deposit from chloroform solution on a NaCl plate): 1589,1535 (NO2); 1133 (C-0) cm-l. IH NMR (CDCI3): 5 1.70-2.18 (m, 4H), 3.73-3.78 (m, 8H), 4.10-4.46 (m, 4H), 7.32 (s, 2H). Anal. Calcd for C14N18N2O8: C, 49.12; H, 5.30. Found: C, 49.06; H, 5.29. 4'-Nitrobenzo-14-crown-4 (144). Using a shorter reaction time (1 h) than given in the general procedure, a yellowish crude product was obtained. After purification by column chromatography on alumina with EtOAc-hexane (1:2) as eluent a yellow oil was obtained in a 79% yield. IR (neat): 1586 (NO2); 1136 (C-0) cm-l. IH NMR (CDCI3): 5 2.00-2.12 (m, 4H), 3.61-3.67 (s, 4H), 3.72-3.82 (m, 4H), 4.18-4.32 (m, 4H), 6.93-7.07 (d, IH), 7.82-7.84 (d, IH), 7.89-7.93 (q, IH). Anal. Calcd for C14H19NO6: C, 56.56; H, 6.44. Found: C, 56.59; H, 6.42. 4*-Nitrobenzo-15-crown-5 (140). A yellow solid with mp 85-87 oc (lit[71] mp 84-850C ) was obtained in 86% yield. IR (deposit from chloroform on a NaCl plate): 1592 (NO2): 1121 (C-0) cm-l. IH 114 NMR (CDCI3): 5 3.67-3.76 (m, 8H), 3.92-3.96 (m, 4H), 4.18-4.24 (m, 4H), 6.86-6.90 (d, IH), 7.71-7.72 (d, IH), 7.86-7.92 (q, IH). 4*-Nitrobenzo-18-crown-6 (141). A yellow solid with mp 69-71 oc (lit[711 mp 70-72OC ) was obtained in 68% yield. IR (deposit from chloroform on a NaCl plate): 1593 (NO2); 1124 (C-0) cm-l. 1H NMR (CDCI3): 5 3.65-3.79 (m, 12H), 3.69-3.98 (m, 4H), 4.21-4.27 (m, 4H), 6.87-6.91 (d, IH), 7.73-7.74 (d, IH), 7.86-7.92 (q, IH). 4*-Nitrobenzo-21-crown-7 (142). A yellow solid with mp 64-66 oc (lit[82] mp 67-68 oc ) was obtained in 83% yield. IR (deposit from chloroform on a NaCl plate): 1587 (NO2): 1102 (C-0) cm-l. IH NMR (CDCI3); 5 3.94-3.84 (m, 14H), 3.93-3.98 (m, 4H), 4.21- 4.28 (m, 4H), 6.88-6.93 (d, IH), 7.74-7.76 (d, IH), 7.86-7.92 (q, IH). General Procedures for the Preparation of 4'-Aminobenzocrown Ethers 132-135 andl45 Procedure A. To a solution of the 4'-nitrobenzocrown ether (25.4 mmol) in 60 mL of dry DMF was added 10% palladium on carbon (100 mg/g of crown ether). The mixture was hydrogenated under 40 psi of hydrogen at room temperature for 24 h. The reaction mixture was filtered through a bed of Celite on a sintered glass funnel. The filtrate was evaporated in vauo to give the desired product. Procedure B. To a solution of the 4'-nitrobenzocrown ether (8.4 mmol) in 100 mL of EtOH-THF (3:7) was added anhydrous hydrazine (50.4 mmol) and 5% palladium on carbon (100 mg/g of 115 crown ether). The reaction mixture was refluxed for 24 h. The reaction mixture was filtered through a bed of Celite on a sintered glass funnel. Evaporation of the filtrate in vacuo gave the desired product. 4*-Aminobenzo-12-crown-4 (132).[81] A yellow oil was obtained in a 92% yield by Procedure B. IR (neat): 3344, 3213 (NH2): 1129 (C-0) cm-l. IH NMR (CDCI3): 5 3.50 (s, NH2), 3.78-3.91 (m, 8H), 4.08-4.14 (m, 4H), 6.22-6.28 (q, IH), 6.32-6.33 (d, IH), 6.81-6.84 (d, IH). 4'-Aminobenzo-14-crown-4 (145). A yellow oil was obtained in a quantitative yield by Procedure B. IR (neat): 3425, 3354 (NH2); 1122 (C-0) cm-l. IH NMR (CDCI3): 5 1.91-2.26 (m, 4H), 3.51-3.80 (m, 8H, NH2), 4.00-4.27 (m, 4H), 6.20-6.26 (q, IH), 6.33 (d, IH), 6.80 (d, IH). Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92. Found: C, 62.85; H, 8.01. 4'-Aminobenzo-15-crown-5 (133).[^2] A red oil was obtained in an 84% yield by Procedure A and in an 84% yield by Procedure B. IR (neat): 3354, 3213 (NH2); 1125 (C-0) cm-l. IH NMR (CDCI3): 5 3.66-3.98 (m, 12H, NH2), 4.04-4.08 (m, 4H), 6.18-6.24 (q, IH), 6.27-6.28 (d, IH), 6.70-6.74 (d, IH). 4'-Aminobenzo-18-crown-6 (134).[72] A red oil was obtained in a quantitative yield by Procedure A. IR (neat): 3396 (NH2); 1120 (C-0) cm-l. IH NMR (CDCI3): 5 3.66-3.94 (m, 20H, NH2), 4.06-4.10 (m, 4H), 6.24-6.28 (q, IH), 6.32-6.34 (d, IH), 6.71-6.75 (d, IH). 116 4'-Aminobenzo-21-crown-7 (135)[82] A yellow oil was obtained in quantitative yield by Procedure B. IR (neat): 3404 (NH2); 1106 (C-0) cm-l. IH NMR (CDCI3): 5 3.66-3.98 (m, 20H, NH2), 4.01-4.14 (m, 4H), 6.19-6.24 (q, IH), 6.28-6.29 (d, IH), 6.76-6.75 (d, IH). General Procedures for Modification of Nafion® 117 Membrane Method A. A T X T piece of 0.007 inch thick Nafion® 117 membrane was immersed in 100 mL of 0.5 N NH4OH aqueous solution for 24 h, washed with distilled water several times and dried under vacuum. The dried membrane piece was refluxed in a mixture of PCI5-POCI3 (30:60 g/g) for 24 h. The PCI5-POCI3 mixture was poured off while hot and the membrane was washed by brief refluxing with CCI4 (100 mL X 4). The resultant flexible white colored membrane was dried under vacuum for one day and then weighed. The resulting Nafion® sulfonyl chloride membrane was placed in a 250 mL round bottomed flask with boiling chips. Monoazacrown ether (2.0 equivalent), triethylamine (1.0 equivalent) and 120 mL of dry DMF was added to the flask. The reaction mixture was refluxed for 2 h. After cooling the reaction mixture, the membrane was removed from the flask, washed with CH2CI2 several times and dried under vacuum. Method B. A 2" X 2" piece of 0.007 inch thick Nafion® 117 membrane was refluxed with PCI5-POCI3 (30:60 g/g) for a period of 3 h. The PCI5-POCI3 mixture was poured off while hot and CCI4 (100 117 mL) was added. Following a brief reflux, the CCI4 was poured off. Twice more fresh CCI4 was added, refluxed and poured off. The resulting membrane was dried under vacuum. The Nafion® sulfonyl chloride membrane was placed in a 250 mL round bottomed flask with boiling chips. To the reaction flask monoazacrown ether (2.0 equivalent), triethylamine (1.0 equivalent) and 120 mL of dry DMF were added and the reaction mixture was heated at 50 oc for 48 h. After cooling down the reaction mixture the membrane was taken out of flask, washed with CH2CI2 thoroughly and immersed in distilled water. Hydrolysis of Nafion® Sulfonvl Chloride Membranes A 2" X 2" Nafion® sulfonyl chloride membrane was immersed in 150 mL of 5% aqueous NaOH solution and refluxed for 24 h. After cooling, the solution was poured out and the membrane was washed thoroughly with distilled water. The membrane piece was immersed in 5% aqueous HCl solution for 1 h at room temperature to convert the sodium sulfonate form into the sulfonic acid form. The membrane was washed several times with distilled water and dried under vacuum for 1 day. fiftneral Procedure for the Preparation of Dimesylates In a salt ice bath, a solution of the diol (60 g, 0.40 mol) in 150 mL of CH2CI2 was addfcd dropwise to a stirred solution of the Et3N 118 (100.0 g, 1.0 mol) dissolved in 350 mL of CH2CI2. The solution was cooled in an ice-salt bath and mesyl chloride (100.8 g, 0.88 mol) was added dropwise during a period of 1 h keeping the temperature of the reaction mixture at 0 oc or below. The reaction mixture was allowed to warm to room temperature during 2 h and 100 mL of 5% aqueous HCl solution was added. After an additional 30 min the organic layer was separated and washed with saturated aqueous NaHCOs (2 X 100 mL), brine (100 mL), water (2 X 100 mL), and dried over MgS04. Evaporation of the solvent in vacuo gave the desired dimesylate. Triethyleneglycol dimesylate (34). A light yellow oil was obtained in 95% yield. IR (neat): (SO2) cm-l. IH NMR (CDCI3): 5 3.08 (s, 6H), 3.64-3.79 (m, 8H), 4.34-4.39 (m, 4H). Tetraethyleneglycol dimesylate (36). A light yellow oil was obtained in 99% yield. IR (neat): (SO2) cm-l. IH NMR (CDCI3): 5 3.07 (s, 6H), 3.61-3.76 (m, 12H), 4.34-4.37 (m, 4H). Bis[3-(mesyloxy)propyloxy)lethylene glycol (35). A light yellow oil was obtained in 89% yield. IR (neat): 1349 (SO2); 1173 (C-0) cm-l. IH NMR (CDCI3): 5 2.00-2.08 (m, 4H), 3.02 (s, 6H), 3.56-3.61 (t, 8H), 4.32-4.38 (t, 4H). Pentaethyleneglycol dimesylate (37). A light yellow oil was obtained in 72% yield. IR (neat): 1352 (SO2); 1170 ( C-0) cm-l. IH NMR: 5 3.17 (s, 6H), 3.62-3.70 (m, 12H), 3.74-3.79 (m, 4H), 4.35- 4.40 (m, 4H). 119 Hexaethyleneglycol dimesylate (38). A light yellow oil was obtained in 82% yield. IR (neat): 1322 (SO2); 1125 (C-0) cm-l . IH NMR (CDCI3): 5 3.10 (s, 6H), 3.61-3.69 (m, 16H), 3.74-3.79 (m, 4H), 4.35-4.40 (m, 4H). Ethyleneglycol dimesylate (42). A light yellow oil was obtained in 43% yield. IR (neat): 1352, 1248 (SO2); 1171 (C-0) cm-l . IH NMR (CDCI3): 5 3.15 (s, 6H), 4.53 (s, 4H). Propyleneglycol dimesylate (43). A light yellow oil was obtained in 53% yield. IR (neat): 1338, 1250 (SO2); 1196 (C-0) cm-l . IH NMR (CDCI3): 5 2.15-2.26 (m, 2H), 3.02-3.05 (s, 4H), 4.34-4.43 (m, 6H). N-Tosyldiethanolamine dimesylate (68). A sticky colorless oil was obtained in 85% yield. IR (neat): 1332, 1255 (SO2); 1123 ( C- O) cm-l . iH NMR (CDCI3): 5 2.25 (s, 3H), 3.04 (s, 6H), 3,47-3.53 (t, 4H), 4.38-4.43 (t, 4H), 7.27-7.38 (d, 2H), 7.62-7.73 (d, 2H). 120 REFERENCES 1. Pedersen, C. J.; J. Am. Chem. Soc. 1968, 80, 2495. 2. Pedersen, C. J.; J. Am. Chem. Soc. 1967. 89, 7017. 3. Izatt, R. M.; Bradshaw, J. S.; Nielsen, S. A.; Lam, J. D.; Christensen, J. J.; Chem. Rev. 1985, 85, 271. 4. Pedersen, C. J.; Frensdorff, H. K; Anpew. Chem. Int. Ed. 1972. 11, 16. 5. Shannon, R. D.; Prewitt, C. T.; Acta Crvst. 1969. B25, 925. 6. Shannon, R. D.; Acta Crvst. 1976. A32, 751. 7. Izatt, R. M.; Eatough, D. 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