CROWN ETHER COMPOUNDS: SYNTHESIS and ALKALI METAL CATION COMPLEXATION by MI-JA GOO, B.S., M.S
CROWN ETHER COMPOUNDS: SYNTHESIS AND ALKALI METAL CATION COMPLEXATION by MI-JA GOO, 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
Accepted
May, 1991 //^ LB
1991, The Graduate School, Texas Tech University.
11 TABLE OF CONTENTS
TABLE OF CONTENTS iii
LIST OF TABLES xii
LIST OF FIGURES xiv
I. INTRODUCTION 1
Discovery of Crown Ethers 1
Nature of Crown Ether Complexes with Cations 3
Assessment of Metal Ion Complexation Abilities of Crown
Ethers by Picrate Extraction 7
Proton-ionizable Crown Ethers 9
Solvent Extraction by Proton-ionizable Crown Ethers 1 1
Liquid Membrane Transport of Metal Ions by
Proton-ionizable Crown Ethers 1 8
Immobilization of Crown Ethers on Silica Gel 2 0
Statement of Research Goals 2 1
II. RESULTS AND DISCUSSION 2 6
Acyclic and Cyclic Polyether Derivatives of Salicylic Acid .... 2 6
Lipophilic Dibenzo-16-crown-5-oxyacetic Acids 3 2
Dibenzo-16-crown-5 Phosphonic Acid Monoalkyl Esters 3 4 Functionalized Crown Ethers for Attachment to Silica Gel 4 4
111 Picrate Extractions 5 1
Benzo-21-crown-7 and Dibenzo-21-crown-7 Compounds.. 5 1
Benzo-13-crown-4 Compounds 5 2
14-Crown-4 Compounds 5 6
Crown Ethers with Pendant Ferrocene Units 5 7
Crown Ethers with Pendant Pyridine Units 6 1
Molecular Receptors 6 5
Summary 7 0
III. EXPERIMENTAL PROCEDURES 7 2
Instrumentation and Reagents 7 2
General Procedure for Preparation of Tosylates of
Monobenzyl Glycols 62-64 7 3
Tosylate of Monobenzyl Ethylene Glycol (62) 7 3
Tosylate of Monobenzyl Diethylene Glycol (63) 7 4
Tosylate of Monobenzyl Triethylene Glycol (64) 7 4 General Procedure for Preparation of Carboxylic Acids
68-70 7 4
Methyl 2-[(l,4-Dioxa-5-phenyl)pentyl]benzoate (65) 7 5
2-[(l,4-Dioxa-5-phenyl)pentyl]benzoic Acid (68) 7 5
Methyl 2-[(l,4,7-Trixa-8-phenyl)octyl]benzoate (66) 7 5 2-[(l,4,7-Trioxa-8-phenyl)octyl]benzoic Acid (69) 7 6
IV Methyl 2-[(l,4,7,10-Tetraoxa-ll-phenyl)undecyl]benzoate (67) 7 6
2-[(l ,4,7,10-Tetraoxa-l l-phenyl)undecyl]benzoic Acid (70) 7 6
Preparation of (Benzyloxy)methyl-substituted Crown Ethers
71-73 7 6
(Benzyloxy)methyl-12-crown-4 (71) 7 6
(Benzyloxy)methyl-15-crown-4 (72) 7 7
(Benzyloxy)methyl-21-crown-4 (73) 7 8
General Procedure for Preparation of Hydroxy methyl Crown
Ethers 74-76 7 8
Hydroxymethyl-12-crown-4 (74) 7 9
Hydroxymethyl-15-crown-4 (75) 7 9
Hydroxymethyl-21-crown-4 (76) 7 9
General Procedure for Preparation of (Tosyloxy)methyl- substituted Crown Ethers 77-82 7 9
(Tosyloxy)methyl-12-crown-4 (77) 8 0
3-[(Tosyloxy)methyl]-13-crown-4 (78) 8 0
(Tosyloxy)methyl-15-crown-5 (79) 8 0
(Tosyloxy)methyl-18-crown-6 (80) 8 0
(Tosyloxy)methyl-21-crown-7 (81) 8 0
(Tosyloxy)methyl-24-crown-8 (82) 8 1
l^fMNH General Procedure for Preparation of Crown Ether
Carboxylic Acids 34, 35, and 38-41 8 1
Methyl 2-[(12-Crown-4)-methyloxy]benzoate (83) 8 2
2-[(12-Crown-4)-methyloxy]benzoic Acid (34) 82
Methyl 2-[3'-(13-Crown-4)-methyloxy]benzoate (84) .... 8 2
2-[3'-(13-Crown-4)-methyloxy]benzoic Acid (35) 8 2
Methyl 2-[(15-Crown-5)-methyloxy]benzoate (85) 8 3
2-f(15-Crown-5)-methyloxy]benzoic Acid (38) 8 3
Methyl 2-[(18-Crown-6)-methyloxy]benzoate (86) 8 3
2-[(18-Crown-6)-methyloxy]benzoic Acid (39) 8 3
Methyl 2-[(21-Crown-7)-methyloxy]benzoate (87) 8 4
2-[(21-Crown-7)-methyloxy]benzoic Acid (40) 8 4 Methyl 2-[(24-Crown-8)-methyloxy]benzoate (88) 8 4
2-[(24-Crown-8)-methyloxy]benzoic Acid (41) 8 4
sym-Ketodibenzo-16-crown-5 (90) 8 4 syni-(Methyl)(hydroxy)dibenzo-16-crown-5 (91) 8 5
General Procedure for Preparation of Crown Ether Alcohols 92 and 93 8 6
sym-(Hexyn(hydroxy)dibenzo-16-crown-5 (92) 8 7
sym-(Decyn(hydroxv)dibenzo-16-crown-5 (93) 8 7
General Procedure for Preparation of Crown Ether Carboxylic Acids 94-96 8 7
VI syirL-(Methyl)dibenzo-16-crown-5-oxyacetic Acid (94) .. 8 8
sym-(Hexyl)dibenzo-16-crown-5-oxyacetic Acid (95) .... 8 8
iym.-(Decyl)dibenzo-16-crown-5-oxyacetic Acid (96) 8 8
Monoethyl sym-Dibenzo-16-crown-5-oxymethylphosphonic Acid (50) 8 9
General Procedure for Preparation of Crown Ethers Phosphonic Acid Monoethyl Esters 47-49 and 51-53 9 0
Diethyl iyi]i-Dibenzo-16-crown-5-oxyethylphosphonate (106) 9 0
Monoethyl sym-Dibenzo-16-crown-5-oxvethvlphosphonic Acid (51) 9 1
Diethyl sym-Dibenzo-16-crown-5-oxypropylphosphonate (107) 9 1
Monoethyl sym-Dibenzo-16-crown-5-ox v propyl phosphonic Acid (52) \ 9 1
Diethyl sym-Dibenzo-16-crown-5-oxvbutvlphosphonate (108) 9 1
Monoethyl sym-Dibenzo-16-crown-5-oxvbutvlphosphonic Acid (53) 9 2
Diethyl sym-(Decyl)dibenzo-16-crown-5-oxvethvl- phosphonate (103) 9 2
Monoethyl sym-(Decyl)dibenzo-16-crown-5-oxyethyl- phosphonic Acid (47) 9 2
Diethyl syni-(Decy l)dibenzo-16-crown-5-oxy propyl- phosphonate (104) 9 2
vii Monoethyl sym-(Decyndibenzo-16-crown-5-oxvpropvl- phosphonic Acid (48) 9 3
Diethyl sym.-(Decy l)dibenzo-16-crown-5-oxy butyl- phosphonate (105) 9 3
Monoethyl svm-(Decyndibenzo-16-crown-5-oxybutyl- phosphonic Acid (49) 9 3
Dimethyl ^yi]i-Dibenzo-16-crown-5-oxyethyl- phosphonate (109) 9 4
Monomethyl sym-Dibenzo-16-crown-5-oxvethyl- phosphonic Acid (110) 9 4
General Procedure for Preparation of Crown Ether Methanesulfonates 115-118 9 5
-(sym-Dibenzo-16-crown-5-oxy)-2- methanesulfonoxy)ethane (117) 9 5
-(sym-Dibenzo-16-crown-5-oxy)-3- methanesulfonoxy)propane (118) 9 5
-(sym-(Decyl)dibenzo-16-crown-5-oxv)-2 methanesulfonoxy)ethane (115) 9 6
-(sym-(Decyndibenzo-16-crown-5-oxy)-3- methanesulfonoxy)propane (116) 9 6
General Procedure for Preparation of Crown Ether Bromides
97, 98, 100, and 101 9 6
1-(sym-Dibenzo-16-crown-5-oxy)-2-bromoethane (100) 9 7
l-(sxni-Dibenzo-16-crown-5-oxy)-3-bromopropane (101) 9 7 l-[(sxi]l-(Decyl)dibenzo-16-crown-5-oxy]-2-bromoethane (97) 9 7
Vlll l-r(sym-(Decyndibenzo-l6-crown-5-oxy1-3-bromopropane (98) 9 7
General Procedure for Preparation of Crown Ether Bromides 99 and 102 9 8
l-(sxDl-Dibenzo-16-crown-5-oxy)-4-bromobutane (99)... 9 8
l-rsym-(Decyl)dibenzo-16-crown-5-oxy]-4-bromobutane (102) 9 8
General Procedure for Preparation of Crown Ether Esters
119-120 9 9
Ethyl (sxiIL-Dibenzo-16-crown-5-oxy)acetate (120) 9 9
Ethyl [(sxQi-(Decyl)dibenzo-16-crown-5-oxy)acetate (119) 9 9 General Procedure for Preparation of Crown Ether Alcohols 111 and 113 100
2-(sym-Dibenzo-16-crown-5-oxy)ethanol (113) 100
2-F(sym-(Decyl)dibenzo-16-crown-5-oxv1ethanol (111) .. 100
General Procedure for Preparation of Allyoxy Crown Ethers
121 and 122 1 0 1
3-(sym-Dibenzo-16-crown-5-oxy)-l-propene (122) 101
3-(sym-(Decyndibenzo-l6-crown-5-oxy1 1 -propene (121) 1 01 General Procedure for Preparation of Crown Ether Alcohols 112-114 102
3-(sym-Dibenzo-16-crown-5-oxy)propan-l-ol (114) 102
IX 3-[sym-(Decyl)dibenzo-16-crown-5-oxyJpropan-l-ol (112) 102
10-Methanesulfonoxy-l-decene (133) 103
10-Bromo-l-decene (134) 103
General Procedure for Preparation of Crown Ether Alcohols
124 and 125 104
sym-(9-Decenyn(hydroxy)dibenzo-14-crown-4 (124) 104
sxQi-(9-Decenyl)(hydroxy)dibenzo-16-crown-5 (125) 105 General Procedure for Preparation of Crown Ether Carboxylic Acids 135 and 136 105
syni-(9-Decenyl)dibenzo-14-crown-4-oxy acetic Acid (135) 105
sjTn-(9-Decenyl)dibenzo-16-crown-5-oxyacetic Acid (136) 106
General Procedure for Preparation of Crown Ether Esters 123 and 124 106
Ethyl sxni-(9-Decenyl)dibenzo-14-crown-4-oxyacetate (123) 106
Ethyl syni-(9-Decenyl)dibenzo-16-crown-5-oxyacetate (124) 107
General Procedure for Preparation of Crown Ether Esters 138 and 139 107
Ethyl syiTi-(10-Hydroxydecyl)dibenzo-14-crown-4- oxyacetate (138) 107
Ethyl sym-(10-Hydroxydecyl)dibenzo-16-crown-5- oxyacetate (139) 108
X
ni . Iii—. ^ 11-Methanesulfonoxy-l-undecene (140) 108
2-Hydroxy-4-(10'-undecenoxy)benzoic Acid (141) 108
Methyl 2-Hydroxy-4-(10'-undecenoxy)benzoate (142) 109
General Procedure for Preparation of Methyl Esters 125-128 1 1 0
Methyl 2-[(12-Crown-4)methyloxy]-4- (lO'-undecenoxy)benzoate (125) 110
Methyl 2-[(15-Crown-5)methyloxy]-4- (lO'-undecenoxy)benzoate (126) 110
Methyl 2-[(18-Crown-6)methyloxy]-4- (lO'-undecenoxy)benzoate (127) Ill
Methyl 2-[(21-Crown-7)methyloxy]-4-
(10*-undecenoxy)benzoate (128) Ill
Preparation of Alkali Metal Picrates 1 1 1
Preparation of Alkylammonium Picrates 1 1 2
Preparation of N,N-Didecyl-7,16-diaza-18-crown-6
(185) 1 1 2
Decanoyl Chloride (183) 1 1 2
N,N-Didecanoyl-7,16-diaza-18-crown-6 (184) 1 12
N,N-Didecyl-7,16-diaza-18-crown-6 (185) 113
Procedure for Picrate Extractions 1 1 3
REFERENCES 1 1 5
XI LIST OF TABLES
1. Comparison of Cation and Cavity Diameters 7
2. Lipophilicity of Salts of Crown Ethers 5-8 1 1
3. The Effect of Organic Solvent upon the Selectivity and Efficiency of Alkali Metal Solvent Extraction by Crown Ether Carboxylic Acid 18 1 8
4. Comparison of Bound and Analogous Unbound Crown Ether Interaction Constants with Metal Cations 2 3
5. Yields of Compounds 62-70 2 8
6. Yields of Compounds 34, 35, 38-41, and 77-88 3 2
7. Hydrolysis of Crown Ether Phosphonic Acid Dialkyl Esters 103-109 3 9
8. Picrate Extraction Data for 21-Crown-7 Compounds 5 3
9. Picrate Extraction Data for Benzo-13-crown-4 Compounds 5 5
10. Picrate Extraction Data for 14-Crown-4 Compounds 5 8
11. Picrate Extraction Data for Crown Ethers 171 and 172 6 0
12. Picrate Extraction Data for Crown Ethers 173-175 6 2
13. Picrate Extraction Data for Crown Ethers 176-178 6 3
14. Picrate Extraction Data for Molecular Receptors 179-181 66
15. Alkylammonium Picrate Data for Molecular Receptors 179-181 6 8 16. Alkylammonium Picrate Data for Molecular Receptor 182 6 9
Xll
•^^N. 17. Alkylammonium Picrate Data for Crown Ether 185 7 0
Xlll LIST OF HGURES
1. Pedersen's Synthesis of Dibenzo-18-crown-6 1
2. A Dibenzo-18-crown-6 Complex with a Sodium Salt 2
3. The Template Effect in the Synthesis of 18-Crown-6 5
4. Reorganization of 18-Crown-6 upon Complexation 7
5. Complexation and Decomplexation of Proton-ionizable Crown Ethers with Metal Cations 9
6. Cram's Early Proton-ionizable Crown Ethers 1 0
7. Bartsch's Dibenzo Crown Ether Carboxylic Acids 1 2
8. Bartsch's Crown Ether Carboxylic Acids with Various
Ring Sizes 1 5
9. The Proposed Crown Ether Carboxylic Acids 1 5
10. Bartsch's Crown Ether Monoethyl Phosphonates 1 6
11. The Proposed Crown Ether Monoethyl Phosphonates 17 12. Mechanism of Metal Cation Transport across a Liquid Membrane by a Proton-ionizable Crown Ether 1 9
13. Synthesis of Silica Gel-bound Crown Ethers by Bradshaw,
Izatt, and Coworkers 2 2
14. Functionalized Crown Ethers for Attachment to Silica Gel .... 4 5
15. Benzo-21-crown-7 and Dibenzo-21-crown-7 Compounds .... 5 2
16. Benzo-13-crown-4 Compounds 5 4
17. 14-Crown-4 Compounds 5 7
xiv 18. Crown Ethers with Pendant Ferrocene Units 5 9
19. Crown Ethers with Pendant Pyridine Units 6 1
20. The Proposed 2:2 Complex between Crown Ether 174 and Alkali Metal Cations 6 4
21. The Proposed 1:1 Complex between Crown Ether 178 and Alkali Metal Cations 6 4
22. Molecular Receptors 6 5
XV CHAPTER I INTRODUCTION
Discovery of Crown Ethers The earliest comprehensive report of macrocyclic polyethers and their unique ability to solubilize metal salts appeared in 1967.ti] Pedersen obtained a very small amount of a white, fibrous, crystalline by-product in a preparation of bis[2-(o.-hydroxy- phenoxy)ethyl] ether (3) by reacting bis(2-chloroethyl) ether (2) with the sodium salt of 2-(o.-hydroxyphenoxy)tetrahydropyran (1) which was contaminated with some catechol (Figure l).^^! The unexpected compound was found to be insoluble in methanol, but dissolved in methanol when sodium hydroxide was added. Pedersen deduced the structure of the compound to be 2,3,11,12-dibenzo- LO ^ ro, - a: :
OH CI CI "^^^=^0 O
4 Figure 1. Pedersen's Synthesis of Dibenzo-18-crown-6. l,4,7,10,13,16-hexaoxacyclooctadeca-2,ll-diene (4) based on its elementary composition, molecular weight, and nmr spectrum. Compound 4 was formed by the reaction of two molecules of bis(2-chloroethyl) ether with two molecules of the catechol contaminant. In trying to explain the unusual solubility characteristics of this compound in the presence of sodium salts, Pedersen realized that the cyclic polyether ring formed a complex with the sodium cation (Figure 2).[3]
O^ % ':I 4. O^^^is^' Anion o' : ''o
Figure 2. A Dibenzo-18-crown-6 Complex with a Sodium Salt.
Since the systematic names of many of these polyethers were too cumbersome for repeated use, abbreviated names have been coined for their ready identification. Because of the appearance of its molecular model and its ability to "crown" the cations, the cyclic polyethers were designated "crown ethers" as a class and host-guest chemistry was born. Pederson's nomenclature consisted of naming in order: (1) the number and kind of substituents on the polyether ring; (2) the total number of atoms in the polyether ring; (3) the class name, crown; and (4) the number of oxygen atoms in the polyether ring. Placement of the hydrocarbon rings and the oxygen atoms is usually symmetrical and the exceptions are indicated by the prefix "asym." Employing this nomenclature, macrocycle 4 is named "Dibenzo-," "18-," "Crown-," and "-6," to give "Dibenzo-18-crown-6." The five different methods for the preparation of the cyclic polyethers reported by Pedersen^] are shown in Scheme 1, where R, S, T, U, V, and W represent divalent organic groups which may or may not be identical. Method 5 consisted of the hydrogenation of benzo compounds to the corresponding cyclohexano derivatives using ruthenium dioxide catalyst in p.-dioxane. Pedersen recognized that method 2 was the most versatile for the preparation of compounds containing two or more benzo groups. For example, method 2 produced dibenzo-14-crown-4 in a 27% yield, but method 3 gave no recoverable amount of the desired product. Pedersen found that the synthesis of crown ethers often proceeded in a surprisingly smooth manner to give high yields of cyclic products even without applying high dilution techniques.t^^l A cation assisted cyclization, as depicted in Figure 3, is considered to be responsible for the high yields. This kind of cyclization assistance is called a template effect.t^^ The extent to which the template effect is noticeable depends on the type of cation present.t^l In a few cases, Cs"*" has proven to be very suitable.f^l
Nature of Crown Ether Complexes with Cations Pedersen established that many crown ethers formed complexes with the salts of the elements belonging to the following Scheme 1
Method 1
,0H + 2NaOH + Cl-R-Cl T X^^ ^OH "^^55^0
Method 2
'O'^O-S-0^ ^ ^^^^" ^ Cl-T-Cl-^ .<^^0-T-0 O-S-0
Method 3 ^O-U-0. 4 NaOH + 2 Cl-U-Cl -c ^^o-u-o
Method 4 s^O-V-O + o iSTnOH ^nr°" • ^^ i^awxx . if M-v<:, 1=^=^0-V- 0
Method 5 a::Do ^ H. -^^ Oil 5 OTs ^OTs r^oH Tso^ ^o- S r^ctK,
OTV
Figure 3. The Template Effect in the Synthesis of 18-Crown-6. groups of the periodic table: all in lA and IB; most in IIA; some in IIB; and a few in IIIA, IIIB, and IVB.tsi The ability of crown ether ligands to complex other cationic species such as diazonium ionst^J and primary or secondary alkyl ammonium saltsf^^.H] has since been recognized. These complexes appeared to be salt-polyether complexes formed by ion-dipole interaction between the cation and the negatively charged oxygen atoms which are symmetrically placed in the crown ether ring. The formation of stable ammonium complexes supported this interpretation. The conditions necessary for the formation and the factors which influence the stability of the complexes include: the relative sizes of the cation and the cavity in the crown ether ring; the number of oxygen atoms in the ring; the coplanarity of the oxygen atoms; the symmetrical placement of the oxygen atoms; the basicity of the oxygen atoms; steric hindrance in the polyether ring; the tendency of the ion to associate with the solvent; and the electrical charge on the ion. A stable complex is not formed if the cation is too large to fit in the cavity of the crown ether ring. The ionic diameters of the alkali metal cations and crown ether cavities are listed in Table 1, which shows that 12-crown-4 and Li+, 15-crown-5 and Na+, and 18-crown- 6 and K+ are well matched. The theoretically predicted spatial relationships with inward-directed oxygen atoms are quite in keeping with an ion-ball model of the 18-crown-6-K+ complex.^41 Measured complexation constants confirm the excellent fit of K+ within the 18-crown-6 ring. Dunitz demonstrated from crystal structures of 18-crown-6 and those of its K+SCN- complex (Figure 4)n5,i6] that the host and its complex have different conformational organizations. The potential crown cavity of the host itself is filled with two inward-turned CH2 groups and the electron pairs of two oxygens face outward and away from the center of the roughly rectangular structure. Thus, the free host does not have a crown shape or a cavity. Only when the oxygens become engaged with a guest such as K+ does a filled cavity develop. The presence of a guest in the complex induces the electron pairs to converge on the center of a crown-shaped object. In other words, the guest conformationally reorganizes the host upon complexation. Solvent molecules may play the same role as a cationic guest. Table 1. Comparision of Cation and Cavity Diameters.t^2,i3]
cation cation diameter[A]a crown ether cavity diameter[A]
U TJe 12-crown-4 1.2b . 1.5c
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. The Shannon and Prewitt crystal radii are adopted because they come closer to representing reality than do the traditional values. b. Estimated from Corey-Pauling-Koltun (CPK) models. c. Estimated from Fisher-Hirschfelder-Taylor (FHT) models.
Figure 4. Reorganization of 18-Crown-6 upon Complexation.
Assessment of Metal Ion Complexation Abilities of Crown Ethers bv Picrate Extraction The use of metal picrate salts as guest cations to provide a spectrometric method for determining the stoichiometry of the crown ether-cation complex was reported by Smid and co workers. ^7,18] The position of the absorption maximum of the 8 picrate anion in THE was noted to be sensitive to the ion pairing nature of metal salt. For crown-cation complexes of 1:1 stoichiometry, the salt forms a tight ion pair which has an absorption maximum between 350 and 362 nm, depending on the alkali metal cation used. When the stoichiometry of the complex was two crown ethers to one cation, the salt formed a "crown-separated" ion pair with an absorption maximum between 375 and 390 nm. Iwachido and co-workers later reported the distribution of alkali metal picrate complexes between an aqueous phase and a benzene solution of dibenzo-18-crown-6.[i9] xhe extraction constant (Kex) was defined by the equilibrium between free metal picrate in the aqueous phase ([M+]a and [A Ja), free crown in the organic phase ([Cr]o), and the complex ion pair in the organic phase ([MCrA]o) according to the relationship shown in Equation 1: [M+]a + [Cr]o + [A-]a ^=f=^ [MCrAJo. (1) Kex = [MCrA]o/[M+]a[Cr]o[A-]a. The extraction constant defined by Iwachido and co-workers represents only the concentration equilibrium constant of the crown ether with a particular metal picrate and does not include ionic activity coefficients or any compensation for the increased lipophilicity of the picrate salts as the ionic diameter increases. Thus, the extraction constant is only a measurement of the activity of the crown ether in single ion solvent extraction systems and has no thermodynamic significance. Proton-ionizable Crown Ethers Crown ethers with ionizable pendant arms are known to form stronger complexes with uni- and multivalent cations than their neutral counterparts because the anion provides an internal counterion for a complexed cation, as shown in Figure 5.
X-H
M"" ^ ( ]\^^ ) + H""
Figure 5. Complexation and Decomplexation of Proton-ionizable Crown Ethers with Metal Cations.
Cram and co-workers synthesized the first ionizable crown ethers which are shown in Figure 6.^^^^ Crown ethers 5-8 possess carboxyl groups but its orientation into crown cavity can hinder ring participation during complexation with the cation. Modification of the pendant arm by insertion of spacer groups between the crown ether ring and the carboxylic acid residue resulted in enhancement of guest complex formation.[^2] Cram and co-workers prepared crown ether carboxylic acids 9-12 which have ionizable pendant arms of sufficient length to allow interaction with the guest by both the crown ether ring oxygens and the ionizable group.[23] 10
n. 5 0 9, A=B=CH20CH2C02H, n=0 6 1 10, A=B=CH20CH2C02H, n=l 7 2 11, A=CH20CH2C02H, B=H, n=0 8 3 12, A=CH20CH2C02H, B=H, n=l
Figure 6. Cram's Early Proton-ionizable Crown Ethers.
Crown ethers 5-8 were tested for their abilities to lipophilize Li+, Na+, K-"-, and Ca^"*" by distributing their salts between dichloromethane and water (Table 2). Maximum lipophilization of each ion depends on the ring size of the host: for Li+, 18-crown-5; for Na"*", 21-crown-6; for K+, 30-crown-8; for Ca^^, 18-crown-5. The crystal structure of 6 showed that the potential cavity within the molecule was filled with the carboxylic acid residue.[24] Therefore, complexation of a guest species by 6 must be associated with a major conformational reorganization of the host. Bartsch and co-workers have synthesized many different types of proton-ionizable crown ethers. Some of these are dibenzo crown ether carboxylic acids and are shown in Figure 7. The two benzene rings reduce the basicity of four ethereal oxygens through electron delocalization, but provide ring rigidity which helps to preorganize the ligand. 11
Table 2. Lipophilicity of Salts of Crown Ethers 5-8.
% of salt in die CH2CI2 layer
salt of Li+ Na+ K+ Ca2+
5 1-4 1.5 1-4 1.1
6 7.2 7.9 6.7 4.8
7 6.1 8.7 6.8 1.8
8 3-4 5.2 8.0 2.9
Solvent Extraction bv Proton-ionizable Crown Ethers Solvent extraction is a method of separation based on the transfer of a solute from one immiscible solvent into another.[25] The extraction efficiency of crown ethers has been markedly enhanced by the introduction of crown ethers which bear a pendant carboxylic acid group.[26] These proton-ionizable crown ethers possess a distinct advantage over neutral crown ether compounds in the extraction of a metal cation from an aqueous phase into an organic medium does not require the concomitant transfer of the aqueous phase anion.[27] Extraction efficiencies for a number of proton-ionizable crown ethers are reported as Kex, the extraction constant. The extraction constant is defined in Equation 2:
iC. = [MLlorg [H+]aq/[HL]org[M+]aq. (2) 12
H^OCHjCOjH H^OCH.CO^H
0^0 c';; o .)3 Y_ 1 7 13 CH2CH2 14 CH2CH2CH2 15 CH2CH2OCH2CH2 16 CH2(CH20CH2)2CH:2
^8^17 H^OCHCOoH CgHjy >^^OCH2C02H cK: ^ o::::o ^0^ ^0^ 18 19
Figure 7. Bartsch's Dibenzo Crown Ether Carboxylic Acids.
Metal ion extraction efficiencies are influenced by many factors. The lipophilicity of the molecule is an important consideration in the design of extractant molecules. A proton- ionizable crown ether extractant will be lost from the organic phase upon deprotonation if it has insufficient lipophilicity, even if the crown ether compound forms stable complexes with the metal ion being extracted. Competitive alkali metal cation extraction from aqueous solution into chloroform by the dibenzo crown ether 13 carboxylic acids 13-16 (see Figure 7) was examined.[27,28] it was found that these proton-ionizable crown ethers were of insufficient lipophilicity to remain completely in the organic phase during extraction of alkali metal cations from alkaline aqueous phases. To avoid such complications in extraction behavior, a lipophilic group was attached either to each benzene ring, to the carboxylic acid containing sidearm, or to the center carbon of the three-carbon bridge of the dibenzo-16-crown-5 compound 15 to produce the lipophilic dibenzo-16-crown-5-carboxylic acids 17, 18, and 19, respectively (see Figure 7).[26-29] Compounds 17-19 were found to be sufficiently lipophilic to remain completely in the chloroform phases even when the contacting aqueous solutions of alkali metal cations were highly alkaline.[26,28] por competitive solvent extraction of alkali metal cations from aqueous solution into chloroform, structural isomers 19 gave much higher Na+ selectivity than did 17 or 18. Hence the lipophilic group attachment site was shown to influence the extraction selectivity. A second factor which influences extraction selectivity is the crown ether ring size. The series of lipophilic crown ether carboxylic acids with varying ring sizes shown in Figure 8 was synthesized by Bartsch and co-workers to study competitive solvent extraction of alkali metal cations.[^0,31] Extraction selectivity for Li+ was observed for crown ethers with 12-15-membered polyether rings containing four oxygen atoms. For the 14-crown-4 carboxylic acids 23 and 24, very high Li+/Na+ selectivity coefficients of 17-20 were observed 14 with no detectable extraction of K+, Rb+, or Cs+. The crown ether carboxylic acids which contain 15-crown-5, 18-crown-6, and 21-crown-7 rings exhibited good selectivities for K+, Rb+, and Cs+ extraction, respectively. In contrast, poor extraction selectivity was observed for crown ether carboxylic acids with 24-crown-8, 27- crown-9, and 30-crown-lO rings. Thermodynamic data for alkali metal cation complexation by this series of compound has not been obtained because of their high lipophilicity which would not provide solubility in the aqueous or aqueous alcoholic solvent in which such measurements are usually performed. A new series of crown ether carboxylic acids 34-41 which has no lipophilic group (Figure 9) is needed for the determination of stability constants for interactions of alkali metal cations by titration calorimetry. Another potentially important structural parameter is the length of the arm that connects the polyether ring to the ionizable group. Unfortunately, systematic structural variation of the pendant arm length for crown ether carboxylic acids presented certain synthetic difficulties. (Surprisingly, there was no reaction of crown ethers containing -0(CH2)nBr side arms with magnesium metal which precluded the formation of Grignard reagents for which subsequent reaction with carbon dioxide could conceivably produce carboxylic acids. When crown ethers with these side arms were treated with cyanide ion, substitution reactions to form the corresponding nitriles did take place. However, no method has been found by which the nitriles can be hydrolyzed to carboxylic acids.)[^2] 15 CioH2iv^!:^^OCH^E
'CO2H
CE CE 2 0 12-crown-4 27 16-crown -5(3) 2 1 13-crown-4(2) 28 18-crown -6 2 2 13-crown-4(3) 2 9 19-crown -6(2) 23 14-crown-4(2) 3 0 21-crown -7 2 4 14-crown-4(3) 3 1 24-crown -8 25 15-crown-4(3) 32 27-crown -9 2 6 15-crown-5 33 30-crown -10
[(2) or (3) designates attachment through a carbon of a two carbon bridge or the central carbon of the three-carbon bridge, respectively]
Figure 8. Bartsch's Crown Ether Carboxylic Acids with Various Ring Sizes.
OCH^E aCO2H
CE CE 3 4 12-crown-4 3 8 15-crown-5 3 5 13-crown-4(3) 3 9 18-crown-6 3 6 14-crown-4(2) 4 0 21-crown-7 3 7 14-crown-4(3) 4 1 24-crown-8
Figure 9. The Proposed Crown Ether Carboxylic Acids. 16 A homologous series of crown ether phosphonic acid monoethyl esters 42-45 which have the same polyether and lipophilic components as crown ether carboxylic acid 17 (Figure 10) was accessible.[33] The observed selectivity orders were: Na'*'> Li+> K+> Rb+, Cs+ for 42; Na-»-» K+> Li+> Cs+> Rb+ for 43; and Li+> Na+> K+> Rb+, Cs+ for 44 and 45- It was proposed that the metal cation was complexed within the crown ether rings of 42 and 43, but coordinated primarily with the monoethyl phosphonate center in 44 and 45. (Lipophilic phosphonic acid monoethyl esters which do not have polyether units exhibited modest Li+ selectivity in competitive solvent extraction of alkali metal cations into chloroform.)
O H^0(CH2i,P0H H r^ C)Et 42 1
(CH3)3C-ft )Q-C(CH3)3 44 3 P O;-^-^ 45 4 ^o^
Figure 10. Bartsch's Crown Ether Monoethyl Phosphonates.
The variation of the lipophilic group attachment site for crown ether carboxylic acids 17-19 has been found to influence the selectivity and efficiency of the solvent extraction process.[34.35] The new series of lipophilic crown ether phosphonic acid monoethyl esters 46-49 shown in Figure 11 would allow the influence of the lipophilic group attachment site upon the sidearm length effect to be compared with that reported for 42-45[331 in solvent extractions of 17 alkali metal cations. For the set of non-lipophilic crown ether phosphonic acid monoethyl esters 50-53, titration calorimetry could be used to assess the influence of side arm variation upon the thermodynamics of alkali metal cation complexation.
O
fl OEt R n. R n O O, 46 C10H21 1 5 0 H 1 47 C10H21 2 5 1 H 2 O O 48 C10H21 3 52 H 3 4 H 4 ^0^ 49 C10H21 53
Figure 11. The Proposed Crown Ether Monoethyl Phosphonates.
The effect of organic solvent variation by lipophilic crown ether carboxylic acid, 2-r(sym-dibenzo-16-crown-5)oxyldecanoic acid (18), was found in the examination of alkali metal solvent extraction in chloroform, 1,1,1-trichloroethane, tetrahydronaphthalene, benzene, toluene, and ^.-xylene as the organic solvents.[36] Table 3 shows the organic phase loading data (assuming formation of 1:1 complexes) as well as the Na+/Li+ and Na+/K+ concentration ratios for all six organic solvents at an aqueous phase equilibrium pH of 8.7. The organic phase loading is highest for chloroform and decreases regularly in the order chloroform> l,l,l-trichloroethane> tetrahydronaphthalene> benzene> toluene> ^.-xylene. This regular ordering contrasts sharply with the observed extraction selectivities. As would be predicted from the ratio of the cavity size of 18 and the 18 alkali metal cation diameters[34], Na+is the best-extracted metal cation for all six organic solvents. However the high selectivity for extraction of Na+ into chloroform is markedly diminished in all five other organic solvents.
Table 3. The Effect of Organic Solvent upon the Selectivity and Efficiency of Alkali Metal Sovent Extraction by Crown Ether Carboxylic Acid 18.[36]
concentration ratio in the organic phase organi c phase solvent loading. % Na+/Li+ Na+/K+
chloroform 62 5.5 6.5
1,1,1-trichloroethane 53 1.7 1.7
tetrahydronaphthalene 47 1.6 1.6
benzene 42 1-4 1-4
toluene 34 1.7 1.8
p.-xylene 25 1.8 1-4
Liquid Membrane Transport of Metal Ions by Proton-ionizable Crown Ethers Liquid membranes are useful devices for the design of systems to separate one solute from another and usually produce higher fluxes and selectivities than polymeric membranes. Coupled transport mediated by mobile carriers is one of the simplest 19 mechanisms for the selective removal of a desired ion from a dilute solution.[37] In such a system, the flux of one ion moving down its concentration gradient may be used to drive the transport of the desired cation up its concentration gradient. A pH gradient with back-transport of protons is used most often to drive the transport of another cationic species from a basic to an acid solution. The mechanism of proton-coupled transport of a monovalent cation across a liquid organic membrane is illustrated in Figure 12. The carrier, which remains in the organic membrane, is deprotonated at the organic phase-alkaline aqueous source phase interface and
Basic Aqueous Organic Phase Acidic Aqeous Source Phase Receiving Phase HO^ H-X
Step 1
Step 2
Step 3 H-X
Step 4 M^ -^ Overall H^
Figure 12. Mechanism of Metal Cation Transport across a Liquid Membrane by a Proton-ionizable Crown Ether. 20 complexes the metal cation (Step 1). The electroneutral complex then diffuses across the organic membrane (Step 2). At the organic phase-acidic aqueous receiving phase interface, the carrier is protonated which releases the metal cation into the receiving phase (Step 3). The carrier molecule then diffuses back across the organic membrane (Step 4) to begin another cycle. Therefore, the net result is transport of the metal ion from the source aqueous phase to the receiving aqueous phase coupled with counter-transport of a proton.
Immobilization of Crown Ethers on Silica Gel Crown ethers covalently attached to silica gel have been prepared by Bradshaw, Izatt and co-workers (Figure 13)[38] to circumvent the problem that the separation of metal ions using crown ethers in extraction or liquid membrane systems may involve the slow, but steady, loss of the expensive crown ether compounds from the organic membrane or organic layer. The log K values for the interaction of the silica gel-bound crown ethers with various cations have been determined.[39] The equilibrium expression for 1:1 cation-crown ether interaction is given by Equation 3:
F(l-fKi[H+]+KiK2[H+]2) ^- (l-f)[Mn+] • ^^ where f=the fraction of ligand sites containing bound cations, Ki and K2 are the protonation constants applicable to 55 , and [M^+] and [H+] are the equilibrium molar free cation and proton concentrations, respectively. The quantities [Mn+] and [H+] are taken to be the
• '^^—*^ 21 Pt cat. Crown-CH2YCH=CH2 mKOCuA Crow„-CH,Y(CH,),-^i(OC3H5), Y=OCH2 i CHo Y=CH2 CH^ ^
silica gel SILICA Crown-CH2Y(CH2)2-^i heat GEL
Crown Substituents
o o r PhCH.-N N-CH.Ph o 2 o o O
54, Y=CH2 55, Y=0CH2
V^ Y n C^ "^ 56 OCH2 0 O O 57 OCH2 1 ( ^ r^) 58 CH2 2 ^O O-^"
Figure 13. Synthesis of Silica Gel-bound Crown Ethers by Bradshaw, Izatt and Co-workers.
- " • .-•-.-«. ».^rw^^-.>^ ^iJTI HI M IMill^ 22 effluent M"+ and H+ concentrations as determined by atomic absorption (AA) spectroscopy and pH measurements when these concentrations are equal to the input concentrations. The total number of moles of ligand sites is known from the organic synthesis and was checked by quantitatively loading every crown ether site with a strongly interacting cation. After equilibrium was reached, the column was stripped with pure water, a complexing agent or an acidic solution. The resulting solution of known volume was analyzed for cation concentration by AA spectroscopy. The fraction of ligand sites containing the cation was calculated as moles of bound cation/mole of ligand. The pKa values were determined by repeating the above log K experiments for cations at several pH values and curve fitting of the results according to Equation 3.
Table 4 shows complexation data for silica gel-bound and analogous free crown ether interaction constants with metal ions. The similarity of the log K values for the bound crown ethers to those involving the unbound crown ethers suggests that metal separations using silica gel-bound crown ether ligands should be possible.
Statement of Research Goals The interest in macrocyclic polyethers as complexing agents for metal cations, primary alkyl ammonium salts and neutral as well as charged substrates has grown exponentially since Pedersen's original publication.[^1 Methods for the design and synthesis of macrocyclic polyethers have been developed to achieve high stability and high selectivity for metal cations. Such development generally requires 23 Table 4. Comparison of Bound and Analogous Unbound Crown Ether Interaction Constants with Metal Cations.[38]
logK
crown ether cation bound unbound
54 H+ 5.10 ±0.20 5.23a
5 4 Ag+ 2.70 ± 0.20 5.50b
5 4 Cu2+ 1.80 ± 0.10 4.63b
5 5 Ag+ 8.20 ± 0.20 7.80C
5 6 Ag+ 0.90 ± 0.15 0.94
57 Ag+ 1.61 ± 0.09 1.50
5 7 Ba2+ 3.56 ± 0.01 3.87t>
5 8 Ba2+ 2.93 ± 0.09 5-44 a. pKa value for pyridine in water.t^oi The pKa value for unbound crown ether has not been reported. b. Log K values measured are in methanol. These values have been shown to be 2-3 log K units higher than the log K values measured in water. c. This value is for diaza-18-crown-6. 24 the use of functionalized macrocyclic polyethers containing structural features that allow for further chemical modification. Indeed, hundreds of original papers relating to various aspects of host-guest chemistry have been published within the past decade and considerable progress has been made. A major portion of this dissertation deals with the synthesis of new proton-ionizable crown ethers which will be utilized by others to determine the effect of structural variation upon metal ion complexation in solvent extraction and titration calorimetric studies. Structural variations within the proton-ionizable crown ethers include: (1) the identity of the proton-ionizable group; (2) the ring size and rigidity of the crown ether ring; (3) the length of the "arm" which connects the proton-ionizable group to the polyether framework; and (4) the attachment site and nature of the lipophilic group which is necessary to retain the ionized crown ether in the organic phase during solvent extraction.[^H These compounds include a series of acyclic and cyclic polyether derivatives of salicylic acid, and series of non-lipophilic dibenzo-16-crown-5 phosphonic acid monoalkyl esters and lipophilic dibenzo-16-crown-5 phosphonic acid monoalkyl esters in which the sidearm length is systematically varied. For attachment to silica gel, functionalized crown ethers which have dibenzo-14-crown-4 and dibenzo-16-crown-5 rings are to be prepared. Also a set of functionalized crown ethers based on salicylic acid are to be synthesized. These crown ether compounds have long 25 lipophilic tails with a terminal carbon-carbon double bond for covalent attachment to silica gel. The second portion of this dissertation will involve a determination of the complexation efficiency of different neutral crown ethers for alkali metal cations by the picrate extraction method. Several series of novel crown ethers are to be investigated in this manner.
- ^ ^ > > - • . ^ ^.-w^^-w„ CHAPTER n RESULTS AND DISCUSSION
Acyclic and Cyclic Polyether Derivatives of Salicylic Acid Acyclic polyether derivatives of salicylic acid 68-70 were synthesized for assessment of their alkali metal cation binding properties by calorimetric titrations. Precursor tosylates 62-6 4 were prepared by reaction of g.-toluenesulfonyl chloride with the corresponding alcohols 59-61, respectively, in pyridine (Scheme 2).
Scheme 2
i-A TsQ ir-\ HO 0)„CH2Ph pyridine ' TsO 0),CH2Ph H 2- 59 1 62 1 6 0 2 63 2 6 13 64 3
The synthetic route to 68-70 is summarized in Scheme 3. Methyl salicylic acid was reacted with NaH (1.1 equivalents) in THE and then tosylate 62 to give the methyl benzoate derivative 65 in 49% yield. The use of more NaH (2.0 or 4.0 equivalents) did not increase the yield. Unreacted tosylate was still detected in the crude reaction product mixture in all cases. Use of 1.1 equivalents of NaH was found to be the best reaction stoichiometry for the coupling of the tosylate 62 with the anion of methyl salicylate to give ester 65. 26 27
This stoichiometry was subsequently utilized for the preparation of esters 66 and 67. Basic hydrolysis of the substituted methyl benzoates 65-67 gave the benzoic acids 68-70. Table 5 shows the yields of compounds 62-70. Evaluation of the binding properties of acyclic polyether carboxylic acids 68-70 for alkali metal cations in water by Dr. Moon Hwan Cho['*2] using titration calorimetry was unsuccessful. The heat change upon complexation was too small to allow for calculation of log K values.[42]
Scheme 3
1) NaH, THE ^Y^ 0),CH2Ph ^. a" ^^C02Me ^===^^C02Me 2) TsO 0)nCH2Ph n. n 6 2 1 65 1 63 2 66 2 64 3 67 3
NaOH ,^c^0^0)„CH2Ph EtOH ^'^:^^C02H
n. 68 1 6 9 2 7 0 3 28 Table 5. Yields of Compounds 62-70.
percent yield of
(T^ r^^^O 0)„CH2Ph ,^=^0 0),CH2Ph TsO 0)„CH2Ph C02Me ^^ CO2H n
95 49 89
79 79 88
67 75 94
Cyclic polyether derivatives of salicylic acid 34,35, and 38-41 (see Figure 9) were prepared for determination of the stability constants (log K values) for alkali metal cation complexation using calorimetric titrations. For the preparation of cyclic polyether derivatives of salicylic acid, hydroxymethyl-substituted crown ethers were needed. Hydroxymethyl-13-crown-4(3), -18-crown-6, and - 24-crown-8 were available from other studies.[^3] The synthetic routes to (benzyloxy)methyl crown ethers 71-73 are depicted in Scheme 4. The (benzyloxy)methyl-12-crown-4 (71) was prepared in 62% yield by Okahara condensation[44] of 3-(benzyloxy)-l,2- propanediol[45] with l,2-bis(2-chloroethoxy)ethane in a LiOtBu/LiBr/ t-BuOH reaction mixture. Cyclization of 3-(benzyloxy)-l,2-propane- diol and tetraethylene glycol ditosylate with NaH in DMF-THF (4:1) gave a 39% yield of (benzyloxy)methyl-15-crown-5 (72). The
'^--*——»" 29
(benzyloxy)methyl-21-crown-7 (73) was synthesized in 28% yield by cyclization of 3,6-dioxo-5-(benzyloxy)methyl-l,8-diol and tetraethylene glycol ditosylate in the presence of NaH in THE. Quantitative hydrogenolysis of the protecting benzyl groups of 71- 73 was achieved with palladium on carbon catalyst and a trace amount of p.-toluenesulfonic acid in aqueous EtOH to yield hydroxymethyl-substituted crown ethers 74-76 (Scheme 5).
Scheme 4
'-0CH2Ph ^O Cl H0,^0CH2Ph LiOt-Bu, t-BuOH^ ^O O L "*" J LiBr, H2O k^ ^J O Cl HO ^K P 7 1
0CH2Ph
h . HO^OCH,Ph NaH [ 3 ( un^ DMF-THF V ^ \ ^O OTs "^ (4-1) k.0^ 72
0CH2Ph
VO + "Y ^ NaH .0 O / THF IQ ^J OTs
73
..,,,- ,.^-—.—. — ,—^——^•. 30 Scheme 5
0CH2Ph ^OH H. ^ ^O O. Pd/C ^o p"^
7 11 74 1 7 2 2 75 2 7 3 4 76 4
The preparation of crown ether carboxylic acids 34, 35, and 38-41 is summarized in Scheme 6. Tosylates 77-82 were synthesized from the corresponding hydroxymethyl crown ethers by the reaction with p.-toluenesulfonyl chloride in pyridine. The tosylates of hydroxymethyl-12-crown-4, -13-crown-4(3), -15- crown-5, -18-crown-6, -21-crown-7, and -24-crown-8 were coupled with methyl salicylate in the presence of NaH in THF.[30.3i] in the initial coupling reaction of methyl salicylate anion with tosylate 79, a very hygroscopic solid was eluted with difficulty when the crude product was subjected to chromatography on alumina with CH2CI2- MeOH (10:1) as eluent. This solid was identified as the crown ether benzoic acid 38 after acidification with 5% HCl solution. Apparently hydrolysis of the crown ether methyl benzoate ester 85 occurred on the alumina column. Another coupling reaction was performed and the crude product was readily purified by chromatography on silica gel to give 85. Due to the success of this purification method. 31 chromatography on silica gel was used for crude crown ether esters 83,84,86-88 as well.
Scheme 6 a°" 1) NaH ^CYOCHZCE CO^Me 2)CECH20Ts M^CQ Me CE CE 7 7 12-crown-4 8 3 12-crown-4 7 8 13-crown-4(3) 8 4 13-crown-4(3) 7 9 15-crown-5 8 5 15-crown-5 8 0 18-crown-6 8 6 18-crown-6 8 1 21-crown-7 8 7 21-crown-7 8 2 24-crown-8 8 8 24-crown-8
NaOH ^ >^2Y^^"2CE EtOH UL^^^^
CE 3 4 12-crown-4 3 5 13-crown-4(3) 3 8 15-crown-5 3 9 18-crown-6 4 0 21-crown-7 4 1 24-crown-8
Base-catalyzed hydrolysis of crown ether methyl benzoates 83-88 with sodium hydroxide in aqueous EtOH followed by acidification gave the crown ether benzoic acids 34,35, and 38-41 in high yields (Table 6). 32 Table 6. Yields of Compounds 34, 35, 38-41, and 77-88.
percent yield of
^^>s-^0CH2CE ^-5^0CH2CE CECH2OTS i ^C02H CE
12-crown-4 97 39 88
13-crown-4(3) 76 57 97
15-crown-5 95 52 93
18-crown-6 98 50 92
21 -crown-7 88 61 84
24-crown-8 86 60 88
The thermodynamics of alkali metal cation complexation by the ionized forms of crown ether carboxylic acids 34,35, and 38-41 in 90% methanol-10% water were determined by Drs. Moon Hwan Cho and Visvanathan Ramesh[46] using titration calorimetry. A marked influence of the crown ether ring size upon the stability constants for alkali metal cation complexation was noted.[^61
Lipophilic Dibenzo-16-crown-5- oxyacetic Acids Lipophilic crown ether carboxylic acids have been utilized for solvent extraction of alkali and alkaline earth cations from aqueous 33 solutions as well as for the transport of these metal cations across bulk liquid and liquid surfactant membranes.["^7.48] Recently Bartsch and coworkers synthesized novel ion-exchange resins by condensation polymerization of crown ether carboxylic acids with formaldehyde in formic acid.['^9] por this project, the crown ether carboxylic acids 94-96 were prepared. The synthetic route to lipophilic crown ether carboxylic acids 94-96 is summarized in Scheme 7. When subjected to Jones oxidation,[50] crown ether alcohol 89 was converted into sym- ketodibenzo-16-crown-5 (90)[5il in 58-78% yields. Reaction of crown ether ketone 90 with Grignard reagents in THE provided 45% and 62% yields of dibenzo crown ether alcohols 92 and 93, respectively. However, the reaction of crown ether ketone 90 with CH3MgI in THF did not give crown ether alcohol 91, because of the limited solubility of the Grignard reagent in THF. When THF-dielhyl ether (2:1) was used as the reaction solvent, crown ether alcohol 91 was produced in 41% yield. Crown ether alcohols 91-93 were transformed into the corresponding lipophilic crown ether carboxylic acids 94-96 in 72-80 % yields by reaction with NaH and then bromoacetic acid in THF at room temperature. These alkylation conditions produced considerably higher yields than when the reaction was conducted at reflux or when a two-step reaction sequence of alkylation with bromoacetate followed by hydrolysis was utilized.[32] 34 Scheme 7
H^OH O
O O A CrO. 1) RMgX •^- o o p o H2SO4 2) NH4CI p o
8 9 90
R^OH R ^0CH2C0^
1) NaH c :3o •2 ) BrCH2C02H -cc:::o \ 15 K IN. 9 1 CH3 9 4 CH3 9 2 C6H13 9 5 C6H13 9 3 C10H21 9 6 C,oH2,
Dibenzo-16-crown-5 Phosphonic Acid Monoalkyl Esters A potentially important structural parameter for determining the selectivity and efficiency of alkali metal cation complexation is the length of the arm that connects the polyether ring to the ionizable group. Since suitable series of crown ether carboxylic acids could not be prepared (see page 14), dibenzo-16-crown-5 phosphonic acid monoethyl esters 47-53 (see Figure 11) were synthesized to probe the influence of this structural variation. In 35 47-53 the number of methylene groups in the side arm is systematically varied from one to four. Dibenzo-16-crown-5 phosphonic acid monoethyl esters 47-49 are designed for use in solvent extraction and are sufficiently lipophilic to avoid loss of complexing agents from an organic phase into a contacting aqueous phase during the solvent extraction of alkali metal cations. The dibenzo-16-crown-5 phosphonic acid monoethyl esters 50-53 which do not possess lipophilic groups are designed for testing of their alkali metal cation complexing abilities by titration calorimetry. Scheme 8 shows the synthetic route to monoethyl sym- dibenzo-16-crown-5-oxymethylphosphonic acid (50) which was prepared in 33% yield by reaction of the alkoxide from crown ether alcohol 89 with monoethyl iodomethylphosphonic acid. Monoethyl I iodomethyl phosphonic acid was prepared by the reaction of diiodomethane with triethyl phosphite, according to the literature method.[52]
Scheme 8 O H^OH ILX)CH2P0F I I OEt o o l)2NaH O O ^^^ o o O 2)lCHoP0H O O I OEt 8 9 50 36 The multistep syntheses of crown ether phosphonic acid monoethyl esters 47-49 and 51-53 involved the initial preparation of the crown ether substituted alkyl bromides 97-102 from crown ether alcohols 89 and 93 by a different route for each bromide (vide infra). Subsequently, bromides 97-102 were reacted with triethyl phosphite to form crown ether phosphonic acid diethyl esters 103- 108 in 82-95% yields which produced monoethyl esters 47-49 and 51-53 upon basic hydrolysis (Scheme 9). Attempts to prepare the crown ether phosphonic acid ester 106 by reaction of the mesylate of 2-(^xQl"<^ib^r^zo-16-crown-5-oxy)ethanol with sodium diethyl phosphonate[53] were unsuccessful. When crown ether phosphonic acid diethyl esters 103 and 106 were subjected to basic hydrolysis by refluxing with NaOH in 95% EtOH for 24 h, crown ether alcohols 89 and 93, respectively, were recovered. Apparently a reverse Michael-type elimination was taking place as shown in Scheme 10. When the basic hydrolyses of 103 and 106 were conducted at room temperature for 10 and 7 days, respectively, crown ether phosphonic acid monoethyl esters 4 7 and 51 were obtained, but in low to fair yields. To improve the competition between the hydrolysis and elimination, crown ether phosphonic acid dimethyl ester 109 was prepared by the reaction of crown ether bromide 100 with trimethyl phosphite in 75% yield (Scheme 11). Basic hydrolysis of 109 at room temperature for 24 h gave a good yield of crown ether phosphonic
...^..^•ww——-•TMMfc"M'>~l'MI'>imfc^^ajifcM 37 Scheme 9
O R^(CH2)„Br R^(CH2)„ P(0Et)2 O O, (EtO)3P O O -^^ p O p O ^0^
R n. R n. 9 7 ^10^21 2 103 ^10^21 2 9 8 ^^10^21 3 104 ^10^21 3 9 9 ^10^21 4 105 ^10^21 4 100 H 2 106 H 2 101 H 3 107 H 3 102 H 4 108 H 4 I 0 R^(CH2)nP0H A A OEt NaOH 95% EtOH -oc :0
R n 4 7 C10H21 2 4 8 C10H21 3 4 9 C10H21 4 51 H 2 52 H 3 53 H 4 38 Scheme 10
R^-CH2- CH-P(OEt)2 ^JxP'
Scheme 11
o H.^OCH2CH2Br IL/)CH2CH2l^(OMe)2 -a:::o ^0^ ^0^ 100 109
O H^CH2CH2POH ll OMe NaOH, EtOH O O, -^ RT,24h *^:^o O
110 39 acid monomethyl ester 110. Thus the problem of completing elimination was greatly suppressed. Table 7 summarizes hydrolysis conditions and yields of crown ether phosphonic acid dialkyl esters. The synthetic route to the precursor crown ether alkyl bromides 97, 98, 100 and 101 is presented in Scheme 12. Crown ether mesylates 115-118 were prepared from the corresponding crown ether alcohols 111-114 by reaction with methanesulfonyl chloride in CH2CI2 in the presence of triethylamine. Subsequently, the crown ether mesylates were reacted with sodium bromide in acetone to form crown ether bromides 97, 98, 100, and 101 in quantitative yields. Attempts to prepare crown ether bromides from
Table 7. Hydrolysis of Crown Ether Phosphonic Acid Dialkyl Esters 103-109.
compound condition yield (%)
103 RT, 10 d 29
104 reflux, 24 h 80
105 reflux, 24 h 80
106 RT, 7 d 40
107 reflux, 24 h 53
108 reflux, 24 h 55
109 RT, 24 h 54 40 crown ether alcohols by the reaction of Vilsmier reagent, phosphorus tribromide in DMF, were unsuccessful. Crown ether bromides 99 and 102 were synthesized in a different way from that which is shown in Scheme 12. Scheme 13 presents the synthetic route to crown ether bromides 99 and 102. A phase transfer catalyzed reaction of crown ether alcohol 89 and
Scheme 12
R^0(CH2)„0H R^^O(CH2)nOMs
O O, o o. MsCl, Et3N o o CH2a: O O
R n R a 111 C10H21 2 115 C10H21 2 112 C10H21 3 11 6 C10H21 3 113 H 2 117 H 2 114 H 3 118 H 3
R^(CH2)„Br
O O, NaBr acetone O O
R n 97 C10H21 2 9 8 C10H21 3 100 H 2 101 H 3 41 1,4-dibromobutane in a mixture of CH2Cl2and 50% aqueous NaOH in the presence of tetrabutylammonium hydrogen sulfate gave crown ether bromide 102 in 76% yield. However, when this method was applied to the synthesis of crown ether bromide 99, the reaction was found to be very sluggish and only a 34% yield of 99 was obtained after 10 days. Presumably, the lipophilicity of crown ether alcohol 93 was the causative factor. If the PTC reaction occurs at the interface between the aqueous and organic phase, the lipophilic group could hinder approach of the crown ether alcohol to the interface.
Scheme 13
R^)H R^(CH2)4Br
Br(CH2)4Br oc::]o CH2Cl2-50% aq NaOH o::::o BU4NHSO4 ^0^ PTC
R R 89 H 102 H 9 3 C10H21 9 9 C10H21
The synthesis of crown ether alcohols 111 and 113, from which the crown ether mesylates 115 and 117 were prepared, is depicted in Scheme 14. Starting with crown ether alcohols 93 and 89, crown ether esters 119 and 120 were prepared by reaction with ethyl bromoacetate in the presence of NaH in 66% and 76% yields. 42 respectively. Subsequent reduction with LiAlH4 in THF gave crown ether alcohols 111 and 113 in quantitative yields.
Scheme 14
RjK^H R^OCH2C02Et
^ 0-v^=^ DNaH ^^-O O O 0^^=^ 2)BrCH2C02Et %^^ ^
R R 9 3 C10H21 119 C10H21 89 H 120 H
R ^OCH2CH20H
LiAlH4 ,^^^0 O THF ^O O
R 111 C10H21 113 H
The synthetic route to crown ether alcohols 112 and 114, which were precursors for the crown ether mesylates 116 and 118, is summarized in Scheme 15. The crown ether primary alcohols were obtained in excellent yields (96-98%) by reaction of the crown ether tertiary alcohol 93 or secondary alcohol 89 with allyl bromide in the presence of KH as a base followed by hydroboration-oxidation. 43 Scheme 15
^xOH R^OCH2CH=CH2
^ ^V^ 1)KH ,^=^0 O O O"^^ 2) BrCH2CH=CH2 "M^Q ^
R R ^3 C10H21 12 1 C10H21 89 H 122 H
R^OCHjCHjCH.OH
1) NaBH4, BF3.Et20 |f^^ ^' 2) H2O2, NaOH ^ "W^o O
R 112 C10H21 114 H
The influence of the side arm length variation upon the selectivity and efficiency of competitive alkali metal cation solvent extraction into chloroform by the lipophilic monoethyl crown ether phosphonates 47-49 was assessed by Dr. Wladyslaw Walkowiak.[54] The side arm selectivity was found to be much higher with 47 than for 48 or 49 which demonstrates a more appropriate sidearm length in 47. The influence of sidearm length variation upon stability 44 constants for alkali metal cation complexation by monoethyl crown ether phosphonates 50-53 in 90% methanol-10% water was determined by Dr. Moon Hwan Cho by titration calorimetry.[^2]
Functionalized Crown Ethers for Attachment to Silica Gel Crown ethers covalently attached to silica gel have two advantages in solvent extraction and liquid membrane transport. The first is to retain the crown ether species in the organic phase. The second is to allow for facile recovery of the crown ether reagent. Functionalized crown ethers 123-128 were synthesized for attachment to silica gel (Figure 14). For binding of the molecules to silica gel through the vinyl groups via the reactions shown in Figure 13, the carboxylic acid groups must be protected as esters. Therefore, functionalized crown ethers 123-128 are esters rather than carboxylic acids. Once bound to silica gel the esters can be hydrolyzed to carboxylic acid functions. Crown ether alcohols 130 and 131 were prepared (Scheme 16) in 74% and 56% yields, respectively, by the reaction of crown ether ketones 129 and 90 with the Grignard reagent obtained from bromide 134. The preparation of bromide 134 is summarized in Scheme 17. The 10-methanesulfonyl-l-decene (133) was prepared from commercially available 9-decen-l-ol (132) in 89% yield by reaction with methanesulfonyl chloride in CHoCh in the presence of triethylamine. Subsequently, mesylate 133 was reacted with 45 OCH2C02Et
O O u
123 CH2CH2CH2 12 4 CH2CH2OCH2CH2 "^7xs:> n. 125 1 126 2 127 3 128 4
Figure 14. Functionalized Crown Ethers for Attachment to Silica Gel.
Scheme 16
O A o o 1) MgBr -^- u 2) NH4CI
12 9 CH2CH2CH2 124 CH2CH2CH2 9 0 CH2CH2OCH2CH2 125 CH2CH2OCH2CH2 46 sodium bromide in acetone to give 10-bromo-l-decene (134) in 69% yield.
Scheme 17
MsCl, Et3N ^« CH2CI2 • " ^^^ 132 133
NaBr ^. acetone
The synthetic route to functionalized crown ethers 123 and 124 for attachment to silica gel is presented in Scheme 18. Crown ether tertiary alcohols 130 and 131 were transformed into the corresponding crown ether carboxylic acids 135 and 136 in 92-97% yields by reaction with NaH and then bromoacetic acid in THF. Subsequently, the crown ether carboxylic acids 135 and 136 were esterified in EtOH with a catalytic amount of concentrated H2SO4 to give crown ether esters 123 and 124 in 78% and 90% yields, respectively. Attempts to directly prepare crown ether esters 123 and 124 from crown ether alcohols 130 and 131, respectively, by the reaction with ethyl bromoacetate in the presence of NaH as a base were unsuccessful (Scheme 19). Only the unreacted crown ether alcohols were recovered. 47 Scheme 18
OH OCH2CO2H
O O 1) NaH O O u 2) BrCH2C02H u
130 CH2CH2CH2 135 CH2CH2CH2 131 CH2CH2OCH2CH2 136 CH2CH2OCH2CH2
OCH2C02Et
H2SO4 EtOH
12 3 CH2CH2CH2 12 4 CH2CH2OCH2CH2
Scheme 19
OCH2C02Et
O O O O 1) NaH •X-^ u 2) BrCH2C02Et u
130 CH2CH2CH2 12 3 CH2CH2CH2 13 1 CH2CH2OCH2CH2 12 4 CH2CH2OCH2CH2 48
Primary crown ether alcohols 138 and 139 were synthesized (Scheme 20) for coupling with chloromethylated polystyrene.[^^1 Hydroboration-oxidation with NaBH4 and BF3Et20 in THF was attempted to convert the terminal carbon-carbon double bond of crown ether ester 125 into a primary alcohol group. However, this reagent combination gave diol 137 from reduction of the ester
Scheme 20
OCH2C02Et
O O u
12 4 CH2CH2CH2 12 5 CH2CH2OCH2CH2
l)NaBH4, BF3.Et20 1) BH3.THF 2) H2O2 2) H2O2
OCH2CH2OH HO, 0CH2C0ft HO. PS PS o o o o u u
137 CH2CH2OCH2CH2 13 8 CH2CH2CH2 13 9 CH2CH2OCH2CH2 49 function as well as conversion of the alkene to an alcohol group. Hydroboration-oxidation of crown ether esters 124 and 125 with BH3THF[56] gave desired products 134 and 135 which have a hydroxyl group at the end of the long lipophilic tail. A second group of functionalized crown ethers for attachment to silica gel was also prepared. For 125-128 (see Figure 14), the crown ether ring sizes are systematically varied from 12-crown-4 to 21-crown-7. The synthetic route to the substituted methyl salicylate 142 is presented in Scheme 21. Reaction of 2,4-dihydroxybenzoic acid with potassium ethoxide and then mesylate 140 gave the substituted salicylic acid 141 in 35% yield. Esterification of 141 in
Scheme 21
HO^^^^^OH .OMs -I- CO2H 140
K'^OEt' .^^.^^^^^^'^^^^0^.^:^^0n EtOH ro2H 141
H2SO4 ,jj;^-^^'^'x^^'v^0,,^^..^^v^0H MeOH C02Me 142 50 MeOH with a catalytic amount of concentrated H2SO4 gave substituted methyl salicylate 142 in 80% yield. Crown ether esters 125-128 were synthesized in 34-42% yields by the coupling reaction of 142 with the corresponding tosylates of hydroxymethyl crown ethers and NaH in THF (Scheme 22).
Scheme 22
'^N^^=^^OH 1) NaH u,r02M e 2) r^ 142 ^0 OYCH20TS ^0 p n. 77 1 7 9 2 80 3 8 1 4 •°^:x? n. 125 1 126 2 127 3 128 4
Attachment of functionalized crown ethers to silica gel by the reactions shown in Figure 13 followed by hydrolysis of the 51 silica gel-bound crown ethers to carboxylic acids will be performed by another member of the Bartsch Research Group. The behavior of the silica gel-bound crown ether carboxylic acids in complexation of alkali metal cation will be conducted by other members of the Bartsch Research Group.
Picrate Extractions The picrate extraction method, as discussed previously, is a means for determining the complexation capacity and cation selectivity of ionophores in a two-phased, single-ion solvent extraction system. A solution of the ionophore to be investigated in CDCI3 is shaken with an aqueous solution of the metal picrate salt. The mixture is allowed to separate into two phases and the equilibrium concentrations of metal picrate in the aqueous and organic phases are determined spectrophotometrically. The degree to which the metal picrate is transferred into the organic phase by the ionophore is a measure of the ionophore's propensity to bind that metal picrate. Extraction constants are calculated by Equation 1.
Benzo-21-crown-7 and Dibenzo- 21-crown-7 Compounds Benzo-21-crown-7 (143), 4-tert-butylbenzo-21 -crown-7 (144), dibenzo-21-crown-7 (145), and sym-dir4(5)-tert-butyl- benzo]-21-crown-7 (146)[57] (Figure 15) were tested for their selectivities in complexation with the alkali metal picrates. For this ring size these crown ethers would be expected to favor extraction of the larger alkali metal cations. Results of the extraction experiments 52 (Table 8) show that the complexation selectivity for crown ethers 143-146 is in the order Cs+, Rb+ > K+ » Na+ > Li+. The ratios of the CsVNa"^ extraction selectivities for the dibenzo-21-crown-7 compounds are noted to be larger than those for the benzo-21- crown-7 compounds. Selectivity for Cs"^ over Na"^ is important for the removal of radioactive Cs"^ in the recycling of nuclear fuel rods.
r^ i^^„o- ^ r^n o ^ R* A Q RfY^ o o R R R 143 H 145 H 144 C(CH3)3 14 6 C(CH3)3
Figure 15. Benzo-21-crown-7 and Dibenzo-21-crown-7 Compounds.
Benzo-13-crown-4 Compounds As a part of a comprehensive study of the complexation of Li"*" and Na"^ with small-ring crown ethers, a series of benzo-13-crown-4 compounds^^^^ was evaluated by the picrate extraction method for their abilities to complex Li"*" and Na"*^. The extraction of lithium picrate from aqueous solution into CDCI3 was compared with the extraction of sodium picrate by these crown ethers in the same system. The benzo-13-crown-4 compounds tested are shown in Figure 16. Table 9 shows that the log Kex values for lithium and 53
Table 8. Picrate Extraction Data for 21-Crown-7 Compounds.
compound M^ %Ex Ke x selectivity'
143 Li; + 0.44 (1.8 ± 0.2) 98
Na^ 1.10 (4.6 ± 0.4) X 10^ 36
K+ 17.3 (1.2 ± 0.1) X 10^ 2.3
Rb+ 38.0 (6.3 ± 0.7) 10^ 1.0
Cs+ 39.1 (6.9 ± 0.1) X 10^^ (1.0)
144 Li+ 0.29 (1.2 ± 0.1) 102 122
Na+ 1.00 (4.1 ± 0.2) X 102 37
K+ 19.3 (1.4 ± 0.2) X 10^ 1.9
Rb-^ 35.5 (5.2 ± 0.1) 10^ 1.0
Cs-^ 36.6 (5.5 ± 0.1) X 10^ (1.0)
145 Li+ 0.17 (6.9 ± 0.7) X 10^ 1 1 1
Na+ 0-41 (1.7 ± 0.2) X 10^ 55
K+ 10.9 (6.2 ± 0.1) X 1()3 2.0
Rb-^ 17.6 (1.3 ± 0.1) X 10"^ 1.0
Cs+ 22.1 (1.9 ± 0.1) 10^ (1.0)
146 Li+ 0.11 (2.8 ± 0.2) X 10' 217
Na-^ 0.39 (1.6 ± 0.2) 102 54 54 Table 8. (cont.)
compound M"^ % Ex Kex selectivity*
14 6 K+ 13.6 (8.1 ±0.1) X 103 1.6
Rb+ 21.0 (1.7 ±0.3) X 10"^ 1.0
Cs+ 21.7 (1.8 ±0.1) X 10-^ (1.0)
* Defined as the ratio of the percent extraction of Cs"*" to the percent extraction of the indicated cation.
sodium picrate extraction into CDCI3 are low in all cases. In general the log Kex values for lithium picrate are somewhat smaller than those for sodium picrate. Compound 148 which contains an exocyclic methylene unit has the best selectivity for Na"^.
O 0-^R^ o o-^R 2
Rl R2 147 H H 14 8 =CH2 1 4 9 -CH2CCI2- 150 Ph H 15 1 Bzl H 15 2 Bzl Bzl 15 3 BZIOCH2 Me 15 4 BZIOCH2 BZIOCH2 15 5 Et Et 156 PhC(0)NH Me
Figure 16. Benzo-13-crown-4 Compounds, 55
Table 9. Picrate Extraction Data for Benzo-13-crown-4 Compounds.
compound M"*" % Ex Kex
r?7 Li+ 0.047 18 ±2
Na+ 0.049 20 ±2
148 Li+ 0.052 21 ±2
Na+ 0.161 64 ±8
149 Li+ 0.071 28 ±5
Na+ 0.134 52 ±5
150 Li+ 0.040 16 ±6
Na+ 0.043 17 ±4
151 Li+ 0.064 22 ±4
Na+ 0.091 34 ±5
152 Li+ 0.030 12 ±3
Na+ 0.043 17 ±3
153 Li+ 0.010 4±2
Na+ 0.023 9±1
154 Li+ 0.072 29 ±2
Na+ 0.023 9±1
155 Li+ 0.055 22 ±5
Na+ 0.076 30 ±4 56 Table 9. (cont.)
compound M+ % Ex Kex
15 6 Li+ 0.040 16 ± 6
Na+ 0.053 21+4
14-Crown-4 Compounds A variety of 14-crown-4 compounds'^^^^ (Figure 17) were tested for their abilities to extract lithium and sodium picrates from aqueous solution into CDCI3 (Table 10). The percentages of lithium and sodium picrates extracted into CDCI3 were low in all cases except for compound 170. The efficiency of lithium extraction is found to be higher than that of sodium extraction. Comparing extraction abilities of the 14-crown-4 compounds with the benzo-13-crown-4 compounds it is noted that the 14-crown-4 compounds are more selective for Li"*". Benzo-13-crown-4 compounds have one "odd side" to the structure, while 14-crown-4 compounds have an equal number of two and three carbon chains between donor atoms. The opportunity for the reintroduction of molecular symmetry was realized with 14-crown-4 compounds by keeping identical bridging arms opposite each other in the ring system, thereby creating extra planes and axes of symmetry with respect to the crown ring structure. It has been found before that symmetry is an important factor in the complexation of guests by the crown ether hosts.^^1 57
Ri>y-o OA,R; R2>-o o-^^''
Rl R2 ^1 R4 157 H H H H 158 =CH2 =CH2 159 Bzl Bzl =CH2 160 -CH2CCI2- -CH2CCI 2- (trans) 161 Bzl Bzl H H 162 Bzl H Bzl H 163 Bzl Bzl Bzl H 164 Bzl Bzl Bzl Bzl 165 Bzl(m-OMe) H Bzl(m-OMe) H 166 BZIOCH2 Me H H 167 BZIOCH2 Me BZIOCH2 Me 168 BZIOCH2 BZIOCH2 BZIOCH2 BZIOCH2 169 Et Et Et Et
Me H H 170tf^"^ ^ C(0)N(Me)2
Figure 17. 14-Crown-4 Compounds.
Crown Ethers with Pendant Ferrocene Units Two crown ethers with pendant ferrocene units^^^l (Figure 18) were tested by the picrate extraction method for their abilities to extract alkali metal cations. Crown ethers 171 and 172 which have 58 Table 10. Picrate Extraction Data for 14-Crown-4 Compounds,
compound M+ % Ex Kex
Li+ 1.35 560 ±8
Na+ 0.079 32 ±5
158 Li+ 1.14 489 ±40
Na+ 0.028 12 ±3
159 Li+ 0.081 31 ±6
Na+ 0.053 21 ±4
160 Li+ 0.85 354 ±20
Na+ 0.60 246 ± 2 2
161 Li+ 0.26 106 ±7
Na+ 0.052 21 ±3
162 Li+ 0.36 144 ± 1 6
Na+ 0.026 10 ±2
163 Li+ 0.15 59 ±5
Na+ 0.026 11 ±2
164 Li+ 0.16 64 ±5
Na+ 0.030 10 ±2
165 Li+ 0.43 170 ±8
Na+ 0.13 53 ±5 59 Table 10. (cont.)
compound M+ %Ex Kex
166 Li+ 0.52 214 ± 19
Na+ 0.34 138 ± 1 1
167 Li+ 0.14 56 ±6
Na+ 0.024 8±2
168 Li+ 0.16 66 ±4
Na+ 0.15 60 ±4
169 Li+ 0.12 49 ±5
Na+ 0.023 9±2
170 Li+ 19.5 15311 ±38
Na+ 18.3 13754 ±63
0- n. 171 0 172 1 Figure 18. Crown Ethers with Pendant Ferrocene Units. 60 15-crown-5 and 18-crown-6 rings were found to preferentially extract Na"*" and K"*" picrate, respectively. Since Na"^ should fit well into a 15-crown-5 cavity and K"*" into a 18-crown-6 cavity the observed selectivity is expected. For 171 the picrate selectivity is in the order Na+ » K+, Li"^ > Rb"^ > Cs+ and for 172 are K"^ » Rb^" > Cs"" » Na-'>Li-^ (Table 11). Table 11. Picrate Extraction Data for Crown Ethers 171 and 172. compound M"*" % Ex Kex TTl Li^Li+^ TJl1.51 (6.3 ± 0.5) X 102 Na+ 9.11 (4.9 ± 0.6) X 103 K+ 1.69 (7.2 ± 0.9) X 102 Rb+ 1.20 (5.0 ± 0.8) X 102 Cs+ 0.74 (3.0 ± 0.1) X 102 17 2 Li+ 0.91 (3.7 ±0.3) x 102 Na+ 2.96 (1.3 ±0.8) X 103 K+ 55.6 (2.6 ± 0.1) X 105 Rb+ 20.5 (1.6 ±0.1) X 104 Cs+ 12.0 (7.1 ± 0.2) X 103 61 Crown Ethers with Pendant Pyridine Units Non-lipophilic and lipophilic crown ethers with pendant pyridine units[^9] (Figure 19) were tested by the picrate extraction method for their selectivities in alkali metal cation complexation. The extraction efficiencies for crown ethers 173-175 with R=H (Table 12) were found to be very high and independent of the number of atoms in the polyether ring and the identity of the alkali metal cation. On the other hand the extraction efficiencies for crown ethers 176-178 with R=alkyl group (Table 13) were very poor, but somewhat selective for Na+. The X-ray crystal structures for 173- 175 [60] reveal that the pendant pyridine rings point away from the crown ether cavities. Therefore the high efficiency but low selectivity observed for compounds 173-175 may result from 2:2 R^0CH2 o o U R Y 173 H CH2CH2 174 H CH2CH2CH2 175 H CH2CH2OCH2CH2 176 C10H21 Cir{'^IrL'^Jji2 177 CH3 CH2CH2OCH2CH2 178 ^10^21 CH2CH2OCH2CH2 Figure 19. Crown Ethers with Pendant Pyridine Units. 62 Table 12. Picrate Extraction Data for Crown Ethers 173-175. compound M+ %Ex Ke: 173 Li+ 67.0 (7.1 ±0.2] • x 105 Na+ 67.5 (7.1 ±0.3] • x 105 K+ 65.3 (5.5 ±0.6] • X 105 Rb+ 69.9 (8.9 ±0.1] I X 105 Cs+ 61.4 (4.5 ±0.5] \ X 105 174 Li+ 62.2 (4.5 ±0.4) X 105 Na+ 59.8 (3.8 ±0.1] X 105 K+ 60.0 (3.6 ±0.6] X 105 Rb+ 61.0 (4.1 ±0.5] 1 X 105 Cs+ 56.1 (2.7 ±0.2] • X 105 175 Li+ 63.9 (5.1 ±0.2] 1 X 105 Na+ 61.8 (4.3 ±0.1] 1 X 105 K+ 57.2 (2.8 ±o.i;1 X 105 Rb+ 60.0 (3.6 ±o.i;1 X 105 Cs+ 57.2 (2.9 ±o.i;) X 105 63 Table 13. Picrate Extraction Data for Crown Ethers 176-178. compound M+ %Ex Kex r76 Li+ 0.15 59.0 ± 8 Na+ 1.07 440 ± 1 7 K+ 0.24 96.3 ± 1 3 Rb+ 0.12 50.0 ± 7 Cs+ 0.09 37.9 ± 8 177 Li+ 0.37 155 ±5 Na+ 1.15 479 ± 2 9 K+ 0.28 112 ±5 Rb+ 0.48 195 ±9 Cs+ 0.44 179 ±9 178 Li+ 0.17 69.6 ± 4 Na+ 0-74 306 ±4 K+ 0.30 121 ±4 Rb+ 0.46 186 ± 17 Cs+ 0.39 157 ±9 64 complex formation between the crown ethers and alkali metal cations as shown in Figure 20. On the other hand for crown ethers 176-178[601 in which R is an alkyl group, it is anticipated that steric repulsions between the alkyl group and the side arm will orient the pyridine ring over the polyether cavity. A 1:1 complex between these crown ethers and alkali metal cations is proposed (Figure 21). Figure 20. The Proposed 2:2 Complex between Crown Ether 174 and Alkali Metal Cations. CH^2 O r-O • fi'^ Figure 21. The Proposed 1:1 Complex between Crown Ether 178 and Alkali Metal Cations. 65 Molecular Receptors The term "receptor" is preferable to define a collection of ligating sites linked by covalent bonds because of the many nonspecific uses of the word "ligand." The receptor-substrate terminology[61] is preferred to the host-guest terminology[62]^ since the latter covers all kinds of intermolecular associations including inclusion compounds that exist only in the solid state, while the former refers to physically characterizable species formed by well- defined associations. Molecular receptors 179-182[58] (Figure 22) which have both hydrophobic and hydrophilic regions with in their cavities were tested by the picrate extraction method to determine their abilities to extract alkali metal cations. Molecular receptor 179 was found to extract K+ the best (Table 14) and molecular receptors 180 and 181 O O N O P^fn m n. 179 1 1 182 180 1 2 181 2 2 Figure 22. Molecular Receptors. 66 Table 14. Picrate Extraction Data for Molecular Receptors 179-181 compound M+ %Ex Ke: 179 Li+ 8.3 (4.3 ± 0.1 X 103 Na+ 11.2 (6.3 ± 0.3 X 103 K+ 33.7 (4.6 ± 0.7 X 104 Rb+ 15.3 (1.0 ± 0. X 104 Cs+ 12.4 (7.4 ± 0. X 103 180 Li+ 9.0 (4.8 ± 0. X 103 Na+ 8.8 (4.6 ± 0. X 103 K+ 12.3 (7.3 ± 0. X 103 Rb+ 12.1 (7.3 ± 0.3 X 103 Cs+ 12.5 (7.3 ± 0. X 103 181 Li+ 6.0 (2.9 ± 0. X 103 Na+ 6.3 (3.0 ± 0. X 103 K+ 8.0 (4.0 ± 0. X 103 Rb+ 10.2 (5.7 ± 0.6 X 103 Cs+ 6.9 (3.4 ± 0.1 X 103 67 to extract alkali metal cations with little selectivity because the host cavities are so large. Molecular receptors 179-181 [58] were also tested for their abilities to extract alkylammonium ions from solutions of alkylammonium picrate in water into CDCI3. Table 15 shows extraction data for molecular receptors 179-181 and 182, which have elongated cavities, with alkylammonium picrates. These molecular receptors were found to extract propylammonium picrate the best and the complexation selectivities are in order: propylammonium > ethylammonium > butylammonium > t-butyl- ammonium, methylammonium. The percent of propylammonium picrate extracted into CDCI3 was the same for molecular receptors 179-182, but the extraction efficiencies for the other alkylammonium picrates was highest with 182 (Table 16). The greatest differences in alkylammonium picrate extraction abilities is noted with receptor 181. The model compound N,N-didecyl-7,16-diaza-18-crown-6 (185) was synthesized[62] (Scheme 23) to compare its complexation selectivity for alkylammonium picrates with that for molecular receptors 179-182. Decanoyl chloride (183) was prepared by the reaction of decanoic acid with an excess of thionyl chloride in 96% yield. Crown ether 185 was synthesized by the reaction of 7,16- diaza-18-crown-6 and decanoyl chloride (183) followed by the reduction of diamide 184 with BH3SMe2 in THF. Table 17 shows that the complexation selectivities for 185 are the same as for the molecular receptor 182. These results indicate that the 68 Table 15. Alkylammonium Picrate Data* for Molecular Receptors 179-181. compound picrate %Ex Ke; 17 9 methylammonium 11.5 (6.7 ± 0.1 X 103 ethylammonium 81.3 (3.6 ± 0.1 X 106 propylammonium 91.3 (2.6 ± 0.2 X 107 butylammonium 35.5 (5.2 ± 0.1 X 104 t-butylammonium 10.9 (6.1 ± 0.2 X 103 18 0 methylammonium 9.8 (5.3 ± 0.1 X 103 ethylammonium 83.6 (5.2 ± 0.2 X 106 propylammonium 90.8 (1.6 ±0.1 X 107 butylammonium 19.0 (1.4 ±0.1 X 104 t-butylammonium 10.5 (5.9 ± 0.6 X 103 18 1 methylammonium 5.8 (2.8 ± 0.1 X 103 ethylammonium 81.6 (4.6 ± 0.2 X 106 butylammonium 15.7 (1.1 ±0.1 X 104 propylammonium 90.8 (1.7 ±0.1 X 107 butylammonium 15-7 (1.1 ±0.1 X 104 t-butylammonium 6.3 (3.1 ± 0.7 X 103 •Corrected from the values in the absence of receptor. 69 Table 16. Alkylammonium Picrate Data* for Molecular Receptor 182. picrate % Ex Kex methylammonium 34.1 (4.6 ± 0.3) x 104 ethylammonium 84.5 (6.1 ± 0.1) x 106 propylammonium 93.0 (3.3 ± 0.1) x 107 butylammonium 60.9 (3.7 ± 0.2) x 105 t-butylammonium 32.3 (4.0 ± 0.1) x 104 •Corrected from the values in the absence of receptor. Scheme 23 O O C9Hi9^0H + SOCI2 ^ C9Hi9('!ci 183 d^^O^ n r^ r-0 O < > II Et3N II \ / 11^ HN NH + C9H19CCI 1 • C9H19C-N N-CC9H19 ^O O-^ 183 ^O O-f 184 O O ^"^•^^^^ . C10H21-N N-C10H21 ^o o-^ 185 70 Table 17. Alkylammonium Picrate Data* for Crown Ether 185. picrate % Ex Kex methylammonium 31.2 (3.8 ± 0.1) x 104 ethylammonium 84.8 (6.5 ± 0.1) x 106 propylammonium 92.6 (2.9 ± 0.1) x 107 butylammonium 60.3 (3.5 ± 0.2) x 105 t-butylammonium 30.8 (3.6 ± 0.1) x 104 *Corrected from the values in the absence of receptor. complexation site for the molecular receptor 182 is the diaza crown ether ring. Summary Several series of proton-ionizable crown ethers have been synthesized to study the effect of structural variation upon metal ion complexation. A series of cyclic polyether derivatives of salicylic acid has been prepared to probe the ring size effect. Series of non- lipophilic and lipophilic dibenzo-16-crown-5 phosphonic acid monoalkyl esters have been prepared to investigate the effect of sidearm length. For attachment to silica gel, functionalized crown ethers which have dibenzo-14-crown-4 and dibenzo-16-crown-5 rings have been synthesized. Also a set of functionalized crown ethers based on salicylic acid has been prepared. 71 Benzo-21-crown-7 and dibenzo-21-crown-7 compounds have been investigated by the picrate extraction method for their abilities to extract the alkali metal cations. The ratio of the Cs+/Na+ extraction selectivities for the dibenzo-21-crown-7 compounds were noted to be larger than those for the benzo-21-crown-7 compounds. Series of benzo-13-crown-4 and 14-crown-4 compounds were tested by the picrate extraction method for their abilities to extract lithium and sodium cations. The effects of substituents attached to the crown ether rings upon complexation selectivity and efficiency were evaluated. Crown ethers with pendant ferrocene units and pyridine units, respectively, were also tested by the picrate extraction method for alkali metal cation complexation selectivity. From the results, it is postulated that crown ethers with pendent pyridine units can form 1:1 or 2:2 complexes with alkali metal cations depending upon the crown ether structures. Finally, molecular receptors were found to extract alkali metal and alkylammonium cations selectively. CHAPTER III EXPERIMENTAL PROCEDURES Instrumentation and Reagents Melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected. ^H NMR spectra were obtained with Varian EM-360, IBM AF-200, or IBM AF-300 spectrometers. The chemical shifts are expressed in parts per million (ppm) downfield from tetramethysilane. Splitting patterns are indicated as: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. Infrared spectra were obtained on either a Nicolet MS-X FT-IR or a Perkin-Elmer 1600 Series FT-IR spectrometer on NaCl plates and are given in wavenumbers (cm^O- Unless specified otherwise, starting materials and solvents were reagent grade and used as received. 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 K2CO3; acetone was distilled from NaHCOs; tetrahydrofuran (THF) was distilled from LiAlILj; tert-butyl alcohol was distilled from CaH2; MeOH was distilled from magnesium turnings with a crystal of added iodine; and EtOH was dried by azeotropic distillation in the presence of benzene. Thin layer chromatography (TLC) was performed with either Analtech Alumina GF or Silica GF prepared plates. The plates were precoated with 250 mm silica gel or alumina. Column 72 73 chromatography was performed using either alumina (80-200 mesh) or silica gel (60-200 mesh) from Fisher Scientific. Elemental analyses were done by Desert Analytics of Tucson, Arizona. Hydroxymethyl-13-crown-4(3), hydroxymethyl-18-crown-6, and hydroxymethyl-24-crown-8 were available from other studies.[43] General Procedure for Preparation of Tosylates of Monobenzyl Glycols 62-64 A solution of the benzyl glycol (15.3 mmol) in 10 mL of pyridine was cooled to -10 °C and a solution of p-toluenesulfonyl chloride (3.64 g, 19.1 mmol) in 10 mL of pyridine was added dropwise. After the reaction mixture was stirred for 1 h at this temperature, it was kept overnight at 4 °C and poured over ice. The reaction mixture was acidified to pH 1 with cold 6N HCl and extracted with CH2CI2 (2 X 30 mL). The combined extracts were washed with water and dried over MgS04. Evaporation of the solvent gave the pure tosylate. Tosylate of Monobenzyl Ethylene Glycol (62) A coloriess oil was obtained in 95% yield. IR (neat): 1357, 1190, 1177 (SO2); 1128, 1097 (C-0) cm-i. m NMR (CDCI3): 5 2.43 (s, 3H), 3.60-3.66 (m, 2H), 4.12-4.25 (m, 2H), 4.52 (s, 2H), 2.75-7.81 (m, 9H). 74 Tosylate of Monobenzyl Diethylene Glycol (63) A colorless oil was obtained in 79% yield. IR (neat): 1357, 1190, 1177 (SO2); 1128, 1097 (C-0) cm-i. ^H NMR (CDCI3): 5 2.43 (s, 3H), 3.55-3.78 (m, 4H), 4.12-4.25 (m, 2H), 4.52 (s, 2H), 7.25-7.81 (m, 9H). Tosylate of Monobenzyl Triethylene Glycol (64) A colorless oil was obtained in 67% yield. IR (neat): 1357, 1190, 1177 (SO2); 1128, 1097 (C-0) cm-i. ^H NMR (CDCIs): 5 2.43 (s, 3H); 3.55-3.78 (m, 4H); 4.12-4.25 (m, 2H); 4.52 (s, 2H); 7.25-7.81 (m, 9H). General Procedure for Preparation of Carboxylic Acids 68-7 0 Sodium hydride (0.50 g, 12.5 mmol, 60% dispersion in mineral oil) was washed with pentane (2 X 20 mL) and suspended in 15 mL of THF. With stirring under nitrogen, a solution of methyl salicylate (1.53 g, 10 mmol) in 15 mL of THF was added dropwise during 45 min. After 1 h a solution of the tosylate of monobenzyl glycol (10 mmol) in 20 mL of THF was added dropwise during 30 min. The reaction mixture was stirred at room temperature overnight and then refluxed for 3 d. The solvent was evaporated in vacuo and CH2CI2 was added. The resulting mixture was filtered and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel with CH2CI2 as eluent to give the carboxylic acid ester. The ester (3.0 mmol) was dissolved in 20 mL of EtOH and a solution of 75 NaOH (1.0 g) in 5 mL of H2O was added. The mixture was refluxed for 4 h and evaporated to dryness in vacuo. Water was added to the residue. The mixture was acidified to pH 1 with 6N HCl and extracted with CH2CI2 (3 X 20 mL). The combined extracts were washed with water (30 mL), dried over MgS04 and evaporated in vacuo to give the carboxylic acid. Methyl 2-[(l,4-Dioxa-5-phenyl)pentyl]- benzoate (65) A colorless oil was obtained in 49% yield. IR (neat): 1730 (C=0); 1132, 1085 (C-0) cm-i. iH NMR (CDCI3): 5 3.86-4.25 (m, 7H), 4.67 (s, 2H), 6.95-7.81 (m, 9H). 2-[(l,4-Dioxa-5-phenyl)pentyl]benzoic Acid (68) Basic hydrolysis of compound 65 gave a colorless oil in 89% yield. IR (neat): 3266 (COOH); 1732 (C=0); 1125, 1105 (C-0) cm-i. IH NMR (CDCI3): 8 3.66-4.40 (m, 4H), 4.62 (s, 2H), 7.00-8.20 (m, 9H), 11.09 (b, s, IH). Anal. Calcd. for C16H16O4: C, 70.57; H, 5.92. Found: C, 70.35; H, 6.00. Methyl 2-[(l,4,7-Trioxa-8-phenyl)octyI]- benzoate (66) A colorless oil was obtained in 79% yield. IR (neat): 1729 (C=0); 1134, 1085 (C-0) cm-i. ^H NMR (CDCI3): 5 3.64-4.23 (m, IIH), 4.57 (s, 2H), 6.95-7.81(m, 9H). 76 2-[(l,4,7-Trioxa-8-phenyl)octyl]benzoic Acid (69) Basic hydrolysis of compound 66 gave a colorless oil in 88% yield. IR (neat): 3269 (COOH); 1731 (C=0); 1127, 1101 (C-0) cm-J. IH NMR (CDCI3): 5 3.66-4.40 (m, 8H), 4.57 (s, 2H), 7.00-8.20 (m, 9H), 11.09 (br s, IH). Anal. Calcd. for C18H20O5: C, 68.34; H, 6.37. Found: C, 68.19; H, 6.46. Methyl 2.[(l,4,7,10-Tetraoxa-ll-phenyl)- undecyljbenzoate (67) A colorless oil was obtained in 75% yield. IR (neat): 1730 (C=0); 1133, 1097 (C-0) cm-i. iH NMR (CDCI3): 5 3.62-4.22 (m, 15H), 4.56 (s, 2H), 6.95-7.81(m, 9H). 2-(l,4,7,10-Tetraoxa-ll-phenyI)- undecyljbenzoic Acid (70) Basic hydrolysis of compound 67 gave a colorless oil in 94% yield. IR (neat): 3274 (COOH); 1732 (C=0); 1126, 1101 (C-0) cm-i. IH NMR (CDCI3): 6 3.62-4.36 (m, 12H), 4.55 (s, 2H), 7.00-8.20 (m, 9H), 11.09 (br s, IH). Anal. Calcl. for Anal. Calcd. for C20H24O6: C, 66.65; H, 6.71. Found: C, 66.54; H, 6.97. Preparation of (Benzyloxy)methyl- substituted Crown Ethers 71-73 (Benzyloxy)methyl-12-crown-4 (71) Under nitrogen, lithium metal (1.14 g, 0.16 mol) was added to 300 mL of tert-BuOH. After refluxing for 1 h, 3-(benzyloxy)-l,2- propanediol[44,45| (lO.O g, 0.054 mol) was added dropwise. To the cloudy, heterogeneous mixture, l,2-bis(2-chloroethoxy)ethane (10.28 77 g, 0.054 mol) was added followed by LiBr (4.69 g, 0.054 mol) and 10 mL of water. The reaction mixture was refluxed for 2 weeks. After the solvent was removed in vacuo. 30 mL of water was added to the residue and the mixture was neutralized with 6N HCl and extracted with CH2Cl2(3 X 30 mL). The CH2CI2 solution was dried over MgS04 and evaporated in vacuo. The residue was purified by column chromatography on alumina with petroleum ether/ethyl acetate (4:1) as eluent to give 9.94 g (62% yield) of the product as a colorless oil. IR (neat): 1249, 1126 (C-0) cm-i. iH NMR (CDCI3): 5 3.45-4.92 (m, 17H), 4.54 (s, 2H), 7.32 (s, 5H). (Benzyloxy)methy-15-crown-5 (72) Tetraethylene glycol ditosylate (2.74 g, 15 mmol) was diluted to 12 mL with anhydrous DMF-THF (4:1) and taken up in a syringe. 3-(Benzyloxy)-l,2-propanediol (7.54 g, 15 mmol) was also diluted to 12 mL with DMF-THF (4:1) and taken up in a syringe. The two solutions were simultaneously added with two syringe pumps during 38 h at room temperature to a mixture of NaH (0.96 g, 24 mmol, 60% dispersion in mineral oil) and 20 mL of DMF-THF (4:1). After a total time of 3 d, the reaction mixture was quenched with 20 mL of saturated NaCl solution and the solution was extracted with CHCl3(3 X 40 mL). The combined CHCI3 extracts were dried over MgS04 and evaporated in vacuo. The residual DMF was removed with high vacuum. The residue was purified by column chromatography on alumina with CH2CI2 and then ethyl acetate as eluents to give 1.90 g (39% yield) of the product as a colorless oil. IR (neat): 1251, 1177 78 (C-O)cm-i. IH NMR (CDCI3): 5 3.50-3.86 (m, 21H), 4.55 (s, 2H), 7,32 (s, 5H). (Benzyloxy) methyl-21-crown-7 (73) Tetraethylene glycol ditosylate (7.54 g, 0.015 mol) was diluted to 45 mL with THF and taken up in a syringe. 3,6-Dioxo-5- (benzyloxy)methyl-l,8-diol (4.02 g, 0.015 mol) was also diluted to 45 mL with THF and taken up in a syringe. The two solutions were simultaneously added with two syringe pumps during 10 h at room temperature to a mixture of NaH (1.80 g, 0.045 mol, 60% dispersion in mineral oil) and 150 mL of THF. After the reaction mixture was refluxed for 24 h, 50 mL of saturated NaCl solution was added. The reaction mixture was extracted with CH2CI2 (3 X 100 mL). The combined CH2CI2 extracts were dried over MgS04 and evaporated i_n vacuo. The residue was purified by column chromatography on alumina with CH2CI2 and then ethyl acetate as eluents to give 1.80 g (28% yield) of the product as a colorless oil. IR (neat): 1250, 1177 (C-O)cm-i. iH NMR (CDCI3): 5 3.50-3.86 (m, 29H), 4.54 (s, 2H), 7.33 (s, 5H). General Procedure for Preparations of Hydroxymethyl Crown Ethers 74-76 To a solution of the (benzyloxy)methyl-substituted crown ether (13-24 mmols) in 50 mL of EtOH was added 10% palladium on carbon (100 mg/g of crown ether) and a catalytic amount of p.-toluene- sulfonic acid monohydrate. The mixture was hydrogenated under 79 25 lbs pressure of hydrogen at room temperature for 48 h. The reaction mixture was filtered and evaporated in vacuo. The residue was taken up in CH2CI2. The CH2CI2 solution was dried over MgS04 and evaporated in vacuo to give the product. Hydroxymethyl-12-crown-4 (74) A colorless oil was obtained in 95% yield. IR (neat): 3237 (0-H); 1245, 1132 (C-0) cm-i. iH NMR (CDCI3): 6 2.34 (s, IH), 3.55- 3.82 (m, 17H). Hydroxymethyl-15-crown-5 (75) A colorless oil was obtained in 86% yield. IR (neat): 3312 (0-H); 1249, 1124 (C-0) cm-i. m NMR (CDCI3): 5 2.62 (br s, IH), 3.55-3.82 (m, 21H). Hydroxymethyl-21-crown-7 (76) A colorless oil was obtained in 91% yield. IR (neat): 3320 (0-H); 1245, 1130 (C-0) cm-i. ^H NMR (CDCI3): 5 2. 92 (br s, IH), 3.55-3.82 (m, 29H). General Procedure for Preparation of (Tosyloxy)- methyl-substituted Crown Ethers 77-82 To a solution of the hydroxymethyl crown ether (9-23 mmoles) in 10 mL of pyridine at -10 °C under nitrogen was added dropwise £-toluenesulfonyl chloride (1.25 equivalents ) in 10 mL of pyridine. After keeping the mixture at 4 "C for 24 h, a cold solution of 6N HCl and ice was added. The organic layer was separated and the aqueous 80 layer was extracted with CH2CI2 (3 X 10 mL). The combined extracts were dried over MgS04 and evaporated in vacuo to give the tosylate. (Tosyloxy)methyl-12-crown-4 (77) A colorless oil was prepared in 97% yield. IR (neat): 1358, 1190, 1171 (SO2); 1129, 1097 (C-0) cm-i. iH NMR (CDCI3): 6 2.45 (s, 3H), 3.50-4.20 (m, 17H), 7.55 (AB q, 4H). 3-[(Tosyloxy)methyl)]-13-crown-4 (78) A colorless oil was prepared in 76% yield. IR (neat): 1358, 1190, 1171 (SO2); 1129, 1097 (C-0) cm-i. iH NMR (CDCI3): 5 2.21- 2.31 (m, IH), 2.45 (s, 3H), 3.30-3.70 (m, 16H), 4.08 (d, 2H), 7.55 (AB q, 4H). (Tosyloxy)methyl-15-crown-5 (79) A colorless oil was prepared in 95% yield. IR (neat): 1358, 1190, 1171 (SO2); 1129, 1097 (C-0) cm-i. iH NMR (CDCI3): 5 2.45 (s, 3H), 3.50-4.20 (m, 21H), 7.55 (AB q, 4H). (Tosyloxy)m ethyl-18-crown-6 (80) A coloriess oil was prepared in 98% yield. IR (neat): 1358, 1190, 1171 (SO2); 1129, 1097 (C-0) cm-i. iH NMR (CDCI3): 5 2.45 (s, 3H), 3.50-4.20 (m, 25H), 7.55 (AB q, 4H). (Tosyloxy)methyl-21-crown-7 (81) A coloriess oil was prepared in 88% yield. IR (neat): 1356, 1189, 1177 (SO2); 1129, 1097 (C-0) cm-i. ^H NMR (CDCI3): 5 2.45 (s, 3H), 3.50-4.20 (m, 29H), 7.55 (AB q, 4H). 81 (Tosyloxy)methyl-24-crown-8 (82) A colorless oil was prepared in 86% yield. IR (neat): 1356, 1189, 1177(S02); 1129, 1097 (C-0) cm-i. iH NMR (CDCI3): 5 2.45 (s, 3H), 3.50-4.20 (m, 33H), 7.55 (AB q, 4H). General Procedure for Preparation of Crown Ether Carboxylic Acids 34. 35. and. 38-41 Under nitrogen, sodium hydride (0.26 g, 6.25 mmol, 60% dispersion in mineral oil) was washed with pentane (2 X 20 mL) to remove the protecting mineral oil and 10 mL of THF was added. To the suspension, methyl salicylate (0.76 g, 5.0 mmol) in 15 mL of THF was added slowly. After stirring at room temperature for 1 h, a solution of the crown ether tosylate (5.0 mmol) in 10 mL of THF was added and the mixture was refluxed for 3 d. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel with CH2CI2 and ethyl acetate as eluents to give the crown ether carboxylic acid ester. The ester (3.0 mmol) was dissolved in 20 mL of EtOH and a solution of NaOH (1.0 g) in 5 mL of water was added. The mixture was refluxed for 4 h and evaporated to dryness in vacuo. Water (10 mL) was added to the residue. The mixture was acidified to pH 1 with 6N HCl and extracted with CH2Cl2(3 X 20 mL). The combined extracts were washed with water (30 mL), dried over MgS04, and evaporated in vacuo to give the crown ether carboxylic acid. 82 Methyl 2-[(12-Crown-4)-methyloxy] benzoate (83) A colorless oil was obtained in 39% yield. IR (neat): 1730 (C=0); 1133, 1084 (C-0) cm-i. iH NMR (CDCI3): 6 3.60-4.20 (m, 20H), 6.96-7.85 (m, 4H). 2-[(12-Crown-4)-methyloxy]benzoic Acid (34) Basic hydrolysis of compound 83 gave a colorless oil in 88% yield. IR (neat): 3250 (COOH); 1729 (C=0); 1135, 1099 (C-0) cm-i. IH NIVIR (CDCI3): 5 3.60-4.18 (m, 15H), 4.25-4.40 (m, 2H), 7.04-8.22 (m, 4H). Anal. Calcd. for C16H22O7: C, 58.88; H, 6.80. Found: C, 58.62; H, 6.90. Methyl 2-[3'-(13-Crown-4)-methyloxy]- benzoate (84) A colorless oil was obtained in 57% yield. IR (neat): 1729 (C=0); 1133, 1085 (C-O) cm-i. IH NMR (CDCI3): 5 2.37-2.60 (m, IH), 3.50-3.78 (m, 16H), 3.86 (s, 3H), 4.15-4.25 (m, 2H), 6.96-7.85 (m, 4H). 2-[3'-(13-Crown-4)-niethyloxy]benzoic Acid (35) Basic hydrolysis of compound 84 gave a colorless oil in 97% yield. IR (neat): 3277 (COOH); 1725 (C=0); 1133, 1107 (C-O) cnri. iH NMR (CDCI3): 5 2.37-2.60 (m, IH), 3.50-3.78 (m, 16H), 4.30-4.40 (m, 2H), 7.09-8.22 (m, 4H). Anal. Calcd. for C17H24O7: C, 59.99; H, 7.11. Found: C, 59.80; H, 7.47. 83 Methyl 2-[(15-Crown-5)-methyIoxy]- benzoate (85) A colorless oil was obtained in 52% yield. IR (neat): 1729 (C=0); 1131, 1049 (C-0) cm-i. ^H NMR (CDCI3): 5 3.60-4.20 (m, 24H), 6.96-7.85 (m, 4H). 2-[(15-Crown-5)-methyloxy]benzoic Acid (38) Basic hydrolysis of compound 85 gave a colorless oil in 93% yield. IR (neat): 3258 (COOH); 1729 (C-0); 1128, 1041 (C-0) cm-i. IH NMR (CDCI3): 5 3.60-4.18 (m, 19H), 4.25-4.40 (m, 2H), 7.04-8.22 (m, 4H). Anal. Calcd. for C18H26O6: C, 58.37; H, 7.08. Found: C, 58.46; H, 7.15. Methyl 2-[(18-Crown-6)-methyIoxy]- benzoate (86) A colorless oil was obtained in 50% yield. IR (neat): 1729 (C=0); 1124, 1049 (C-0). iH NMR (CDCI3): 6 3.60-4.20 (m, 28H), 6.96- 7.85 (m, 4H). 2-[(18-Crown-6)-methyloxy]benzoic Acid (39) Basic hydrolysis of compound 86 gave a colorless oil in 92% yield. IR (neat): 3260 (COOH); 1731 (C=0); 1119, 1041 (C-0) cm-i. IH NMR (CDCI3): 5 3.60-4.00 (m, 22H), 4.01-4.15 (m, IH), 4.28-4.50 (m, 2H), 7.04-8.22 (m, 4H). Anal. Calcd. for C20H30O9: C, 57.96; H, 7.30. Found: C, 57.71; H, 7.44. 84 Methyl 2-[(21-Crown-7)-methyloxy] benzoate (87) A colorless oil was obtained in 61% yield. IR (neat): 1732 (C=0); 1118, 1048 (C-0) cm-i. iH NMR (CDCI3): 5 3.60-4.20 (m, 32H). 6.96-7.85 (m, 4H). 2-[(21-Crown-7)-methyloxy]benzoic Acid (40) Basic hydrolysis of compound 87 gave a colorless oil in 84% yield. IR (neat): 3261 (COOH); 1732 (C=0); 1114, 1041 (C-0) cm-i. IH NMR (CDCI3): 5 3.60-4.00 (m, 26H), 4.01-4.15 (m, IH), 4.30-4.50 (m, 2H), 7.04-8.22 (m, 4H). Anal. Calcd. for C22H34O10: C, 57.63; H, 7.47. Found: C, 57.49; H, 7.78. Methyl 2-[(24-Crown-8)-methyloxy]- benzoate (88) A colorless oil was obtained in 60% yield. IR (neat): 1732 (C=0); 1124, 1048 (C-0) cm-i. IH NMR (CDCI3): 5 3.60-4.20 (m, 36H), 6.96-7.85 (m, 4H). 2-[(24-Crown-8)-methyloxy]benzoic Acid (41) Basic hydrolysis of compound 88 gave a colorless oil in 88% yield. IR (neat): 3260 (COOH); 1731 (C=0); 1114, 1041 (C-0) cm-i. Anal. Calcd. for C24H38O11: C, 57.36; H, 7.62. Found: C, 57.04; H, 7.90. <^yin-Ketodibenzo-16-crown-5[5i] (90) With mechanical stirring, crown ether alcohol 89 (20.0 g, 57.8 mmol) was dissolved in 400 mL of acetone. To the cooled (ice bath) 85 and vigorously stirred solution was added 60 mL of Jones reagent[50] (16.02 g of Cr03, 13.8 mL of concentrated H2SO4, and sufficient H2O to make a 60 mL volume) over 2 h. After an additional 2 h of stirring, the reaction mixture consisted of a tan solution and a green precipitate. The tan solution was decanted, and the green precipitate was washed with acetone (2 X 20 mL). The acetone washings were combined with the tan solution. The solvent was evaporated partly (to about 200 mL) in vacuo and 500 mL of water was added. After the reaction mixture was kept in the refrigerator for 2 h, the resulting solid was collected by filtration. The crude product was dissolved in 400 mL of acetone, and decolorizing carbon was added to remove yellow color. The mixture was refluxed for 30 min and filtered while the mixture was still hot. The acetone was evaporated partly in vacuo again. The resulting solid was filtered and allowed to dry to give 90 in 58-78% yields with mp 141-143 «C (lit. mp 138- 139 °C). IR (deposit): 1737 (C=0) cm-i. m NMR (CDCI3): 3.80-4.50 (m, 12H), 4.93 (s, 4H), 6.85-7.05 (m, 8H). fiXOL-(Me thy 1) (hydroxy )dibenzo- 16-crown-5 (91) To 0.84 g (34.5 mmol) of magnesium turnings in 150 mL of anhydrous diethyl ether under nitrogen was added methyl iodide (4.90 g, 34.5 mmol) dropwise. The reaction mixture was refluxed undl the magnesium disappeared. Crown ether ketone 90 (4.0 g, 11.6 mmol) in 300 mL of THF was added to the Grignard reagent solution dropwise, and refluxing was continued for 24 h. After cooling the reaction mixture, 90 mL of 5% aqueous NH4CI solution 86 was added and the mixture was stirred for 2h. The solvent was evaporated in vacuo and the residue was extracted with CH2CI2 (2 X 100 mL). The CH2CI2 solution was dried over MgS04 and evaporated in vacuo. The crude product was recrystallized from pentane. The white solid was purified by column chromatography on silica gel with CH2Cl2as eluent to give 1.73 g (41%) of 91 as a white solid with mp 110-111 °C. IR (deposit): 3460 (0-H); 1124, 1039 (C-0) cm-i. ^H NMR (CDCI3): 6 0.88 (s, 3H), 3.45 (br s, IH), 3.90-4.30 (m, 12H), 6.84- 7.02 (m, 8H). General Procedure for Preparation of Crown Ether Alcohols 92 and 93 To 0.56 g (23.0 mmol) of magnesium turnings under nitrogen was added 40 mL of THF and 23.0 mmol of the 1-bromoalkane. The mixture was refluxed until most of the magnesium had been consumed. Then crown ether ketone 90 (3.96 g, 11.5 mmol) was added and refluxing was continued for 5 h. After cooling the reaction mixture to room temperature, 30 mL of 5% aqueous NH4CI solution was added and the mixture was stirred for 10 h. The THF was evaporated in vacuo and the residue was extracted with 50 mL of CH2CI2. The CH2CI2 solution was dried over MgS04 and evaporated in vacuo to afford a white solid which was stirred with 200 mL of pentane for 1 h. The solid was filtered and dissolved in a small amount of CH2CI2 and loaded onto a silica gel column. Elution with CH2CI2 afforded the pure product as a white solid. 87 fiXm.-(Hexyl) (hydroxy) dibenzo- 16-crown-5 (92) A white solid with mp 121-123 ''C was obtained in 45% yield. IR (deposit): 3395 (OH); 1122, 1039 (C-0) cm-i. iH NMR (CDCI3): 5 0.88 (t, 3H), 1.15-1.55 (m, 8H), 1.80-1.92 (m, 2H), 3.45 (br s, IH), 3.90-4.30 (m, 12H), 6.84-7.02 (m, 8H). SXDL-(Decyl) (hydroxy )dibenzo- 16-crown-5 (93) A white solid with mp 90-92 °C was obtained in 62% yield. IR (deposit): 3350 (0-H); 1125, 1039 (C-0) cm-i. ^H NMR (CDCI3): 6 0.88 (t, 3H), 1.15-1.55 (m, 16H), 1.80-1.92 (m, 2H), 3.45 (br s, IH), 3.90-4.30 (m, 12H), 6.84-7.02 (m, 8H). General Procedure for Preparation of Crown Ether Carboxylic Acids 94-96 After removal of the protecting mineral oil from NaH (1.43 g, 35.8 mmol, 60% dispersion in mineral oil) by washing with pentane (2 X 30 mL) under nitrogen, the crown ether alcohol 91-93 (6.0 mmol) in 200 mL of THF was added dropwise. The mixture was stirred for 30 min at room temperature, and then bromoacetic acid (1.78 g, 12.8 mmol) in 20 mL of THF was added dropwise. The reaction mixture was stirred for 3 d at toom temperature. Careful addition of ice (to decompose the excess NaH) and then 50 mL of water was followed by evaporation of the THF in vacuo. To the oily residue was added 20 mL of CH2CI2 and the mixture was acidified to pH 1 with 6N HCl. The organic layer was separated, washed with 20 88 mL of water, dried over MgS04, and evaporated in vacuo to give a white solid which was recrystallized from ethyl acetate. sym- (Methyl)dibenzo-16-crown-5- oxyacetic Acid (94) White crystals with mp 100-102 °C were prepared in 80% yield. IR (deposit): 3400-3000 (weak) (COOH); 1766, 1736 (C=0); 1122, 1053 (C-0) cm-i. IH NMR (CDCI3): 5 1.50 (s, 3H), 3.80-4.15 (m, lOH), 4.60 (d, 2H), 4.85 (s, 2H), 6.84-7.02 (m, 8H), 8.88 (br s, IH). sym- (Hexyl)dibenzo-16-crown-5- oxyacetic Acid (95) White crystals with mp 135-136 °C were prepared in 72% yield. IR (deposit): 3400-3000 (weak) (COOH); 1735, 1699 (C=0); 1122, 1053 (C-0) cm-i. m NMR (CDCI3): 5 0.93 (t, 3H), 1.25-1.50 (m, 8H), 1.93-1.97 (m, 2H), 3.80-4.15 (m, lOH), 4.60 (d, 2H), 4.85 (s, 2H), 6.84-7.02 (m, 8H), 9.90 (br s, IH). sym-(Decvl)dibenzo-16-crown-5- oxyacetic Acid (96) White crystals with mp 101-102 °C were prepared in 78% yield. IR (deposit): 3400-3000 (weak) (COOH); 1766, 1745 (C=0); 1124, 1058 (C-O) cm-i. ^H NMR (CDCI3): 6 0.89 (t, 3H), 1.25-1.50 (m, 18H), 1.93-1.97 (m, 2H), 3.80-4.15 (m, lOH), 4.60 (d, 2H), 4.85 (s, 2H), 6.84-7.02 (m, 8H). 89 Monoethyl svm-Dibenzo-16-crown-5 oxymethylphosphonic Acid (50) Under nitrogen NaH (0.32 g, 8.0 mmol, 60% dispersion in mineral oil) was washed with pentane (2 X 20 mL) to remove the mineral oil and was suspended in 50 mL of THF. A solution of sym- hydroxydibenzo-16-crown-5 (1.36 g, 3.0 mmol) in 30 mL of THF was added and the mixture was stirred for 1 h. A solution of monoethyl iodomethylphosphonic acid (1.0 g, 4.0 mmol) in 40 mL of THF was added during 30 min followed by stirring at room temperature for 5 h and refluxing for 24 h. The reaction mixture was evaporated in vacuo and 10 mL of water was added to the cooled reaction mixture followed by addition of 6N HCl to pH 1. The mixture was extracted with CH2CI2 (3 X 50 mL), dried over MgS04, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with CH2CI2 and CH2Cl2:MeOH (1:1) as eluents. Evaporation of eluent gave the salt of 50. Water (lOmL) was added to the salt. The solution was acidified to pH 1 with concentrated HCl, extracted with CH2CI2 (3 X 20 mL), and evaporated in vacuo to give 0.61 g (33% yield) of 50 as a white crystalline solid with mp 91-92 °C (lit. mp 48- 52 °C). IR (deposit): 3472, 2292, 1707 (PO-H); 1253 (P=0); 1041, 990, 935 (POEt) cm-i. iH NMR (CDCI3): 5 1.35 (t, 3H), 3.90-4.40 (m, 17H), 6.81-7.02 (m, 8H), 7,80 (br s, IH). Anal. Calcd. for C22H29O9PO.25 CH2CI2: C, 54.57; H, 6.07. Found: C, 54,82; H, 5.93. 90 General Procedure for Preparation of Crown Ether Phosphonic Acid Monoethyl Esters 47-49 and •^1-i^3 Under nitrogen, the sxin-dibenzo-16-crown-5-oxyalkyl bromide (1.1 mmol) and triethyl phosphite (0.42 g, 2.5 mmol) were stirred at 140 °C for 24 h. Excess triethyl phosphite was removed by vacuum distillation and the residue was purified by column chromatography on silica gel with CH2CI2 and CH2Cl2-MeOH (10:1) as eluents. The resultant diethyl phosphonate (1.0 mmol) was refluxed for 24 h or stirred for 7 d at room temperature with 0.25 g of NaOH in 50 mL of EtOH. The solution was cooled to 5 °C and evaporated in vacuo. The residue was acidified to pH 1 with 6N HCl, extracted with CH2CI2 (3 X 30 mL), dried over MgS04, and evaporated in vacuo to give the crude product which was purified by column chromatography on silica gel with CH2Cl2-MeOH (1:1) as eluent. Evaporation of the eluent gave the salt of 47-49 and 51-53 which was acidified to pH 1 with concentrated HCl. The acqueous solution was extracted with CH2CI2 (3 X 20 mL) to give 47-49 and 51-53. Diethyl svm-Dibenzo-16-crown-5- oxyethylphosphonate (106) A colorless oil was obtained in 90% yield. IR (neat): 1259 (P=0); 1041, 950 (POEt) cm-i. ^H NMR (CDCI3): 6 1.41 (t, 6H), 2.00- 2.72 (m, 2H), 3.69-4.40 (m, 19H), 6,81-7.02 (m, 8H). 91 Monoethyl svm-Dibenzo-16-crown-5- oxyethyl-phosphonic Acid (51) Hydrolysis of 106 for 7d at room temperature gave a white solid with mp 55-57 °C in 40% yield. IR (deposit): 3427, 2237, 1697 (PO-H); 1257 (P=0); 1055, 990, 931 (POEt) cm-i. iH NMR (CDCI3): 5 1.32 (t, 3H), 2.08-2.30 (m, 2H), 3.87-4.35 (m, 17H), 6,81-7.02 (m, 8H), 9.25 (br s, IH). Anal. Calcd. for C23H31O9PO.5 H2O: C, 56.21; H, 6.56. Found: C, 56.35; H, 6.67. Diethyl sym-Dibenzo-16-crown-5- oxypropyl-phosphonate (107) A colorless oil was obtained in 82% yield. IR (neat): 1259 (P=0); 1041, 950 (POEt) cm-i. iH NMR (CDCI3): 6 1.41 (t, 6H), 1.92- 2.20 (m, 4H), 3.69-4.40 (m, 19H), 6,81-7.02 (m, 8H). Monoethyl sym-Dibenzo-16-crown-5- oxypropyl-phosphonic Acid (52) Hydrolysis of 107 for 24 h at reflux gave a white solid with mp 101-103 °C in 53% yield. IR (deposit): 3427, 2237, 1697 (PO-H); 1257 (P=0); 1055, 990, 931 (POEt) cm-i. iH NMR (CDCI3): 8 1.32 (t, 3H), 1.80-2.20 (m, 4H), 3.87-4.35 (m, 17H), 6,81-7.02 (m, 8H). Anal. Calcd. for C24H3309P-2H20: C, 54.13; H, 6.25. Found: C, 54.78; H, 6.41. Diethyl sym-Dibenzo-16-crown-5- oxybutyl-phosphonate (108) A colorless oil was obtained in 94% yield. IR (neat): 1253 (P=0); 1039, 962 (POEt) cm-i. iH NMR (CDCI3): 5 1.41 (t, 6H), 1.92- 2.20 (m, 4H), 3.69-4.40 (m, 19H), 6,81-7.02 (m, 8H). if: 92 Monoethyl &xiIL-l>ibenzo-16-crown-5- oxybutyl-phosphonic Acid (53) Hydrolysis of 108 for 24 h at reflux gave a colorless oil in 55% yield. IR (neat): 3354,2276,1658 (PO-H); 1261 (P=0); 1045, 977 (POEt) cm-i. iH NMR (CDCI3): 6 1.32 (t, 3H), 1.80-2.20 (m, 6H), 3.87- 4.35 (m, 17H), 6,81-7.02 (m, 8H). Anal. Calcd. for C25H35O9P: C, 58.81; H, 6.91. Found: C, 58.60; H, 6.81. Diethyl iXQL-(Decyl )dibenzo-16-crown-5- oxyethyl-phosphonate (103) A colorless oil was obtained in 90% yield. IR (neat): 1257 (P=0); 1043, 958 (POEt) cm-i. iH NMR (CDCI3): 5 1.41 (t, 3H), 1.22- 1.38 (m, 22H), 1.80-2.20 (m, 2H), 2.04-2.23 (m, 2H), 3.91-4.36 (m, 18H), 6.81-7.02 (m, 8H). Anal. Calcd. for C35H55O9P: C, 64.59; H, 8.52. Found: C, 64.77; H, 8.62. Monoethyl sym-(Decyndibenzo-16- crown-5-oxyethylphosphonic Acid (47) Hydrolysis of 103 for 10 d at room temperature gave a colorless oil in 29% yield. IR (neat): 3400, 2358, 1682 (PO-H); 1257 (P=0); 1046, 960 (POEt) cm-i. m NMR (CDCI3): 5 0.88 (t, 3H), 1.22- 1.38 (19H), 1.80-2.20 (m, 2H), 2.04-2.23 (m, 2H). 3.91-4.36 (m, 16H), 6.81-7.02 (m, 8H). Anal. Calcd. for C33H5iO9P-0.5H2O: C, 62.74; H, 8.14. Found: C, 62.78; H, 8.35. Diethyl sym-(Decvl)dibenzo-16-crown- 5-oxypropyl-phosphonate (104) A colorless oil was obtained in 85% yield. IR (neat): 1257 (P=0); 1056, 958 (POEt) cm-i. m NMR (CDCI3): 5 0.88 (t, 3H), 1.22- 93 1.38 (m, 22H), 1.80-2.20 (m, 6H), 3.91-4.36 (m, 16H), 6,85-5.94 (m, 8H). Anal. Calcd. for C36H57O9PITHF: C, 65.19; H, 8.89. Found: C, 65.56; H, 8.97. Monoethyl &XQL-(Decyl) dibenzo-16- crown-5-oxypropylphosphonic Acid (48) Hydrolysis of 104 for 24 h at refluxing temperature gave a colorless oil in 80% yield. IR (neat): 3520, 2330, 1684 (PO-H); 1257 (P=0); 1046, 985 (POEt) cm-i. iH NMR (CDCI3): 5 0.88 (t, 3H), 1.22- 1.38 (m, 19H), 1.80-2.20 (m, 6H), 3.91-4.36 (m, 16H), 6.81-7.02 (m, 8H). Anal. Calcd. for C34H5309P-1THF: C, 65.19; H, 8.89. Found: C, 65.56; H, 8.89. Diethyl SJJQL-(Decyl)dibenzo-16-crown-5- oxybutyl-phosphonate (105) A colorless oil was obtained in 95% yield. IR (neat): 1257 (P=0); 1029, 959 (POEt) cm-i. iH NMR (CDCI3): 6 0.88 (t, 3H), 1.22- 1.38 (m, 22H), 1.80-2.20 (m, 8H), 3.91-4.36 (m, 18H), 6,81-7.02 (m, 8H). Anal. Calcd. for C37H59O9P: C, 65.46; H, 8.76. Found: C, 65.01; H, 8.94. Monoethyl sym-(Decyl)dibenzo-16- crown-5-oxybutyl-phosphonic Acid (49) Hydrolysis of 105 for 24 h at refluxing temperature gave a colorless oil in 80% yield. IR (neat): 3500, 2299, 1693 (PO-H); 1257 (P=0); 1046, 985 (POEt) cm-i. IH NMR (CDCI3): 5 0.88 (t, 3H), 1.22- 1.38 (m, 19H), 1.80-2.20 (m, 8H), 3.91-4.36 (m, 16H), 6.81-7.02 (m, 94 8H). Anal. Calcd. for C35H55O9PO.5H2O: C, 63.71; H, 8.40. Found: C, 63.97; H, 8.58. Dimethyl sym-Dibenzo-16-crown-5- oxyethyl-phophonate (109) Under nitrogen, sym.-dibenzo-16-crown-5-oxyethyl bromide (0.45 g, 1.1 mmol) and trimethyl phosphite (0.31 g, 2.5 mmol) were stirred at 140 °C for 24 h. Excess trimethyl phosphite was removed by vacuum distillation and the residue was purified by column chromatography on silica gel with CH2CI2 and CH2Cl2-MeOH (10:1) as eluents to give 0.40 g (75% yield) of the product as a colorless oil. IR (neat): 1259 (P=0); 1041, 950 (POMe) cm-i. iH NMR (CDCI3): 5 2.11- 2.32 (m, 2H), 3.70-4.52 (m, 21H), 6.81-7.02 (m, 8H). Anal. Calcd. for C23H31O9P: C, 57.26; H, 6.48. Found: C, 57.59; H, 6.32. Monomethyl sym-Dibenzo-16-crown-5- oxyethyphosphonic Acid (110) A solution of the dimethyl crown ether phosphonate 109 (0.40 g, 0.83 mmol) and NaOH (0.17 g, 4.15 mmol) in 15 mL of 95% EtOH was stirred for 24 h. The solvent was removed in vacuo, and 5 mL of water was added to the residue. The aqueous solution was acidified to pH 1 with 6N HCl and extracted with CH2CI2 (3 X 20 mL). The CH2CI2 solution was dried over MgS04 and evaporated in vacuo. The residue was purified by column chromatography on silica gel with CH2Cl2-MeOH (1:1) as eluent. Evaporation of the eluent gave a salt of 110 which was acidified to pH 1 with concentrated HCl. The aqueous solution was extracted with CH2CI2 (3 X 20 mL). The CH2CI2 solution 95 was dried over MgS04 and evaporated in vacuo to give 0.21 g (54% yield) of the product as white crystals with mp 100-102 °C. IR (deposit): 3427, 2237, 1697 (PO-H); 1257 (P=0); 1055, 990, 931 (POMe) cm-i. iH NMR (CDCI3): 5 2.61-2.80 (m, 2H), 3.75-4.42 (m, 18H), 6.81-7.02 (m, 8H). Anal. Calcd. for C22H29O9P: C, 56.41; H, 6.24. Found: C, 56.47; H, 6.39. General Procedure for Preparation of Crown Ether Methanesulfonates 115-118 To a solution of the sxni-dibenzo-16-crown-5-oxyalkyl alcohol (10 mmol) and triethylamine (1.01 g, 10 mmol) in 100 mL of CH2CI2 which was cooled by an ice-salt bath, methanesulfonyl chloride (1.15 g, 10 mmol) was added dropwise. After the addition was completed, the reaction mixture was stirred for 30 min at 0-10 ^C. The reaction mixture was washed with water (2 X 100 mL), dried over MgS04, and evaporated in vacuo without heating to give the mesylate. l-(sym-Dibenzo-16-crown-5-oxy)-2- (methanesulfonoxy)ethane (117) A colorless oil was obtained in 98% yield. IR (neat): 1350, 1174 (SO2); 1259, 1126 (C-0) cm-i. iH NMR (CDCI3): 5 3.08 (s, 3H), 3.85-4.27 (m, 17H), 6.81-6.98 (m, 8H). Anal. Calcd. for C22H28O9S: C, 56.40; H, 6.02. Found: C, 56.33; H, 6.05. l-(svm-Dibenzo-16-crown-5-oxy)-3- (methanesulfonoxy)propane (118) A coloriess oil was obtained in 95% yield. IR (neat): 1361, 1176 (SO2); 1251, 1140 (C-0) cm-i. ^H NMR (CDCI3): 1.85-2.15 (m. 96 2H), 2.95 (s, 3H), 3.81-4.52 (m, 17H), 6.81-6.98 (m, 8H). Anal. Calcd. for C23H30O9S: C, 57.25; H, 6.27. Found: C, 57.04; H, 6.10. 1-[SXIlL-(Decyl)d ibenzo-16-crown-5-oxy]- 2-(methane-sulfonoxy)ethane (115) A coloriess oil was obtained in 93% yield. IR (neat): 1354, 1174 (SO2); 1257, 1123 cm-i. iH NMR (CDCI3): 6 0.89 (t, 3H), 1.20- 1.35 (m, 16H), 1.80-1.94 (m, 2H), 3.06 (s, 3H), 3.66-4.47 (m, 16H), 6.81-6.96 (m, 8H). Anal. Calcd. for C32H48O9S: C, 63.13; H, 7.95. Found: C, 63.33; H, 7.98. 1-[SXUL-(Decyl) dibenzo-16-crown-5-oxy]- 3-(methane-sulfonoxy)propane (116) A colorless oil was obtained in 82% yield. IR (neat): 1356, 1175 (SO2); 1257, 1123 cm-i. IH NMR (CDCI3): 5 0.88 (t, 3H), 1.20- 1.35 (m, 16H), 1.82-1.95 (m, 2H), 1.95-2.08 (m, 2H), 2.89 (s, 3H), 3.89-4.41 (m, 16H), 6.82-6.96 (m, 8H). Anal. Calcd. for C33H5o09S-lCH2Cl2: C, 55.23; H, 7.12. Found: C, 55.65; H, 7.29. General Procedure for Preparation of Crown Ether Bromides 97. 98. 100. and 101 A solution of the £XQl"di^^"zo-16-crown-5-oxy(methane- sulfonoxy)alkane (5.0 mmol) in 50 mL of acetone was added to sodium bromide (2.0 g) in 150 mL of acetone. The reaction mixture was refluxed for 3 d. After the acetone was evaporated in vacuo. 20 mL of water and 20 mL of CH2CI2 were added to the residue. The CH2CI2 layer was separated, washed with water (2 X 40 mL), dried 97 over MgS04, and evaporated in vacuo to give the sxni-dibenzo-16- crown-5-oxyalkyl bromide. l-(5XQL-Dibenzo-16-crown-5-oxy)-2- bromoethane (100) A white solid with mp 100-102 °C was prepared in 65% yield. IR (deposit): 1259, 1126 (C-0) cm-i. iH NMR (CDCI3): 6 3.32-4.50 (m, 17H), 6.81-6.98 (m, 8H). Anal. Calcd. for C2iH2506Br: C, 55.64; H, 5.56. Found: C, 55.52; H, 5.63. 1 - (SXQL-D i b e n z o -16 - c r o w n - 5 - o X y) - 3- bromopropane (101) A white solid with mp 94-95 °C was prepared in 85% yield. IR (deposit): 1253, 1125 (C-0) cm-i. iH NMR (CDCI3): 6 1.85-2.15 (m, 2H), 3.80-4.52 (m, 17H), 6.81-6.98 (m, 8H). Anal. Calcd. for C22H26O6Br0.5THF: C, 57.26; H, 6.21. Found: C, 57.13; H, 5.83. 1-[SXDI-(Decyl) dibenzo-16-crown-5-oxy]- 2-bromoethane (97) A colorless oil was prepared in 90% yield. IR (neat): 1257, 1122 (C-0) cm-i. m NMR (CDCI3): 6 0.89 (t, 3H), 1.20-1.35 (m, 16H), 1.98-2.10 (m, 2H), 3.25 (t, 2H), 3.94-4.41 (m, 14H), 6.81-6.98 (m, 8H). Anal. Calcd. for C3iH4506Br: C, 62.72; H, 7.64. Found: C, 62.89; H, 7.82. 1 - [iXHL-(D e cy 1) d i b e n z o -16 - c r o wn - 5 - oxy ]- 3-bromo-propane (98) A colorless oil was prepared in 92% yield. IR (neat): 1257, 1126 (C-0) cm-i. iH NMR (CDCI3): 5 0.88 (t, 3H), 1.20-1.35 (m, 16H), 98 1.81-1.92 (m, 2H), 2.05-2.16 (m, 2H), 3.57 (t, 3H), 3.86-4.33 (m, 14H), 6.81-6.98 (m, 8H). Anal. Calcd. for C32H4706Br-2THF: C,63.89; H, 8.40. Found: C, 64.12; H, 8.20. General Procedure for Preparation of Crown Ether Bromides 99 and 102 A solution of 1,4-dibromobutane (10.36 g, 48 mmol) and the crown ether alcohol (16 mmol) in 36 mL of CH2CI2 was stirred vigorously with tetrabutylammonium hydrogen sulfate (0.27 g, 0.8 mmol) in 50% aqueous NaOH (12 mL). After 24 h (for 99) or 10 d (for 102), 40 mL of water and 200 mL of CH2CI2 were added. The CH2CI2 layer was separated, washed with water (3 X 200 mL), dried over MgS04, and evaporated in vacuo. The resultant oily residue was purified by chromatography on silica gel with CH2CI2 and then ethyl acetate as eluents to give the sym-dibenzo-16-crown-5-oxyalkyl bromide. 1-(svm-Dibenzo-16-crown-5-oxy)-4- bromobutane (99) A coloriess oil was obtained in 76% yield. IR (neat): 1251, 1114 (C-0) cm-i. m NMR (CDCI3): 1.81-2.25 (m, 4H), 3.42-4.50 (m, 17H), 6.81-6.98 (m, 8H). Anal. Calcd. for C23H29O6Br0.5THF: C,58.03; H, 6.43. Found: C, 57.99; H, 6.12. 1-[SJJH-(Decyl)-dibenzo-16-crown-5- oxy]-4-bromo-butane (102) A coloriess oil was obtained in 34% yield. IR (neat): 1257, 1140 (C-0) cm-i. iH NMR (CDCI3): 6 0.88 (t, 3H), 1.20-1.31 (m, 16H), 99 1.69-1.76 (m, 2H), 1.83-2.10 (m, 6H), 3.47 (t, 2H), 3.77-4.35 (m, 14H), 6.81-6.98 (m, 8H). Anal. Calcd. for C33H4906Br: C, 63.76; H, 7.95. Found: C, 63.54; H, 8.04. General Procedure for Preparation of Crown Ether Esters 119 and 120 The protecting mineral oil from NaH (1.44 g, 36 mmol, 60% dispersion in mineral oil) was removed by washing with pentane (2 X 20 mL) under nitrogen, and the deprotected NaH was suspended in 100 mL of THF. A solution of the crown ether alcohol (11.6 mmol) in 150 mL of THF was added dropwise. After a solution of ethyl bromoacetate (2.32 g, 13.9 mmol) in 50 mL of THF was added dropwise during 1 h, the mixture was stirred for an additional 6 h and refluxed for 30 min. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The crude product was recrystallized from EtOH. Ethyl (sxQL-Dibenzo-16-crown-5-oxy)- acetate (120) A white solid with mp 44-46 ®C was prepared in 76% yield. IR (neat): 1755 (C=0); 1259, 1136 (C-0) cm-i. iH NMR (CDCI3): 6 1.29 (t, 3H), 3.88-4.45 (m, 15H), 4.58 (s, 2H), 6.81-7.03 (m, 8H). Ethyl [sxni-(Decyl)dibenzo-16-crown-5- oxy]acetate (119) A white solid with 80-81 °C was prepared in 66% yield. IR (deposit): 1758 (C=0); 1258, 1122 (C-0) cm-i. ^H NMR (CDCI3): 6 0.88 4 100 (t, 3H), 1.23-1.55 (m, 19H), 1.90-2.07 (m, 2H), 3.84-4.50(m, 14H), 4.75 (s, 2H), 6.81-7.03 (m, 8H). General Procedure for Preparation of Crown Ether Alcohols 111 and 113 Under nitrogen, the crown ether ester (11.56 mmol) in 50 mL of THF was added dropwise to a mixture of LiAlH4 (1.75 g, 46.24 mmol) and 90 mL of THF at refluxing temperature with stirring during 1 h. The mixture was refluxed for an additional 4 h and cooled to room temperature. The unreacted LiAlH4 in the mixture was decomposed carefully by adding ethyl acetate dropwise. The mixture was poured into a cold solution of dilute sulfuric acid and extracted with CH2CI2 (2 X 100 mL). The CH2CI2 solution washed with water (2 X 100 mL), dried over MgS04 and evaporated in vacuo. The crude product was recrystallized from CHCI3 to give white crystals. 2-(sym-Dibenzo-16-crown-5-oxv)ethanol (113) A white solid with mp 127-129 °C was obtained in 90% yield. IR (deposit): 3398 (0-H); 1263, 1132 (C-0) cm-i. m NMR (CDCI3): 6 2.90 (br s, IH), 3.80-4.35 (m, 17H), 6.83-7.02 (m, 8H). Anal. Calcd. for C21H26O7: C, 64.60; H, 6.71. Found: C, 64.66; H, 6.74. 2-[s ym-(Dec vl) dibenzo-16-crown-5- oxy]ethanol (111) A colorless oil was obtained in 98% yield. IR (neat): 3278 (O- H); 1219, 1125 (C-0) cm-i. iH NMR (CDCI3): 5 0.88 (t, 3H), 1.10-1.48 (m, 16H), 1.90-2.07 (m, 2H), 2.55 (br s, IH), 3.68-4.57 (m, 16H), 6.83- 101 7.02 (m, 8H). Anal. Calcd. for C31H46O7: C, 70.16; H, 8.74. Found: C, 70.57; H, 8.86. General Procedure for Preparation of Allyoxy Crown Ethers 121 and 122 The protecting mineral oil from KH (1.15 g, 10 mmol, 35% dispersion in mineral oil) was removed by washing with pentane (2 X 30 mL) under nitrogen. THF (20 mL) was added to the powdery KH and a solution of the crown ether alcohol (5.0 mmol) in 20 mL of THF was added dropwise. After the mixture was stirred for 1 h, a solution of allyl bromide (1.73 g, 6.0 mmol) in 10 mL of THF was added dropwise. The reaction mixture was stirred at room temperature for 6 h and filtered. The filtrate was evaporated rn vacuo., and the residue was purified by column chromatography on silica gel with CH2CI2 as eluent to give the allyoxy crown ether. 3-(svm-Dibenzo-16-crown-5-oxy)-l- propene (122) A white solid with mp 108-110 °C was obtained in 96% yield. IR (deposit): 1290, 1129 (C-0) cm-i. iH NMR (CDCI3): 6 3.85-4.41 (m, 15H), 5.13-5.42 (m, 2H), 5.88-6.05 (m, IH), 6.82-7.06 (m, 8H). 3-[SXDL-(Decyl)-dibenzo-16-crown-5- oxy]-l-propene (121) A coloriess oil was obtained in 98% yield. IR (neat): 1225, 1140 (C-0) cm-i. m NMR (CDCI3): 5 0.88 (t, 3H), 1.15-1.58 (m, 16H), 1.90-2.02 (m, 2H), 3.86-4.50 (m, 14H), 5.13-5.42 (m, 2H), 5.88-6.05 ^ 102 (m, IH), 6.82-7.06 (m, 8H). Anal. Calcd. for C32H46O6: C, 72.97; H, 8.80. Found: C, 72.99; H, 8.88. General Procedure for Preparation of Crown Ether Alcohols 112 and 114 A solution of the allyloxy crown ether (13 mmol) in 120 mL of THF was added dropwise to NaBH4 (0.50 g, 13 mmol) in 30 mL of THF dropwise. Boron trifluoride etherate (2.25 mL) was added dropwise at 0 °C, and the reaction mixture was stirred at this temperature for 2 h. Water (1.5 mL) was added to destroy the excess NaBH4. After the addition of 7.5 mL of 2N aqueous NaOH, 9 mL of 30% H2O2 was slowly added, and the reaction mixture was stirred overnight at room temperature. The THF was evaporated in vacuo. The crude product was extracted with CH2CI2 (2 X 50 mL) and dried over MgS04. Evaporation of the CH2CI2 gave crown ether alcohol. 3-(svm-Dibenzo-16-crown-5-oxy)propan- l-ol (114) A white solid with mp 82-83 °C was obtained in 26% yield. IR (deposit): 3385 (OH); 1257, 1124 (C-0) cm-i. ^H NMR (CDCI3): 5 1.68-2.15 (m, 2H), 2.90 (br s, IH), 3.80-4.23 (m, 17H), 6.83-7.02 (m, 8H). Anal. Calcd. for C22H28O7: C, 65.33; H, 6.98. Found: C, 65.12; H, 6.74. 3 - [ iXiS-" (D e c y 1) d i b e n z o -16 - c r o w n - 5- oxy]propan-l-ol (112) A colorless oil was obtained in 91% yield. IR (neat): 3314 (O- H); 1256, 1129 (C-0) cm-^. iH NMR (CDCI3): 5 0.88 (t, 3H), 5 1.15-1.58 103 (m, 16H), 1.68-2.20 (m, 4H), 3.74-4.51 (m, 16H), 6.83-7.02 (m, 8H). Anal. Calcd. for C32H48O7I.25H2O: C, 67.76; H, 8.53. Found: C, 67.80; H, 8.68. 10-Methanesulfonoxy-l-decene (133) Methanesulfonyl chloride (3.45 g, 0.03 mol) was added to a solution of 9-decen-l-ol (5.0 g, 0.03 mol) and triethylamine (3.04 g, 0.03 mol) in 100 mL of CH2CI2 in an ice-salt bath. The reaction mixture was stirred for an additional 1 h at room temperature and washed with water (2 X 50 mL). The CH2CI2 solution was dried over MgS04 and evaporated in vacuo to give 6.64 g (89% yield) of the mesylate. IR (neat): 1640 (C=C); 1356, 1176 (SO2) cm-i. ^H NMR (CDCI3): 5 1.23-1.48 (m, lOH), 1.65-2.21 (m, 4H), 3.01 (s, 3H), 4.23 (t, 2H), 4.90-5.18 (m, 2H), 5.71-5.92 (m, IH). 10-Bromo-l-decene (134) A solution of 10-methane-sulfonoxy-l-decene (6.50 g, 0.026 mol) and sodium bromide (6.69 g, 0.065 mol) in 20 mL of acetone was refluxed for 5 d. After the mixture was cooled to room temperature, the acetone was evaporated in vacuo. Then CH2CI2 (50 mL) and water (50 mL) were added to the residue. The CH2CI2 layer was separated, washed with water (2 X 50 mL), dried over MgS04 and evaporated in vacuo to giye an oily residue which was purified by column chromatography on silica gel with petroleum ether as eluent. The product was obtained in 69% yield (3.92 g) as a colorless oil. IR (neat): 1640 (C=C); 1254, 1126 (C-0) cm-i. iH NMR (CDCI3): 5 •Sf 104 1.23-1.48 (m, lOH), 1.65-2.21 (m, 4H), 3.41 (t, 2H), 4.90-5.18 (m, 2H), 5.71-5.92 (m, IH). General Procedure for Preparation of Crown Ether Alcohols 124 and 125 To 0.26 g of magnesium turnings under nitrogen was added 30 mL of THF and 10-bromo-l-decene (2.30 g, 10.5 mmol). The mixture was refluxed for 3 h, and the crown ether ketone (4.78 mmol) in 30 mL of THF was added dropwise at room temperature. The reaction mixture was refluxed for 3 h. After 30 mL of 5% aqueous NH4CI was added, the reaction mixture was stirred for 2 h. The THF was evaporated in vacuo and the residue was extracted with CH2CI2. The CH2CI2 solution was dried over MgS04 and evaporated in vacuo. The resultant oil was purified by column chromatography on silica gel with CH2Cl2and CH2Cl2-Et20 (1:1) as eluents to give the product. sym-(9-Decenvl) (hydroxy )dibenzo- 14-crown-4 (124) A white solid with mp 64-65 °C was prepared in 74% yield. IR (deposit): 3375 (0-H); 1640 (C=C); 1254, 1120 (C-0) cm-i. ^H NMR (CDCI3): 5 1.32-1.71 (m, 14H), 1.90-2.11 (m, 2H), 2.28-2.37 (m, 2H), 3.60 (br s, IH), 4.01-4.30 (m, 8H), 4.90-5.04 (m, 2H), 5.70-5.90 (m, IH), 6.89-7.00 (m, 8H). Anal. Calcd. for C28H38O5I.25H2O: C, 73.25; H, 8.45. Found: C, 73.40; H, 8.41. 105 &XQL-(9-Decenyl) (hydroxy )dibenzo- 16-crown-5 (125) A white solid with mp 82-83 °C was prepared in 56% yield. IR (deposit): 3462 (0-H); 1640 (C-C); 1263, 1046 (C-0) cm-i. ^H NMR (CDCI3): 5 1.32-2.05 (m, 16H), 3.26 (br s, IH), 3.90-4.26 (m, 12H), 4.90-5.04 (m, 2H), 5.70-5.90 (m, IH), 6.89-7.00 (m, 8H). Anal. Calcd. for C29H40O6: C, 71.87; H, 8.32. Found: C, 71.88; H, 8.37. General Procedure for Preparation of Crown Ether Carboxylic Acids 135 and 136 The protecting mineral oil from NaH (1.26 g, 31.5 mmol, 60% dispersion in mineral oil) was removed by washing with pentane (2 X 20 mL) and 20 mL of THF was added to the powdery NaH. The crown ether alcohol (5.24 mmol) in 20 mL of THF was added dropwise, and the mixture was stirred for 1 h. After a solution of bromoacetic acid (1.46 g, 10.5 mmol) in 20 mL of THF was added dropwise, the reaction mixture was stirred overnight at room temperature and then refluxed for 6 h. After cooling, 40 mL of water was added carefully to the reaction mixture to destroy the excess NaH. The THF was evaporated in vacuo and the residue was acidified to pH 1 with 6N HCl. The aqueous solution was extracted with CH2CI2 (2 X 60 mL). The CH2CI2 solution was dried over MgS04 and evaporated in vacuo to give the product. sym- (9-Decenyl)dibenzo-14-crown-4- oxyacetic Acid (135) A colorless oil was prepared in 92% yield. IR (neat): 3450- 2600 (COOH); 1744 (C=0); 1251, 1120 (C-0) cm^. m NMR (CDCI3): 6 106 1.32-2.05 (m, 16H), 2.15-2.55 (m, 2H), 4.01-4.30 (m, 8H), 4.45 (s, 2H), 4.90-5.04 (m, 2H), 5.70-5.90 (m, IH), 6.89-7.00 (m, 8H). Anal. Calcd. for C30H40O7: C, 70.29; H, 7.87. Found: C, 69.98; H, 8.01. SXQL-(9 - D e c e n y 1) d i b e n z o -16 - c r o w n - 5- oxyacetic Acid (136) A colorless oil was prepared in 97% yield. IR (deposit): 3357- 2600 (COOH); 1746 (C=0); 1256, 1154 (CO) cm-'. iH NMR (CDCI3): 6 1.32-2.05 (m, 16H), 3.90-4.26 (m, lOH), 4.56-4.62 (d, 2H), 4.85 (s. 2H), 4.90-5.04 (m,lH), 6.89-7.00 (m, 8H). Anal. Calcd. for C31H42O8: C, 68.61; H, 7.80. Found: C, 68.51; H, 7.51. General Procedure for Preparation of Crown Ether Esters 123 and 124 A solution of the crown ether carboxylic acid (5.53 mmol) and 2 drops of concentrated H2SO4 in 200 mL of absolute EtOH was refluxed for 24 h. The water produced during the reaction was removed by use of a Soxhlet thimble filled with anhydrous Na2S04. After cooling, Na2C03 was added to neutralize the acid catalyst. EtOH was evaporated in vacuo. The crude product was recrystallized from EtOH. Ethyl sym-(9-Decenyl)dibenzo- 14-crown-4-oxyacetate (123) A colorless oil was obtained in 78% yield. IR (neat): 1757 (C=0); 1640 (C=C); 1256, 1119 (C-0) cm-i. iH NMR (CDCI3): 6 1.32- 2.05 (m, 19H), 2.15-2.55 (m, 2H), 4.01-4.30 (m, 8H), 4.49 (s, 2H), 107 4.90-5.04 (m, 2H), 5.70-5.90 (m, IH), 6.89-7.00 (m, 8H). Anal. Calcd. forC32H4407: C, 71.08; H, 8.20. Found: C, 71.52; H, 8.11. Ethyl sxiIL-(9-Decenyl)dibenzo- 16-crown-5-oxyacetate (124) A white solid with mp 85-86 °C was obtained in 90% yield. IR (deposit): 1757 (C=0); 1640 (C=C); 1256, 1123 (C-0) cm-i. iH NMR (CDCI3): 5 1.16-2.05 (m, 19H), 3.90-4.49 (m, 14H), 4.75 (s, 2H), 4.90- 5.04 (m, 2H), 5.70-5.90 (m, IH), 6.89-7.00 (m, 8H). Anal. Calcd. for C33H46O8: C, 69.45; H, 8.13. Found: C, 69.50; H, 8.02. General Procedure for Preparation of Crown Ether Esters 138 and 13 9 To the unsaturated crown ether ester (1.0 mmol) was added 0.5 M BH3.THF (0.70 mL, 0.35 mmol) at 0 °C. After the reaction mixture had been stirred for 2 h at this temperature and 2 h at room temperature, IN NaOH (0.21 mL) and 30% H2O2 (0.14 mL) were added. The reaction mixture was extracted with CH2CI2. The CH2CI2 solution was dried over MgS04 and evaporated in vacuo to give the product. Ethyl sym-(10-Hydroxydecyl)dibenzo- 14-crown-4-oxyacetate (138) A coloriess oil was obtained in 77% yield. IR (neat): 3412 (O- H); 1754 (C=0); 1256, 1119 (C-0) cm-i. m NMR (CDCI3): 5 1.32-2.05 (m, 19H), 2.15-2.55 (m, 2H), 3.63 (t, 2H), 4.01-4.30 (m, lOH), 4.49 (s, 2H), 6.89-7.00 (m, 8H). Anal. Calcd. for C32H46O8-0.17CH2C12: C, 67.45; H, 8.16. Found: C, 67.63; H, 8.16. 108 Ethyl &xilL-(10-Hydroxydecyl)dibenzo- 16-crown-5-oxy acetate (139) A colorless oil was obtained in 86% yield. IR (neat): 3412 (O- H); 1754 (C=0); 1256, 1124 (C-0) cm-i. IH NMR (CDCI3): 6 1.16-2.05 (m, 21H), 3.64 (t, 2H), 4.01-4.49 (m, 14H), 4.75 (s, 2H), 6.89-7.00 (m, 8H). Anal. Calcd. for C32H46O8: C, 67.32; H, 8.23. Found: C, 67.54; H, 8.32. 11-Methanesulfonoxy-l-undecene (140) A solution of methanesulfonyl chloride (11.31 g, 0.099 mol) in 75 mL of CH2CI2 was added to a cooled mixture of 10-undecen-l-ol (13.50 g, 0.079 mol) and triethylamine (12.79 g, 0.13 mol) in 75 mL of CH2CI2. The reaction mixture was stirred for 1 h at 0-10 "C and washed with water (2 X 100 mL). The CH2CI2 solution was dried over MgS04 and evaporated in vacuo to give 19.50 g (99.5% yield) of the product as a colorless oil. IR (neat): 1640 (C=C); 1356, 1177 (SO2) cm-i. IH NMR (CDCI3): 5 1.20-1.48 (m, 12H), 1.68-1.85 (m, 2H), 1.48- 2.15 (m, 2H), 3.00 (s, 3H), 4.22 (t, 2H), 4.89-5.07 (m, 2H), 5.68-5.95 (m, IH). 2-Hydroxy-4-(10*-undecenoxy)benzoic Acid (141) Potassium metal (8.89 g, 0.227 mol) was added to 600 mL of absolute EtOH, and the mixture was stirred until the potassium metal disappeared. A solution of 2,4-dihydroxybenzoic acid (12.86 g, 0.083 mol) in 100 mL of EtOH was added, and the mixture was refluxed for 2 h. After a solution of mesylate 140 (18.80 g, 0.0758 mol) in 50 ml of EtOH was added, the reaction mixture was refluxed for 6 d. The 109 solvent was evaporated in vacuo. The residue was dissolved in 50 mL of water, acidified to pH 1 with 6N HCl and extracted with CH2CI2 (2 X 50 mL). The combined extracts were washed with 50 mL of water, dried over MgS04, and evaporated in vacuo. The crude product was recrystallized from petroleum ether and a minimum amount of CH2CI2 to give 8.15 g (35% yield) of the product as a solid with mp 110-112 °C. IR (deposit): 3100-3050 (COOH); 1644, 1622 (C=0); 1242, 1176 (C-0) cm-i. iH NMR (CDCI3): 6 1.18-1.53 (m, 12H), 1.65-1.85 (m, 2H), 1.93-2.15 (m, 2H), 3.99 (t, 2H), 4.85-5.05 (m, 2H), 5.65-5.95 (m, IH), 6.35-6.50 (m, 2H), 7.79 (m, IH), 10.13 (br s, IH). Methyl 2-Hydroxy-4-(10*-undecenoxy)- benzoate (142) A solution of the benzoic acid 141 (5.61 g, 18.3 mmol) and 2 g of concentrated sulfuric acid in 200 mL of CH3OH was refluxed for 48 h. The reaction mixture was cooled, and the solvent was removed in vacuo. The residue was poured into ice-water (30 mL) and extracted with diethyl ether (2 X 50 mL). The combined extracts were washed with saturated aqueous NaHC03 (50 mL) and then with 50 mL of water. The ether solution was dried over MgS04 and evaporated rn vacuo to give 4.67 g (80% yield) of the product as a colorless oil. IR (neat): 3077 (0-H); 1668, 1623 (C=0); 1224, 1191 (C-0) cm-i. iH NMR (CDCI3): 5 1.18-1.53 (m, 12H), 1.65-1.85 (m, 2H), 1.93-2.15 (m, 2H), 3.82-4.04 (m, 5H), 4.85-5.05 (m, 2H), 5.65-5.95 (m, IH), 6.35- 6.50 (m, 2H), 7.65-7.78 (m, IH), 10.96 (s, IH). I 10 General Procedure for Preparation of Methyl Esters 125-128 The protecting mineral oil from NaH (0.30 g, 7.56 mmol, 60% dispersion in mineral oil) was removed by washing with pentane (2 X 20 mL) under nitrogen. THF (20 mL) was added to the powdery NaH, and a solution of phenolic ester 142 (6.05 mmol) in 10 mL of THF was added dropwise. After 1 h, a solution of the crown ether tosylate (6.05 mmol) in 10 mL of THF was added dropwise. The reaction mixture was refluxed for 3 d and filtered. The filtrate was evaporated in vacuo, and the residue was purified by column chromatography on silica gel with CH2CI2 and then ethyl acetate as eluents to give the product. Methyl 2-[(12-Crown-4)methyloxyJ-4- (lO'-undecenoxy)-benzoate (125) A white solid with mp 52-53 °C was prepared in 36% yield. IR (deposit): 1727, 1700 (C=0); 1640 (C=C); 1246, 1192 (C-0) cm-i. m NMR (CDCI3): 5 1.18-1.53 (m, 12H), 1.65-1.85 (m, 2H), 1.93-2.15 (m, 2H), 3.56-4.18 (m, 22H), 4.85-5.05 (m, 2H), 5.65-5.95 (m, IH), 6.35- 6.50 (m, 2H), 7.80-7.89 (m, IH). Anal. Calcd. for C28H44O8: C, 66.11; H, 8.72. Found: C, 66.16; H, 8.47. Methyl 2-[(15-Crown-5)methyloxy]-4- (lO'-undecenoxy)benzoate (126) A colorless oil was prepared in 34% yield. IR (neat): 1726,1699 (C=0); 1640 (C=C); 1251, 1193 (C-0) cm-i. ^H NMR (CDCI3): 5 1.18-1.53 (m, 12H), 1.65-1.85 (m, 2H), 1.93-2.15 (m, 2H), 3.56-4.18 (m, 26H), 4.85-5.05 (m, 2H), 5.65-5.95 (m, IH), 6.35-6.50 (m, 2H), 111 7.80-7.89 (m, IH). Anal. Calcd. for C30H48O9: C, 65.19; H, 8.75. Found: C, 65.33; H, 8.58. Methyl 2-[(18-Crown-6)methyloxy]-4- (lO'-undecenoxy)benzoate (127) A colorless oil was prepared in 42% yield. IR (neat): 1726, 1700 (C=0); 1640 (C=C); 1249, 1194 (C-0) cm-i. iH NMR (CDCI3): 6 1.18-1.53 (m, 12H), 1.65-1.85 (m, 2H), 1.93-2.15 (m, 2H), 3.56-4.18 (m, 30H), 4.85-5.05 (m, 2H), 5.65-5.95 (m, IH), 6.35-6.50 (m, 2H), 7.80-7.89 (m, IH). Anal. Calcd. for C32H52O10O.2CH2CI2: C, 62.01; H, 8.61. Found: C, 63.19; H, 8.42. Methyl 2-[(21-Crown-7)methyloxy]-4- (lO'-undecenoxy)benzoate (128) A colorless oil was prepared in 34% yield. IR (neat): 1725, 1700 (C=0); 1640 (C=C); 1251, 1193 (C-0) cm-i. 'H NMR (CDCI3): 6 1.18-1.53 (m, 12H), 1.65-1.85 (m, 2H), 1.93-2.15 (m, 2H), 3.56-4.18 (m, 34H), 4.85-5.05 (m, 2H), 5.65-5.95 (m, IH), 6.35-6.50 (m, 2H), 7.80-7.89 (m, IH). Anal. Calcd. for C34H56O11: C, 63.72; H, 8.81. Found: C, 63.77; H, 9.01. Preparation of Alkali Metal Picrates Alkali metal picrates were prepared by dissolving picric acid in a minimum amount of boiling distilled, deionized water and slowly adding a stoichiometric amount of the alkali metal carbonate. After allowing the solution to cool to room temperature, it was cooled in an ice bath to promote crystallization. Crystals were collected, air-dried, and recrystallized from distilled, deionized water. The recrystallized 1 12 alkali metal picrates were collected, air-dried, and dried in a vacuum oven at 100 °C for 4 h. The dry alkali metal picrates were stored under vacuum in the dark. Preparation of Alkylammonium Picrates The alkylamine was added to a saturated solution of picric acid in distilled, deionized water. A precipitate was formed as the alkylamine was added. The reaction mixture was filtered to give the alkylammonium picrate as a yellow solid which was recrystallized from distilled, deionized water. Preparation of N.N-Didecyl-7.16-diaza- 18-crown-6 (185) Decanoyl Chloride (183) Fresh distilled thionyl chloride (20 mL) was added to decanoic acid (7.30 g, 42 mmol). The reaction mixture was heated slowly and refluxed for 5 h. Excess thionyl chloride was evaporated in vacuo to give 7.69 g of the product (96% yield) as a colorless oil. IR (neat): 1801 (C=0); cm-i. ^H NMR (CDCI3): 6 0.88 (t, 3H), 1.19-1.35 (m, 12H), 1.65-1.76 (m, 2H), 2.88 (t, 2H). N,N-Didecanoyl-7,16-diaza-18-crown-6 (184) A solution of decanoyl chloride (1.60 g, 8.38 mmol) in 15 mL of THF was added dropwise to a stirred solution of 7,16-diaza-18- crown-6 (1.00 g, 3.81 mmol) and triethylamine (0.93 g, 9.14 mmol) in 30 mL of THF under nitrogen at 50 °C. After the reaction mixture was stirred for 1 h at this temperature, it was filtered and 113 evaporated in vacuo. The crude product was recrystallized from petroleum ether to give 1.82 g of the product (84% yield) as a white solid with mp 64-65 °C. IR (deposit): 1639 (C=:0); 1250, 1120 (C-0) cm-i. iH NMR (CDCI3): 6 0.88 (t, 6H), 1.19-1.35 (m, 2H), 1.63 (t, 4H), 2.33 (t, 4H), 3.49-3.75 (m, 24H). Anal. Calcd. for C32H62O6N2-0.1CH2C12: C, 66.67; H, 10.84. Found: C, 66.88; H, 10.97. N,N-Didecyl-7,16-diaza-18-crown-6 (185) To a solution of compound 184 (1.14 g, 2.0 mmol) in 10 mL of THF was added 8.0 mL of 2M BH3-SMe2 complex. After the reaction mixture was refluxed for 9 h, 5 mL of water was added slowly and the solvent was evaporated in vacuo. The residue was treated with 6N HCl (10 mL) and water (10 mL). The resultant solution was refluxed for 12 h, then aqueous ammonium hydroxide was added to adjust the pH to 10. The aqueous solution was extracted with CH2CI2 (3 X 50 mL), dried over MgS04 and evaporated in vacuo. The crude product was purified by column chromatography on alumina with CH2Cl2-MeOH (1:1) as eluent to give 0.79 g of the product (73% yield) as a colorless oil. IR (neat): 1250, 1178 (C-0) cm-i. 'H NMR (CDCI3): 5 0.88 (t, 6H), 1.12-1.38 (m, 32H), 2.48 (t, 4H), 2.78 (t, 8H), 3.51-3.72 (m, 16H). Anal. Calcd. for C32H66O4N2-0.13CH2C12: C, 69.67; H, 12.06. Found: C, 69.85; H, 12.30. Procedure for Picrate Extractions Crown ether solutions (5.0 mM) were prepared in ethanol-free deutriochloroform. Extraction experiments were conducted by 1 14 adding 0.50 mL of a 5.0 mM crown ether solution in deuteriochloroform to 0.50 mL of 5.0 mM picrate solution in a centrifuge tube and agitating the mixture with a vortex mixer for 1 min. Five identical samples were run concurrently. The mixture were centrifuged for 10 min to assure complete separation of the layers. Precisely measured aliquots were removed from each layer with microsyringes and diluted in acetonitrile. Visible spectra of these solutions were measured in the region 300-500 nm. The absorbance at absorption maximum (375 nm) was measured and compared with that for a known concentration of the alkali picrate. From the absorbance values, the percent extraction was calculated. From the percent extraction values, the log Kex value was calculated using a computer program written by David A. Babb.[64] REFERENCES 1. Pedersen, C. J. J. Am. Chem. Soc. 1967,89,7017. 2. Pedersen, C. J. Aldrichimica Acta 1967, 4, 1. 3. Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 2495. 4. Pedersen, C. J. Organic Synthesis 1972, 51, 66. 5. Mandolini, L.; Masci, B. J. Am. Chem. Soc. 1984. 106. 168. 6. Cook, F. L.; Caruson, T. C; Byrne, M. P.; Bowers, C. W.; Speck, D. H.; Liotta, C. L. Tetrahedron Lett. 1974, 4029. 7. Piepers, O.; Kellogg, R. M. J. Chem. Soc. Chem. Commun. 1978, 383. 8. Pedersen, C. J. J. Am. Chem. Soc. 1969, 91, 386. 9. Gokel, G. W.; Cram, D. J. J. Chem. Soc. Chem. Commun. 1973, 481. 10. Beckford, H. F.; King, R. F.; Stoddart, J. F.; Newton, R. F. Tetrahedron Lett. 1978, 171. 11. Larson, J. M.; Sousa, L. R. J. Am. Chem. Soc. 1978,100, 1943. 12. Shannon, R. D.; Prewitt, C. T. Acta Crvst. 1969, B15, 925. 13. Shannon, R. D. Acta Crvst. 1976, A31, 751. 14. Weber, E.; Vogtle, F. Host Guest Chemistry Macrocvcles: Springer-Verlag, 1985; p 18. 15. Dunitz, J. D.; Dobler, M.; Seller, P.; Phizackerley, R. P. Acta Cryst. 1974, B30. 2733. 16. Dunitz, J. D.; Seller, P. Acta Crvst. 1974, BM, 2739. 17. Wong, K. H.; Bourgoin, M.; Smid, J. .1. Chem. Soc, Chem. Commun. 1974, 715. 1 15 116 18. Bourgoin, M.; Wong, K. H.; Hui, J. Y.; Smid, J. J. Am. Chem. Soc. 1975, 91, 3462. 19. Sadkane, A.; Iwachido, T.; Toei, K. Bull. Chem. Soc. Jpn. 1975, 48. 20. Nakamura, H.; Nishido,H.; Tadagi, M.; Ueno, K. Anal. Chim. Acta. 1982, 139., 219. 21. Newcomb, M.; Cram, D. J. J. Am. Chem. Soc. 1975, 97, 1257. 22. Wierenga, W.; Evans, B. R.; Woltersom, J. A. J. Am. Chem. Soc. 1979, Ml, 1334. 23. Helgeson, R. C; Timko, J. M.; Cram, D. J. J. Am. Chem. Soc. 1973, 95., 3023. 24. Goldberg, 1. Acta Crvst. 1975, B31. 2592. 25. Nakamura, H.; Takagi, M.; Ueno, K. Anal. Chem. 1980, 52, 1668. 26. Bartsch, R. A.; Heo, G. S.; Kang, S. 1.; Liu, Y.; Strzelbicki, J. J- Org. Chem. 1982, 47, 257. 27. Strzelbicki, J.; Bartsch, R. A. Anal. Chem. 1981, 51, 1894. 28. Strzelbicki, J.; Heo, G. S.; Bartsch, R. A. Sep. Sci. Technol. 1982, LT., 635. 29. Strzelbicki, J.; Bartsch, R. A. Anal. Chem. 1981, 53, 2251. 30. Czech, B.; Son, B.; Bartsch, R. A. Tetrahedron Lett. 1983, 24, 2923. 31. Czech, B.; Czech, A.; Son, B.; Lee, H. K.; Bartsch, R. A. L Heterocyclic Chem. 1986, 2i, 465. 32. Bartsch, R. A. and co-workers, unpublished results, 1991. 33. Pugia, M. J.; Ndip. G.; Lee, H. K.; Yang, I. W.; Bartsch, R. A. Anal. Chem. 1986, 58., 2723. 34. Charewicz, W. A.; Bartsch, R. A. Anal. Chem. 1982, 52, 1668. 1 17 35. Charewicz, W. A.; Heo, G. S.; Bartsch, R. A. Anal. Chem. 1982, 54, 2094. 36. Charewicz, W. A.; Walkowiak, W.; Bartsch, R. A. Anal. Chem. 1987, 59., 494. 37. Bartsch, R. A.; Charewicz, W. A.; Kang, S. 1.; Walkowiak, W. Liquid Membranes: Theory and Applications: ACS Symposium Series 347; American Chemical Society: Washington, D. C, 1987, p 86. 38. Bradshaw, J. S.; Bruening, R. L.; Krakowiak, K. E., Tarbet, B. J.; Bruening, M. L.; Izatt, R. M.; Christensen, J. J. J. Chem. Soc. Chem. Commun. 1988, 812. 39. Izatt, R. M.; Bradshaw, J. S.; Nielsen, S. A.; Lamb, J. D.; Christensen, 1 J. Pure Appl. Chem. 1985, 85, 271. 40. Bradshaw, J. S.; Nielsen, R. B.; Tse, R. K.; Arena, G.; Wilson, B. E.; Dalley, N. K.; Lamb, J. D. J. Heterocyclic Chem. 1986, 21, 361. 41. Bartsch, R. A. Sol. Extr. Ion Exch. 1989, 7, 829. 42. Cho, M. H.; Bartsch, R. A., unpublished results,1991. 43. Provided by J. Krzykawski, T. W. Robinson, and J. L. Hallman, Texas Tech University. 44. Miyazaki, T.; Yanagida, S.; Itoh, A.; Okahara, M. Bull. Chem. Soc, Jpn. 1982, 55, 2005. 45. Golding, B. T.; loannou, P. V. Synthesis 1977, 423. 46. Cho, M. H.; Ramash, V.; Bartsch, R. A., unpublished results,1991. 47. Strzelbicki, J.; Bartsch, R. A. L Membr. Sci. 1982, 10, 35. 48. Strzelbicki, J.; Bartsch, R. A. T. Membr. Sci. 1983, 12, 323. 49. Hayashita, T.; Goo, M.-J.; Lee, J. C; Kim, J. S.; Krzykawski, J.; Bartsch, R. A. Anal. Chem. 1990, 62, 2283. 118 50. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis: Wiley: New York, 1967; Vol. 1, p. 142. 51. Eastman, M. P.; Patterson, D. E.; Bartsch, R. A.; Liu, Y.; Filer, P. G. L Phvs. Chem. 1982, 86, 2052. 52. Ford-Moore, A. H.; Williams, J. H. J. Am. Chem. Soc. 1947, 69, 1465. 53. Myers, T. C; Preis, S.; Jensen, E. V. J. Am. Chem. Soc. 1954, 76. 4172. 54. Walkowiak, W.; Bartsch, R.A., unpublished results, 1991. 55. Blasius, E.; Janzen, K.-P.; Adrian, W.; Klautke, G.; Lorscheider, R.; Maurer, P.-G.; Nguyen, V.P.; Nguyen, T. T.; Scholten, G.; Stockemer, J. Z. Anal. Chem. 1977, 284, 337. 56. Brown, H. C; Keblys, K. A. J. Am. Chem. Soc. 1964, 86, 1795. 57. Provided by J. McDonough, Texas Tech University, 1990. 58. Provided by B. P. Czech, Technicon Instruments Corporation, 1990. 59. Provided by J. C. Lee, Texas Tech University, 1990. 60. Olsher, U.; Dalley, N. K.; Bartsch, R. A., unpublished results, 1991. 61. Lehn, J. M. Science 1985, 227, 849. 62. Cram, D. J.; Cram, J. M. Science 1974, HI, 803. 63. Cinquini, M. Synthesis 1976, 516. 64. Babb, D.A., Ph.D. Dissertation, Texas Tech University, 1985.