New Crown Ether Compounds and Their Alkali Metal Ion Complexation

NEW CROWN ETHER COMPOUNDS AND THEIR ALKALI METAL ION COMPLEXATION

by LOKMAN TORUN, B.S., M.S.

A THESIS IN CHEMISTRY Submitted to the Graduate Faculty of Texas Tech University in Partial Fulfillment of the Requirements for the Degree of

MASTER OF SCIENCE

Approved

May, 1994 fie

Copyright 1994, Lokman Torun ACKNOWLEDGMENT

I would like to acknowledge Dr. Richard A. Bartsch for his guidance, help and understanding. I would also like to thank all faculty members of the Chemistry Department, whose guidance made this work possible. I would like to recognize the friendly co-workers of the Bartsch's group. I would like to thank University of Yuzuncu Yil for much of the financial support.

11 TABLE OF CONTENTS

ACKNOWLEDGEMENTS ii

LIST OF TABLES vi

LIST OF FIGURES vii

LIST OF SCHEMES ix

CHAPTER

I. INTRODUCTION 1

Discovery of Crown Ethers 1

Proton-Ionizable Crown Ethers 8

Crown Ethers with Naphthalene Subunits 15

Statement of Research Goals 19

II. SYNTHESIS AND COMPLEXATION STUDIES OF NOVEL

BENZOIC ACID CROWN ETHERS 20

Synthesis of Benzoic Acid Crown Ethers 62 and 63 20

^H-NMR Spectroscopic Results 25

Experimental Procedures 37

Instrumentation and Reagents 37

o-Methylbenzoyl Chloride (66) 38

t-Butyl o-Methylbenzoate (67) 38 t-Butyl 2-(Bromomethyl)benzoate (NBS method) (68) 39 iii t-Butyl 2-(Bromomethyl)benzoate (Brom 55P

method) (68) 39

Benzyl-protected Solketal (70) 40

3-(Benzyloxy)-1,2-propanediol (71) 40

2-(Benzyloxymethyl)-12-crown-4 (76) 41

Tetraethyleneglycol Ditosylate (72) 42

2-(Benzyloxymethyl)-15-crown-5 (73) 42

Hydroxymethyl-15-crown-5 (74) 43

Hydroxymethyl-12-crown-4 (77) 44 t-Butyl 2-[ (0xymethyl-15-crown-5)methyl] benzoate (79) 44 t-Butyl 2-[(0xymethyl-12-crown-4)methyl] benzoate (78) 45

2-[(Oxymethyl-12-crown-4)methyl]benzoic acid (62) 46

2-[(0xymethyl-15-crown-5)methyl]benzoic acid (63) 47

General Procedure for Preparation of Sodium, Potassium, Rubidium and Cesium Crown Ether Carboxylates 47

Preparation of Lithium Crown Ether Carboxylates 48

III. SYNTHESIS AND STRUCTURE OF DI (1,8-NAPHTHYL) CROWN ETHERS 4 9

Results and Discussion 50

Synthesis of Bis-1,3-(8-hydroxy-l-naphthoxy) propane (104) 50

Synthesis of sym-Di(1,8-naphtho)-16-crown-4 (99) and sym-Methylene-di(1,8-naphthyl)-16- crown-4 (100) and the Solid State Structure of Crown Ether 100 52

IV Attempted Synthesis of sym-(Hydroxy)di (1,8-naphtho)-16-crown-4 (113), sym-(Keto) di (1,8-naphtho)-16-crown-4 (115) and sym- (Dimethylene)di(1,8-naphtho)-16-crown-4 (116) 58 Summary 62 Experimental Procedures 64 1,8-Dihydroxynaphthalene (102) 64 Monobenzyl-protected 1,8-Dihydroxynaphthalene (106) 64 Bis-1,3-(8-Hydroxy-l-naphthoxy)propane (104) 65 Dimesylate of 1,3-Propanediol (108) 66 sym-(Methylene)dinaphtho-16-crown-4 (100) 66 Di(1,8-naphtho)-16-Crown-4 (99) 67 REFERENCES 69 LIST OF TABLES 1. Metal cation and crown ether cavity diameters 7 2. Chemical shifts (5), changes in chemical shift (A5), and the chemical shift differences (AD) for the benzylic protons of crown ether carboxylic acids 62-64 and their alkali metal salts 29

VI LIST OF FIGURES 1. Illustration of the template effect 4 2. Illustration of typical cation/ligand arrangements in crystalline crown ether complexes 8 3. Illustration of metal ion complexation by a proton-ionizable crown ether 10 4 Some examples of proton-ionizable crown ethers 12 5. Some examples of naphtho- and dinaphtho-crown ethers. 16 6. Equilibration of enantiomeric conformations of l,5-naphtho-22-crown-6 (55) 18 7. Proton-ionizable crown ethers that may exhibit an AB pattern when they complex with alkaline metal cations 20

8. Preparation of alkali metal salts for ^H-NMR study 27 9. The change in chemical shift of the benzylic hydrogens in going from the lariat ether carboxylic acid to the corresponding alkali metal lariat ether carboxylate as a function of radius of the alkali metal cation 30 10. Crown ether analogous of 62-64 33 11. An illustration of the complexes 34 12. Crystal structure of simi-methylanedinaphtho-16- crown-4 (100) 57

Vll LIST OF SCHEMES

1. Synthesis of dibenzo-18-crown-6 (8) by Pedersen 2

2. Five general methods for the synthesis of crown ethers 5

3. Synthesis of bromo t-butyl ester 68 22

4. Synthesis of hydroxymethyl crown ethers 74 and 77 23

5. Synthesis of crown ether carboxylic acids 62

and 63 2 6

6. Synthesis of intermediate 104 51

7. Synthesis of dinaphtho-16-crown-4 99 53

8. Synthesis of 1,8-naphtho-8-crown-2 (109) 54 9. Synthesis of sym-methylenedinaphtho-16-crown-4 (100) 55

10. Attempted synthesis of methylenedinaphtho-16- crown-4 100 by use of a LiH-THF base-solvent system 55

11. Attempted synthesis of sym-(Hydroxy)di(1,8- naphtho)-16-crown-4 (113) 59

12. Attempted synthesis of ketodinaphtho-16-crown-4 (115) 61

13 Synthesis of methylene-1,8-naphtho-8-crown-2 (111)63

Vlll CHAPTER I INTRODUCTION

Discovery of Crown Ethers Although the first crown ether 1 was reported in 1937, the fascinating aspects of cyclic polyethers were not appreciated until after the accidental rediscovery of crown ethers by Pedersen in 1967-1'2 The first "accidental" crown ether was dibenzo-18-crown-6 (2). Pedersen was attempting to synthesize an acyclic phenolic ligand to study the catalytic properties of the vanadyl ion VO+2. The desired

product of the reaction was bis-[2-(o-hydroxyphenoxy] ethyl ether (8) (Scheme 1) . However, he did not purify the product obtained from the first step, which is protection of catechol (3) with dihydropyran (4). Therefore about 10% of the catechol was left unprotected. The second step involved the reaction of this unpurified mixture with OH + H+, EtjO OH O 4

1-butanoI

H+ CH, OH

+ O R ^ "O O o

o o o

Scheme 1: Synthesis of dibenzo-18-crown-6 (2) by Pedersen^'^ bis-(2-chloroethyl) ether (6) under basic conditions in 1- butanol to give 7. Hydrolysis under acidic conditions gave desired compound 8. In addition to 8, Pedersen isolated a 3 white solid from an "unattractive goo." The isolated white crystalline compound was identified as the cyclic polyether 2. Pedersen named such cyclic polyether compounds "crown ethers" due to their crown-like shape. Pedersen prepared more than 60 crown ethers which show interesting physical properties.^'^ Pedersen developed five general synthetic methods which were based on catechol or substituted catechols as reactants.2 The usual solvent for these reactions was 1- butanol. The methods are shown in Scheme 2 where R, S, T, U, V, and W represent bifunctional organic groups. Method II is the most versatile route for the preparation of compounds containing two or more benzo groups. It also gives the highest yields.^

A notable feature is that surprisingly good yields of the cyclic polyethers may be obtained without using high dilution techniques (0.1 mole in 300-500 ml of solvent) .'^'5'^ The reason high dilution is not needed is due to a "template effect" (Figure 1).'^'8 This shows a favoring of the intramolecular reaction by such a template effect, complexation of acyclic polyether with cations to bring the two chain ends into close proximity- This is a favored and very useful method for improving product yields in crown ether synthesis. 5'^'^'^"^ The template effect has been studied by Mesci and co-workers.18,19 They Method I 2NaOH OH Cl-R-Cl O R OH O

Method II ,OH HO. 2NaOH O^T--o. Cl-T-CI O o^s^o O-^S-0'

Method m OH 4NaOH ,o^u-o. 2 Cl-U-CI Q Q OH ^o—u-o"

Method IV ,OH ,o^v^o. 2NaOH Q Q O-^^^Cl ^o-^v^o"

Method V H2 (l(X)0-1500psi) ,CKW--O. ruthenium dioxide Q • dioxane ^o-^w-o"

Scheme 2: Five general methods for the synthesis of crown ethers used the Okahara procedure^^'^i^ 22 ^o study cyciization yields of differentpolyethylene glycols in the presence of sodium, potassium and cesium cations. They found that the highest yielding reactions were for the formation of the 15-crown-5, 18-crown-6 and 21-crown-7 with sodium, potassium and cesium cations, respectively. This is expected from the principle of size complementary.8'23 Thus the cavity sizes of 15-crown-5, 18-crown-6 and 21-crown-7 best match the diameters of sodium, potassium and cesium cations, respectively. In a few cases cesium gives very good yields of cyciization products.^3

OH OH I c ^cr I ^O' V^° o o.

Figure 1: Illustration of the template effect

Pedersen found that a crown ether is capable of providing cation stabilization or solvation within its cavity, which is defined by the cyclic array of oxygen atoms. In the complex between a cation and an organic complexing agent, the cation is held by ion-dipole interaction between the cation and electron-rich oxygen atoms. Crown ether molecules complex not only with metal 6 cations but also organic species, such as diazonium ions^^ and primary and secondary alkyl ammonium salts.25,26 Although many crown ethers are sparingly soluble in methanol, they become quite soluble in the presence of appropriate metal salts. While trying to explain the unusual solubility characteristics of this new class of compounds, Pedersen proposed several factors which influence the stability of a crown ether-metal salt complex: (i) the relative size of the cation and the cavity of the crown ether ring; (ii) the number of oxygens in the crown ether ring; (iii) coplanarity of the oxygens; (iv) symmetrical placement of the oxygens; (v) basicity of the oxygen atoms; (vi) steric hindrance in the crown ether ring, which may hinder formation of the complex; (vii) the tendency of the ion to associate with the solvent; and (viii) the electrical charge on the ion.2 The strength of complexation between the crown ether "host" and the cationic "guest" depends on the cavity size of the polyether ring and the relative size of the cation (Table 1).27,28,29,30 Best complexation occurs when the size of the cation matches well with the size of the crown ether cavity. Dibenzo-18-crown-6 (8) complexes with thiocyanates in the following stoichiometry: potassium,1:1; rubidium,1:1 and 2:1, and cesium, 2:1 and 3:2^1 The complex with a 2:1 stoichiometry has a structure consisting of (crown ether)- (cation)-(crown ether) and that of the 3:2 complex a (crown Table 1: Metal cation and crown ether cavity diameters

Metal Cation Diameter (A) Crown ether Diameter(A)

Li + 1.20 12-crown-4 1.2

Na+ 1.90 14-crown-4 1.2-1.5

K+ 2.66 15-crown-5 1.7-2.2

Rb+ 2.96 18-crown-6 2.6-3.2

Cs + 3.83 21-crown-7 3.4-4.3

Ag+ 2.52

Mg+2 1.30

Ca+2 1.98

Sr+2 2.26

Ba+2 2.70

ether)-(cat ion)-(crown ether)-(cation)-(crown ether)

structure. If the cation is larger than the cavity a

"sandwich" structure is preferred for the 2:1 complex in which two relatively flat large molecules are held together by a small sphere, particularly when the attractive forces are located on the sphere and toward the centers of the

large molecules.^'^8 similarly, the structure of the 3:2 complex consists of three molecules of the polyether arranged flatwise and each separated from the next by a cation. The term "club-sandwich" is used for the 3:2 complexes.3/28,31,32 on the other hand, a cyclic polyether with an extremely large cavity may accommodate two cations within its cavity.^3,34 some of these geometries are illustrated in Figure 2.

Figure 2: Illustration of typical cation/ligand arrangements in crystalline crown ether complexes .28,35,36,37,38

Proton-ionizable Crown Ethers Although crown ethers exhibit good complexing capabilities with various inorganic and organic cations, there is a great deal of effort to improve stability and selectivity of the host-guest complexes.

Crown ethers with a proton-ionizable side arm are efficient reagents for the solvent extraction. These crown ethers have a distinct advantage compared with neutral 9 crown ethers for transporting a metal cation from the aqueous phase into the organic media. For the latter the electron-rich interiors and lipophilic exteriors of crown ethers help them solubilize a metal ion in an organic medium. The complex must have the counteranion present to maintain electroneutrality. One problem with the stability of the complex in an organic medium is the counteranion. If the counteranion is a hard anion, it will not be solvated well in a non-polar organic solvent.28 However, if the counteanion is a soft anion, such as thiocyanate, perchlorate, or picrate, a complex can form which is soluble in a non-polar organic solvent. However in most industrial applications, hard anions, such as chloride, nitrate and sulfate are involved. Thus it is difficult to extract a metal ion into the organic phase in the presence of such anions. Therefore even if a complex is formed, it tends to stay in the aqueous phase in a solvent extraction system.28,39,40

One solution to this problem is to control the nature of the anion by attaching an ionizable pendant arm directly to the macrocyclic ring, thereby eliminating the need for extraction of a counteranion (Figure 3) . The ionizable substituents are usually carboxylic acid, sulfonic acid, phosphonic acid monoalkyl ester or phosphonic acid groups which are known to form stronger complexes with mono- or multi-valent cations than their neutral counterparts.'^^ 10 To have selective complexation of one guest over another with proton ionizable crown ethers, there are several structural variations which must be considered: (i) the ring size of the crown ether; (ii) the length of "arm" which connects the proton-ionizable group to the polyether ring; (iii) the attachment site(s) for lipophilic group(s); (iv) the rigidity of the polyether ring; and (v) the identity of the proton ionizable group. "^2-44

Figure 3: Illustration of metal ion complexation by a proton-ionizable crown ether

Crown ethers with smaller ring sizes will be selective for smaller cationic species and those with larger ring sizes will be selective for larger cations.'^^'''^ Crown ethers with a pendant proton-ionizable group show good stability constants when the side arm is long enough for a good complexation.^"^ The lipophilicity of the molecule is also important in the design of crown ethers. Lipophilic groups are necessary to retain the ionized crown ether in the organic phase and to protect the proton-ionizable crown ether from loss into the aqueous phase upon deprotonation. 11 The rigidity of crown ether is another important factor which influences extraction selectivity. Aromatic subunits reduce the basicity of benzylic ethereal oxygens of the macrocyclic ring through electron delocalization, but help to preorganize the ligand by providing rigidity. Bartsch and co-workers have synthesized many kinds of proton-ionizable crown ethers, such as 9-12, 17-21, 24 (Figure 4). In the benzoic acid crown ether compounds 9- 12, the ionizable groups projects directly into the cavity of the macrocyclic polyether ring. This reduces of the size of the cavity. For the chiral binaphthyl crown ethers 13-16 synthesized by Cram, the carboxylic acid groups are ionized to give the corresponding dicarboxylate salts when they come into contact with basic solution. In compound 14, a 1,1'- binaphthyl group substituted in the 2,2'- positions with oxygens provides a unit that possesses a useful shape. It is conformationally stable and possesses a C2 axis that can render two faces of an attached macrocyclic ring stereochemically equivalent to each other. The substituents in 3- and 3'-positions of the unit provide side arms, one that extends across one face and one that extends across the other face of the polyether ring. In compounds 17-21, 23-29, 31-39 the ionizable group can extend over the cavity and participate in complexation.50- 52,55,57,60 Crown ether phosphonic acid monoethyl esters 25-28 have the same polyether ring and lipophilic group as 12

/ \,

48 i49 9 13 0 A = B = CH2OCH2CO2H 10 14 1 A = B = CH2OCH2CO2H 11 15 0 A = CH20CH2CO^H, B = H 12 16 1 A = CH20CH2CO^H, B = H

H O ^COzH

o o.

o O (CH3)3C-^^ C(CH3)3

50-52 17 18 50-52 19

Figure 4: Some examples of proton-ionizable crown ethers. 13

C«8"1H 7 H O- -CO2H H17C8. 0-^''^COoH H O O ,0 Ov

O O Q a ^O O'

o- 50-52 50-52 20 21

CR8J^1H 7 C02H O HO2C,, /O O.^ ^CO,H

HOjC^ o or ''CO2H .0. or°-^ 53 55-57 22 23

55-57 24

Figure 4: (continued). 14

O O—(CH2)—P—OEt H2iCio-^/OCH2C02H OH

(CH3)3C C(CH3)3 -O o~

O O

-0~ 50 n 1 57,58 25 29 26 2 27 3 28 4

H21C10

60 n 31 1 32 2 33 3 34 4 35 5 36 6 37 7

Figure 4: (continued). 15

H 0(CH2)3SC^H ro r^

55-57 39

Figure 4: (continued). does crown ether 19 but differing side arm lengths. Crown ether 30 has two carboxylic groups which converge on each other to provide an ideal hydrogen bonding arrangement,^® Crown ethers 31-37 contain a benzoic acid ionozable side arm represent another type of lipophilic crown ether carboxylic acid which provide useful reagents for extraction of alkali metal and alkaline earth metal cations- These crown ethers are sufficiently lipophilic to remain in the organic phase without detectable loss. Extraction selectivities with lipophilic crown carboxylic acids 31-34 were found to be: Li+ > Ma* > K* > Rb+ > Cs+; Ma+ > K* > Kb+ > Li+ * Cs+; K* > Rb* > 11+ > Cs* > ]Ma+; Cs+ > Kb* > K* > Li* > Ma*, respectively-*® Compound 3 9 contains a sulfonic acid function as the ionizable group. 16 Crown Ethers with Naphthalene Subunits A number of crown ethers with naphthalene rings has been synthesized^^'^^ (Figure 5) to study the interaction of the aromatic system and a cation complexed by these crown ethers.^^ Some of the studies focused on the response of naphthalene photoexcited states to complexed and, therefore oriented, alkali metal cations. X-ray structure determinations of 52"^! show it to prefer chiral conformations in the solid state, as does 43 when complexed with potassium thiocyanate. However, the enantiomeric conformations of 40-43, 49, 51-52, 58 and 57 are interconverted by relatively facile changes in the dihedral angles around the macrocyclic ring.^2 Experimental evidence for equilibration of the enantiomeric conformations of naphthocrown ethers 54 and 55 is given by the ^H-NMR signals of the naphthalenic hydrogens (H^ and HB in Figure 6). When the ethyleneoxy chain is over a face of naphthalene ring, one hydrogen (H^) on each naphthalene carbon is directed in the general direction of the peri hydrogen, and the other (HB) is directed away from the naphthalene ring. Rope skipping of the polyether linkage would interchange the magnetic environment of the A and B hydrogens (Figure 6) . Equilibration of the enantiomeric conformations of 55 has an energy of activation of 6.3 kcal/mol, while the corresponding barrier for 54 is greater than 21 kcal/mole.^^ 17

62 "• 40 1 El R2 62 63-66 41 2 H 62 43 H 42 3 Br 44^^-^^ H Br 45''-'' Br r~\

viy n. 31,72 46 X Jl 1 62,70 "~ 31,72 49 O 0 47 2 31,72 50 ^^•^'^ S 48 1 3 5^62,70 Q 1 52 ^''^° O 2

67,68 53

Figure 5: Some examples of naphtho- and dinaphthocrown ethers. 18 r^ r^

62 U 54 0 55

62 58 62 57

Figure 5: (Continued).

Compounds 46-48 were synthesized in very good yields by a new method developed by Bartsch and co-workers. "^2 This method involves the use of cesium carbonate as the base in acetonitrile. With this method, crown ethers 46, 47, and 48 were prepared in 77, 80 and 54% yields, respectively. 19

Figure 6: Equilibration of enantiomeric conformations of l,5-naphtho-22-crown-6 (55).^2

The previously reported yields for naphthocrown ethers 46

and 47 were 63 and 53%, respectively."^^

Statement of Research Goal

There has been a great deal of interest in developing new complexing agents. To this end, numerous research projects have been undertaken to design and synthesize macrocyclic polyethers. New and more efficient methods have been developed.

The first objective of this research is to synthesis new proton-ionizable crown ethers for complexation of monovalent cations. To probe the degree with which the ionized side arm and the macrocyclic ring participate in 20 coordination of alkaline metal cations, ^H-NMR and 13C-NMR spectroscopy will be utilized for these compounds. Crown ethers with 2,3-naphthalene units^"^'^^ have been made. The second objective deals with the synthesis of a new type of dinaphthocrown ether based upon 1,8-naphthalene units. Molecular modelling suggests that the preparation of 1,8-dinaphtho crown ethers with three-carbon bridges should be feasible. These new dinaphthocrown ethers bear a structural relationship to the well-studied dibenzocrown ethers. CHAPTER II SYNTHESIS AND COMPLEXATION STUDIES OF NOVEL BENZOIC ACID CROWN ETHERS

This chapter includes the synthesis and complexation studies of the novel benzoic acid crown ethers 62 and 63.

Synthesis of Benzoic Acid Crown Ethers 62 and 63 It was found that benzylic protons in crown ethers 59- 61 and 64 (Figure 7) give a sharp singlet in the ^H-NMR in their unionized forms, but may give an AB pattern when they are transformed into the corresponding alkali metal phosphonate and carboxylate salts. "^^f "^5 The cations bring

r^ o

oc» fO OH V

n 59^^ 1 62 1 74 60 2 63 74 74 61 3 64

Figure 7: Proton-ionizable crown ethers that may exhibit AB patterns when they complex with alkaline metal cations.

21 22 the macrocyclic polyether ring and the ionizable side arms together and make a complex. In the complex, the ionized side arms in the crown ethers 59-61 and 64 may lose their flexibility. Therefore, the benzylic protons in the complexes may be in very different chemical environments from one another. In each case each proton will give rise to an absorption and each absorption appears as a doublet. To further investigate this phenomena, two new crown ether carboxylic acids 62 and 63 were synthesized. High field IH-NMR spectroscopy was used to probe the complexation of alkali metal cations by these crown ether carboxylic acids. Adaptations of previously reported procedures'^^'"^5 were used to synthesize the crown ethers 62 and 63. The synthetic route involves preparation of the subunits 68, 74 and 77 (Schemes 3 and 4). Subunit 68 was then coupled with crown ether alcohols 74 and 77.

Acid chloride 66 was obtained by reaction of o-toluic acid (65) with thionyl chloride at 80oc (Scheme 3) . The acid chloride 66 was then converted into t-butyl ester 67 by reaction with t-BuGH in the presence of pyridine. Bromo ester 68 was obtained with two different reagents, N- bromosuccinimide (NBS) and N,N'-dibromo-5,5- dimethylhydantion (Brom 55 P). Photochemical bromination of t-butyl ester 67 with NBS in carbon tetrachloride gave a 61% yield of bromo t-butyl ester 68 and with Brom 55P a 59% 23 yield was realized. TLC analysis and the ^H-NMR spectrum of the crude product obtained by both methods indicated that some unbrominated starting material and dibrominated t-butyl ester were also present. The mixtures were purified by column chromatography to give 68.

OH socio

65 66 t-BuOH Pyridine

NBS or Brom 55 P CCI4 ho) 68 67

Scheme 3: Synthesis of bromo t-butyl ester 68.

Crown ether alcohols 74 and 77 were synthesized by the procedure reported by Goo'^^ (Scheme 4) . Benzyl-protected

Solketal (70) was prepared in 89% yield by the reaction of

Solketal (69) with benzyl bromide and KOH in benzene followed by high vacuum distillation of the resulting mixture. Refluxing of 70 with H2SO4 gave the key intermediate 71 in 82% yield. 24

^OH BnBr OBn KOH 69 k 70

H2SO4

OBn

^A -0 ,0 Ov OBn ^OBn o o ^o O" 73 V y 76

H2 H2 Pd/C Pd/C r^ -0 .0 O. OH ^OH O o ^O O" ^_y 74 77

Scheme 4: Synthesis of hydroxymethyl crown ethers 74 and 77. 25

Ditosylate 72, which was required for the diol- ditosylate cyciization, was prepared by a new tosylation procedure reported by OuchL^^ Ditosylate 72 was synthesized in high yield by use of NaOH as the base and THF-water as the solvent combination. This method gave the desired product in 90% yield.

The synthetic routes to (benzyloxy)methyl crown ethers 73 and 76 are depicted in Scheme 4. Reaction of diol 71 with NaH in THF and ditosylate 72 under an inert atmosphere gave 2-(benzyloxymethyl)-15-crown-5 (73). Because polymerization is a competitive side reaction, specialized reaction conditions were employed. This was achieved by maintaining low and equal concentrations of each reactant during the course of the reaction. For convenience, the diol 71 and the ditosylate 72 were dissolved in the same amount of THF. The two solutions were mixed and drawn into the same syringe. This solution was then added slowly over several hours with a syringe pump to a large volume of THF which contained the NaH. This gave a 44% yield of desired product 73. This hydroxymethyl crown ether was also obtained in 39% yield by the same method but with DMF-THF (4:1) as the solvent"^5.

Crown ether 77 was prepared as reported by Okahara and coworkers'^'^ from reaction of diol 71 with 1,2-bis (2-chloro- ethoxy)ethane (75) and Li/LiBr/t-BuOH in a 50% yield. 26 Hydrogenolysis of the benzyl-protected crown ethers alcohols 73 and 76 was achieved with palladium on carbon and a trace amount of p-toluenesulfonic acid as a catalyst in 95% ethanol to provide hydroxymethyl-15-crown-5 (74) and 12-crown-4 (77) in 80 and 92% yields, respectively. The coupling with bromo t-butyl ester 68 after reaction of hydroxymethyl-12-crown-4 (77) with NaH in THF gave a 70% yield of the t-butyl benzoate 12-crown-4 compound 78 (Scheme 5). Similarly the use of hydroxymethyl-15-crown-5 (74) gave a 76% yield of crown ether ester 79. Conversion of 78 and 79 to the corresponding crown ether benzoic acids 62 and 63 was achieved in 55% and 56% yields, respectively, with potassium t-butoxide in toluene at reflux under nitrogen. The yields of crown ether benzoic acids 62 and 63 were lower than anticipated. It is believed that the low yield resulted from the complex formation with potassium t- butoxide. The structures of crown ether benzoic acids 62 and 63 were verified by IR and ^H-NMR spectroscopy and by elemental analysis.

iH-NMR Spectroscopic Results Chemical shifts (5) and the chemical shift difference (A5) for the AB pattern when exhibited by the diastereotopic benzylic protons in crown ether carboxylic acids 62 and 63 and their alkali metal cation salts are 27

O

O Br 68 .0 O^^ ( > OH NaH NaH \ I (. J THF THF\ ^^^''^^ 79

,/^A o. o

o .0 O X) O' o o \^ O o 78 79

1) t-BuOK 1) t-BuOK Toluene Toluene 2) H3O+ 2) H3O+

r^ ./^^. O. o

Q .0 O SD O' o o

OH OH 62 63

Scheme 5: Synthesis of crown ether carboxylic acids 62 and 63. 28 listed in Table 2. The chemical shift values for the AB system are based on calculations for the center of gravity ."^8

The alkali metal salt complexes 81-84 and 86-89 were prepared (Figure 8). Acid 62 or 63 was dissolved in CDCI3 and stirred for one hour at room temperature in the

V. 1)M2C03 ^ CDC13 2) Filter

0-M+

M= Na, K, Rb, Cs

R n M"^ n M+ 62 1 80'^ 1 Li+ 85 2 Li+

63 81 1 Na+ 86 2 Na^

82 1 K+ 87 2 K+

83 1 Rb+ 88 2 Rb^

84 1 Cs+ 89 2 Cs+

Figure 8: Preparation of alkali metal salts for ^H-NMR study, a) The lithium carboxylates were prepared by a different method. presence of the anhydrous alkali metal carbonates. The resulting solution was filtered through a short bed of Celite directly into the NMR tube. All ^H-NMR spectra of 29

Table 2:. Chemical shifts, 8, changes in chemical shift, A5, and the chemical shift difference, Ao), for the benzylic protons of crown ether carboxylic acids 62-64 and their alkali metal salts

Compound 8(ppm^^ A6(ppm)t Al) fHz^C 62 4.91 d 80 4.73 0.21 e 81 4.85 0.09 11.44 82 4.80 0.14 32.78 83 4.81 0.13 e 84 4.82 0.12 e 63 4.96 d 85 4.79 0.17 29.46 86 4.88 0.08 24.77 87 4.93 0.03 43.44 88 4.92 0.04 17.33 89 4.93 0.03 17.86

6474 4.94 e Li 4.92 0.02 e Na+ 4.84 0.10 45.92 K+ 4.89 0.05 56.94 Rb+ 4.94 0.00 63.17 Cs + 4.96 -0.02 21.50 a. Chemical shift for the singlet or the average chemical shift for benzylic protons in the AB pattern. b. The difference in the chemical shift from the corresponding acid. c. Values were calculated based on the center of gravity for the AB quartet. d. The peak appears as a sharp singlet in the ^H-NMR spectrum. e. The peak appears as a broad singlet in the ^H-NMR spectrum. 30 the metal complexes were measured with an IBM-AF-300 spectrometer. The lithium crown ether carboxylates were prepared by dissolving the crown ether carboxylic acid 62 or 63 in dry THF and cooling the solution to -78oc. One equivalent of n-butyllithium in THF was added and the solution was stirred for 30 minutes at -7 8°C. A few drops of water were added. The solvent was removed in vacuo and the solid residue was dissolved in dichloromethane. The dichloromethane solution was dried, filtered, and evaporated in vacuo to give the lithium carboxylate 80 or

85. The ^H-nuclear magnetic resonance data are presented in Table 2 for the diastereotopic benzylic hydrogens of 12- crown-4 and 15-crown-5 carboxylic acids 62 and 63 respectively, and for their alkali metal cation salts 80- 89. Also listed in Table 2 are corresponding data reported by Robinson'^'' for the 18-crown-6 carboxylic acid 64 and its alkali metal carboxylates. The data includes the chemical shift for benzylic hydrogens obtained directly from the singlet or calculated as the center of the AB pattern. The next column gives the change in chemical shift (A5) for the benzylic hydrogens in going from the crown ether carboxylic acid to the designated alkali metal crown ether carboxylate. The final column shows the calculated difference in chemical shifts for the benzylic hydrogens in 31 the AB pattern, Av, when such a pattern was observed.

These values were calculated by the "center of gravity- method. 78

The change in chemical shift of benzylic hydrogens as a function of identity of the crown ether ring size and the radius of the alkali metal cation for the alkali metal crown ether carboxylates is shown in Figure 9. It is readily evident that the patterns are quite different for

E Q. CL to <

Radius (A)

Figure 9: The change in chemical shift of the benzylic hydrogens in going from the lariat ether carboxylic acid to the corresponding alkali metal lariat ether ether carboxylate as a function of radius of the alkali metal cation.

the 12-crown-4, 15-crown-5, and 18-crown-6 carboxylates. As a whole the change is chemical shift values in going from crown ether carboxylic acid 62 to its carboxylates is 32 larger than those for the 15-crown-5 and 18-crown-6 analogues. The change in chemical shift value indicates a variation in electron density at the benzylic position when the crown ether carboxylic acid is transformed into the carboxylate salt. Since the crown ether ring size in 62 is too small to accommodate even lithium cations, the alkali metal cations must perch on the metal ion to interact with ether oxygen of the side arm and decrease its electron density which is felt in turn by the benzylic carbon and its hydrogens. The upfield shifts noted for benzylic hydrogens in the 12-crown-4 carboxylates 80-84 are consistent with such electron withdrawal from the ether oxygen in the side arm by the metal ion. When the polyether ring is expanded in the 15-crown-5 carboxylates 85-89 the change in chemical shift for going from the crown ether carboxylic acids to the crown ether carboxylates is generally smaller than noted with the 12-crown-4 analogues. This suggests lesser interaction of the complexed alkali metal cation with the ether oxygen in the side arm in the former. In a continuation of the trend, the change in chemical shift values are lower yet for the carboxylates derived from the 18-crown-6 carboxylic acid 64. When the side arm is flexible, the benzylic hydrogens are magnetically equivalent on the time scale of the nuclear magnetic resonance measurement and a singlet is observed. Thus the benzylic hydrogens of crown ether 33 carboxylic acids 62 and 63 appear as sharp singlets. For the corresponding 18-crown-6 carboxylates, Robinson reported a broadened singlet which may indicate hydrogen bonding of the carboxylic acid group of the side arm with the oxygens of the crown ether ring.74 if rotation is restricted due to simultaneous interaction of the carboxylate group in the side arm and the crown ether ring oxygens with the metal ion, the diastereotopic benzylic hydrogens are no longer magnetically equivalent and split each other to give an AB pattern. For the 12-crown-4 carboxylates 80-84, broadened singlets are observed when the complexed alkali metal cation is lithium, rubidium, or cesium (Table 2). Thus the alkali metal cation is associating with either the carboxylate group of the side arm or with the oxygens of the crown ether ring. On the other hand, for the sodium and potassium carboxylates distinct AB pattern are found. If the magnitude of the chemical shift difference can be taken as a measure of the degree of rotational restriction of the side arm, then there is less side arm flexibility in the potassium 12-crown-4 carboxylate 82 than in the sodium salt 81. Considering now the alkali metal 15-crown-5 carboxylates 85-89 for which pronounced AB patterns are observed in all cases. Due to its larger size, a 15-crown- 5 ring is expected to be a stronger complexing agent for 34 all alkali metal cations than a 12-crown-4 ring. Simultaneous coordination of all five alkali metal cation species by both the carboxylate group in the side arm and the oxygens of the crown ether ring is evident. Of the alkali metal cations the difference in chemical shifts of the diastereotopic benzylic hydrogens is greatest for potassium ion. This metal ion is slightly too large to fit within the 15-crown-5 ring. When the metal ion perches on the crown ether ring oxygens, the carboxylate group in the side arm can easily participate in its coordination. In like fashion Robinson^^ found that the difference in chemical shifts for alkali metal carboxylates of the 18- crown-6 carboxylic acid 64 was greatest for rubidium ion. Once again the alkali metal cation which is slightly too large to fit within the crown ether cavity gives the greatest restriction of the side arm.

To better understand how the side arm and size of the crown ether ring influence the stability of the crown ether metal ion complex, I suggest that crown ethers with different ring sizes, such as 15-crown-4, 16-crown-5 and 19-crown-6, and different length side arms, such as -OCH2C6H4CO2H and -CH2CH2OCH2C6H4CO2H (Figure 10) should be synthesized. The anionic oxygen in the side arm of the crown ethers 62-64 is attached to the macrocyclic ring with seven atoms (Figure 11) . This is a relatively long side arm. Therefore these crown ethers may not give good 35

n U U 90 1 93 1 96 1 91 2 94 2 97 2 92 3 95 3 98 3

Figure 10: Crown ether analogues of 62-64, complexes. It is possible that the degree of coordination of the anionic oxygen with alkali metal cation decreases with increasing length of the side arm, resulting in poorer complexation. The anionic oxygen of the side arm is attached to the macrocyclic ring with six atoms in compounds 90-92, seven atoms in compounds 93-95 and eight atoms in compound 96-98.

To study this phenomena more systematically and obtain general information, a comparative study should be made between the alkali metal carboxylates of crown ethers 62-64 36 and the alkali metal carboxylates of crown ethers 90-98 in terms of the chemical shift (5) the change in chemical shift (A5) and the difference in chemical shift (A\)) .

(Y° o

.':o-

Figure 11: An illustration of the complexes.

Figure 11 illustrates the distance between alkali metal cation and the anionic oxygen of the side arm. All complexes represent the complexation of crown ethers 62-64 and 90-98 with alkali metal cations. Investigation of crown ethers 90-98 which contain a three-carbon bridge in the 37 macrocycle and varying lengths of the side arm will provide a better understanding of the optimal length of the side arm for the complexed metal cation and the optimal size of the crown ether ring for the complexed metal cation.

Experimental Prncerinrpp

Instrumentation and Reagents

Melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected. Proton and '^^C NMR spectra were obtained with an IBM AF-200 or AF-300 spectrometer. The chemical shifts are expressed in parts per million (ppm) downfield from tetramethylsilane. Infrared spectra were obtained on a Perkin-Elmer Model 1600 FT-IR spectrophotometer on NaCl plates and absorbances are given in wavenumbers (cm"^) . Starting materials and solvents were reagent grade and used as received unless stated otherwise. Dry solvents were prepared as follows: pyridine was dried over KOH pellets; N,N-dimethyformamide (DMF) and acetonitrile were dried over 4A molecular sieves or K2CO3; tetrahydrofuran (THF) was distilled from sodium; and tert-butvl alcohol was distilled from calcium hydride. Thin layer chromatograpy (TLC) was performed with either Analtech Alumina GF or Silica GF prepared plates. The plates were precoated with 250 mm silica gel or alumina respectively. Column chromatograpy was performed using 38 either alumina (80-200 mesh) or silica gel (60-200 mesh) from Fisher Scientific. Elemental analyses were done by Desert Analytics of Tucson, Arizona. n-MPl-hy1benzovl ChlnrirJP fgg^H

o-Toluic acid (5.00 g, 36.7 mmol) was suspended in dry benzene (30 ml) and oxalyl chloride (9.32 g, 73.50 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 14 hours under nitrogen. The solvent and excess oxalyl chloride were removed in vacuo to give a quantitative yield of the acid chloride as a light green oil. IR (neat): 1773 (C=0) cm"!. t-Butyl o-Methylbenzoate (61)21 Pyridine (8.90 ml, 110 mmol) and i.-butyl alcohol (10.41 ml, 110 mmol) were added dropwise to a flask containing o-methyl-benzoyl chloride (37.60 mmol). After stirring overnight at room temperature, a white precipitate had formed. Dichloromethane was added to the flask and the organic solution was washed with 5% aqueous HCl followed by water. Drying over Na2S04 followed by passage of the crude product through a short bed of alumina using petroleum ether as eluent gave the desired ester (6.02 g, 85%) as a colorless oil. IR (neat): 1718 (C=0) cm"!- 1H NMR (CDCI3) : 5 1.59 (s, 9H), 2.57 (s, 3H), 7.18-7.24 (m, 2H) , 7.33 (dd,

IH), 7.83 (dd, IH). 39 ^-pni-yT 2-(Bromomethvnbpn7.nafP mRS mPt-hnd^ ^68)^

t-Butyl o-methylbenzoate (1.68 g, 8.76 mmol) was dissolved in carbon tetrachloride (20 ml) . N- Bromosuccinimide (1.81 g, 10.52 mmol) and benzoyl peroxide (0.20 g) were added and the mixture was irradiated with a 500-watt tungsten lamp for 2 hours. The lamp was placed 2 inches from the flask. The reaction mixture was cooled to room temperature and washed with water. The organic layer was dried over MgS04 and the solvent was removed in vacuo to give a viscous oil. Chromatography on silica gel with carbon tetrachloride as eluent gave the monobrominated product (1.49 g, 61%) as a colorless oil. IR (neat): 1714 (C-0) cm-i iH NMR (CDCI3) : 5 1.62 (s, 9H) , 4.93 (s, 2H) ,

7.29-7.48 (m, 3H), 7.87 (dd, IH) .

t-Butyl 2-mromonie1-hynhpn7.nate (Rrom55P method)—(MI

t-Butyl o-methylbenzoate (1.68 g, 8.76 mmol) was dissolved in carbon tetrachloride (20 ml). N,N'-Dibromo- 5,5-dimethylhydantion (Brom 55P) (1.25 g, 4.38 mmol) and benzoyl peroxide (0.01 g) were added and the mixture was irradiated with a 500 watt tungsten lamp for 3 hours. The lamp was placed about 2 inches from the flask. The reaction mixture was cooled to room temperature and washed with water. The organic layer was dried over MgS04 and the solvent was removed in Vr^CUQ to give a viscous oil. Chromatography on silica gel with carbon tetrachloride as 40 eluent gave the monobrominated product (1.49 g, 59%) as a colorless oil. IR (neat): 1714 (C-0) cm-i 1H NMR

(CDCI3): 5 1.62 (s, 9H), 4.93 (s, 2H), 7.29-7.48 (m, 3H) ,

7.87 (dd, IH).

ppn7.y1-protected Snlketal CJQ)!^

Solketal (95.50 g, 0.72 mol), benzyl chloride (190.00 g, 1.50 mol) and KOH (85.00 g, 1.51 mol) were added to 500 ml of benzene in a 3-necked flask equipped with a mechanical stirrer, CaCl2 drying tube, condenser, and a Dean-Stark trap. The reaction mixture was refluxed for 4 8 hours. The resulting mixture was washed with 100 ml of water, 0.1 N

HCl, and 5% NaHCOs, and dried over Na2S04. The solvent was removed in vacuo and the residue was distilled under high vacuum. A colorless oil (148.97 g, 89%) was collected at

112 °C/0.4 mm Hg. Excess benzyl chloride (47 g) was recovered. ^H NMR (CDCI3) : 5 1.40 (d, 6H) , 3.40-3.60 (m,

2H) , 3.70-3.80 (m, IH) , 4.00-4.10 (m, IH), 4.25-4.35 (m,

IH), 4.60 (s, 2H), 7.20-7.35 (m, 5H)

3-men7.yloxy) -1, 2-prnpane(ii ol (71)^

Benzyl-protected Solketal (135.00 g, 0.60 mol) was added to 400 ml of 1.5 N H2SO4 and the solution was refluxed for 2.5 hours. The reaction mixture was cooled to room temperature, neutralized with 5 N NaOH and extracted with ethyl acetate (3 x 50 ml). The combined organic extracts 41 were dried over MgS04 and the solvent was removed in var.nn. The residue was distilled at 130OC/0.5 mm Hg to give 90.90 g (82%) of the desired product. IR (neat): 3400 (O-H) cm"!. IH NMR (CDCls): 5 3.05 (s, IH), 3.35 (s, IH) , 3.45-3.70 (m, 4H), 3.80-3.90 (m, IH), 5.00 (s, 2H), 7.35-7.45 (m, 5 H).

?- menzvloxvmethvl ) -1 ?-crnwn-4 ('J^)23.

Under nitrogen, lithium metal (1.14 g, 0.16 mol) was added to 300 ml of t-BuOH. The mixture was stirred at reflux for one hour and 3-(benzyloxy)-1,2-propanediol (10.00 g, 0.054 mol) was added dropwise. To the cloudy heterogeneous mixture, bis (2-chloroethoxy) ethane (10.28 g, 0.054 mol) was added followed by LiBr (4.96 g, 0.054 mol) and water (0.97 g, 0.054 mol). (LiBr-H20 would give better results.) The reaction mixture was refluxed for 2 weeks. After the solvent was removed in vacuo 30 ml of water was added to the residue. The mixture was neutralized with 6 N HCl and extracted with dichloromethane (3 X 50 ml) . The combined organic extracts were dried over MgS04 and evaporated in vacuo. The residue was chromatographed on alumina using hexane-EtOAc (4:1) as eluent to give 7.55 g (50%) of colorless oil product. IR (neat): 1106 (C-0) cm-l. 1H NMR (CDCI3) : 8 3.46-4.13 (m, 17H) , 4.54 (s, 2H) ,

7.30 (s, 5H). 42 Tg.tT'^f^t--hvlenealvcn1 ni i-nc;vi ^fP ^72)^

Sodium hydroxide (8.00 g, 0.20 mol) was dissolved in water (40 ml) and added to tetraethyleneglycol (15.00 g, 0.070 mol) in THF (40 ml). The mixture was cooled in an ice-bath with magnetic stirring. To the stirred mixture at 0-5 °C was added dropwise a solution of p-toluenesulfonyl chloride (24.30 g, 0.13 mol) in THF (40 ml) over 2 hours The solution was stirred at O-50C for an additional 2 hours and then poured into ice-water (200 ml) . The resulting mixture was extracted twice with dichloromethane. The combined organic extracts were washed with water and once with saturated aqueous NaCl solution and then dried over MgS04. After evaporation of the solvent in vacuo^ the ditosylate was purified by column chromatography on silica gel with dichloromethane as the eluent to give a colorless oil (24.46 g, 90%). IR (neat): 1354, 1175, (SO2), 1093 (C-

0) cm-l; iH NMR (CDCI3) : 8 2.44 (s, 6H) , 3.52-3.71 (m,

12H) , 4.12-4.16 (m, 4H) , 7.26-7.36 (m, 4H), 7.77-7.82 (m,

4H) .

2-(Benzyloxymethyl ^-15-r-rnwn-5 (73)^

Tetraethyleneglycol ditosylate (8.76 g, 2.00 mmol) was diluted to 100 ml with anhydrous THF. A 100 ml solution of 3-benzyloxy-l,2-propanediol (0.36 g, 2.00 mmol) in anhydrous THF was prepared similarly. The two solutions were mixed and taken up into a syringe. The mixed solution was added 43 with a syringe pump during 12 hours to a stirred mixture of NaH (60% dispersion in mineral oil, 0.96 g, 24 mmol) in 40 ml of THF at room temperature. After a total time of three days, the solvent was evaporated in vanno. To the residue was added dichloromethane and water and the mixture was extracted with dichloromethane. The combined extracts were dried over MgS04. After evaporation of the solvent in vaCUQ/ the residue was purified by column chromatography on silica gel with dichloromethane-ethyl acetate (1:4) as eluent to give 1.01 g (44%) of a colorless oil product. IR (neat): 1153-1060 (C-O) cm"!. iH NMR (CDCI3) : 8 3.30-3.70

(m, 21H), 4.34 (s, 2H), 7.0-7.14 (s, 5H) .

Hydroxymethyl-15-crown-5 (74)-^ To a solution of 2-(benzyloxymethyl)-15-crown-5 (4.40 g, 12.94 mmol) in 40 ml of 95% ethanol 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 50 lbs of hydrogen pressure for 24 hours. The mixture was filtered and the solvent was evaporated in vacuo. The residue was taken up in dichloromethane and the solution was dried over MgS04 Evaporation of the solvent and filtration of the residue through a short bed of alumina using dichloromethane as eluent gave a colorless oil (2.54 g, 80%). IR (neat): 3250 44 (O-H) cm-l; IH NMR (CDCI3): 8 2.25-2.35 (t,IH), 3.55-3.90 (m, 21H) .

Pydroxvmethvl-12-crown-4 (77^25

To a solution of 2-(benzyloxymethyl)-12-crown-4 (5.00 g, 24.27 mmol) in 40 ml of 95% ethanol was added 10% palladium on carbon (100 mg/g of crown ether) and a catalytic amount of p-toluenesulfonic acid monohydrate. The mixture was hydrogenated under 50 lbs of hydrogen pressure for 24 hours. The mixture was filtered and the solvent was evaporated in vacuo. The residue was taken up in dichloromethane and the solution was dried over MgS04 • Evaporation of the solvent and filtration of the residue through a short bed of alumina using dichloromethane as eluent gave a colorless oil (3.2 g, 92%). IR (neat): 3250 (O-H) cm-l; 1H NMR (CDCI3) : 8 2.25-2.35 (t,IH), 3.55-3.90

(m, 17H) . t-Butyl 2-r (Oxymethyl-15-crown-5)methvl1 benzoate (79)

Hydroxymethyl-15-crown-5 (1.00 g, 3.98 mmol) was dissolved in dry THF (25 ml) and added to a flask containing NaH (60% dispersion in mineral oil, 0.207 g, 5.18 mmol). After stirring for five minutes, t-butyl 2-bromomethyl benzoate (1.03 g, 3.98 mmol) in 10 ml of dry THF was added dropwise. The solution was stirred for three hours at room temperature. The solvent was removed in V^QVQ. To the 45 residue was added dichloromethane and water and the mixture was extracted with dichloromethane. The combined extracts were dried over MgS04 and the solvent was evaporated in YAQUD.. The residue was chromatographed on alumina with dichloromethane-methanol (49:1) as eluent to give 0.35 g (76%) of a colorless viscous oil. IR (neat): 1706 (C=0), 1134 (C-0) cm-l; IR NMR (CDCI3) : 8 1.58 (s, 9H) , 3.60-3.88 (m, 21H), 4.91 (s, 2H), 7.20-7.90 (m, 4H). Anal. Calcd. for C23H36O8: C: 62.71, H: 8.23. Found: C: 62.92, H: 7.96 t-Butvl 2-r (Oxvmethvl-]2-crnwn-4^TnPthy1 1hPn7oate (78^

Hydroxymethyl-12-crown-4 (0.51 g, 2.05 mmol) was dissolved in dry THF (25 ml) and added to a flask containing NaH (60% dispersion in mineral oil, 0.24 g, 5.30 mmol). After stirring for five minutes, t-butyl 2-bromomethyl benzoate (0.67 g, 2.05 mmol) in 10 ml of dry THF was added. The solution was stirred for three hours at room temperature. The solvent was removed in vacuo. To the residue was added dichloromethane and water and the mixture was extracted with dichloromethane. The combined extracts were dried over MgS04 and the solvent was evaporated in vacnn. The residue was chromatographed on alumina with dichloromethane-methanol (49:1) as eluent to give 0.68 g (70%) of colorless viscous oil. IR (neat): 1705 (C=0) , 1134 (C-0) cm-l; IR NMR (CDCI3) : 8 1.58 (s, 9H) , 3.50-4.00 46 (m, 17H), 4.91 (s, 2H), 7.25-7.90 (m, 4H). Anal. Calcd. for C21H32O7: C: 63.60, H: 8.14. Found: C: 63.42, H: 7.83

?-r (Oxvmethvl-12-crQwn-4) methyl ihPn^oin ;^piH 1^2)

t-Butyl 2-[(oxymethyl-12-crown-4)methyl]benzoate (1.20 g, 3.03 mmol) was dissolved in 25 ml of toluene. Potassium t-butoxide (0.51 g, 4.54 mmol) was added, which caused the solution to turn a dark brown color. After refluxing under nitrogen for 40 minutes, another portion of potassium t- butoxide (0.51 g, 4.54 mmol) was added. Refluxing was continued for an additional hour. The solvent was removed in vacuo and the residue was dissolved in dichloromethane- water and the mixture was extracted with dichloromethane to remove the unreacted ester. The aqueous phase was acidified with 6 N HCl and extracted with dichloromethane (5 x 50 ml) . The combined extracts from the second extraction were dried over MgS04 and passed through a short bed of silica gel with dichloromethane as eluent to give the desired product (0.55 g, 55%). IR (neat): 2864 (COOH),

1715 (C=0), 1136 (C-0) cm-l- IRNMR (CDCI3): 8 3.40-3.95

(m, 17 H) , 4.92 (s, 2H), 6.60-6.80 (broads, IH), 7.25-7.45 (t, IH), 7.50-7.60 (m, 2H) , 7.93-8.05 (d, IH). Anal. Calcd. for C17H24O7: C: 59.96, H: 7.11. Found: C: 59.96, H: 7.23. 47 ?-r (Oxvmethvl-15-crQwn-5)methyi ihPnzoic arirj /gg)

t-Butyl 2-[(oxymethyl-15-crown-5)methyl]benzoate (0.24 g, 0.38 mmol) was dissolved in 25 ml of toluene. Potassium t-butoxide (0.42 g, 0.38 mmol) was added which caused the solution to turn a dark brown color. After refluxing under nitrogen for 40 minutes, another portion of potassium t- butoxide (0.42 g, 0.38 mmol) was added. Refluxing was continued for an additional hour. The solvent was removed in vacuo and the residue was dissolved in dichloromethane- water and the mixture was extracted with dichloromethane to remove the unreacted ester. The aqueous phase was acidified with 6 N HCl and extracted with dichloromethane (5 x 50 ml) . The combined extracts from the second extraction were dried over MgS04 and passed through a short bed of silica gel with dichloromethane as eluent to give the desired product (0.116 g, 56.5%). IR (neat): 2870 (COOH), 1713 (C=0), 1119 (C-0) cm-l. iH NMR (CDCI3): 5 3.55-3.95 (m, 21 H), 4.93 (s, 2H),

6.60-6.80 (broad s, IH) , 7.28-7.43 (t, IH), 7.50-7.60 (t, IH), 7.60-7.70 (d, IH) 8.00-8.10 (d, IH) . Anal. Calcd. for C19H28O8: C: 59.39, H: 7.34. Found: C: 59.44, H: 7.26

General ProcedurP for Prpparation of Sodi nm, Pota.SSJUff r Rubidium and Ce.=:ium Crown F.ther rarhnxvlates The crown ether carboxylic acid (0.12 g) was dissolved in 7.5 ml of CDCI3. The solution was divided into five

shell-capped vials (1.50 ml of solution per vial). For each of four vials, a small magnetic bar was added together with 48 0.10 g of the appropriate anhydrous alkali metal carbonate. Each vial was capped and the mixture was stirred for one hour at room temperature. The mixture was then filtered directly into an NMR tube by use of a disposable pipet packed with glass wool and a short bed of Celite filter aid. The solution in the fifth vial (which had no metal carbonate) was simply added to the fifth NMR tube.

Preparation of Lithium Crown Ether Carboxylates

The lithium crown ether carboxylate was prepared by dissolving the crown ether carboxylic acid in dry THF and

cooling the solution to -78°C. One equivalent of n- butyllithium in THF was added and the solution was stirred for 30 minutes at -78°C. A few drops of water were added. The solvent was removed in vacuo and the solid residue was dissolved in dichloromethane. The dichloromethane solution was dried over MgS04, filtered, and evaporated in vacuo to give the lithium carboxylate. CHAPTER III

SYNTHESIS AND STRUCTURE OF DI(1,8-NAPHTHYL)CROWN ETHERS

In this Chapter the synthesis of crown ethers 99 and 100, which are the first examples of di-(1,8-naptho)c] ;rown ethers, will be described.

99 100

The target compounds 99 and 100 were synthesized in three steps, starting from the commercially available starting material, 1,8-naphthosultone (101). Two molecules of dihydroxynaphthalene 102, which was obtained from naphthosultone 101, were coupled with one molecule of dibromide 103 to provide intermediate 102. This intermediate was used as the starting material for the ring closure reactions attempted in this research. Unsubstituted dinaphtho-16-crown-4 (99) was obtained from the cyciization of intermediate 104 with 1,3-dibromopropane (103) in the

49 50 presence of CS2CO3 in CH3CN. The methylene substituted ring closure product 100 was achieved by the reaction of intermediate 104 with 3-chloro-2-chloromethyl propene (110) with CS2CO3 in CH3CN. Ring-closure reactions to form other examples of this crown ether ring system were attempted but were unsuccessful.

Results And Discussion Synthesis of Bis-1.3-(8-hydroxy-l-naphthnxy^ prnpnne (104)

Reaction of 1, 8-naphthosultone (102) with KOH at 250 °C for 2.5 hours, followed by treatment of the resulting mixture with 6 N HCl gave a crude product which was recr y s t al 1 i z ed from methanol to give 1^8- dihydroxynaphthalene (102) in 54 % yield. Two different routes were considered for conversion of 102 into intermediate 104 (Scheme 6) . The first strategy tried was protection of one of two hydroxyl groups of 1,8- dihydroxy-naphthalene (102) to prevent alkylation at both sites in a subsequent step. Mono-protection was achieved through the reaction of 102 with benzyl bromide (105) in the presence of K2CO3 in CH3CN. This reaction gave monobenzyl- protected 1, 8-dihydroxynaphthalene 106 in 82 % yield. The resulting mono-protected compound 106 would be reacted with half an equivalent of 1,3-dibromopropane (103) to obtain compound 107, followed by hydrolysis of compound 107 with H2 with Pd/C. 51

QH OH

KOH 250 OC

0.5Eq. I I Br Br 103 ^ CS2CO3 CH3CN

Br Br 103 /CS2CO3 CH3CN

107

Scheme 6: Synthesis of intermediate 104,

However, a second route was pursued simultaneously and it was found that protection was not needed. Direct reaction of 1,8-dihydroxynaphthalene (102), 1,3- 52 dibromopropane (103) and K2CO3 in CH3CN gave an 85% yield of 104 (Scheme 6).

.Synthesis of Di (1. S-naphthn)-1 ^-crnwn-4 (gg) and svm-Methvlene-di (1. R-naphl-hyl) -i6-crnwn-4 (100) and the Solid State StrnntnrP of Crnwn F.ther 100

The ring closure reaction step for the parent dinaphtho-16-crown-4 (99) was performed between intermediate 104 and the dimesylate of 1,3-propanediol (108). The base- solvent combination utilized was CS2CO3-CH3CN. A minimum amount of CH3CN was used to dissolve intermediate 104. An equivalent of dimesylate 108 was added and the solution was drawn into a syringe. The mixture added dropwise to a flask containing CS2CO3 in CH3CN at reflux during a period of several hours under nitrogen (Scheme 7). The crude product was purified by recrystallization to give a 71% yield of 99.

Another route attempted for the synthesis of dinaphtho- 16-crown-4 (99) was the [2+2] cyciization reaction of 1,8- dihydroxynaphthalene (102) and 1,3-dibromopropane (103) in the presence of CS2CO3. Compounds 102 and 103 were dissolved in CH3CN and the solution was added dropwise to a flask containing CS2CO3. The mixture was refluxed overnight. After workup, the product was purified by recrystallization from dichloromethane. The compound was identified by mass spectral analysis (M+, 200), iH-NMR spectroscopy and elemental analysis as the [1+1] cyciization 53 product 109 instead of the desired [2+2] cyciization product 99 (Scheme 8) .

CS2CO3 MsO OMs CH3CN

104 108

99

Scheme 7: Synthesis of dinaphtho-16-crown-4 (99)

Dinaphthol 102 was also employed for the synthesis of .axm.-(methylene) dinaphtho-16-crown-4 (100) (Scheme 9). Dinaphthol 102 and 2-chloromethyl-3-chloro-l-propene (110) were dissolved in acetonitrile. The solution was then taken into a syringe and added to a flask containing CS2CO3 in CH3CN over a period of eight hours under nitrogen at reflux. After workup, the crude product was purified by recrystallization to give 100 in 71% yield. The preparation of sym- (methylene) dinaphtho-16-crown-4 was also attempted by the reaction of intermediate 104 with 54

HO OH 103 Br Br /r~S CS2CO3 \ y V^. CH3CN / \

102

CS2CO3 99 CH3CN

109

Scheme 8: Synthesis of 1,8-naphtho-8-crown-2 (109)

2-chloromethyl-3-chloro-l-propene (110) with LiH as the base in THF (Scheme 10) . This base-solvent combination was not effective and the reaction resulted in recovery of the starting material. Compound 104 was dissolved in THF and added to a flask containing LiH in THF. After refluxing under nitrogen for two hours, 2-chloromethyl-3-chloro-l- propene (110) was added and the mixture was refluxed for 48 hours. TLC and iH-NMR spectroscopic analysis indicated that reaction did not occur and starting material 104 was recovered quantitatively. 55

H HO + CS2CO3 CI CI CH3CN

104 110

100

Scheme 9: Synthesis of £ym-methylenedinaphtho-16-crown-4 (100) .

H n ci CI /r^

LiH THp/^

104 100

Scheme 10: Attempted synthesis of .sym-(methylene) dinaphtho- 16-crown-4 (100) by use of LiH-THF. 56

A solid state structure of compound 100 was determined by professor G. I. Shoha. and his co-„orters at the Hebrew university of Jerusalem. The crystal structure (Figure 12) shows that the hydrogen atoms on carbons 23 and 25 are pointing into the cavity. Thus structural reorganization of the crown ether compound would be required before cation complexation.

several other ring closure reactions involving bisnahthol 104 were attempted. Ten different base-solvent combinations and reaction conditions were utilized for the

104

attempted cyclizations of bis-1,3-(8-hydroxy-l- naphthoxy) propane (104) and various reagents. Two of the attempted ring closures resulted in a decomposition of starting material 104. One reaction gave decomposition of the starting material 104 as well as recovery of some unreacted starting material. Three of these attempts resulted in no reaction between the potential reactants. Two sets of reaction conditions were effective for the ring 57

Figure 12: Crystal structure of ^ynj-Methylenedinaphtho- 16-crown-4 (100). 58 closure but formed the undesired products, 1,8-naphtho-! crown-2 (109) and ^m-3-methylene-6, 8-(1, 8-naphthyl)-J crown-2 (111) .

Ill

Attempted Syntheses of svm-(Hydroxy)di (1.S-naohthn^- 16-crQwn-4 (113). svm-(Keto)di(1.8-naphtho)- 16-crown-4 (115) and sym-(Dimethylene)di (1.8-naphtho)-16-crown-4 (Hj)

The original intention of this research was to synthesize a .aym-di (1, 8-naphthyl)-16-crown-4 compound with a functional group attached to the macrocyclic ring, such as a double bond, followed by replacement of this functional group with a desired substituent. Other attempts were made to synthesize dinaphtho-16-crown-4 compounds with a hydroxyl or a keto group (Scheme 11). Epichlorohydrin (112) has been used in the Bartsch Research Group for the formation of dibenzocrown ether alcohols.79 For this reason epichlorohydrin was chosen an appropriate reagent for the attempted cyciization of 59 dinaphthocrown ether alcohols. Four different base-solvent combinations were utilized.

104

?>x/Cl ?X^ci ?X^ci ^iX^ci 112 112 112 112 LiOH CS2CO3 NaH LiOH THF/HjO CH3CN DMF H2O > < > ^ > < > < \ I

113

Scheme 11: Attempted synthesis of sym- (Hydroxy)di(1, 8- naphtho)-16-crown-4 (113) 60 Bisnaphthol 104 was added to a flask containing LiOH-H20 in water. After refluxing for twelve hours, epichlorohydrin was added and the mixture was refluxed for three days. No cyciization product 113 was obtained and the iH-NMR spectrum indicated recovery of the starting material For the second attempt, THF-H2O (1:1) was utilized as the solvent. A mixture of dinaphthol 104 and LiOH-H20 in THF-H2O was stirred at 550C for four hours. Then epichlorohydrin was added with continuous stirring during a twelve hour period. After a second addition of Li0H-H20 and epichlorohydrin, the mixture was stirred for an additional twelve hours. After workup, TLC analysis and the iH-NMR spectrum of the product mixture showed decomposition products and some recovery of the starting material 104. These two attempted cyciization reactions resulted in no reaction. This may be due to the lipophilic nature of the starting material and subsequent low solubility in the reaction conditions. In a reaction designed to utilize a stronger base in a solvent which would allow for a higher reflux temperature, dinaphthol 104 was added to a flask containing NaH in DMF. After stirring the mixture for ten minutes, epichlorohydrin was added and the mixture was refluxed under nitrogen for three days. After workup, TLC analysis and the iH-NMR spectrum of the product mixture indicated decomposition products and some recovery of the starting material. 61 in the fourth attempt, dinaphthol 104 was added to a flask containing CS2CO3 in CH3CN (Scheme 11) . After refluxing for ten minutes, epichlorohydrin was added and the mixture was refluxed for one day. TLC analysis and the iH- NMR spectrum of the recovered product showed decomposition of the starting material 104. After the several unsuccessful attempts to synthesize compound 113, interest in the attachment a functional group to the macrocyclic ring other than a hydroxy group lead to the attempted synthesis of sym-(keto)dinaphtho-16-crown-4 (115) by reaction of compound 104 with 1,3-dichloroacetone (114) in the presence of LiH in THF (Scheme 12). Compound 104 was dissolved in THF and added to a flask containing

104 115

Scheme 12: Attempted synthesis of sym-(keto)di-(1, 8- naphtho)-16-crown-4 (115)

LiH in THF. After refluxing under nitrogen for two hours, 1,3-dichloroacetone (114) was added and the mixture was 62 refluxed for 48 hours. TLC and IR-NMR sspectral analysis indicated that starting material 104 was recovered quantitatively. The unstable nature of 1,3-dichloroacetone (114) may be responsible. For this reason other reaction conditions and base-solvent combinations were not attempted. After unsuccessful attempts to obtain alcohol 113 ketone 115, attention was focused on synthesizing sym- (dimethylene) dinaphthyl-16-crown-4 (116) via a [2+2] cyciization of dihydroxy naphthalene 102 with 3-chloro-3- chloromethyl-1-propene (110) . Dihydroxy naphthalene 102 and 3-chloro-3-chloromethyl-l-propene (110) were dissolved in CH3CN and the solution was added dropwise to a flask containing CS2CO3. The mixture was refluxed overnight, and after workup, the product was obtained by recrystallization from dichloromethane. The compound was identified by its mass spectrum (M+, 212), 1H-NMR spectrum and elemental analysis as the [1+1] cyciization product 111 instead of the desired [2+2] cyciization product 116 (Scheme 13).

Summary

Different base-solvent combinations with three different reagents for the cyciization have been investigated. Four new crown ethers have been synthesized: sym-di (1,8-naphtho)-

16-crown-4 (99), ^ym-(methylene)-di(1,8-naphthyl)-16-crown-4

(100) ,l,8-naphtho-8-crown-2 (110), and sym-(methylene)-1, 8- naphtho-8-crown-2 (111). 63

110 CI CI CS2C03 CH3CN ^

102

CS2CO3 CH3CN 116

111

Scheme 13: Synthesis of methylene-1,8-naphtho-8-crown-2 (111)

However, three other new crown ether compounds could not be realized: sym-(hydroxy)di(1.8-naphtho)-16-crown-4 (113), .sym-(keto) di (1, 8-naphtho)-16-crown-4 (115) and sym- (dimethylene) di (1, 8-naphtho) -16-crown-4 (116) . 64 Experimental Pi^n^^^,^^^^ 1 .8-Dihvdroxynaphth;^lPT^o (Iffg)^"

Potassium hydroxide (30 g, 0.53 mol) was dissolved in 10 ml of water and added to a preheated crucible containing 1,8-naphthosultone (6.00 g, 29.12 mmol). The mixture was heated in an oven at 250oc for 2 hours. The black viscous mixture was cooled to room temperature and treated with 300 ml of 6 N HCl. The mixture was extracted with dichloromethane (4 x 50 ml) . The combined extracts were dried over MgS04. Activated carbon (5 g) was added and the mixture was stirred and filtered. The solution was concentrated and crystallized to obtain 102 as light yellow crystalline needles (2.56 g, 54%), m.p. 138°C, lit. m.p. 140OC. IR (neat): 3280 (O-H) cm-l. 1H NMR (CDCI3): 8

6.73-6.80 (m, 2H) , 7.26-7.31 (m, 4H), 10.87 (s, 2H)

Monobenzyl-protected 1 ^ 8-Dihydroxynaphth3l enp (jLQg)

The 1, 8-dihydroxynaphthalene (0.80 g, 5.00 mmol) was added to a flask containing K2CO3 (1.73 g, 12.50 mmol) and 40 ml of CH3CN. The mixture was refluxed for 30 minutes. To the mixture was added benzyl bromide (0.85 g, 5.00 mmol) and refluxing was continued for an additional 30 minutes. The solvent was removed in vacuo. Dichloromethane and water were added to the residue. After shaking the dichloromethane layer was separated, washed with water, and dried over MgS04. Evaporation of the solvent in vacuo gave 65 the crude product which was crystallized from methanol to give 1.02 g (82%) of 106. iH NMR (CDCI3) : 8 5.21 (s, 2H) , 6.70-7.00 (m, 2H) , 7.20-7.50 (m, 9H) , 9.39 (s, IH) . Anal. Calcd. for C17H14O2: C: 81.56, H: 5.64. Found: C: 81.21, H: 5.92.

Ris-1. 3- (8-HvdrQxy-l-naphthr>xy)prnn3nP (IQ4)

The 1, 8-dihydroxynaphthalene (5.00 g, 31.25 mmol) and 1,3-dibromopropene (3.47 g, 17.18 mmol) were dissolved in 150 ml of CH3CN and the solution was added dropwise during two hours at reflux to a flask containing K2CO3 (6.46 g, 46 mmol) and 15 ml of CH3CN and refluxed for 8 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was taken into dichloromethane-water. The mixture was acidified with 6 N HCl and extracted with dichloromethane (3 x 50 ml) . The combined extracts were dried over MgS04. The solution was concentrated and allowed to crystallize to give 4.79 g (85.17%) of 104 as a white solid with m.p. 137oc. IR (neat): 3290 cm-i (O-H). iH NMR (CDCI3): 8 2.52-2.64 (p,

5H) , 4.48-4.51 (t, 4H) , 6.78-6.94 (m, 4H) , 7.23-7.45 (m,

8H) , 9.28 (s, 2 H) . l^C NMR (CDCL3) : 8 28.97, 65.70,

105.11, 110.45, 115.00, 119.05, 122.25, 125.58, 127.69,

136.74, 154.24, 154.90. Anal Calcd. for C23H20O4: C: 76.63,

H: 5.59. Found: C: 76.83, H: 5.52. 66 pime.qvlate of 1. 3-Prnpanedi n1 (IQf})

A solution of 1,3-propanediol (10.0 g, 0.13 mol) and triethylamine (39.94 g, 0.39 mol) in 50 ml of dichloromethane was added dropwise to a flask containing methanesulfonyl chloride (30.00 g, 0.26 mol) at QOC over a period of 20 minutes. The mixture was stirred for 3 hours at room temperature. Water (200 ml) was added and the mixture was acidified with 5% HCl. The mixture was extracted with dichloromethane (3 x 50 ml) . The combined extracts were dried over MgS04. The solvent was evaporated to give a crude oily product which was purified by column chromatography on silica gel with dichloromethane as eluent. A light yellow, viscous oil was obtained (21.14 g, 82%). iH NMR (CDCI3): 8 2.13-2.30 (p, 2H), 3.05 (s, 6H), 4.31-4.43

(t, 4H) .

sym- (Methyl ene) di - (1. R-naphtho) -1 6-crown-4 (100) In 75 ml of acetonitrile,1,8-dihydroxynaphthalene (1.00 g, 2.77 mmol) and 3-chloro-2-chloromethyl-l-propene (0.64 g, 2.77 mmol) were dissolved. The solution was added over a period of 8 hours with a syringe pump to a flask (equipped with a condenser and a Dean-Stark trap) containing CS2CO3 (2.25 g, 6.92 mmol) and 15 ml of acetonitrile at reflux. During addition of the solution to the flask, the volume in the flask was kept about 30-35 ml by removal of the solvent with the Dean-Stark trap. After the addition was completed, 67 the mixture was stirred overnight at 80oc. The solvent was removed in vacuo. Water (30 ml) was added and the solution was extracted with dichloromethane (4 x 50 ml) . The combined extracts were dried over MgS04. The solution was passed through a short bed of alumina with dichloromethane- hexane (1:5) as the eluent. The solution was concentrated and 100 (0.91 g, 71%) was crystallized from dichloromethane- ethyl acetate to give white crystals with m.p. 163oc. 1H NMR (CDCI3) 5 2.42-2.54 (p, 2H), 4.30-4.36 (t, 4H) , 4.77 (s, 4H), 5.63 (s, 2H), 6.92-6.98 (m, 4H) , 7.24-7.46 (m, 8H) . 13c NMR (CDCI3): d 30.19, 68.58, 71.19, 110.19, 111.49, 117.28, 119.83, 121.72, 121.94, 126.10, 126.37, 137.44, 141.69, 155.65, 156.11. Anal Calcd. for C27H24O4: C: 78.61, H: 5.57. Found: C: 78.87, H: 5.89.

Di(1. 8-naphtho)-16-Crown-4 (99)

The 1,8-dihydroxynaphthalene ( 1.00 g, 2.77 mmol) and the dimesylate of 1,3-propanediol (0.64 g, 2.77 mmol) were dissolved in 75 ml of acetonitrile. The solution was added with a syringe pump to a flask (equipped with a condenser and a Dean-Stark trap) containing CS2CO3 (2.25 g, 6.92 mmol) and 15 ml of acetonitrile at reflux over a period of 8 hours. During addition of the solution to the flask, the volume in the flask was kept about 30-35 ml by removal of the solvent with the Dean-Stark trap. After the addition was completed, the mixture was stirred overnight at 80 °C. 68 The solvent was removed iji_yaim

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