crown ether compounds: synthesis and a dissertation …

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

I I I . 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



General Procedure for Preparation of Hydroxy methyl Crown

Ethers 74-76 7 8

Hydroxymethyl-12-crown-4 (74) 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





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


2-f(15-Crown-5)-methyloxy]benzoic Acid (38) 8 3


2-[(18-Crown-6)-methyloxy]benzoic Acid (39) 8 3





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

v i i

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

V l l l

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 ( 1 2 1 ) 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


Ethyl syiTi-(10-Hydroxydecyl)dibenzo-14-crown-4-oxyacetate (138) 107

Ethyl sym-(10-Hydroxydecyl)dibenzo-16-crown-5-oxyacetate (139) 108

X

ni . I i i — . ^

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) I l l

Methyl 2-[(21-Crown-7)methyloxy]-4-

(10*-undecenoxy)benzoate (128) I l l

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

Xl l

• ^ ^ N .

17. Alkylammonium Picrate Data for Crown Ether 185 7 0

Xl l l

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^ : O^^^is^ Anion % I ' 4. '

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

ÔH "^^55^0 + 2NaOH + Cl-R-Cl T X ^ ^

Method 2

' O ' ^ O - S - 0 ^ ^ ^ ^ ^ ^ " ^ C l - T - C l - ^ .<^^0-T-0

Method 5

O-S-0

Method 3

Method 4

^nr°" M-v<:,

4 NaOH + 2 Cl-U-Cl

+ o iSTnOH • ^^ iâwxx

- c

. if 1=

^ O - U - 0 .

^ô-u-o

sÔ-V-O

= ^ 0 - V - 0

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 6 1 7 2 8 3

9, A=B=CH20CH2C02H, n=0 10, A=B=CH20CH2C02H, n=l 11, A=CH20CH2C02H, B=H, n=0 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.

salt of

5

6

7

8

% of salt in die CH2CI2

Li+

1-4

7.2

6.1

3-4

Na+

1.5

7.9

8.7

5.2

K+

1-4

6.7

6.8

8.0

layer

Ca2+

1.1

4.8

1.8

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:

i C . = [MLlorg [H+]aq/[HL]org[M+]aq. ( 2 )

12

c 13 14 15 16

c

HÔCHjCOjH

';;o Y_

CH2CH2 CH2CH2CH2 CH2CH2OCH2CH2 CH2(CH20CH2)2CH:

^ 8 ^ 1 7

HÔCHCOoH

K : ^ ^ 0 ^

HÔCH.CO^H

0 ^ 0

1 7

2

CgHjy >^ÔCH2C02H

o::::o ^ 0 ^

.)3

18 1 9

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^!:^ÔCHÊ

'CO2H

2 0 2 1 2 2 2 3 2 4 2 5 2 6

CE 12-crown-4 13-crown-4(2) 13-crown-4(3) 14-crown-4(2) 14-crown-4(3) 15-crown-4(3) 15-crown-5

2 7 2 8 2 9 3 0 3 1 3 2 3 3

CE 16-crown 18-crown 19-crown 21-crown 24-crown 27-crown 30-crown

-5(3) -6 -6(2) -7 -8 -9 -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.

aOCHÊ

CO2H

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 4 3 , but

coordinated primarily with the monoethyl phosphonate center in 4 4

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

f l OEt O O,

O O

^ 0 ^

46 47 48 49

R C10H21

C10H21

C10H21

C10H21

n. 1 2 3 4

5 0 5 1 5 2 5 3

R H H H H

n 1 2 3 4

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]

orga solvent

chloroform

1,1,1-trichloroethane

tetrahydronaphthalene

benzene

nic phase loading.

62

53

47

42

%

concentration ratio in the organic

Na+/Li+

5.5

1.7

1.6

1-4

phase

Na+/K+

6.5

1.7

1.6

1-4

toluene

p.-xylene

34

25

1.7

1.8

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 Source Phase

H O ^ H-X

Organic Phase

H-X

M^

H^

Acidic Aqeous Receiving Phase

Step 1

- ^

Step 2

Step 3

Step 4

Overall

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

Crown-CH2YCH=CH2

Y=OCH2 Y=CH2

Pt cat. mKOCuA Crow„-CH,Y(CH,),-^i(OC3H5),

i CHo CH^ ^

silica gel

hea t Crown-CH2Y(CH2)2-^i SILICA

GEL

Crown Substituents

r o

o o

o o

54, Y=CH2

PhCH.-N N-CH.Ph 2

O

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.

- " • . - • - . - « . » . ^ r w ^ ^ - . > ^ ^ i J T I HI M I M i l l ^

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]

crown ether

5 4

5 4

5 4

5 5

5 6

5 7

5 7

5 8

cation

H+

Ag+

Cu2+

Ag+

Ag+

Ag+

Ba2+

Ba2+

logK

bound

5.10

2.70

1.80

8.20

0.90

1.61

3.56

2.93

± 0 . 2 0

± 0.20

± 0.10

± 0.20

± 0.15

± 0.09

± 0.01

± 0.09

unbound

5.23a

5.50b

4.63b

7.80C

0.94

1.50

3.87t>

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 2-5 9 1 6 2 1 6 0 2 6 3 2 6 1 3 6 4 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

a" === ^C02Me

1) NaH, THE ^ .

2) TsO 0)nCH2Ph

n. 6 2 1 6 3 2 6 4 3

^ Y ^ 0),CH2Ph

^ ^ C 0 2 M e

n 6 5 1 6 6 2 6 7 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

Ô Cl H 0 , ^ 0 C H 2 P h LiOt-Bu, t-BuOH^ Ô O

L "*" J LiBr, H2O k^ ^J O Cl HO ^K P

7 1

0CH2Ph

h . HOÔCH,Ph NaH [ 3 ( un^ DMF-THF V ^ \ ^ O OTs " ^ (4-1) k . 0 ^

72

0CH2Ph

O + V " Y ^ NaH .0 O

/ THF IQ ^J

7 3

OTs

. . , , , - , . ^ - — . — . — , — ^ — — ^ • .

Scheme 5 30

0CH2Ph ^ O H

H. ^ ^O O.

^o p"^ Pd/C

7 1 1 7 4 1 7 2 2 7 5 2 7 3 4 7 6 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

8 3 , 8 4 , 8 6 - 8 8 as well.

Scheme 6

a° " 1) NaH ^ C Y O C H Z C E

CO^Me 2)CECH20Ts M ^ C Q 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 ^ > ^ 2 Y ^ ^ " 2 C E

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.

CE

12-crown-4

13-crown-4(3)

15-crown-5

18-crown-6

21 -c rown-7

24 -c rown-8

CECH2OTS

97

76

95

98

88

86

percent yield

^^>s-^0CH2CE

39

57

5 2

5 0

61

60

of

i ^-5^0CH2CE

^ C 0 2 H

88

97

93

92

84

88

The thermodynamics of alkali metal cation complexation by the

ionized forms of crown ether carboxylic acids 3 4 , 3 5 , 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]

Scheme 7 34

H^OH

O O

p o

8 9

CrO. • ^ -

H2SO4

O

A o o

p o

90

1) RMgX 2) NH4CI

R^OH

c :3o • 15

K 9 1 CH3 9 2 C6H13 9 3 C10H21

1) NaH 2) BrCH2C02H

R ^ 0 C H 2 C 0 ^

-cc:::o IN.

9 4 CH3 9 5 C6H13 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

iodomethyl phosphonic acid was prepared by the reaction of

diiodomethane with triethyl phosphite, according to the literature

method.[52]

I

Scheme 8

H ^ O H

o o

o o

8 9

l)2NaH

O

2)lCHoP0H I

OEt

O

ILX)CH2P0F

I I OEt O O ^^^

O O

5 0

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

Scheme 9 37

R^(CH2)„Br

O O,

p O (EtO)3P

-^^

O

R^(CH2)„ P(0Et)2

O O

p O

^ 0 ^

9 7 9 8 9 9 100 101 102

R ^10^21

^ 10 21

^10^21 H H H

n. 2 3 4 2 3 4

103 104 105 106 107 108

R

^10^21

^10^21

^10^21

H H H

n. 2 3 4 2 3 4

I

NaOH 95% EtOH

0

R^(CH2)nP0H

A A OEt

-oc :0 R n

4 7 C10H21 2 4 8 C10H21 3 4 9 C10H21 4 5 1 H 2 5 2 H 3 5 3 H 4

Scheme 10

R ^ - C H 2 - CH-P(OEt)2 ^JxP'

38

Scheme 11

H.^OCH2CH2Br

^ 0 ^

o IL/)CH2CH2l^(OMe)2

-a:::o ^ 0 ^

100 109

O

NaOH, EtOH - ^

H^CH2CH2POH l l OMe

O O,

RT,24h * ^ : ^ o O

1 1 0

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

1 0 3

1 0 4

1 0 5

1 0 6

1 0 7

1 0 8

1 0 9

condition

RT, 10 d

reflux, 24 h

reflux, 24 h

RT, 7 d

reflux, 24 h

reflux, 24 h

RT, 24 h

yield (%)

29

80

80

40

53

55

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

o o.

o o

R n 1 1 1 C10H21 2 1 1 2 C10H21 3 1 1 3 H 2 1 1 4 H 3

MsCl, Et3N

CH2a:

R^^O(CH2)nOMs

O O,

O O

R a 1 1 5 C10H21 2 1 1 6 C10H21 3 1 1 7 H 2 1 1 8 H 3

NaBr

acetone

R ^ ( C H 2 ) „ B r

O O,

O O

9 7 9 8

1 0 0 1 0 1

R n C10H21 2 C10H21 3 H 2 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

oc::]o ^ 0 ^

R 8 9 H 9 3 C10H21

Br(CH2)4Br

CH2Cl2-50% aq NaOH BU4NHSO4

PTC

R^(CH2)4Br

o::::o R

1 0 2 H 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.

4 2

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^=^ D N a H ^ ^ - O O

O 0 ^ ^ = ^ 2)BrCH2C02Et %^^ ^

R R 9 3 C10H21 1 1 9 C10H21 8 9 H 1 2 0 H

R ^OCH2CH20H

LiAlH4 , ^ ^ ^ 0 O

O O THF

R 1 1 1 C10H21 1 1 3 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

^ x O H R^OCH2CH=CH2

^ ^ V ^ 1)KH , ^ = ^ 0 O

O O " ^ ^ 2) BrCH2CH=CH2 " M ^ Q ^

R R ^ 3 C10H21 12 1 C10H21 8 9 H 1 2 2 H

R^OCHjCHjCH.OH

1) NaBH4, BF3.Et20 | f ^ ^ ^ ' 2) H2O2, NaOH ^ " W ^ o O

R 1 1 2 C10H21 1 1 4 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

4 4

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

OCH2C02Et 45

O O

u 1 2 3 CH2CH2CH2 1 2 4 CH2CH2OCH2CH2

"^7xs:> 1 2 5 1 2 6 1 2 7 1 2 8

n. 1 2 3 4

Figure 14. Functionalized Crown Ethers for Attachment to Silica Gel.

Scheme 16

O

A o o

u 1)

2) NH4CI

MgBr - ^ -

1 2 9 CH2CH2CH2 9 0 CH2CH2OCH2CH2

1 2 4 CH2CH2CH2 125 CH2CH2OCH2CH2

46

sodium bromide in acetone to give 10-bromo-l-decene (134) in 69%

yield.

Scheme 17

MsCl, Et3N

^ « CH2CI2 • " ^ ^ ^ 1 3 2 1 3 3

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.

Scheme 18 47

OH

O O

u 1) NaH 2) BrCH2C02H

OCH2CO2H

O O


1 3 5 CH2CH2CH2 136 CH2CH2OCH2CH2

H2SO4 EtOH

OCH2C02Et

Scheme 19

1 2 3 CH2CH2CH2 1 2 4 CH2CH2OCH2CH2

O O

u 1) NaH 2) BrCH2C02Et

• X - ^

OCH2C02Et

O O


1 2 3 CH2CH2CH2 1 2 4 CH2CH2OCH2CH2

4 8

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


l)NaBH4, BF3.Et20

2) H2O2 1) BH3.THF

2) H2O2

HO. PS o o

u OCH2CH2OH HO,

PS o o

u 0CH2C0ft

1 3 7 CH2CH2OCH2CH2 1 3 8 CH2CH2CH2 1 3 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

1 4 0

K' OEt' .^^.^^^^^^'^^^^0^.^:^^0n

ro2H

1 4 1

EtOH

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

r02Me u, 1 4 2

2) r^

^0 O Y C H 2 0 T S

^0 p

7 7 7 9 8 0 8 1

n. 1 2 3 4

•°^:x? n.

1 2 5 1 1 2 6 2 1 2 7 3 1 2 8 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.

i ^ ^ „ ^ n ^ r^ o- r o

R* A Q RfY^ o o

R R 1 4 3 H 1 4 5 H

R

1 4 4 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 K ex selectivity'

1 4 3

1 4 4

1 4 5

1 4 6

;+ Li

Na

0.44

1.10

K+

Rb+

Cs+

Li+

Na+

K+

Rb-

Cs-

Li+

Na+

K+

Rb-

Cs+

Li+

Na-

17.3

38.0

39.1

0.29

1.00

19.3

35.5

36.6

0.17

0-41

10.9

17.6

22.1

0.11

0.39

(1.8

(4.6

(1.2

(6.3

(6.9

(1.2

(4.1

(1.4

(5.2

(5.5

(6.9

(1.7

(6.2

(1.3

(1.9

(2.8

(1.6

±

±

±

±

±

±

±

±

±

±

±

±

±

±

±

±

±

0.2)

0.4)

0.1)

0.7)

0.1)

0.1)

0.2)

0.2)

0.1)

0.1)

0.7)

0.2)

0.1)

0.1)

0.1)

0.2)

0.2)

X 10^

X 10^

10^

X 10 ^

102

X 102

X 10^

10^

X 10^

X 10^

X 10^

X 1()3

X 10"

10

X 10'

102

98

36

2.3

1.0

(1.0)

122

37

1.9

1.0

(1.0)

1 1 1

55

2.0

1.0

(1.0)

217

54

54

Table 8. (cont.)

K+

Rb+

Cs+

13.6

21.0

21.7

compound M" % Ex Kex selectivity*

1 4 6 K+ 13.6 (8.1 ± 0 . 1 ) X 103 1.6

(1.7 ± 0 . 3 ) X 10" 1.0

(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 - ^ R2

Rl R2 1 4 7 H H 1 4 8 =CH2 1 4 9 -CH2CCI2-1 5 0 Ph H 1 5 1 Bzl H 1 5 2 Bzl Bzl 1 5 3 BZIOCH2 Me 1 5 4 BZIOCH2 BZIOCH2 15 5 Et Et 1 5 6 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

148

149

150

151

152

153

154

155

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

0.047

0.049

0.052

0.161

0.071

0.134

0.040

0.043

0.064

0.091

0.030

0.043

0.010

0.023

0.072

0.023

0.055

0.076

18 ± 2

20 ± 2

21 ± 2

64 ± 8

28 ± 5

52 ± 5

16 ± 6

17 ± 4

22 ± 4

34 ± 5

12 ± 3

17 ± 3

4 ± 2

9 ± 1

29 ± 2

9 ± 1

22 ± 5

30 ± 4

56 Table 9. (cont.)

compound M+ % Ex Kex

15 6 Li+ 0.040 16 ± 6

Na+ 0.053 2 1 + 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

R i > y - o O A , R ; R 2 > - o o - ^ ^ ' '

157 158 159 160 1 6 1 1 6 2 1 6 3 164 165 166 167 168 169

Rl H

=CH2 Bzl

-CH2CCI2-Bzl Bzl Bzl Bzl Bzl(m-OMe) BZIOCH2 BZIOCH2 BZIOCH2 Et

170tf^"^ ^ C(0)N(Me)2

R2 H

Bzl

Bzl H Bzl Bzl H Me Me BZIOCH2 Et

Me

^1 H

=CH2 =CH2

-CH2CCI H Bzl Bzl Bzl Bzl(m-OMe) H BZIOCH2 BZIOCH2 Et

H

R4 H

2- (trans) H H H Bzl H H Me BZIOCH2 Et

H

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

158

159

160

161

162

163

164

165

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

1.35

0.079

1.14

0.028

0.081

0.053

0.85

0.60

0.26

0.052

0.36

0.026

0.15

0.026

0.16

0.030

0.43

0.13

560 ± 8

32 ± 5

489 ± 4 0

12 ± 3

31 ± 6

21 ± 4

354 ± 2 0

246 ± 2 2

106 ± 7

21 ± 3

144 ± 1 6

10 ± 2

59 ± 5

11 ± 2

64 ± 5

10 ± 2

170 ± 8

53 ± 5

59 Table 10. (cont.)

compound

1 6 6

1 6 7

1 6 8

1 6 9

1 7 0

M+

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

Li+

Na+

%Ex

0.52

0.34

0.14

0.024

0.16

0.15

0.12

0.023

19.5

18.3

0-<sIo o Fe

n. 1 7 1 0 172 1

Kex

214 ± 19

138 ± 1 1

56 ± 6

8 ± 2

66 ± 4

60 ± 4

49 ± 5

9 ± 2

15311 ± 3 8

13754 ± 6 3

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

T T l Li ^ TJl (6.3 ± 0.5) X 102

(4.9 ± 0.6) X 103

(7.2 ± 0.9) X 102

(5.0 ± 0.8) X 102

(3.0 ± 0.1) X 102

17 2 Li+ 0.91 (3.7 ±0.3) x 102

(1.3 ±0.8) X 103

(2.6 ± 0.1) X 105

(1.6 ±0.1) X 104

(7.1 ± 0.2) X 103

Li+

Na+

K+

Rb+

Cs+

Li+

Na+

K+

Rb+

Cs+

1.51

9.11

1.69

1.20

0.74

0.91

2.96

55.6

20.5

12.0

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 1 7 3 1 7 4 1 7 5 1 7 6 1 7 7 1 7 8

R H H H C10H21 CH3

^10^21

Y CH2CH2 CH2CH2CH2 CH2CH2OCH2CH2

Cir{'^IrL'^Jji2 CH2CH2OCH2CH2 CH2CH2OCH2CH2

Figure 19. Crown Ethers with Pendant Pyridine Units.

Table 12. Picrate Extraction Data for Crown Ethers 173-175. 62

compound M+ %Ex Ke:

1 7 3

1 7 4

1 7 5

Li+

Na+

K+

Rb+

Cs+

Li+

Na+

K+

Rb+

Cs+

Li+

Na+

K+

Rb+

Cs+

67.0

67.5

65.3

69.9

61.4

62.2

59.8

60.0

61.0

56.1

63.9

61.8

57.2

60.0

57.2

(7.1

(7.1

(5.5

(8.9

(4.5

(4.5

(3.8

(3.6

(4.1

(2.7

(5.1

(4.3

(2.8

(3.6

(2.9

±0.2]

±0.3]

±0.6]

±0.1]

±0.5]

±0.4)

±0.1]

±0.6]

±0.5]

±0.2]

±0.2]

±0.1]

±o.i;

±o.i;

±o.i;

• x 105

• x 105

• X 105

I X 105

\ X 105

X 105

X 105

X 105

1 X 105

• X 105

1 X 105

1 X 105

1 X 105

1 X 105

) X 105

63 Table 13. Picrate Extraction Data for Crown Ethers 176-178.

compound M+ %Ex Kex

r76

177

178

Li+

Na+

K+

Rb+

Cs+

Li+

Na+

K+

Rb+

Cs+

Li+

Na+

K+

Rb+

Cs+

0.15

1.07

0.24

0.12

0.09

0.37

1.15

0.28

0.48

0.44

0.17

0-74

0.30

0.46

0.39

59.0 ± 8

440 ± 1 7

96.3 ± 1 3

50.0 ± 7

37.9 ± 8

155 ± 5

479 ± 2 9

112 ± 5

195 ± 9

179 ± 9

69.6 ± 4

306 ± 4

121 ± 4

186 ± 17

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.

CH2 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 ^ f n

1 7 9 1 8 0 1 8 1

m 1 1 2

n. 1 2 2

1 8 2

Figure 22. Molecular Receptors.

66

Table 14. Picrate Extraction Data for Molecular Receptors 179-181

compound M+ %Ex Ke:

1 7 9

1 8 0

1 8 1

Li+

Na+

K+

Rb+

Cs+

Li+

Na+

K+

Rb+

Cs+

Li+

Na+

K+

Rb+

Cs+

8.3

11.2

33.7

15.3

12.4

9.0

8.8

12.3

12.1

12.5

6.0

6.3

8.0

10.2

6.9

(4.3 ± 0.1

(6.3 ± 0.3

(4.6 ± 0.7

(1.0 ± 0.

(7.4 ± 0.

(4.8 ± 0.

(4.6 ± 0.

(7.3 ± 0.

(7.3 ± 0.3

(7.3 ± 0.

(2.9 ± 0.

(3.0 ± 0.

(4.0 ± 0.

(5.7 ± 0.6

(3.4 ± 0.1

X 103

X 103

X 104

X 104

X 103

X 103

X 103

X 103

X 103

X 103

X 103

X 103

X 103

X 103

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

1 7 9 - 1 8 1 .

compound picrate %Ex Ke;

17 9 methylammonium

ethylammonium

propylammonium

butylammonium

t-butylammonium

18 0 methylammonium

ethylammonium

propylammonium

butylammonium

t-butylammonium

18 1 methylammonium

ethylammonium

butylammonium

propylammonium

butylammonium

t-butylammonium

11.5

81.3

91.3

35.5

10.9

9.8

83.6

90.8

19.0

10.5

5.8

81.6

15.7

90.8

15-7

6.3

(6.7 ± 0.1

(3.6 ± 0.1

(2.6 ± 0.2

(5.2 ± 0.1

(6.1 ± 0.2

(5.3 ± 0.1

(5.2 ± 0.2

(1.6 ±0 .1

(1.4 ±0 .1

(5.9 ± 0.6

(2.8 ± 0.1

(4.6 ± 0.2

(1.1 ±0 .1

(1.7 ±0 .1

(1.1 ±0 .1

(3.1 ± 0.7

X 103

X 106

X 107

X 104

X 103

X 103

X 106

X 107

X 104

X 103

X 103

X 106

X 104

X 107

X 104

X 103

•Corrected from the values in the absence of receptor.

69 Table 16. Alkylammonium Picrate Data* for Molecular Receptor 182.

picrate % Ex Kex

methy lammonium 34.1 (4.6 ± 0.3) x 104

e thy lammonium 84.5 (6.1 ± 0.1) x 106

propy lammonium 93.0 (3.3 ± 0.1) x 107

bu ty lammonium 60.9 (3.7 ± 0.2) x 105

t -bu ty lammonium 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

1 8 3

d ^ ^ O ^ n r^ r-0 O < > II Et3N II \ / 11^

HN NH + C9H19CCI 1 • C9H19C-N N-CC9H19

^ O O - ^ 1 8 3 ^ O O-f

1 8 4

O O

^ " ^ • ^ ^ ^ ^ . C10H21-N N-C10H21

^ o o-^

1 8 5

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)


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 -pheny l )penty l ]benzo ic 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)


(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 - T r i o x a - 8 - p h e n y l ) o c t y l ] b e n z o i c Acid (69)


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.

M e t h y l 2 . [ ( l , 4 , 7 , 1 0 - T e t r a o x a - l l - p h e n y l ) -undecyljbenzoate (67)



4.56 (s, 2H), 6.95-7.81(m, 9H).

2 - ( l , 4 , 7 , 1 0 - T e t r a o x a - l l - p h e n y I ) -undecyljbenzoic Acid (70)



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 7 1 - 7 3

( B e n z y l o x y ) m e t h y l - 1 2 - c r o w n - 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

7 9

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.

H y d r o x y m e t h y l - 1 2 - c r o w n - 4 (74)


(0-H); 1245, 1132 (C-0) cm-i. iH NMR (CDCI3): 6 2.34 (s, IH), 3.55-

3.82 (m, 17H).



(0-H); 1249, 1124 (C-0) cm-i. m NMR (CDCI3): 5 2.62 (br s, IH),

3.55-3.82 (m, 21H).



(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.

( T o s y l o x y ) m e t h y l - 1 2 - c r o w n - 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 - [ ( T o s y l o x y ) m e t h y l ) ] - 1 3 - c r o w n - 4 (78)


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).




3H), 3.50-4.20 (m, 21H), 7.55 (AB q, 4H).

(Tosy loxy)m e t h y l - 1 8 - c r o w n - 6 (80)

A coloriess oil was prepared in 98% yield. IR (neat): 1358,


3H), 3.50-4.20 (m, 25H), 7.55 (AB q, 4H).


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



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)



6.96-7.85 (m, 4H).

2 - [ ( 1 2 - C r o w n - 4 ) - m e t h y l o x y ] b e n z o i c Acid (34)



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 ' - ( 1 3 - C r o w n - 4 ) - m e t h y l o x y ] -benzoate (84)


(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 ' - ( 1 3 - C r o w n - 4 ) - n i e t h y l o x y ] b e n z o i c Acid (35)


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)


(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) -methy loxy]benzo ic Acid (38)


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)


(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) -methy loxy]benzo ic Acid (39)



IH NMR (CDCI3): 5 3.60-4.00 (m, 22H), 4.01-4.15 (m, IH), 4.28-4.50


7.30. Found: C, 57.71; H, 7.44.

84 Methyl 2-[(21-Crown-7)-methyloxy] benzoate (87)


(C=0); 1118, 1048 (C-0) cm-i. iH NMR (CDCI3): 5 3.60-4.20 (m, 32H).

6.96-7.85 (m, 4H).




IH NMR (CDCI3): 5 3.60-4.00 (m, 26H), 4.01-4.15 (m, IH), 4.30-4.50


7.47. Found: C, 57.49; H, 7.78.

Methyl 2-[ (24-Crown-8)-methyloxy]-benzoate (88)


(C=0); 1124, 1048 (C-0) cm-i. IH NMR (CDCI3): 5 3.60-4.20 (m, 36H),

6.96-7.85 (m, 4H).




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) ( h y d r o x y ) d i b e n z o -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) ( h y d r o x y ) d i b e n z o -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) ( h y d r o x y ) d i b e n z o -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.

s y m - ( M e t h y l ) d i b e n z o - 1 6 - c r o w n - 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).

s y m - ( H e x y l ) d i b e n z o - 1 6 - c r o w n - 5 -oxyacetic Acid (95)



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).

s y m - ( D e c v l ) d i b e n z o - 1 6 - c r o w n - 5 -oxyacetic Acid (96)



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 s v m - D i b e n z o - 1 6 - c r o w n - 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.

9 0 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 s v m - D i b e n z o - 1 6 - c r o w n - 5 -oxye thy lphosphonate (106)


(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 s v m - D i b e n z o - 1 6 - c r o w n - 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 s y m - D i b e n z o - 1 6 - c r o w n - 5 -oxypropy l -phosphonate (107)


(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 s y m - D i b e n z o - 1 6 - c r o w n - 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 s y m - D i b e n z o - 1 6 - c r o w n - 5 -oxybuty l -phosphonate (108)



2.20 (m, 4H), 3.69-4.40 (m, 19H), 6,81-7.02 (m, 8H).

if:

9 2

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 ) d i b e n z o - 1 6 - c r o w n - 5 -oxyethy l -phosphonate (103)



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 s y m - ( D e c y n d i b e n z o - 1 6 -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 s y m - ( D e c v l ) d i b e n z o - 1 6 - c r o w n -5 -oxypropy l -phosphonate (104)


(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



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)



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-(Decy l )d ibenzo-16-crown-5-oxybutyl-phosphonic Acid (49)

Hydrolysis of 105 for 24 h at refluxing temperature gave a


(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 s y m - D i b e n z o - 1 6 - c r o w n - 5 -oxye thy l -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 s y m - D i b e n z o - 1 6 - c r o w n - 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 - ( s y m - D i b e n z o - 1 6 - c r o w n - 5 - o x y ) - 2 -(methanesu l fonoxy)e thane (117)


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 - ( s v m - D i b e n z o - 1 6 - c r o w n - 5 - o x y ) - 3 -(methanesu l fonoxy)propane (118)


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)


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) d ibenzo -16 -crown-5 -oxy ] -3-(methane-sulfonoxy)propane (116)


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) d ibenzo-16 -crown-5 -oxy ] -2-bromoethane (97)


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)


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 - ( s v m - D i b e n z o - 1 6 - c r o w n - 5 - o x y ) - 4 -bromobutane (99)


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 - [ S J J H - ( D e c y l ) - d i b e n z o - 1 6 - c r o w n - 5 -oxy] -4 -bromo-butane (102)


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 ( s x Q L - D i b e n z o - 1 6 - c r o w n - 5 - o x y ) -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 [ s x n i - ( D e c y l ) d i b e n z o - 1 6 - c r o w n - 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).


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 - ( s y m - D i b e n z o - 1 6 - c r o w n - 5 - o x v ) e t h a n o l ( 1 1 3 )

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 y m - ( D e c vl) d i b e n z o - 1 6 - c r o w n - 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%


(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 - ( s v m - D i b e n z o - 1 6 - c r o w n - 5 - o x y ) - 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 - [ S X D L - ( D e c y l ) - d i b e n z o - 1 6 - c r o w n - 5 -o x y ] - l - p r o p e n e (121)


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.


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 - ( s v m - D i b e n z o - 1 6 - c r o w n - 5 - o x y ) p r o p a n -l-ol (114)


(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)


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

M g S 0 4 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).


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.

s y m - ( 9 - D e c e n v l ) ( h y d r o x y ) d i b e n z o -14-crown-4 (124)


(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) ( h y d r o x y ) d i b e n z o -16-crown-5 (125)


(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%


(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.

s y m - ( 9 - D e c e n y l ) d i b e n z o - 1 4 - c r o w n - 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 s y m - ( 9 - D e c e n y l ) d i b e n z o -1 4 - c r o w n - 4 - o x y a c e t a t e (123)


(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)


(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.


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 s y m - ( 1 0 - H y d r o x y d e c y l ) d i b e n z o -14-crown-4-oxyace ta te (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 &xi lL- (10-Hydroxydecy l )d ibenzo-16-crown -5 -oxy a c e t a t e (139)


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.

1 1 - M e t h a n e s u l f o n o x y - l - u n d e c e n e (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

M g S 0 4 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 - H y d r o x y - 4 - ( 1 0 * - u n d e c e n o x y ) b e n z o i c 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


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)


(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 )methy loxy ] -4 -( lO' -undecenoxy)benzoate (127)


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 )methy loxy] -4 -( lO' -undecenoxy)benzoate (128)


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 - D i d e c a n o y l - 7 , 1 6 - d i a z a - 1 8 - c r o w n - 6 ( 1 8 4 )

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 - D i d e c y l - 7 , 1 6 - d i a z a - 1 8 - c r o w n - 6 ( 1 8 5 )

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]

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crown ether compounds: synthesis and a dissertation …

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