synthesis of novel crown ether compounds and …

SYNTHESIS OF NOVEL CROWN ETHER COMPOUNDS AND

lONOMER MODIFICATION OF NAFION

by

JONG CHAN LEE, B.S., M.S.

A DISSERTATION

IN

CHEMISTRY

Submitted to the Graduate Faculty of Texas Tech University

in Partial Fulfillment of the Requirements for

the Degree of

DOCTOR OF PHILOSOPHY

Approved

August, 1992

L3

ACKNOWLEDGEMENTS

I am deeply indebted to Dr. Richard A. Bartsch for his constant

encouragement and patience throughout my graduate career. His

diligent pursuit of excellence in science inspired me to perform

research for the love of it. I would like to thank Drs. Robert D.

Walkup, Allan D. Headley, Dennis C. Shelly, Bruce R. Whittlesey.

John N. Marx for their willingness to provide help and advice. I

would also like to thank friendly co-workers. Dr. T. Hayashita, Marty

Utterback, John Knobeloch, Zuan Cong Lu, J. S. Kim, and Dr. Joe

McDonough for the wonderful times in the laboratory. I would like to

thank Dow Chemical Company U. S. A. and Texas Advanced

Technology Program for much of the funding of this research project.

I would like to extend gratitude to my wonderful parents and

sisters for their support throughout the years that I have spent

abroad. Most importantly, I thank my wife Sun Yong without whose

endless love and patience none of this would have been possible.

11

TABLE OF CONTENTS

ACKNOWLEDGEMENS ii

LIST OF TABLES xi

LISTOFHGURES xii

I. INTRODUCnON 1

Crown Ether Background 1

Cation Complexation by Crown Ethers 2

Synthesis of Monobenzo and Dibenzocrown Ethers 4

Lariat Ethers 1 0

Chromogenic Crown Ethers 1 3

Acyclic Polyether Compounds 1 5

Nafion® lonomer Membrane 1 7

Statement of Research Goal 2 0

II. RESULTS AND DISCUSSION 2 2

Crown Ethers with Aromatic Rings as Part of

the Polyether Ring 2 2

Benzo and Dibenzocrown Ethers-Cesium Effect 2 2

1.3-Xylyl Crown Ethers 4 1

Crown Ethers with Pendant Groups 4 3

Pyridyl Crown Ethers 4 3

Crown Ether Xanthates 5 4

Methoxy Crown Ethers 5 7

Chromogenic Crown Ethers 5 9

Acyclic Polyether Carboxylic Acids 6 0

111

Chemical ModiHcaiton of Nafion® lonomer Membrane.. 65

Summary 8 3

III. EXPERIMENTAL PROCEDURES 8 5

Instrumentation and Reagents 8 5

General Procedure for the Preparation

of Benzo- and Dibenzocrown Ethers 8 6

Monobenzo-12-crown-4 (30) 8 7

Monobenzo-14-crown-4 (39)..... 8 7




Mono[4(5)-tert-butylbenzo]-

21-crown-7 (41) 8 8

Dibenzo-12-crown-4 (54) 8 8





unsvm-Dibenzo-18-crown-6 (45) 8 9



svm-Dir4(5)-tert-buttvlbenzol-

21 -crown-7 (49) ~ 8 9

l,8-Naphtho-16-crown-5 {S6) 9 0

l,8-Naphtho-19-crown-5 (57) 9 0

l,8-Naphtho-22-crown-7 (58) 9 0

IV

o,o'-Biphenyl-17-crown-5 (59) 9 0

o,o'-Biphenyl-20-crown-6 (60) 90

o,o'-Biphenyl-23-crown-7 (61) 91

2,2'-Binaphtho-17-crown-5 (62) 91



N,N'-Ditosyl-4,I3-diazadibenzo-

18-crown-6 (69) 9 1

N-Tosylmonoazadibenzo-18-crown-6 (70) 9 2

2,3 -Pyridino-15 -crown-5 (71) 9 2

2,3-Pyridino-18-crown-6 (72) 9 2

2,3-Pyridino-21-crown-7 (73) 9 2

General Procedure for Preparation

of 1,3-Xylyl Crown Ethers 76-78 9 2

l,3-Xylyl-18-crown-5 (76) 93

l,3-Xylyl-21-crown-6 (77) 93

l,3-Xylyl-24-crown-7 (78) 9 3

l,3-Bis(bromomethyl)benzene (74) 9 3 General Procedure for the Preparation of sym-(Hydroxy)(methyl)dibenzocrown Ethers 87 and 95 94

Procedure A 9 5

Procedure B 9 6

sym-(Hydroxv)(methvl)dibenzo-16-crown-5 (87) 95

svm-(Hydroxv)(methyl)dibenzo-14-crown-4 (95) 9 5

General Procedures for the Preparation of Pyridyl Substituted Crown Ethers Using Sodium Hydride 9 5

Syin-(2-Picolyloxy)dibenzo-13-crown-4 (82) 9 6

5^III-(2-Picolyloxy)dibenzo-14-crown-4 (83) 9 6

&XIIl-(Methyl)(2-picolyloxy)dibenzo-14-crown-4 (98) 9 7

SXni-(2-Picolyloxy)dibenzo-16-crown-5 (84) 9 7

fiyni-(Propyl)(2-picolyloxy)dibenzo-

16-crown-5 (91) 97

2-Picolyl dodecyl ether (104) 9 8

General Procedure for the Preparation of Pyridyl Substituted Crown Ethers Using Potassium Hydride 9 8

sym-(Methyn(2-piclyloxy)dibenzo-16-crown-5 (90) 9 9

sym-(Decyn(2-picoyloxy)dibenzo-16-crown-5 (92) 9 9

sym-(Propyn(benzvloxv)dibenzo-16-crown-5 (103) 9 9

Sodium sym-Dibenzo-16-crown-5-oxyxanthate (105) 100

Methyl sym-Dibenzo-16-crown-5-oxyxanthate (107) 101

Methyl sym-Dir3(4)-tert-butvlbenzo1-16-crown-5-oxyxanthate (108) 101

General Procedure for Preparation of svm (Alkyl)(methoxy)dibenzocrown Ethers 111-113 102

sym-(Methvn(methoxv)dibenzo-16-crown-5 (111) 10 2

VI

SXIII-(Propyl)(methoxy)dibenzo-16-crown-5 (112) 102

&yiTi-(Decyl)(methoxy)dibenzo-16-crown-5 (113) 103

General Procedure for Preparation of N-(2-Trifluoro-4,6-dinitrophenyl)-4'-Aminobenzocrown Ethers 114 and 116 103

N-(2-Trifluoro-4,6-dinitrophenyl)-4'-aminobenzo-14-crown-4 (116) 103

N-(2-Trifluoro-4,6-dinitrophenyl)-4'-aminobenzo-15-crown-5 (114) 104

N-(2-Trifluoro-4,6-dinitrophenyl)-5'-nitro-4'-aminobenzo-15-crown-5 (115) 104

General Procedure for the Preparation of Acyclic Polyether Secondary Alcohols 117 , 119 and 120 1 05

1,3-Bis(ii-niethoyphenoxy)-2-propanol (117) 105

l,3-Bis(2.-methoxyphenoxy)-2-propanol (119) 105

l,3-Bis(a-methoxyphenoxy)-2-propanone (120) 106

General Procedure for the Preparation of Acyclic Polyether Tertiary Alcohols 121 and 122. 1 06

2-[(Q.-Methoxyphenoxy)methyl]-l-(fi.-methoxyphenoxy)-2-pentanol (121) 107

2-[(fi.-Methoxyphenoxy)methyl] -1 -(fl.-methoxyphenoxy)-2-dodecanol (122) 107

General Procedure for the Preparation of Acyclic Polyether Carboxylic Acids 123-127 108

Vl l

1,3-Di(fi.-methoxyphenoxy)-2-(oxyacetoxy)propane (123) 1 0 8

1,3-Di(iTj.-methoxyphenoxy)-2-(oxyacetoxy)propane (126) 10 8

1,3-Di(p.-methoxyphenoxy)-2-(oxyacetoxy)propane (127) 109

4,4'-Bis[(ii-methoxyphenoxy)methyl]-3-oxaheptanoic acid (124) 109

4,4'-Bis[(ii-methoxyphenoxy)methyl]-3-oxatridecanoic acid (125) 1 09

3,9-Dioxa-6-(N-tosylaza)-undecane-l,ll-diol (146) 109

1,11 -Dimethoxy-3,9-dioxa-6-(N-tosylaza)undecane (147) 1 10

l , l l-Dimethoxy-3,9-dioxa-6-

azaundecane (148) 1 10

N-Tosyldiethanolamine (137) 1 11

N-Tosylmonoaza-15-crown-5 (138) 1 11

Monoaza-15-crown-5 (130) 1 13


of 4'-Nitrobenzocrown Ethers 139-144 113

4'-Nitrobenzo-12-crown-4 (139) 1 14

4',5'-Dinitrobenzo-14-crown-4 (143) 114

4'-Nitrobenzo-14-crown-4 (144) 1 14

4'-Nitrobenzo-15-crown-5 (140) 114



V l l l

General Procedures for the Preparation of 4'-Aminobenzocrown Ethers 132-135 and 145 1 15

Procedure A 1 15

Procedure B 115

4'-Aminobenzo-12-crown-4 (132) 116



4'-Aminobenzo-18-crown-6 (134) 1 1 6


General Procedures for Modification of

Nafion® 117 Membrane 1 1 7

Method A 1 17

Method B 117 Hydrolysis of Nafion® Sulfonyl Chloride Membranes 11 8


ofDimesylates 118

Triethleneglycol dimesylate (34) 1 19

Tetraethyleneglycol dimesylate (36) 1 19

1,2-Bis[3-(mesyloxy)propyloxy]

ethyleneglycol dimesylate (35) 119

Pentaethyleneglycol dimesylate (37) 119

Hexaethyleneglycol dimesylate (38) 1 20 Ethyleneglycol dimesylate (42) 1 20

IX

Propyleneglycol dimesylate (43) 1 20

N-Tosyl-diethanolamine dimesylate (68) 1 20

REFERENCES 1 21

LIST OF TABLES

1. Cation Diameters and Cavity Sizes of Crown Ethers 3

2. Yields of the Benzo-18-crown-6 in Ring Closure Reactions with Different Alkali Metal Fluorides 1 0

3. Comparison of Yields for Benzo-12-crown-4 from Alternative Methods 27

4. Comparison of Yields for Monobenzocrown Ethers from Alternative Methods 2 9

5. Cyclization Yields for Dibenzocrown Ethers 3 2

6. Comparison of Cyclization Yields from Different Reaction Conditions 3 6

7. Comparison of Cyclization Yields for 54-56 from Differrent Reagent 3 8

8. Yields of Compounds 82-84 4 5

9. Yields of Compounds 90-92 and 98-100 4 9

10. Chemical Modification of Nafion® Membrane by Method 1 7 4

11. Conversion of Nafion® Membrane to the Sulfonyl Chloride Form Followed by Hydrolysis 7 5

12. Effect of Chlorination Time Upon Alkali-metal Cation Permeation 7 6

13. Chemical Modification of Nafion® Membrane with Monoaza-15-crown-5 by Method II 7 9

14. Influence of Coupling Agents upon Alkali-Metal Cation Permeation 8 1

XI

LISTOFHGURES

1. The First Crown Ethers with Cyclic Hexaethers 1

2. Log Ks versus the Ratio of Cation Diameter to Cavity Size for Alkali Metal Complexed Dicyclohexano-18-crown-6 4

3. Synthetic Approaches for Cyclization Reactions 5

4. The Template Effect in the Synthesis of 18-crown-6 7

5. Complexation of Metal Ion by Lariat Ether 1 1

6. Carbon-pivot and Nitrogen-pivot Lariat Ethers 11

7. Double Armed Diaza-18-crown-6 Compounds 12

8. Typical Chromogenic Crown Ethers 14

9. Cation Complexation Mode of lonizable Crown Ether 21 14

10. The First Acyclic Polyether Compound which Shows

Potassium Ion Slectivity 1 5

11. Bartsch's Acyclic Polyether Ligands 1 6

12. Structure of Nafion® Sulfonate Membrane 17

13. Ion-Cluster Structure of Nafion® Membrane 18 14. Schematical View of Cesium-Assisted Cyclization 3 0

15. Structure of the 2 + 2 Adduct of Dibenzo-13-crown-4 3 4

16. Proposed Complexation of Silver Cation by Pyridyl Pendant Crown Ether 98 5 2

17. X-ray Crystal Structure of Pyridyl Pendant Crown Ether 82 5 3



20. THF-Insoluble Complex of Methoxy Crown Ether with Nal 5 8

Xll

21. Model of Acyclic Polyether Carboxylate Complexation with a Lithium Cation 6 1

22. Structures of Nafion® 117 and Crown Ethers to be Attached to the Membranes 65

23. IR Spectrum of Nafion® 117 (*), Nafion®-monoaza-12-crown-4 (**) and Nafion®-monoaza-15-crown-5 (#) 83

Xll l

CHAPTER I

INTRODUCnON

Crown Ether Background

The systematic synthetic method of crown ether synthesis was

reported by Pedersen in 1967.HI Various kinds of crown ethers with

different ring sizes and rigidity were prepared by an adaptation of

the Williamson ether synthesis. Crown ethers 1 and 2 exhibit good

selectivity for potassium cation in extraction from aqueous solution

into organic solvents in the presence of the other alkali metal cations.

The hydrocarbon portion of the macrocyclic ring orients itself

o o

1 2

Figure 1. The First Crown Ethers with Cyclic Hexaethers.

outwards from the cation which provides lipophilicity to solubilize

the cation in the organic solvent. The metal ion selectivity of the

macrocyclic ring is related to the size of the cavity formed by the

ether oxygen atoms.

A convenient nomenclature for crown ethers was proposed by

Pedersenni in which macrocyclic ring 1 and 2 are designated 18-

crown-6 and dibenzo-18-crown-6, respectively. The specific

1

designation "crown" is preceded by the kind and number of

substituents on the polyether ring, and the total number of atoms

which constitute the polyether ring and is followed by the number of

heteroatoms in the ring. The term dibenzo refers to the two benzene

rings connected on the ring.

Cation Complexation by Crown Ethers

Pedersen first discovered the complexation of crown ethers

with alkali metal ions.t^l The formation of complexes by binding of

metal cations is caused by electrostatic ion-dipole interaction

between cations and electron-rich oxygen donor atoms. The stability

of these complexes depends on the relative sizes of the cation and

the cavity size of the polyether ring. Pedersen proposedt^^ the

factors which influence the stability of crown ether-metal cation

complexes are: the relative sizes of the crown ether cavity and the

metal ion; the number of oxygen atoms in the crown ether ring (the

more the better); the coplanarity of the crown ether ring; the

symmetrical placement of the oxygen atoms; the basicity of the

oxygen donor atoms (the stability of the complex increases with

increasing basicity); steric hindrance in the crown ether ring (the less

steric hindrance, the more stable is the complex formed); the

tendency of the ion to associate with the solvent (complexation of the

metal ion requires desolvation); and, the electrical charge on the

cation.

The stability of a crown ether complex is measured by the

stability constant Kg which is defined by the law of mass

equilibrium.[3] A high stability constant can be obtained when the

size of metal ion matches well the cavity size of crown ether ring. In

other words the relationship between cavity size of crown ether ring

and cation diameter is very important in determining the stability of

the complex. The cavity sizes of several crown ether rings and alkali

metal ion diameters are summarized in Table 1. 4] As shown in the

table, Li+and 14-crown-4, Na+ and 15-crown-5, K"*" and 18-crown-6,

Cs"*" and 21-crown-7 fit best in size.

Table 1. Cation Diameters and Cavity Sizes of Crown Ethers.

Cation Cation Diameter [A]t5,6] Crown Ether Cavity Diameter [A]

Li

Na

K

Rb

Cs

1.36

1.90

2.66

2.98

3.38

14-crown-4

15-crown-5

18-crown-6

19-crown-6

21-crown-7

1.2a . 1.5b

1.7 - 2.2

2.6 - 3.2

3.0 - 3.5

3.4 - 4.3

a Lower values estimated from Corey-Pauling-Koltun (CPK) models,

b Higher values from Fisher-Hirschfelder-Taylor (FHT) models.

The stability constant versus the ratio of cation diameter to

cavity size for dicyclohexano-18-crown-6 complexes with alkali

metal ions is plotted in Figure 2.t7] As expected by the cavity size

and metal ion size relationship, dicyclohexano-18-crown-6

complexes best with potassium ion and shows highest stability

constant. The other alkali metal ions have lower stability in

complexation due to the difference of cavity size and ion diameter.

Figure 2.

LogK

0.6 0.2 1.0 1.2

cation diameter/cavity size Log Ks vs. the Ratio of Cation Diameter to Cavity Size for Alkali Metal Complexed Dicyclohexano-18-crown-6.

Synthesis of Monobenzo- and Dibenzocrown Ethers

The synthesis of macrocyclic ring compound usually gave low

yields and oligomers. These problems can be avoided by use of high

dilution conditionf^l which facilitates the cyclization reaction by use

of very low concentrations of reactants. The presence of one or more

rigid groups also enhances of cyclization yields by reducing the

conformational possibilities of the reactants.[2]

The most widely used approaches for cyclization are shown in

Figure 3.t9] Approaches 2 and 3 provide the most efficient one-pot

Approach 1.

-X C I mol base / '"^n

-Y

Approach 2.

-X Y-

C * ) ^ X Y-^

j ^ mol base

-X Y-

Approach 3. ^^^^

1 C + 2 ^ 4 mol base ^ / ^ ^ \

X . , z

Approach 4.

C ^^-^ 2 mol base. ^ ^ ^ ^ \ f ^ ^

Approach 5.

C ^ " \ 1 mol base, ^ Dimerization ^ / ' ^ ^ ^

X X-^ ^ Z Y ^ 7 Z-^

Figure 3. Synthetic Approaches for Cyclization Reactions.

synthesis of monobenzocrown ethers. The stepwise Approach 4

provides the most versatile synthesis of dibenzocrown ethers. In an

adaptation of Approach 1, Pedersen first synthesized 18-crown-6 by

cyclization of hexaethyleneglycol monochloride using tert-BuOK as a

base under high dilution conditions (Scheme 1).^! The yield was

only 2%. Cram et al. prepared 12-crown-4, 15-crown-5 and 18

Scheme 1

c o o-^^ci O OH

tert-BuOK CH3OCH2CH2OCH3

-crown-6 by the reactions of dichlorides and diols using lithium,

sodium and potassium hydroxides, respectively (Scheme 2).HO]

Scheme 2

I O CI U<0. + ^ n

O CI H-O-^ NaOH 1,4-Dioxanc

4^3

KOT" THF-H2O

^O-N, o o

Yield 13 %

o o

Yield 14 %

o o o o k , o ^ 1

Yield 40-60 %

The relatively high yields of cyclic crown ethers 1, 3 and 4 were

obtained without use of high dilution conditions. The striking

increase in yield for 18-crown-6 can be rationalized by a template

effect of the potassium cation which keeps the chains together during

reaction (Figure 4).ni]

CI r u ^ ( c i

Figure 4. The Template Effect in the Synthesis of 18-crown-6.

In consideration of the results shown in Scheme 2, the optimal

template effect is achieved when the diameter of cation fits best to

the cavity of the crown ether being formed.

Dibenzo-18-crown-6 (2) was synthesized by utilizing

Approaches 3 and 4 in 45% and 80% yields, respectively (Scheme

3).[2]

Scheme 3

OH , , ^ , _ P 0^,^^. „ , / \ / \ tcrt-BuOK jtf^^S/ V{[ I! X ^ CI o CI r r x j

OH ^ ^ ^ O O

2) CI O CI ^ rr^TT^i^ tClt-BuOK

^. OTHP THPO

THP = tetrahydropyranyl

The reaction of partially protected catechol with bis(2-chloroethyl)

ether via Approach 4 gave a higher yield than the condensation

reaction of catechol and bis(2-chloroethyl)ether which utilized

Approach 3. The template effect of potassium cation is important to

obtain a good yield.

For preparation of monobenzocrown ethers the reaction of

catechol salts with polyethylene glycol derivatives such as halides,[2]

p-toluenesulfonates,n2] ©r methanesulfonatesHS] have been used

most frequently. Luis et al. evaluated several synthetic routes to

benzocrown ethers with different ring sizes and found that the most

8

convenient synthetic method was the reaction of o-bis(2-

hydroxyethoxy)benzene 5 and oligoethyleneglycol-p-tosylates

(Scheme 4).n4] xhe yields for monobenzocrown ethers 6-8 ranged

from 30-64%. In addition to the high dilution method and template

effect for macrocyclization reactions, cesium assisted ring closure

reactions have been used for synthesis of medium and large

Scheme 4

I f

5 n Yield

6 2 53 % 7 3 64 % 8 4 30 %

macrocyclic compounds.[15] Benzo-18-crown-6 was prepared by the

reaction of pentaethylene glycol tosylate with catechol (Scheme 5).[16]

Scheme 5

aDH MF/CH3(J

OH TsO O OTs

LiF, NaF

KF

CsF

no reaction

52

60

Among the alkali metal cations used in the reaction cesium exhibited

the highest yield and shortest reaction time. Yields and reaction

times for benzo-18-crown-6 forming cyclization reactions are

summarized in Table 2.

Table 2. Yields of the Benzo-18-crown-6 in Ring Closure Reactions with Different Alkali Metal Fluorides.

Base Isolated Yields (%) Reaction Time (h)

140

69

12

The cesium assisted synthesis of benzocrown ethers often

provides higher yields of cyclization reaction products without the

use of the high dilution method.^V]

Lariat Ethers

A simple crown ether complex lacks the ability to envelop a

cation and thereby enhance the binding strength. To overcome this

drawback crown ethers with a side arm which provides an additional

binding site have been synthesized and named as "lariat" ethers.t^^]

Their complexes with metal ions usually show additional stability

relative to those of the simple crown ethers.

10

The lariat ether concept is represented schematically in Figure

5. At first the crown ether ring would complex with the metal ion

M ^

D: Additional donor atom

M: Metal Ion

Figure 5. Complexation of Metal Ion by a Lariat Ether.

in the way normally associated with crown ether binding and then

the donor group attached to the side arm further solvates the cation

in the crown ether ring.

Lariat ethers can be separated into two classes by the identity

of the pivot atom which attaches the side arm to the polyether ring.

Typical lariat ethers are shown in Figure 6. The carbon-pivot lariat

CH2OR /_^ . R

^ o r ^ ^ o ^ o o'

R_ 9 ^ 9 CH2OH 1 0 CH2OCH3 ^ 1 1 CH2C6H4OCH3-0 1 3 OH 1 2 CH2OC6H4OCH3-P 1 4 OCH3

Figure 6. Carbon-pivot and Nitrogen-pivot Lariat Ethers.

1 1

ethers can be prepared by synthetic manipulation of glycerol

(HOCH2CHOHCH2OH). The nitrogen-pivot lariat ether are normally

prepared by N-alkylation of azacrown ethers and are easier to

synthesize than their carbon-pivot counterparts. The carbon-pivot

lariat ethers are more chemically stable but less dynamic than the

nitrogen-pivot analogues because of the facile inversion of the

nitrogen atom.

Lariat ether 11 showed better extractability for sodium cation

than the para substituted one 12.n8] xhe former is able to complex

the metal cation with the methoxy group, but the latter cannot utilize

the additional binding site of the side arm due to the an unfavorable

alignment of the donor group.

Tsukube et al. has prepared pyridino- and quinolino-

incorporating diaza-18-crown-6 compounds (Figure 7).tl9]

D

1 5 - Q

16

17

D-- ' 18

D = Donor Group 1 9

Figure 7. Double Armed Diaza-18-crown-6 Compounds.

12

These new series of double-armed diazacrown ethers provided

excellent transport ability toward transition metal cations, such as

Cu, Co and Zn cations, which is rarely seen with simple crown ethers.

The cooperative action of the crown ether ring and additional cation

ligating donor groups provide three-dimensional complexation of

metal ions. The lariat ethers 15 and 17 with pyridine and quinoline

rings as secondary donor groups exhibited good transport ability

toward Cu, Zn, Ba and Pb cations. However related compounds 16,

18, and 19 showed very low transport ability for transition metals

because of an inappropriate orientation of the donor group in the

complex or a lack of electron donating ability of the side arm.

Chromogenic Crown Ethers

A series of crown ether derivatives have been prepared which

have color-inducing functional groups.t20] These compounds are

designed to become colored when complexed with alkali and alkaline

earth metal ions which are normally colorless. This type of

compound has been developed for use as spectrophotometric

analytical reagents for specific cations. The selectivity for cation

complexation can be controlled by choosing a suitable cavity size in

the crown ether portion. The color changes of these compounds are

related to the charge transfer transitions of their dye moieties.

Chromogenic crown ethers may be either non-ionizable or ionizable

compounds as shown in Figure 8.

13

2 0 ^ ' 2 1 ^ O ^ O - ^

Non-ionizable Compound lonizable Compound

Figure 8. Typical Chromogenic Crown Ethers.

Non-ionizable crown ether 20 showed that the modified rings

retain the metal ion discriminating ability which is present in the

corresponding simple crown ethers.t^l] The color change of ionizable

compound 21 is associated with ionization of the proton which is

assisted by complexation of the metal cation in the crown ether ring.

The chromogenic crown ether 21 selectively extracts specific alkali

metal ions from water into organic solvents via the structure shown

in Figure 9.t22] The chromogenic crown ether 21 has been

demonstrated to be suitable for the extraction and

spectrophotometric determination of sodium in human blood.[22]

-N—M---0

Figure 9. Cation Complexation Mode of lonizable Crown Ether 21

14

Acyclic Polvether Compounds

Open chain analogues of crown ethers have attracted

considerable attention because of the advantage of facile synthesis,

versatile variation of structures, inexpensive starting materials and

their rapid complexation of metal cations.[23] Their use as phase

transfer catalysts[24] and extractants[25] is well documented.

An acyclic polyether compound which complexes with alkali

and alkali earth metals is the bis(quinoline) oligoether 22 which has

an 8-hydroxyquinoIine residue at the end of chain structure (Figure

10).[26] This compound showed potassium ion selectivity in the

presence of other alkali metal ions. The introduction of aromatic

substituents carrying electron-donating centers at the ends of the

oligoethyleneglycol chain enhances the rigidity of the ligands and

considerably increases complexation ability. The 8-quinolinole, o-

hydroxy, o-methoxy, o-carboxylic acid and tropolone units can be

used as rigid end groups.[27,28] Also the flexible ethylene glycol units

in ligand molecules can be replaced by rigid aromatic group.[29]

o o

22 Figure 10. The First Acyclic Polyether Compound which Shows

Potassium Ion Selectivity.

15

The creation of lithium selective acyclic compounds is difficult

because the lithium ion has the smallest radius among alkali metals

and exhibits a very high hydration energy. However, a lithium-

selective acyclic ligand 23 was prepared which has four oxygen

atoms and a 8-quinolinol moiety as donor groups.[301

Bartsch and co-workers prepared various kind of lipophilic

acyclic diioniazble polyethers.[3I] Some of these acyclic ligands are

shown in Figure 11. Acyclic ligands 24 and 25 showed barium ion

\ _ 0 OH ^jj COJHHOJC

-ta n 24 2 25 3 26 4

HiiCio'^ CO2H HO2C C10H21

n 27 1 28 2 29 3

Figure 11. Bartsch's Acyclic Polyether Ligands.

16

selectivity in the presence of magnesium, calcium and strontium

cations. The highest barium selectivity was observed for compound

25. Acyclic polyether dicarboxylic acid 28 with lipophilic groups

exhibited excellent selectivity for barium ion in competitive solvent

extraction. Compounds 27 and 29 which have one less or one more

ethylenoxy unit than compound 28 showed decreased barium

selectivity. Examination of Corey-Pauling-Koltun (CPK) space filling

model showed a pseudocyclic conformation when ligand molecule 28

was complexed with a barium cation.

Nafion® lonomer Membrane

The perfluorosulfonate ionomers marked by Dupont as Nafion®

products exhibit remarkable chemical and thermal stability and have

been used as ion exchange resins,[32] as a membrane separator in

electrochemical applications[32] and as an acid catalyst in synthetic

organic chemistry.[34] Nafion® perfluorinated membranes are

constructed from a perfluorinated resin which has the general

chemical structure shown in Figure 12 where the value of m can be

as low as 1. The pendant ionic groups interact to form ion-rich

-K3'2CF2-i5-CF2CF-

(OCF2CF)„OCF2CF2S03Na*

CF3

Figure 12. Structure of Nafion® Membrane.

17

aggregates contained in a nonpolar matrix which strongly influences

polymer properties and applications. Although Nafion® is not

covalently crosslinked, it has a highly ordered structure. The

ionizable sulfonate groups form clusters, which cause the production

of water containing pockets in a hydrophobic matrix. At low

temperature, the Nafion® membrane containing water molecules

possesses the rigidity of a crosslinked polymer.[34] The molecular

organization of a cluster of Nafion® membrane is shown in Figure

13.[35] Counterions are largely concentrated in high-charge

^''^'^'-y/y y yy / y y yy -' .y .y j:i—^yy y y >-r^yy y

Figure 13. Ion-Cluster Structure of Nafion® Membrane.

shaded regions which provide continuous diffusion channels.

The first surface modification of Nafion membrane was

conducted by Lowry et al.[36] in the study, Nafion® 117

perfluorosulfonic acid membrane was converted to the reactive

18

sulfonyl chloride form by refluxing in a 33 weight % solution of PCI5

in POCI3 for 96 hours. The sulfonyl chloride intermediate was

converted to a sulfonamide form by contacting the polymer with a

95% ethylenediamine solution (5% water) at room temperature for

up to 250 hours. The quantitative conversion of the sulfonic acid

polymer to its sulfonyl chloride form was verified by the

disappearance of the S-0 symmetric stretch (1060 cm-1) in the

infrared spectrum. This diamine-modified Nafion® membrane

showed improved cation selectivity over the original Nafion®

membrane.

A Japanese patent[37] also describes the conversion of Nafion®

perfluorosulfonic acid resin to the sulfonyl chloride form by refluxing

in a mixture of PCI5 and POCI3 for 24 hours. Nearly 100% efficiency

was achieved if the membrane was converted into the ammonium

form before transformation to the sulfonyl chloride form.

Hayashita conducted dialysis experiment with Nafion®

perfluorinated acid membrane by utilizing proton-coupled

transport.[39] The mechanism for the proton-driven permeation

system involves transport of alkali metal cations from the source

solution (aqueous solution containing 1 mM alkali metal chlorides,

pH=11.0) to the receiving solution (0.1 M HCl solution) accompanied

by back transport of protons from the receiving phase to the source

phase. The result showed the permeation selectivity ordering of

K+>Rb+>Cs+>Na+>Li+ after 7 hours.

19

Statement of Research nnal

During the past two decades, much attention has been given to

the design and synthesis of macrocyclic compounds capable of

selective recognition for ionic species. Among them, crown ethers

are finding many practical applications due to their unique metal ion

complexation and transport ability.

The major portion of this dissertation encompasses the

development of new efficient cyclization methods for monobenzo- or

dibenzocrown ethers as well as the synthesis of lariat ethers and the

preparation of acyclic polyether compounds.

A new cyclization method for aromatic ring containing crown

ethers with various ring sizes is to be developed and evaluated by

comparison with reported methods. Lariat ethers possessing high

potential for complexation of either alkali or transition metal ions are

to be synthesized by introduction of carefully chosen pendant side

arm groups. Acyclic polyether carboxylic acids with methoxy donor

groups which are useful for preparation of metal ion selective

condensation polymers are to be prepared.

The second portion of this dissertation is the chemical

modification of Nafion® ionomer membrane which may be used to

separate one ionic species from the others. The goal is to provide

barrier layers on each side of the membrane through which metal

ion permeation will be controlled by the identify of the ionic species.

20

To achieve this goal, the feasibility of attaching ionophore molecules

onto the surface of Nafion® perfluorosulfonic acid will be examined.

21

CHAPTER n RESULTS AND DISCUSSION

Crown Ethers with Aromatic Rings as Part

of the Polvether Ring

Benzo- and Dibenzocrown Ethers-Cesium Effect

After discovery and first synthesis of crown ethers by

Pedersen, numerous attempts have been made to find more efficient

synthetic methods. Among the many different kinds of crown ether

compounds, some of the most popular and fundamental types are

monobenzo and dibenzocrown ethers. By introduction of various

kinds of functionalities on the aromatic unit of such crown ethers

through electrophilic substitution reactions, the properties of crown

ethers may be altered to give improved metal ion complexation and

transport ability. Initially, Pedersen prepared monobenzo crown

ethers by the reaction of catechol and a dihalide in the presence of

NaOH in 1-butanol (Scheme 6).[2]

Scheme 6

^ ° \ c i - R - C l - 4 ^ 0 H ^ r Y ° ) R . 2 N a a . 2 H 2 0 ^ ^ O H 1-butanol " V ^ Q

R = A divalent organic group.

The yields of cyclization products were found to be highly

dependent on the size of the polyether rings. Crown ethers with five

or six oxygen atoms were always formed in higher yields than their

22

smaller-ring analogues. The synthetic strategy for this method is

utilization of the S N 2 substitution reaction of catechol anions with

polyethyleneoxy compounds which have suitable leaving groups,

such as halide. However, the overall yield which could be obtained

by this method were only modest. With increasing demand for a

variety of crown ether compounds, the development of higher

yielding synthetic methods was sought. Several groups have

reported improved synthetic methods for the preparation of benzo-

and dibenzocrown ethers. Cesium-assisted synthesis of crown ethers

with aromatic subunits was found to provide superior yields

compared with other alternative synthetic routes.[39]

Macrocyclization of catechol either with a polyethyleneglycol

dihalide and CS2CO3 or with a polyethyleneglycol ditosylate[40] and

CsF gave good yields.[39] The former combination was used by

Kellogg and coworkers who obtained very good yields of monobenzo-

15-crown-5 and monobenzo-21-crown-7 (Scheme 7). Although this

Scheme 7

1) CS2CO3

• v ^ O H 2) Br Br ^ - ^ O j ^ n

n Yield(%) DMF 6 3 50

4 days 7 4 74 8 5 78

23

procedure utilized some laborious steps and less accessible starting

materials (dihalides of polyethylene glycols) the yields were

remarkable. The latter method which was developed by Bartsch and

coworkers also gave high yields for the synthesis of crown ethers

with benzo group substituents. Benzo-12-crown-4 30 was obtained

29% yield by this method (Scheme 8).

Scheme 8

^xNÔH I 1 0 1 + CsF + j r y r y i - r CH3CN ^r^sô o-i K^nu TsO O O OTs — ^ H T

OH 80 °C "^^^^Ô O-I 1-3 days ' ' 3 0

Ts= p-Toluenesulfonate ^^^

It was clearly established that the presence of cesium cations

was necessary to promote the enhanced yields of crown ether

product during the macrocyclization step. Although these methods

showed high efficiency for benzocrown ether synthesis, they also

have certain disadvantages. Kellogg's method has serious

shortcomings for the preparation of benzocrown ethers with ring

sizes smaller than 18-crown-6. Thus, the 50% yield of benzo-15-

crown-5 6 is low compared with yields obtained through alternative

routes.[14]

Bartsch's approach used CsF which is more expensive than

CS2CO3. Also fluoride anion can act as a nucleophilie and produce

competitive displacement reactions on polyethylene glycol

24

ditosylates.[4l] Therefore, optimization of reaction conditions

becomes very important.

In the current research, a new combination of reagents for the

cesium-assisted cyclization was discovered and evaluated for the

preparation of monobenzo or dibenzocrown ethers with varying ring

sizes. Cesium carbonate was chosen as the base due to its cheaper

price than cesium fluoride, availability and a proven effectiveness

for macrocyclization. Mesylate was selected as the leaving group

because of its higher reactivity than tosylate. Acetonitrile was used

as the reaction solvent because its appropriate boiling point as well

as high dielectric constant and polar aprotic nature which should

provide good solubility for the reactants and possible rate

enhancement of reaction.

The first evaluation of this system (Cs2C03/polyethyleneglycol

dimesylate/CH3CN) was attempted for the preparation of

monobenzo-12-crown-4. Cyclization of catechol 33 with the

dimesylate of triethyleneglycol (34) induced by CS2CO3 in CH3CN at

reflux was performed to produce monobenzo-12-crown-4 (30)

(Scheme 9). An acetonitrile solution of dimesylate 34 (1 equiv) was

added dropwise with a syringe pump to a reaction mixture of

catechol 33 (1 equiv) and CS2CO3 (2-3 equiv) at reflux. Under these

reaction conditions, the 1 + 1 adduct 30 was obtained in 45% yield

which is far superior to yields reported for other methods. Although

high dilution techniques usually are advantageous for

macrocyclization, in this reaction a high yield of cyclized product was

obtained without the use of such kind of methods.

25

Scheme 9

OH

l ! ^ ^ ^ MsO O O CMS CH3CN ' i ^ ^ o o-J

3 3 34 80°C ' ' 3 0

(trace)

A trace amount of 2 + 2 product 31 was detected by TLC, but was

easily removed from the crude product by recrystallization from

heptane. Table 3 compares the yields for monobenzo-12-crown-4

obtained by alternative synthetic method. This comparison clearly

demonstrates that the Cs2C03/dimesylate combination is the most

efficient for the cyclization reaction to produce monobenzo-12-

crown-4.

26

Table 3. Comparison of Yields for Benzo-12-crown-4 from Alternative Methods.

Reactants and Solvent Yield (%) Reference

catechol, dichloride, NaOH, 1-BuOH 4 1

catechol, ditosylate, CsF, CH3CN 2 9 3 9

catechol, dimesylate, CS2CO3, CH3CN 4 5

Encouraged by this result, the synthesis of previously

unreported monobenzo-14-crown-4 was undertaken. Reaction of

catechol and polyethyleneglycol dimesylate (35) in the presence of

CS2CO3 in CH3CN gave desired product 39 in 76% yield (Scheme 10).

Scheme 10

OH . . ^

l ^ * MsO O O CMS CH3CN " i s A o O-I

3 8 80°C k ^ 39

c? o ( trace )

27

The very high yield of this small ring crown ether illustrates the

advantage of the new synthetic method. A trace amount of the 2 + 2

product 40 was detected by TLC. It was easily separated from 3 9

by column chromatography and was identified by mass

spectrometry. Benzo-14-crown-4 has been found to exhibit excellent

complexation selectivity toward lithium cation.[42]

For further evaluation of the Cs2C03/dimesylate/CH3CN

combination, several already reported monobenzocrown ethers with

varying ring sizes (15, 18 and 21 members) were synthesized

(Scheme 11).

Scheme 11

r> MsO O O CMS cHjQJ '^ Kf^O ^ >

A V " XL

3 4 1 6 H 1 ^ ^ 2 7 H 2 37 3 8 H 3 ^* " 4 1 t-Bu 3

All reactions gave only the 1 + 1 adduct with no detectable 2 + 2

adduct (TLC). The cyclization yields are summarized in Table 4 and

compared with yields reported for other preparative methods. As

28

can be seen the new method always produced higher or comparable

yields than those which have been reported previously.

Table 4. Comparison of Yields for Monobenzocrown ethers from

Alternative Methods.

Compound

6

6

6

7

7

7

8

8

8

4 1

Leaving Group

a OTs

OMs

a OTs

OMs

a OTs

OMs

OMs

Base

NaOH

CsF

Cs2CC>3

NaOH

CsF

CS2CO3

NaOH

CsF

Cs2CC>3

CS2CO3

Solvent

1-BuOH

CH3CN

CH3CN

1-BuOH

CH3CN

CH3CN

1-BuOH

CH3CN

CH3CN

CH3CN

Yields(%)

62

61

71

60

60

75

50

65

81

77

Reference

2

16

2

16

43

16

It has been proposed that the large surface area of the cesium

cation can coordinate both the negatively charged phenolate anion

and a partial negative charge on the leaving group to promote

intramolecular cyclization.[44] This proposal for the new synthetic

method is depicted in Figure 14.

29

Figure 14. Schematical View of Cesium-Assisted Cyclization.

In addition to monobenzocrown ethers, dibenzocrown ethers

have received a great deal of attention due to their selectivity in

metal ion complexation ability as well as their versatility for

functionalization on the aromatic rings. Furthermore many kinds of

crown ether polymers could be made by utilizing dibenzocrown

ethers as monomers. In consideration of their importance to crown

ether chemistry, the limited number of synthetic methods for their

synthesis is surprising. The most popular method for the

preparation of dibenzocrown ethers was developed by Pedersen

(Scheme 12).[1]

Scheme 12.

ar ":o ™ ^ ocf o + 2 NaCl + 2 H2O

30

However, this method gave only modest or low yields for most

dibenzocrown ethers and the procedure is somewhat tedious. A

simpler and more efficient synthetic method would be beneficial.

Therefore, the potential of the new cyclization method was also

evaluated for preparation of dibenzocrown ethers.

Initially dibenzocrown ethers with relatively large ring sizes (15-

21 members) were prepared (Scheme 13). Bis(hydroxyaromatic)

Scheme 13

OH HO. a: „X) A 43 44 I"

MsO CMS 45 2

^ O O ; " ^ 2 47

^ 0 0 .

aoHHo.,*** r\r~\r\. r -v- ° v ^ ^ ^J3-RMSOOOCMS , 0 ; ^ ^ ) ^ ,

4 8 R=H 4 9 R= t-butyl

31

compounds were reacted with polyethyleneglycol dimesylates in the

presence of CS2CO3 in CH3CN at reflux to give the desired

dibenzocrown ethers. The yields obtained by this method are

summarized in Table 5 and compared with those reported by

Pedersen. As illustrated in Table 5 the Cs2C03/dimesylate/CH3CN

Table 5. Cyclization Yields for Dibenzocrown Ethers

Compound

4 4

4 5

4 6

4 7

4 8

4 9

Ring Size

15C5

18C6

16C5

19C6

21C7

21C7

Yield (%) for Synthesis with

Cs2C03/dimesylate KOH/dichloride^

57

75

83

61

78

67

43

25

18

16

36

^Reference [1].

system gave much higher yields than the KOH/dichloride/1-butanol

combination. Apparently cesium cations assist dibenzocrown ether

formation.

To investigate the applicability of the new synthetic method to

the preparation of small-ring dibenzocrown ethers, the reaction of

bis-l,3-(2-hydroxyphenoxy)propane with 1,3-propanediol

32

dimesylate (50) in die presence of CS2CO3 in refluxing CH3CN was

performed (Scheme 14). After work up and purification by column

Scheme 14

^ ^ .OH H O ^ ^ y \ 0 0

5 1

chromatography dibenzo-14-crown-4 (51) was obtained in 92%

yield. This is a dramatic yield improvement from the 27% reported

by Pedersen.[ll No 2 + 2 adduct was detected by TLC. In view of the

smaller ring size, the absence of 2 + 2 adduct is remarkable.

Buchanan reported the first synthesis of dibenzo-13-crown-4 in

33% yield by the reaction of 1,2-bis(o-hydroxyphenoxy)ethane with

1,3-dibromopropane and LiOHH20 in l-butanol.[45] The synthesis of

dibenzo-13-crown-4 by the reaction of a bisphenol with a glycol

dimesylate and CS2CO3 in CH3CN was attempted. Two different

pathways to dibenzo-13-crown-4 are possible (Scheme 15). Dibenzo-

13-crown-4 (52) was obtained in 72% yield by Pathway A and 52%

by Pathway B. For Pathway A a trace of 2 + 2 product 53 was

33

Scheme 15

.OH HO OH HO ^

* - ^ 0 0 - ^ ' * ° ° * C3%CII \ / \

1—1 '' 0 O

Pathway B

formed but was readily separated from 52 by recrystallization from

CH2Cl2-MeOH. A larger amount of 2 + 2 adduct (Figure 15) was

obtained for Pathway B so its removal was more difficult than in the

[ ]

53 Figure 15. Structure of the 2 + 2 Adduct of Dibenzo-13-

crown-4.

34

case of Pathway A. Therefore Pathway A is the route of choice for

the preparation of dibenzo-13-crown-4.

Preparation of dibenzo-12-crown-4 was also attempted by the

use of the Cs2C03/dimesylate/CH3CN system (Scheme 16).

Unfortunately, the amount of cyclization product formed was too

small to allow complete separation of the 2 + 2 adduct 55 and the

1 + 1 adduct. The major product was the 2 + 2 adduct and the 1 + 1

adduct was obtained in a 12% crude yield. Although the melting

point (208 oC) of the crude 1 + 1 adduct was identical with the

reported value (208-209 oC),[ll the presence of the 2 + 2 adduct was

detectable in the mass spectrum. Thus the Cs2C03/dimesylate/CH3CN

Scheme 16

OH HO I ' OH HO,^^ ^ Cs,C03 ^ O O

I I 80°C ? ? 54

a; X) •0 O" [ ]

a X) 55

35

system was found to be ineffective for the synthesis of dibenzo-12-

crown-4. In Table 6, the yields of dibenzocrown ethers 51, 52 and

Table 6. Comparison of Cyclization Yields for Different Reaction Conditions.

Compound

5 1

5 2

5 4

Ring Size

14C4

13C4

12C4

Yield r% for

CS2CO3/ dimesvlate

92

74

12a

Svnthesis with

MOH/ dihalide

27

33

1 1

Reference

1

45

1

^Crude yield.

54 obtained with the new synthetic method are compared with

those reported for reactions in which MOH and dihalides were

involved.

For further evaluation of the new synthetic method, crown ethers

were synthesized which have aromatic units derived from 1,8-

dihydroxynaphthalene, 2,2'-biphenol and 2,2'-binapthol in their

molecular structures. These dihydroxyaromatic compounds were

reacted with glycol dimesylates to give the corresponding crown

ethers (Scheme 17).

36

Scheme 17

HO OH

rAr^/H/n ^ ^ ^ MsO 0 0 0 OMs CUgCN

n=l,2,3 80°C

n. 56 1 57 2 58 3

n. 62 1 63 2 64 3

The yields of crown ethers 56-64 are shown in Table 7 and

compared to yields from alternative synthetic methods. The yields

from the new reaction procedure are comparable to those from

reported ring closure reactions.

37

Table 7. Comparison of Cyclization Yields for 56-64 for Different Reagents

Compound

5 6

5 7

5 8

5 9

6 0

6 1

6 2

6 3

6 4

Ring

Size

16C5

19C6

22C7

17C5

20C6

23C7

17C5

20C6

23C7

CS2CO3/

dimesylate

77%

80%

54%

64%

75%

73%

52%

80%

85%

Alternative routes

reagents yield(%)

CsF/Tosylate

CsF/Tosylate

Okahara method^

CsF/Tosylate

Okahara method^

Okahara method*

t-BuOK/Tosylate

Okahara method*

63

53

64

23

73

54

60

59

reference

39

39

46

16

46

46

47

46

^Reaction of diol with tosylchloride and alkali metal hydoxide.[48]

N,N'-Ditosyl-4,13-diazadibenzo-18-crown-6 (69) is a precursor for

the preparation of 4,13-diazadibenzo-18-crown-6, which is widely

used as a starting material for the synthesis of various types of

cryptands. Macrocycle 69 has been prepared by reported procedure

which used the reaction of N-tosyl-bis-[2-(2-hydroxyphenoxy)-ethyl]

amine and tritosyl diethanolamine in the presence of potassium tert-

butoxide.[49] However, the procedure is tiresome and time

38

consuming (5 days). A more efficient and simpler synthetic method

would be highly beneficial for large scale synthesis. The new

cyclization method of Cs2C03/dimesylate/CH3CN was used for the

synthesis of 69. The reaction of N-tosyl-bis-[2-(2-

hydroxyphenoxy)ethyl]amine (67) with N-tosyl diethanolamine

dimesylate (68) and CS2CO3 in CH3CN at reflux for 24 h gave the

desired compound 69 in 74% yield (Scheme 18).

Scheme 18

^ 66 Ts r\i/-i

OH ^^^OH 65 I

Ts 67

CS2C03,CH3CN K^Q Q-K^

Ts

69

39

The synthetic precursors mono-THP-protected catechol (65),

tritosyl diethanolamine (66) and N-tosyldiethanolamine ditosylate

were prepared by literature methods.[49] it is interesting to note

that when granular CS2CO3 was used for conversion of 67 into 69,

the yield dropped to around 50%. When powdered CS2CO3 was used,

the yield increased to 74%. This indicates that powered CS2CO3

should be used for the cyclization reaction to obtain the highest yield.

The cyclization yield for N-tosyl monoazadibenzo-18-crown-6

(70) synthesis was also enhanced by use of the new method.

Previously 70 was prepared by Hogberg and Cram in 34% yield by

reaction of bis[2-(o-hydroxyphenoxy)ethyl]ether with N-tritosyl

diethanolamine and K2CO3 in DMF.[50] By use of the new method

compound 70 was obtained in 72% yield (Scheme 19).

Scheme 19

Ts

r T ' ' " " ' ' n + nln cs,co3, fyQ o ^ K^Q O ^ ^ MsO N OMs - ^ ^ ^ p I^A^ ^XJ

70

Kellogg and co-workers have synthesized crown ethers which

contain a pyridine unit.[40] Reaction of 2,3-dihydroxypyridine with

CS2CO3 in MeOH was followed by addition of the polyethyleneglycol

dibromide in DMF. However, cyclization yields were only modest

40

(14-31%) due to the formation of 2-pyridone. Three different ring-

sized crown ethers 71-73 were prepared by the reaction of 2,3-

dihydroxypyridine with polyethyleneglycol dimesylates and CS2CO3

in CH3CN (Scheme 20). Yields for the cyclization reactions shown

Scheme 20

\ O"^

i X ^ MsO O O OMs ^ ^ ' 11 S N^OH ™3CN N O o j S n

A ^ Yieldr%^

This method Reported method

n 7 1 1 14 14^ 72 2 3 7 23^

7 3 3 22 31^

a: Kellogg's yields (ref. 40)

in Scheme 18 are very similar to those obtained by Kellogg and

co-workers.

1.3-Xvlyl Crown Ethers

For comparison of alkali metal binding properties by

calorimetry with analogous compounds which have intraanular -

CO2H, -OCH3 and -OCH2CO2H groups 1,3-xylyl crown ethers were

prepared. Reinhoudt and co-workers reported the first synthesis of

1,3-xylyl crown ethers by the reaction of l,3-bis(bromomethyl)-

benzene with polyethyleneglycol and potassium tert-butoxide in

41

toluene.[5II The driving force for the reaction was thought to be a

template effect of the potassium cation. In this study potassium

hydride in THF was utilized as the base-solvent combination. The

approach used to synthesize the 1,3-xylyl crown ethers is illustrated

in Scheme 21. Precursor dibromide[52] 74 was prepared by

Scheme 21

CH Ac„ CH. Br

I

+ cH3-r yo O ^ N

Br

r\n/i HOOO(H t-BuOK Toluene

A' VO o-y

I—I 75

ecu hv A

Br B Br 7 4

Hoo oai KH THF

A n O O. 76 2

V o oJ^ II 3 78 4

irradiation (500 W lamp) of m-xylene in the presence of 1,3-

dibromo-5,5-dimethylhydantoin in 38% yield after recrystallization

of the crude product from absolute methanol. A condensation

reaction of compound 74 with the polyethylene glycols having

various sizes in dry THF containing potassium hydride produced

compounds 76,77 and 78 in 53, 30 and 20% yields, respectively.

42

after column chromatography. The polyethyleneglycol reactants

were carefully dried before use with a benzene azeotrope and a

Soxhlet apparatus. The yields of 76, 77 and 78 obtained from the

present cyclizations are comparable to those of Reinhoudt and co

workers. However, the attempt to prepare the 15-membered (n=l)

1,3-xylyl crown ether by use of this method gave a complicated

product mixture. A change of the base to NaH did not help to

complete the reaction. Probably the poor solubility of the dialkoxide

in THF is responsible for the poor reaction. By use of the procedure

of Reinhoudt and co-workers, l,3-xylyl-15-crown-4 (75) was

prepared in 11% yield after vacuum distillation.

The highest yield was obtained for compound 76 which would

be expected for a template effect of the potassium ion. Apparently

for smaller (75) or larger (78) ring sized crown ethers the template

effect is less effective due to their inappropriate geometry when

complexed with potassium ion.

Crown Ethers with Pendant Groups

Pyridyl Crown Ethers

It is well-known that the incorporation of nitrogen atoms into a

crown ether ring usually improves the complexation ability for

transition metals since it is a soft donor atom.[53] Introduction of a

nitrogen atom to replace an oxygen atom in a crown ether also alters

the complexation behavior toward alkali metal cations.[54]

43

For study of the influence of attaching a pendant pyridyl unit

to a crown ether ring, a series of new ligands has been prepared.

From such crown ethers cooperative action of the crown ether ring

and pendant pyridyl unit might be expected to enhance the

complexation ability toward certain metal cations.

The initial synthetic approach toward pyridyl pendant crown

ethers involved two different routes (Scheme 22). In Method A

Scheme 22

Method A

79-CH2CH2- 82-CH2CH2-8 0 -CH2CH2CH2- 8 3 -CH2CH2CH2-8 1 -CH2CH20C:H2CH2— 8 4 -CH2CH2OCH2CH2-

44

MeUiod B

H .OH

KXQ Q A J V2 NaH

HQ

H, yOa\^^

O O

crown ether alcohols 79-81 were reacted with picoylcholoride

hydrochloride and two equivalents of NaH in DMF. Method B used

THF as a reaction medium, the crown ether alkoxide, and free

picoylchloride. Yields of ligands 82-84 obtained by Methods A and

B are shown in Table 8.

Table 8. Yields of Compounds 82-84.

Compound

8 2

8 3

8 4

Method A

18%

33%

35%

Method B

36%

63%

56%

45

The results demonstrate that Method B is superior to Method A.

Therefore, Method B was adopted as the synthetic method for

attachment of pyridyl unit to crown ethers.

The synthetic routes to pyridyl-pendant lipophilic dibenzo-16

crown-5 derivatives are summarized in Scheme 23. Crown ether

Scheme 23

.OH H ^

voy

Tone's oxidation

O

8 5 CHsMgl

KH THF

^ v X ) H

a;:p HCl

9 0

C3H7MgBr

C3H7^H

OCX)

HQ

KH THF

C S H T ^ O I N

OClp voy

9 1

CioH2fS<OH

<x:p a° HQ

KH THF

OClp voy

92

46

alcohol 85 was treated with Jones reagent[55] to produce sym-

ketodibenzo-16-crown-5 (86) in 65% yield. Reaction of crown ether

ketone 86 witii CsU-jMgBT and CioH2iMgBr in THF gave 88 and 89,

respectively, after quenching with a saturated aqueous solution of

NH4CI. In the case of crown ether alcohol 87, a mixed solvent system

of THF-Et20 (1:1) was used as a reaction medium for the Grignard

reaction due to the poor solubility of CHsMgl in THF. Magnesium

turnings were added to a solution of methyl iodide in Et20 at room

temperature to make a white emulsion of the Grignard reagent

(CHsMgl) followed by addition of keto crown ether 86 in THF. In

this way crown ether alcohol 87 was obtained in 72% yield. This

procedure gave much higher yield than that for the reported

procedure[56] which used THF-Et20 (2:1) as solvent for the

preparation of CHsMgl.

Crown ether alcohols 87-89 were then converted into the

corresponding pyridyl pendant crown ether compounds 90-92. The

first attempts to make pyridyl pendant lipophilic crown ethers used

NaH as the base and gave only poor yields, probably due to the steric

bulkness of the lipophilic groups. When the stronger base KH was

substituted for NaH, novel ligands 90, 91 and 92 were obtained in

17, 22 and 36% yields, respectively.

To investigate the ring size effect on metal ion complexation,

pyridyl pendant dibenzo-14-crown-4 derivatives were also

synthesized (Scheme 24). The ixiIl-hydroxybenzo-14-crown-4 (93)

was prepared by the reported method.[57] By treatment of 93 with

Jones reagent, sym-ketodibenzo-14-crown-4 (94) was obtained in

34% yield. Thorough drying under vacuum was necessary before

47

further use to eliminate facile reaction of 94 with moisture in die

atmosphere. Reaction of Grignard reagents witii keto crown ether 94

gave crown ethers 95-97. For the preparation of 95, CHsMgl was

Scheme 24

CH^^H

H Q

CioHzjMgBr

CiAivOH

NaH THF

CH- OCHr-N'-' HCl

u 97

NaH THF

KH THF

u 98 aVoX) l j « 9

HQ

U 100

produced first by the reaction of CH3I and Mg turnings in Et20 and

then 94 was added to obtain the product. Pyridyl-pendant dibenzo-

14-crown-4 compounds 98, 99 and 100 were prepared by Method

B (Scheme 20). For the preparation of decyl group containing crown

48

ether 100, KH was used as a base. Crown ether 98 was the only

solid compound among the pyridyl-pendant crown ethers with a

general alkyl group and pyridyl-containing side arm.

Yields for the preparation of the lipophilic pyridyl pendant

dibenzo-16-crown-5 and dibenzo-14-crown-4 compounds are given

in Table 9.

Attachment of a pyridyl unit to sym-(methylhydrQxy)dibenzo-

14-crown-4 (102) was also attempted. By use of the reported

method of Tomoi[58] and co-workers, sym-vinylidenedibenzo-14-

crown-4 (101) was prepared. Reaction of bis-l,3-(2-

hydroxyphenoxy)propane, methallyl dichloride and NaOH in aqueous

1-BuOH gave a cyclization yield of 66%. Reduction of vinylidene

crown compound 101 with BH3-THF followed by treatment of

Table 9. Yields of Compounds 90-92 and 98-100.

Compound Base Yield (%)

9 0 KH 17

9 1 KH 22

9 2 KH 36

9 8 NaH 3 0

9 9 NaH 5 9

1 0 0 KH 66

49

H202-NaOH gave crown ether alchol 102 in 20% yield.[59] The

reaction of crown ether alcohol 102 with picoyl chloride

hydrochloride by Methods A and B was attempted (Scheme 25).

Neither of the methods gave the desired product.

Scheme 25

.OH HO,

^ * ^ 0 O-"^^ NaOH, 1-BuOH ^^*^o O

1 0 1 H^^^CHgOH

1 1 NalJ.^ No reaction

2)H202, NaOH

,0 o,

'O O'

1 0 2

NaH D M h X Decomposition A products

No reaction occurred with NaH in THF and decomposition products

were obtained when the reaction was conducted in DMF at reflux.

To investigate how the pyridyl-pendant crown ethers would

compare with either a benzyl-pendant crown ether or a pyridyl

compound without a crown ether ring, model compounds 103 and

104 were prepared (Scheme 26).

50

Scheme 26

C3H7V ^OH C3H7. . O C H B

88 103

CH3(CH,),oCH,OH + Q ^ c , ^ • | Q L O C H , ( C H , ) , „ C H 3

HCl A 104

The benzyl pendant crown ether 103 was synthesized in 80% yield

by the reaction of crown ether 88 with benzyl bromide in the

presence of KH. Pyridyl dodecyl ether 104 was obtained in 8% yield.

This poor yield may result from the high basicity of the alkoxide

from dodecyl alcohol which could react with pyridyl unit of

compound 104.

Extractions of metal picrates into chloroform were conducted

by Mark Eley of the Bartsch Research Group. The pyridyl crown

ethers showed poor extractability of alkali metal picrates in general.

Crown ethers 98-100 which possess the dibenzo-14-crown-4 unit

exhibited selectivity for lithium picrate over other alkali metal

picrates. On the other hand, the crown ethers which have an 16-

crown-5 unit exhibited extraction selectivity for sodium picrate as

would be predicted from their size. The dibenzo-16-crown-5 103

which has benzyl side arm group showed very poor extractability for

51

alkali metal picrates. However, these crown ethers with pendant

pyridyl groups exhibited outstanding extraction ability for silver

picrate. Among the pyridine containing crown ethers, 98 showed

highest extractability for silver picrate. For 98 which has a methyl

group and a pyridyl pendant dibenzo-14-crown-4 unit, the percent

extraction of silver picrate was 15 times greater than that for lithium

picrate, the best extracted alkali metal picrate. Presumably this

exceptionally high extractability arises from preorganization of

binding site as illustrated in Figure 16. The affinity of nitrogen

c^^X^

Figure 16. Proposed Complexation of Silver Cation by Pyridyl Pendant Crown Ether 98.

toward silver cation is well known.[60] Therefore cooperative binding

of the silver cation by both the pyridyl side arm and the dibenzo-14-

crown-4 ring is postulated.

The X-ray crystal structures for 82-84[61] which have no alkyl

groups geminal to the pendant pyridyl unit shows that the pendant

pyridine rings point away from the crown ether ring in the solid

state (Figures 17-19).

52

Figure 17. X-ray Crystal Structure of Pyridyl-Pendant Crown Ether 82.

Nl C24

C23

Figure 18. X-ray Crystal Structure of Pyridyl-Pendant Crown Ether 83.

53

ClI 04 C12 013 ^^5

Figure 19. X-ray Crystal Structure of Pyridyl-Pendant Crown Ether 84,

Crown Ether Xanthates

Dibenzo-16-crown-5 xanthates were prepared for evaluation of

their alkali metal cation binding properties. Scheme 27 illustrates

the synthesis of the crown ether xanthates by reaction of crown

ether alcohols with NaH and then carbon disulfide. In the case of

crown ether xanthate 105, the pure product was isolated in 56%

yield as a yellow solid by recrystallization. Purification of the crude

54

product from the reaction to form 106 was unsuccessful because of

the instability of the bright yellow solid product which decomposed

Scheme 27

r^s^N^O O

H. OH § HxDCS-Na*

105 R=H 106 R=t-butyl

on prolonged exposure to air. Differentiation of crown ether

xanthates 105 and 106 from their precursor alcohols by H and l^c

NMR and IR spectroscopy was difficult.

Formation of crown ether xanthates was verified by treatment

with methyl iodide to produce the corresponding xanthanthate

methyl esters (Scheme 28). The reactions were followed by TLC and

55

Scheme 28

R-f-oc: :x>^ * CH3. w- «cx: :i>^ ^"'•"•>' III K b u t y l

newly formed products were isolated by column chromatography.

^H NMR spectra of both products 107 and 108 clearly showed -SCH3

peak in the region of 2.5-2.6 ppm. Also elemental analysis confirmed

formation of the xanthate methyl esters. Attempts to prepare the

xanthate from sym-(decyl)hydroxydibenzo-16-crown-5 (109) by

reaction of crown alcohol 89 with NaH or KH then carbon disulfide

were unsuccessful (Scheme 29). Probably steric bulkness of decyl

group prevented the suitable approach of the crown alcohol anion to

the carbon disulfide.

Scheme 29 S

CioH2iv^OH CioHjiv^O-C-SM-^

<J M. N.»K <^^J

56

Methoxy Crown Ethers

Major disadvantages of crown ethers for practical use are their

high cost and some toxic properties.[62] An attractive method of

circumvent both problems is to incorporate the crown ethers in a

polymer backbone. The resultant polymer resin can be used as

stationary phases for the chromatographic separation of alkali metal

and alkaline earth metal cations and their counter anions.

Methoxy crown ethers were prepared for use in preparation of

ion-exchange resins by condensation polymerization with

formaldehyde in formic acid.[63]

The synthetic route to methoxy crown ethers is presented in

Scheme 30. The straight forward nucleophilie substitution reaction

of crown ether alkoxide with methyl iodide was utilized to produce

methoxy crown ethers which was previously employed for

preparation of compound 110.[64] Crown ether alcohols were reacted

Scheme 30

CHJ

R OCH3

.0 O,

NaH THF

a )0 R

1 1 0 H 1 1 1 CH3 1 1 2 C3H7 1 1 3 C10H21

57

with two equivalents of methyl iodide and three equivalents of NaH

in THF to give corresponding methoxy crown ethers 110-113. In all

cases, THF-insoluble precipitates were formed which were thought to

be the complex of crown ether with Nal and were unique among the

crown ether synthesis. Probably the poor solubility of

methoxycrown ethers complexes with the sodium cation in organic

solvents is caused by formation of stable complexes with the rather

soft counter anion of I" (Figure 20). To circumvent this problem, the

crude products were washed with 1 N-NaOH aqueous solution. After

evaporation of the reaction solvent, CH2CI2 was added to the crude

R ^OCH,

.Q ,0 , I

Figure 20. THF-insoluble Complex of Methoxy Crown Ether with Nal.

solid product followed by washing with 1 N-NaOH solution several

times to make a homogeneous solution of salt-free methoxy crown

ethers. Further purification of the crude product by recrystallization

from hexane-THF or column chromatography on alumina with EtOAc-

hexane (1:2) solvent mixture gave compounds 110-113 in 56-90%

yield.

58

Chromogenic Crown Ethers

For the extractive photometric determination of alkali metal

ions, two new chromogenic crown ethers were prepared. A

trifluoromethyphenylamino functionality was selected as an

appropriate chromogenic group to be incorporated into the

benzocrown ether ligands. Enhancement of acidity and improved

solubility in aqueous media are expected to result from attachment

of a trifluoromethylphenyl group to an amino benzocrown ether.

Synthetic attempts were made to also introduce a nitro group onto

the benzene ring of the crown ether to further enhance the acidity of

the chromogenic crown ethers. Scheme 31 shows the synthetic route

to a potentially Na-selective chromogenic crown ether 115.

Compound 114 prepared by the reaction of 4'-aminobenzo-15-

crown-5 with l-chloro-4,6-dinitro-2-trifluoromethylbenzene,

according to the literature method.[65] Treatment of 114 with a

Scheme 31

CI CF, """Ccf 3 * "X> NaHCO.

MeOH

1 3 3

L v ° - ^ CHCI3 N 0 / ^ k / ° ^ 1 1 5

59

solution of equal amount of acetic acid, fuming HNO3 and chloroform

gave the desired chromogenic crown ether 115 in 22% yield as a

reddish solid after purification of the crude product by column

chromatography.

For the potential application in selective photometric extraction

of lithium ion, chromogenic crown ether 116 which is based on

benzo-14-crown-4 was synthesized (Scheme 32). The aminobenzo

Scheme 32

1 4 5 ^ '^0^ 1 1 6 ^

crown ether was reacted with l-chloro-4,6-dinitro-2-

trifluoromethylbenzene and sodium bicarbonate in MeOH to give

116 in 22% yield. The introduction of a nitro group onto the benzene

ring of 116 was attempted by treatment with AcOH, fuming HNO3

and chloroform. However none of the desired product could be

isolated from the complex reaction mixture.

Acyclic Polvether Carboxvlic Acids

Although cyclic ligand systems generally exhibit better

complexation ability for metal ions than their acyclic counterparts,

metal ion complexation by acyclic ligands is a topic of considerable

60

interest. It is well-known that the complexation and decomplexation

of metal ions by acyclic ligands are more rapid than for closely

related cyclic systems.[66]

In a few cases acyclic ligands showed better complexation

ability than their cyclic analogues.[67] Inspired by these results

acyclic ligand systems were designed and synthesized in the present

work. Examination of CPK models indicates that an acyclic system

with four oxygens and a carboxylic acid side arm should provide a

suitable complexation site for a lithium cation. Also positioning of

the carboxylic acid group might be influenced by attachment of an

alkyl group to the same carbon which bears the side arm (Figure 21).

Figure 21. Model of Acyclic Polyether Carboxylate Complexation with a Lithium Cation.

Acyclic polyether carboxylic acids with four ethereal oxygens

were prepared for investigation of their complexation behavior

toward alkali metal cations. Precursor alcohols 117-119 were

synthesized by reaction of epichlorohydrin with corresponding

methoxyphenoxide in aqueous THF (Scheme 33). The reaction was

61

Scheme 33

A H OH

a HpmiF p 1^] CH30 0CH3

-OCH3:0-m -OCHs.O- 1 1 7 p- m- 1 1 8

P- 1 1 9

carried out under high dilution conditions and progress of the

reaction was followed by TLC. Initially 0.5 equivalent of

epichlorohydrin was used. Subsequently, it was found that the

addition of another portion (0.5 equiv) of epichlorohydrin enhanced

the yield. The yields acyclic polyether alcohols ranged from 42% to

66%.

Acyclic polyether alcohol 117 was oxidized to ketone 120 by

Jones reagent in 65% yield. Acyclic polyether compounds with alkyl

groups (-C3H7, -C10H21) were prepared by the reaction of ketone 120

with corresponding Grignard reagents in THF to give acyclic

polyether alcohols 121 and 122 in 69% and 47% yields, respectively

(Scheme 34).

62

Scheme 34

H_OH

o o o o / \ u C H / CH, 12 0

CH/ CH

CsHvMgBr / \C10H21MgBr

CaHv^OH / \ Cio"2i wOH

o 0 / 0 0

CH3/ CH3 C^3 CH3

1 2 1 1 2 2

Acyclic polyether alcohols 117-119 and 121-122 were

converted into the corresponding acyclic polyether carboxylic acids

123-127 by reaction with KH (6 equivalents of 35% dispersion in

mineral oil) in THF followed by addition of bromoacetic acid (Scheme

35). The crude products were purified either by recrystallization or

column chromatography to give acyclic polyether carboxylic acids

123-127 in 67-90% yields.

63

Scheme 35

RÔH

.0 O a p + BrCHnCOOH KH THF

.0 O CH CH, /

3

J, H C3H7 ^10^21

RÔCHjCOOH

a p o q

C H / CH3

H 1 2 3 C3H7 12 4

^10^21 ^ ^ ^

RÔH

.0 O

CH

(^ I Q ) + BrCH2C00H O OCH,

KH THF

-OCH; m 1 1 8

p 1 1 9

RÔCHjCOOH

.0 o

CH30 0 Q

-0CH2

m 1 2 6 P 1 2 7

The alkali metal cation binding property of acyclic polyether

ligands prepared in this study will be tested by titration calorimetry.

Recently, Dr. Hayashita of the Bartsch Research Group prepared the

condensation polymers of acyclic monomers 123 and 124 and the

resultant resin showed lithium selective sorption ability.[68]

64

Chemical Modification of Nafion® lonomer Membrane

The goal of this phase of the research was to prepare new

synthetic polymeric ionomer membrane materials by attachment of

alkali metal ion chelating reagents to the surface of a commercially

available membrane to produce a metal ion recognition site or ion

channel gate. As the commercially available membrane Nafion® 117

128 (0.007 inch Uiick, equivalent weight 1100)[69] was selected

because of its cation exchange properties and chemical inertness.

Monoazacrown ethers and 4'-aminobenzo-crown-ethers which have

specific interactions with alkali metal cations were chosen as the

chelating agents to be attached to the surface of the Nafion® 117

membrane. The structure of Nafion® 117 and the crown ether

compounds are shown in Figure 22.

OCFj-CF-O-CFj-CFj-SOjH CF3

s RfSOsH (Nafion® 117)

128

(^O^ H2N, '^

129 1 132 1 130 2 133 2 131 3 134 3

135 4 Figure 22. Structures of Nafion® 117 and Crown Ethers to be

Attached to the Membranes.

65

Preparation of the known monoaza crown ether compounds

was attempted by three different synthetic routes. The first route

was reaction of diethanolamine with sodium metal in t-BuOH to

produce dianion 136 followed by addition of polyethyleneglycol

ditosylate in dioxane (Scheme 36).[70] Purification of the crude

Scheme 36

H I ^ v ' r ^ n ^ XT t - B u O H

HO N OH + Na

TsO 0 O OTs p-Dioxane

n= 1, 2

H . I— ' —I

Na -O N CTNa

H

' O 0 ^ °

a 1 130 2 1 3 1

products by high vacuum (1 X 10-3 mm Hg) distillation only gave

modest yields because the products were thermally decomposing

during the distillation process. The second route utilized N-tosyl

protected diethanolamine 137 followed by removal of the tosyl

group (Scheme 37). Reaction of diethanolamine with p.-toluene

sulfonyl chloride in the presence of potassium carbonate gave N-

tosyl diethanolamine 137 in 70% yield.[71] N-Tosylmonoaza-15-

crown-5 (138) was obtained by the reaction of 137 and

triethyleneglycol ditosylate in 31% yield.

66

Scheme 37

w Ts

H O ^ N ^ H ^ C H 3 - Q ^ S 0 2 a ^ | j 0 ^ HO N Q H

1 3 7

Ts H I '

1) 2 NaH / - N - \ y ^ N " \ THF-DMF (1:4) < > 6% Na(Hg) < > ^ ,-0 o--, r—^ r^ o-

r^r\r-\ r ^ ^ 1 Na2HP04 L ^ J 2)TsO O O OTs ^O^^ MeOH O^J^

1 3 8

Removal of the tosyl group was carried out by treatment with

6% sodium amalgam to give monoaza-15-crown-5 (130). The third

route followed a procedure reported by Gokel,[72] which provided

rather clean and high yield syntheses of the monoazacrown ethers.

In this route, a benzyl group was used as the protecting group of the

amine function of diethanolamine. Almost quantitative deprotection

was accomplished by catalytic hydrogenation. By use of this route,

large amounts of monoaza-15-crown-5 (130) and monoaza-18-

crown-6 (131) were prepared.

Preparation of the 4'-aminobenzo crown ethers with various

ring sizes was carried out by nitration and reduction of the

appropriate benzocrown ethers. The synthetic route for the 4'-

aminobenzocrown ethers is summarized in Scheme 38. Nitration of

the benzocrown ethers was achieved by treatment with a solution of

67

Scheme 38

' ^ ? ) HNO3 O . N ^ ^ ^ ^ O ' ^ f Y ^ O' "^^ > 0,N.^^^ > 139 J " i v : ^ O. AcOH O J L ^ ^S 1 4 0 3

1 4 2 5

10% Pd/C

133 J m l y ™^NH. 5% Pd/C

n 3

1 3 4 4

--al n. 1 3 2 2 1 3 5 5

glacial acetic acid, fuming nitric acid and chloroform.[73] Compounds

139-142 were obtained in 68-86% yield. Reduction of the nitro

group was performed by two different methods. For compounds

133 and 134, catalytic hydrogenation with 10% Pd on carbon at 40

psi of hydrogen in DMF was used to give desired products in 84-

100% yields.[74] Reaction of 132 and 135 with anhydrous hydrazine

and 5% Pd on carbon in THF-EtOH at reflux provided the reduced

products 132 and 135 in 92% and 100% yields, respectively. There

was no substantial difference in effectiveness between these two

hydrogenation methods.

Preparation of 4'-aminobenzo-14-crown-4 was also attempted

(Scheme 39). Initial reaction of benzo-14-crown-4 with fuming

nitric acid, AcOH and chloroform for 24 h gave only dinitrated

compound 143 in 62% yield. However, by use of a shorter reaction

68

Scheme 39

n ^ v *= 0 o

HN03 AcOH CHCI3 12 h

t

U^OO^ 14 4 \ ^

HNO3

AcOH CHCI3 24 h

NH2NH2

5% Pd/C

143

HzN^^^^cfi X A O O 1 4 5

time (1 h) only the mononitrated product 144 was obtained in 79%

yield. Reduction of 144 by use of anhydrous hydrazine and 5% Pd

on carbon provided 4'-aminobenzo-14-crown-4 (145) in

quantitative yield.

To investigate potential structural effects of the coupling

reagent when bonded to Nafion®, an acyclic polyether compound 148

with a secondary amine group was prepared. Scheme 40 shows the

synthetic route to 8-aza-2,5,ll,14-tetraoxapentadecane. Reaction of

p.-toluenesulfonamide with 2-(2-chloroethoxy)ethanol in the

presence of anhydrous potassium carbonate gave tosyl-protected diol

146 in 68% yield.['73] Subsequent treatment with sodium hydride

and methyl iodide produced dimethoxy compound 147 in 81% yield.

69

Scheme 40

r - T T _ / = \ o ^ / v / — V K2CO3 / \/ \ ™ 3 - A /~S02NH2 + n''^ U Viu • Ts-N O OH

^^_J ^ 2 CI O OH DMF Y O OH

146

CH3l,NaH / y O o r H 6%Na(Hg) O / ^

THF V _ / \ _ J ^ ^ Na2HP04 ^ O OCH3

^ 0 C H 3

147 148

The desired acyclic polyether compound 148 was obtained by

removal of the tosyl group in 60% yield with 6% sodium amalgam in

dioxane-methanol.

For attachment of crown ethers with secondary or primary

amine groups to the Nafion®-H, the sulfonic acid groups must be

transformed into reactive sulfonyl chloride functions. Based upon

the literature precedent,[74] it should be possible to convert Nafion®

perfluorosulfonic acid membrane 128 into the sulfonyl chloride form

149 followed by reaction with monoazacrown ethers or 4'-

aminobenzo crown ethers to provide different types of ionophoric

sulfonamides (Scheme 41).

70

Scheme 41

^<^o^ p C M O

Monoazacrown ethers ^ i f. , \

/ " o k^o^ RfSOsH —<- RfS02a n=1 - 3

149 \ O H y—, 4'-Aminobenzocrown ethers * f \) V^^V^ I

^ ^ O 0 ^ " ^ ^

n = l-4

For the first attempted chlorination of Nafion® 117 membrane,

the procedure reported in a Japanese patent was employed (Method

I).[37] Thus, a 2" X 2" piece of Nafion® 117 membrane was immersed

in 0.5 N-NH4OH aqueous solution for 48 h then washed with water to

neutral pH and dried to give the ammonium sulfonate form 150. It

was noted that this pre-treatment stiffened the membrane and made

it difficult to stretch. Compared with the original Nafion®-H

membrane, a weight loss of about 3.5% was noted for the ammonium

sulfonate form. The membrane piece 150 was refluxed in the

mixture of PCI5-POCI3 (1:2 w/w) for 24 h to make sulfonyl chloride

form 151 (Scheme 42).

71

Scheme 42 (Method I)

0 O P " ^ „ 1)0.5 NNH4OH n . + R f - S - O H :i ^ R S-ONH4

O 2) Washed with H2O ^ 3) Dried

1 5 0

1) PCl5-POCl3(l:2 w/w) A, 24 h II

^ Rf-S—a 2) Washed with CCI4 6 3) Dried 1^1

The sulfonyl chloride form of the membrane 151 was flexible and

white in color. Compared with the original Nafion®-H membrane

piece, the sulfonyl chloride forms usually showed a very modest

weight gain (Table 10). Another four sulfonyl chloride membranes

(152-155) were prepared by the same procedure and reacted with

monoaza crown ethers 129-131 and 4'-aminobenzo-15-crown-5

(133) in the presence of triethylamine (Scheme 43).

Scheme 43

Et3N,THF 1 5 1 + Monoaza-15-crown-5 •Membrane 156

A , ^ - , w i c if Et3N,DMF 15 2 + Monoaza-15-crown-5 L_ »• Membrane 157

O D c ^ i c ^ ^ w 10 A Et3N,DMF R f ~ S — a 1 5 3 + Monoaza-18-crown-6 £: • Membrane 158

O ^ , Et3N, DMF

1 5 4 + Monoaza-12-crown-4 f l - »• Membrane 159

^ Et3N, DMF 1 5 5 + 4 ' -Aminobenzo-15-crown-5 »-Membrane 160

72

The first coupling reaction of monoaza-15-crown-5 (130) with

the sulfonyl chloride membrane 151 in refluxing THF for 12 h

produced an inhomogeneous membrane 156 with a bubbled surface.

This problem disappeared when the solvent was changed to DMF

(membrane 157). Membranes 158 and 159 which were obtained in

DMF had good physical appearance. However, the 4'-aminobenzo-

15-crown-5 coupled membrane 160 appeared to be very

inhomogeneous. In view of these initial results, the synthetic efforts

for modification of Nafion®-H membrane were mainly made with

monoazacrown ethers. The results of chemical modification of

Nafion®-H by Method I are summarized on Table 10.

Permeation testing[38] of membranes 156-159 showed no

transportation of alkali metal ions under conditions for which

unmodified Nafion® gave good transport. Thus, it appeared that the

chemical procedures which were utilized for covalent attachment of

the crown ethers were highly disruptive to the membrane

properties. To determine if the problem was in the sulfonyl

chloride-forming step, a series of experiments was conducted in

which Nafion®-H membrane was converted into the sulfonyl chloride

form and then hydrolyzed back to the sulfonic acid form. Three

different Nafion®-H (2" X 2" size) were refluxed with PCI5-POCI3 (1:2

w/w) for varying periods of time to give sulfonyl chloride forms

73

Table 10. Chemical Modification of Nafion® Membrane by Method I.

Weight change Coupling product for RfSOiCl Coupling Weight form, % Agent^ Solvent Shape change^, %

156

157

158

159

160

+7.5

-0.3

+2.0

+0.1

+3.5

130

130

131

129

133

THpd

DMFd

DMFd

DMpd

DMFe

bad

OK

OK

OK

OK

-9.0

-5.6

-9.4

-9.6

-14.6

^With 2.0 equiv of the crown ether compound and 1.0 equiv of triethylamine.

^Relative to the weight of the original RfSOsH form.

^Relative to the weight of the RfS02Cl form.

^Refluxed for 12 hours. ^Refluxed for 24 hours.

161-163 and which were then hydrolyzed to sulfonic acid forms

164-166 by refluxing in 5% NaOH aqueous solution followed by

acidic treatment with 5% HCl aqueous solution. Also Nafion®-H

membrane was refluxed in 5% NaOH for 24 hours and then acidified

with 5% HCl (membrane 167) for comparison with untreated

Nafion®-H (Scheme 44). The results are summarized in Table 11. The

membrane from the shorter chlorination time showed a weight

increase. When membranes 164-167 were subjected to permeation

74

Scheme 44

PCI5-POCI3

RfS03H ^ ' ^^^)> RfS02a 1)5% NaOH, 24 h, A

2)5% HCl, 1 h 1)5% NaOH

24 h, A 2)5% HQ

1 h

Chlorination time

24 h 1 6 1 4 h 1 6 2 1 h 1 6 3

— ^ RfSOsH*

1 6 4 1 6 5 1 6 6

* Regenerated Nafion®-H

Table 11. Conversion of Nafion® Membrane to the Sulfonyl Chloride Form Followed by Hydrolysis.

Reflux with

Membrane PCI5-POCI3, h

RfSOiCl form

weight change^ % Appearance

164

165

166

167

24

1

0

-2.4

+3.2

+5.2

flexible with

white color

flexible with

white color

stiffened

^Relative to the weight of original RfSOsH form.

75

testing, membranes 166 and 167 gave very good metal cation

permeation with a selectivity order which is very similar to diat of

unmodified Nafion® membrane. On the other hand, membranes 164

and 165 gave very low alkali metal cation permeation (Table 12).[38]

Table 12. Effect of Chlorination Time upon Alkali-metal Cation Permeation.[38]

Reaction Permeation Cone in Receiving Phase (mM)

Membrane time, h time, h Li+ Na+ K+ Rb+ Cs"*-

3.19 3.78 4.44 4.22 3.90

0.03 0.11 0.09 0.00 0.00

0.00 0.34 0.16 0.00 0.00

4.65 6.27 6.46 6.45 6.35

5.89 7.71 8.40 8.50 8.30

fion 117

1 6 4

1 6 5

1 6 6

1 6 7

24

4

1

0

7

24

15

15

15

These results indicate the use of longer chlorination times is

detrimental to the permeation properties of the membranes.

To investigate the dependence of time and temperature on the

coupling reaction of the sulfonyl chloride membrane with

monoazacrown ethers, a set of experiments was conducted. For these

experiments, monoaza-15-crown-5 was chosen as a model coupling

agent. Five pieces of Nafion®-H membranes were converted into the

sulfonyl chloride forms 168-172 with reaction times varying from 1

to 3 hours. After the reaction, the membranes were washed several

76

times with brief refluxing in CCI4 and then dried for one day under

vacuum. The sulfonyl chloride forms 168-171 were then reacted

with two equivalents of monoaza-15-crown-5 and one equivalent of

triethylamine in DMF at reflux or 50^0 to produce membranes 173-

176. In addition one sulfonyl chloride membrane 172 was heated

for 48 h in DMF in the absence of the monoazacrown ether to give

membrane 177. The procedures are summarized in Scheme 45.

There was a 3-5% weight increase for sulfonyl chloride membranes

Scheme 45 (Method II)

PCI5-POCI3 f^O 0, (1:2 w/w) _ -_. ^ Monoaza-15-crown-5 „ gQ ^ J

RfSOsH -RfSOaQ ^ ^ ^ ^ f m j

Chlorination time (h) Reflux ^ ^ ^

1 1 6 8 ^ 1 7 3 Reflux

2 1 6 9 ^ 1 7 4 Reflux

3 1 7 0 ^ 1 7 5 50°C

3 1 7 1 ^ 1 7 6

3 1 7 2

RfS02a ^ ^ ^ RfSOiQ* 17 2 50 °C.48 h 17 7

168-172 compared to corresponding original Nafion®-H membranes.

Membranes 173-175 which were formed by coupling at reflux were

swollen and remained so even after drying. When the temperature

77

for coupling was reduced to 50 ^C, membrane 176 was produced

which was initially swollen, but returned nearly to its original size

after drying. Contrary to membranes 173-175 for which the

coupling was performed at reflux and a significant weight increase

with membrane 176 for which the coupling was conducted at 50 °C.

For membrane 177, a swollen membrane was produced which

returned nearly to the original size after drying. However, a

significant weight loss was experienced instead of the weight gain

which was found with membrane 176. The results are summarized

in Table 13. Based upon these results, a coupling reaction of the

sulfonyl chloride membrane obtained from a 3 hour chlorination

reaction with a monoazacrown ether for 48 hour at 50 ^C was

selected as the optimum reaction conditions.

Having determined the best chlorination time and coupling

reaction condition, membranes modified with monoazacrown ethers

and other secondary amines were prepared. Membranes modified

with diethylamine, dibutylamine, morpholine bis(2-

methoxyethyl)amine, and 8-aza-2,5,ll,14-tetraoxapentadecane

(148) were also prepared to compare their permeation properties

with those for monoazacrown ether modified membranes (Scheme

46). After the coupling reactions the resultant membranes were

washed with CH2CI2 and then immersed in water. Modified

membranes 178-185 had good physical appearance (transparent

yellowish film). The modified membranes were subjected to

78

Table 13. Chemical Modification of Nafion® Membrane with Monoaza-15-crown-5 by Method II.

Membrane

RfS02Cl form

Weight Appearance Coupling

change^ Time Temp.

% h

Coupling product

Weight Appearance

change,^%

1 7 3

1 7 4

1 7 5

1 7 6

177d

+5.0

+3.2

+4.8

+4.1

+3.5

stiffened

stiffened

flexible

flexible

flexible

12

20

24

48

48

reflux

reflux

reflux

50 oc

50 oc

-24.0

-8.2

-7.2

+6.2

-6.4

swollen

swollen

badly

distorted

c

c

^Relative to weight of original RfSOsH form.

^Relative to the weight of the RfS02Cl form.

cSwollen but returned nearly to the original size after drying.

^Obtained without use of coupling agent.

79

Scheme 46

RfS02Cl*+H-N j ^

\y Et^, DMF 48 h, 50°C

RfSOrN / \

\y 178

H-N

H-N O

H-N .AsÔCH.

V ^ , OCH,

(Ô OCH3 H-N

OCH,

H-N O

Co O. H-N J

H-N ^ O

\J * Made from 3 h

chlorination time

• ^ —

- ^

RfSOrN^^^

179

RfSOr-Nô^gQ

^^s^0CH3

^^^0CH3 r- 181

'^^^°-l^0j)CH3 ^ 182

RfSOrN o

RfSOrN f O o

k.oj). 184

Co o^ RfSOrN ^ o,

V7 185

permeation testing toward alkali metal cationst^S] with a dialysis

experiment. The results are recorded in Table 14.

When diethylamine, dibutylamine, and morpholine were

coupled with the sulfonyl chloride form, little permeation of the

80

alkali metal cations was observed in the resultant membranes.

When the oxygen number of the secondary amine was increased,

however, the permeation efficiency was improved. The membranes

which had been coupled with acyclic amine 182 or cyclic polyether

amine 183-185 having more than three oxygen atoms gave efficient

permeation that was comparable with that for the original Nafion®-H

membrane. Membrane 182 exhibited intermediate permeation.

Table 14. Influence of Coupling Agents upon Alkali-Metal Cation Permeationt38]

Membrai

Nafion®

1 7 8

1 7 9

1 8 0

1 8 1

1 8 2

1 8 3

1 8 4

1 8 5

ne

117

Permeation

Time (h)

7

7

7

7

7

7

7

7

7

Concentration in

Li+

3.19

0.00

0.00

0.00

0.11

1.98

0.53

1.40

0.51

Na+

3.78

0.04

0.00

0.02

0.23

2.95

1.40

2.47

0.91

receiving

K+

4.44

0.12

0.00

0.19

0.47

4.10

3.03

4.28

1.47

Dhase

Rb+

4.22

0.13

0.00

0.00

0.58

4.17

3.65

4.63

1.58

Cmmol/L)

Cs+

3.90

0.00

0.00

0.00

0.76

4.59

4.25

5.08

1.95

aThe source solution was 1.0 mM in each of the five alkali metal cations at pH=ll.

81

These results suggests that the hydrophilicity of the channel site of

the membrane plays an important role in metal ion permeation.

These results indicate that the polyether units can behave as a

channel gate for metal permeation. The permeation selectivity order

for the monoazacrown ether-modified Nafion® membrane was

Cs+>Rb+>K+>Na+>Li+ which differs from the ordering of

K+>Rb''">Cs+>Na+>Li+ observed for unmodified Nafion® membrane. In

addition, the overall range of selectivities for the modified Nafion®

membranes is greater than that for unmodified Nafion® membrane.

These results verify that the covalent attachment of the

monoazacrown ethers onto the surface of Nafion®-H membrane was

successful.

To further confirm the presence of monoazacrown ethers in the

modified membrane, FT-IR spectra of Nafion®-117, Nafion®-

monoaza-12-crown-4 (183) and Nafion®-monoaza-15-crown-5

(184) membranes were investigated by attenuated total reflectance

(ATR) analysis.['^'7] Figure 23 shows the ATR spectra for the three

membranes. For the crown ether-modified membranes, there are

significant decreases in the strength of the 1057 cm-1 absorption due

to the symmetric S-0 stretching vibration for sulfonic acid. This

would be expected if sulfonamide groups were present in the

Nafion®-H membrane. This result again verifies the covalent

attachment of monoazacrown ethers onto the Nafion®-H membrane.

82

O.OB-

0 . 0 6 -

0 . 0 4 -

0 . 0 2 -

0 . 0 0 -

M ^^

i 1 1 1 1 1

«

1

1*

1

» ^ - ^ ^

i 1350 1300 1250 1200 1150 1100 1050 1000

Hdventisibers 950

Figure 23. IR Spectrum of Nafion® 117 (*), Nafion®-monoaza-12-crown-4 (**) and Nafion®-monoaza-15-crown-5 (#).

Summary

The highly efficient cyclization method for aromatic group

containing crown ethers utilizing cesium carbonate,

polyethyleneglycol dimesylate and CH3CN has been discovered. A

series of 1,3-xylyl crown ethers has been prepared to study their

alkali metal binding properties by calorimetry. Various kinds of

pyridyl crown ethers with different size of the macrorings and sizes

of alkyl group have been synthesized. Among them

83

sym-(methyl)picolyoxy-dibenzo-14-crown-4 exhibited outstanding

extraction ability toward silver picrate. Acyclic polyether carboxylic

acids and methoxy crown ethers have been prepared to make ion-

exchange polymer resins by condensation polymerization of crown

ether carboxylic acids with formaldehyde in formic acid. Two new

chromogenic crown ethers which have potential for selective

extraction of lithium and sodium cations have been prepared.

The optimum reaction time for surface chlorination of Nafion®-

H membrane was found. The best coupling reaction condition

between Nafion® sulfonyl chloride form and monoazacrown ethers

were established. By use of these results, ionophore molecules have

been successfully introduced at or near the two surfaces of Nafion®

membrane.

84

CHAPTER m

EXPERIMENTAL PROCEDURES

Instrumentation and Reagents

Melting points were determined with a Fisher Johns melting

point apparatus and are uncorrected. iH NMR spectra were taken

with an IBM AF-200 nuclear magnetic resonance spectrometer. The

chemical shifts are expressed in parts per million (ppm) downfield

from tetramethylsilane. Infrared spectra were taken with a Nicolet

MS-X FT-IR or Perkin-Elmer 1600 Series FT-IR spectrophotometer on

NaCl plates and are given in wavenumbers (cm^l). Mass spectra

were obtained with Hewlett Packard 5995 GC/MS spectrometer.

Unless specified otherwise starting materials and solvents were

reagent grade and used as received from chemical suppliers. Dry

solvents were prepared as follows: pyridine and pentane were dried

over KOH pellets, N,N-dimethylformamide (DMF) was dried over 4A

molecular sieves or MgS04; tetrahydrofuran (THF) was distilled from

Na and benzophenone; tert-butyl alcohol was distilled from CaH2;

MeOH was distilled from magnesium turnings to which a crystal of

iodine had been added; and EtOH was dried by azeotropic distillation

in the presence of benzene.

Thin layer chromatography (TLC) was performed with either

Analtech Alumina OF or Silica GF prepared plates. The glass plates

were precoated with 250 mm thicknesses of silica gel and alumina.

85

Column chromotography was performed using either alumina (80-

200 mesh) or silica gel (60-200 mesh) from Fisher Scientific.

Elemental analysis was performed by Desert Analytics (Tucson,

AZ) and Galbraith Laboratories (Knoxville, TN).

l,3-Bis(m-methoxyphenoxy)-2-propanol (118) and monoaza-

12-crown-4 (129) were available from other studies.^78.79] sym-

(Hydroxy)(propyl)dibenzocrown ethers 88 and 96 were prepared by

reported procedures.t68,80] Nafion® 117 membrane was purchased

from Aldrich Chemical Company.

General Procedure for the Preparation of Benzo-and Dibenzocrown Ethers

Under nitrogen, the diol or bisphenol (2.09 g, 19.0 mmol) was

dissolved in 100 mL of MeCN and powdered CS2CO3 (15.48 g, 47.50

mmol) was added. The resulting mixture was refluxed for 3 h. To

the mixture, the appropriate dimesylate (6.48 g, 19.0 mmol) in 50

mL of MeCN was added during an 8-h period with a syringe pump.

After an additional 24 h at reflux, the reaction mixture was cooled to

room temperature and filtered through a pad of Celite on a sintered

glass funnel. The collected solid was washed with CH2CI2 (20 mL).

The combined filtrate and washing were evaporated in vacuo and the

residue was dissolved in CH2CI2 (100 mL). The solution was washed

with water (50 mL) and dried over MgS04. After evaporation of

solvent in vacuo, the residue was chromatographed on alumina with

EtOAc as eluent.

86

Monobenzo-12-crown-4 (30). A white solid with mp 44-46

OC (lit[2] mp 45-46 oC ) was obtained in 45% yield. IR (deposit from

chloroform on NaCl plate): 1060 (C-0) cm-l. iH NMR (CDCI3): 5 3.32-

4.35 (m, 12H), 6.48-7.12 (m, 4H).

Monobenzo-14-crown-4 (39). After chromotography the

2 + 2 cyclization product was separated by recrystallization from

benzene to provide monobenzo-14-crown-4 as a colorless oil in 76%

yield. IR (neat): 1120 (C-0) cm-l. 1H NMR (CDCI3): 6 1.96-2.07 (m,

4H), 3.61-3.85 (m, 8H), 4.01-4.35 (m, 4H), 6.88-7.11 (m, 4H). Anal.

Calcd for C14H20O4: C, 66.64; H, 7.99. Found; C, 66.66; H, 7.88. The

2 + 2 cyclization product, dibenzo-28-crown-8, had mp 98-99 ^C. IR

(deposit from chloroform on a NaCl plate): 1124 (C-0) cm-l. 1 H NMR

(CDCI3): 5 1.98-2.11 (m, 8H), 3.46-3.70 (m, 16H), 4.03-4.08 (m, 8H),

6.89-7.06 (m,8H). Anal. Calcd. for C28H40O8: C, 66.64; H, 7.99. Found:

C, 67.00; H, 8.16.

Monobenzo-15-crown-5 (6). A white solid with mp (litt^l

mp 79-79.5 ^C) was obtained in 71% yield. IR (deposit from

chloroform on a NaCl plate): 1121 (C-0) cm-l. 1H NMR (CDCI3): 5 3.78

(S, 8H), 3.69-3.93 (m, 4H), 4.11-4.16 (m, 4H), 6.84-6.94 (m, 4H).

Monobenzo-18-crown-6 (7).t2] A yellowish oil was obtained

in 65% yield. IR (neat): 1128 (C-0) cm-l. I R NMR (CDCI3): 5 3.55-

3.94 (m, 16H), 4.13-4.18 (m, 4H), 6.80 (s, 4H).

Monobenzo-21-crown-7 (8).t43] A colorless oil was obtained

in 81% yield. IR (neat): 1113 (C-0) cm-l. I R NMR (CDCI3): 5 3.64-

4.42 (m, 24H), 6.89-7.12 (m, 4H).

87

Mono[4(5 ) - t er t -buty lbenzo] -21-crown-7 (41).[58] A

colorless oil was obtained in 77% yield. IR (neat): 1121 (C-0) cm-l-

IH NMR (CDCI3): 5 1.3 (S.9H) 3.4-4.3 (m, 24H) 6.64-7.18 (m,3H).

Dibenzo-12-crown-4 (54). The crude product was

chromatographed on silica gel with EtOAc-hexane (1:2) as eluent and

then recrystallized from CH2Cl2-hexane to give a white solid with mp

208 OC (lit[2] mp 208-209 oC) in a 12% crude yield. MS: m/z 272

(M+). IR (deposit from chloroform on a NaCl plate): 1129 (C-0) cm-l.

IH NMR (CDCI3): 5 4.33 (s, 8H), 6.97-7.05 (m, 8H).

D ibenzo -13 -c rown-4 (52). The crude product was

chromatographed on alumina with EtOAc-hexane (1:2) as eluent and

recrystallized from CH2CI2-CH3OH to give a white solid with mp 134-

135 oc (lit[45] mp 134-136 o Q in a 74% yield. MS m/z 286 (M+). IR

(deposit from chloroform on a NaCl plate): 1116 (C-0) cm-l. i n NMR

(CDCI3): 5 2.10-2.21 (m, 2H), 4.08-4.34 (m, 8H), 6.86-7.07 (m, 8H).


chromatographed on alumina with EtOAc-hexane (1:3) as eluent to

give a white solid with mp 149-151 oc (lit[2] mp 150-152 o Q in 92%

yield. IR (deposit from chloroform on a NaCl plate): 1126 (C-0) cm-l.

IH NMR (CDCI3): 5 2.28 (m, 4H), 4.25 (t, 8H), 6.92 (m, 8H).


chromatographed on alumina with EtOAc-hexane (1:4) as eluent to

give a white solid with mpll l-114 oc (lit[2] mp 113-115 o Q in a 57%


88

IH NMR (CDCI3): 5 3.95 (t, 4H), 4.19 (t, 4H), 4.38 (s, 4H), 6.92-6.94 (m,

8H).

Dibenzo-16-crown-5 (46). A white solid with mp 115-117

oc (lit[2] mp 117-118 o Q was obtained in a 83% yield. IR (deposit

from chloroform on a NaCl plate) 1123 (C-0) cm-l. I R NMR (CDCI3):

5 2.15-2.34 (m, 2H), 3.62-4.29 (m, 12H), 6.83-7.04 (m, 8H).

lLILSXm.-Dibenzo-18-crown-6 (45). A white solid with mp

117-119 oc (lit[2] mp 117-118 o Q was obtained in a 75% yield. IR

(deposit from chloroform on a NaCl plate): 1128 (C-0) cm-l. i j j NMR

(CDCI3): 5 3.82-3.93 (m, 8H), 4.16-4.20 (m, 4H), 4.42-4.57 (m, 4H),

6.89-6.99 (m, 8H).

Dlbenzo-19-crown-6 (47). The crude product was

chromatographed on silica gel with EtOAc-hexane (1:2) as eluent to

give a white solid with mp 84-86 oC (lit[2] mp 85-86 o Q in a 61%


IH NMR (CDCI3): 5 2.20 (m, 2H), 3.74-3.82 (m, 8H), 3.99-4.19 (m, 8H),

6.76-6.91 (m, 8H).

Dibenzo-21-crown-7 (48). A white solid with mp 104-106

oc (lit[2] mp 106.5-107.5 oC) was obtained in 78% yield. IR (deposit

from chloroform on a NaCl plate): 1125 (C-0) cm-l. 1 H NMR (CDCI3):

5 3.87-4.21 (m, 20H), 6.86-6.94 (m, 8H).

svm-Di r4 (5 ) - t e r t -bu tv lbenzo1-2 l - c rown-7 (49) The

crude product was chromatographed on alumina with EtOAc-hexane

(1:2) as eluent and then recrystallized from Et20 to give white solid

with mp 87-89 oc (lit[58] mp 86-88 oC) in 67% yield. IR (deposit

89

from chloroform on a NaCl plate): 1146 (C-0) cm-l. 1H NMR (CDCI3):

5 1.28 (s, 18H), 3.84-4.23 (m, 20H), 6.77-7.26 (m, 6H).

l , 8 -Naphtho-16-crown-5 (56). A white solid with mp 112-

114 oc (lit[39] mp 110-112 oc) was obtained in 77% yield. IR (deposit

from dichloromethane on a NaCl plate): 1281, 1114 (C-0) cm-l. 1H

NMR (CDCI3): 5 3.65-3.85 (m, 8H), 3.99-4.26 (m, 8H), 6.77-6.81 (m,

2H), 7.26-7.39 (m, 4H).

l ,8 -Naphtho-19-crown-5 (57).[39] A yellow oil was

obtained in 80% yield. IR (deposit from dichloromethane on a NaCl

plate): 1281, 1111 (C-0) cm-l. 1H NMR (CDCI3): 5 3.64-3.87 (m, 12H),

4.02-4.27 (m, 8H), 6.79-6.86 (q, 2H), 7.26-7.42 (m, 4H).

l ,8 -Naphtho-22-crown-7 (58). A colorless oil was obtained

in 54% yield. IR (deposit from dichloromethane on a NaCl plate):

1280, 1112 (C-0) cm-l. 1H NMR (CDCI3): 5 3.68-3.85 (m, 16H), 3.99-

4.14 (m, 4H), 4.23-4.28 (m, 4H), 6.83-6.87 (q, 2H), 7.26-7.42 (m, 4H).

Anal. Calcd for C22H30O7: C, 65.01; H, 7.44. Found: C, 65.07; H, 7.26.

o ,o' -Biphenyl-17-crown-5 (59). A white solid with mp

105-108 oc (lit[46] mp 105-107 oC) was obtained in 64% yield. IR

(deposit from dichloromethane on a NaCl plate): 1264, 1130 (C-0)

cm-l. IH NMR (CDCI3): 5 3.47-3.61 (m, 12H), 3.98-4.22 (m, 4H), 6.92-

7.34 (m, 8H).

o,o'-BiphenyI-20-crown-6 (60).[46] A colorless, sticky oil

was obtained in 75% yield. IR (deposit from dichloromethane on a

NaCl plate): 1263, 1126 (C-0) cm-l. 1H NMR (CDCI3): 5 3.55-3.76 (m,

16H), 3.98-4.22 (m, 4H), 6.94-7.34 (m, 8H).

90

o,o*-Biphenyl-23-crown-7 (61).[46] A colorless oil was


plate): 1263, 1125 (C-0) cm-l. I R NMR (CDCI3): 5 3.51-3.75 (m,

20H), 4.06-4.26 (m, 4H), 6.95-7.33 (m, 8H).

2,2'-Binaphtho-17-crown-5 (62).[46] A white solid with

mp 112-113 oc (lit[46]ii4-115 oC) was prepared in 52% yield. IR


cm-l. IH NMR (CDCI3): 5 3.20-3.68 (m, 12H), 3.97-4.26 (m, 4H), 7.13-

7.34 (m, 6H), 7.41-7.50 (d, 2H), 7.83-7.95 (m, 4H).

2,2*-Binaptho-20-crown-6 (63). A colorless solid with mp

129-131 oc was obtained in 80% yield. IR (deposit from

dichloromethane on a NaCl plate): 1271, 1132 (C-0) cm-l. 1H NMR

(CDCI3): 5 3.35-3.67 (m, 16H), 4.00-4.20 (m, 4H), 7.14-7.35 (m, 6H)

7.44-7.48 (d, 2H), 7.83-7.95 (m, 4H).

2,2*-Binaptho-23-crown-7 (64).[46] A colorless oil was


plate): 1265, 1133 (C-0) cm-l. I R NMR (CDCI3): 5 3.31-3.66 (m,

20H), 4.02-4.17 (m, 4H), 7.06-7.35 (d, 2H), 7.83-7.95 (m, 4H).

N ,N' -Di tosy l -4 ,13-d iazadibenzo-18-crown-6 (69). A

white solid with mp 218-219 oc (lit[48] 219-220 oC) was obtained in

74% yield. IR (nujol): 1461, 1328 (S=0); 1115 (C-0) cm-l . i n NMR

(CDCI3): 5 2.41 (s, 6H), 3.71-3.77 (m, 8H), 4.09-4.15 (m, 8H), 7.30 (d,

4H), 7.72 (d, 4H).

91

N-Tosy lmonoazadibenzo-18-crown-6 (70). A white solid

with mp 159-160 oc (lit[49] mp 159-160 oC) was obtained in 72%

yield. IR (deposit from dichloromethane on a NaCl plate): 1332,1255

(S=0); 1124 (C-0) cm-l . I H NMR ( CDCI3): 5 2.37 (s, 3H), 3.75-4.21 (m,

16H), 6.71-6.91 (m, 8H), 7.26 (s, 2H), 7.74 (s, 2H).

2,3-Pyridino-15-crown-5 (71).[40] A white solid with mp

63-65 oc (lit[40] mp 64.5-65.5oC) was obtained in 14% yield. IR


cm-l. IH NMR (CDCI3): 5 3.69-3.94 (m, 12H), 3.87-3.94 (t, 2H), 4.47-

4.51 (t, 2H), 6.77-6.98 (q, IH), 7.04-7.09 (d, IH), 7.70-7.74 (d, IH).

2,3-Pyridino-18-crown-6 (72).[40] A yellow solid with mp

76-78 oc was obtained in 37% yield. IR (deposit from

dichloromethane on a NaCl plate): 1204, 1125 (C-0) cm-l. I H NMR

(CDCI3): 5 3.63-3.95 (m, 16H), 4.13-4.17 (m, 2H), 4.50-4.54 (m, 2H),

6.77-6.84 (q, IH), 7.0-7.07 (d, IH), 7.69-7.72 (d, IH).

2,3-Pyridino-21-crown-7 (73).[40] A colorless oil was


plate): 1257, 1123 (C-0) cm-l. I H NMR (CDCI3): S 3.63-3.96 (m,

20H), 4.14-4.18(m, 2H), 4.50-4.54 (m, 2H), 6.78-6.84 (q, IH), 7.05-

7.09 (d, IH), 7.70-7.73 (d, IH).

General Procedure for Preparation of 1.3-Xvlvl Crown Ethers 76-78

Potassium hydride (3.43 g, 30.0 mmol, 35% dispersion in

mineral oil) was washed with pentane (2 X 20 mL) and suspended in

50 mL of THF. With stirring under nitrogen, a solution of

92

http://64.5-65.5oC

polyethylene glycol (10.0 mmol) in 50 mL of THF was added

dropwise during 30 min. After 1 h a solution of 1,3-

bis(bromomethyl)benzene (2.64 g, 10.0 mmol) in 60 mL of THF was

added dropwise during a period of 30 min. The reaction mixture was

stirred at room temperature for 24 h. Water (10 mL) was added and

the solvent was evaporated in vacuo. The aqueous mixture was

extracted with CH2CI2 (2 X 50 mL). The combined extracts were

washed with water (30 mL), dried over MgS04 and evaporated in

vacuo. The residue was purified by chromatography on alumina

with ethyl acetate as eluent.

l,3-Xylyl-18-crown-5 (76).[50] A colorless oil was obtained

in 53% yield. IR (neat): 1353, 1102 (C-0) cm-l. IH NMR (CDCI3): 5

3.65-3.72 (m, 16H), 4.65 (s, 4H), 7.11-7.30 (m, 3H), 7.72 (s, IH).

l ,3-Xylyl-21-crown-6 (77).[50] A colorless oil was obtained

in 30% yield. IR (neat): 1352, 1111 (C-0) cm-l. i n NMR (CDCI3): 5

3.69-4.04 (m, 20H), 4.60 (s, 4H), 7.11-7.33 (m, 3H), 7.72 (s, IH).

l ,3-Xylyl -24-crown-7 (78).[50] A colorless oil was obtained

in 20% yield after precipitation of a side product from diethyl ether-

hexane. IR (neat): 1351, 1113 (C-0) cm-l. I H NMR (CDCI3): 5 3.28-

4.23 (m, 24H), 4.63 (s, 4H), 7.19-7.43 (m, 3H), 7.46 (s, IH).

l ,3-Bis(bromomethyl)benzene (74). To a suspension of

l,3-dibromo-5.5-dimethylhydantoin (68.62 g, 0.24 mol) in 300 mL of

CCI4 was added nL-xylene (21.23 g, 0.20 mol) and 1.50 g of benzoyl

peroxide. The suspension was irradiated with a 500 W lamp for a 4

h period. The reaction was followed by TLC. The reaction mixture

93

was cooled to room temperature after a light yellowish suspension

was obtained. The reaction mixture was washed with water (4 X 200

mL) and dried over MgS04. The solvent was evaporated in vacuo to

give a yellowish liquid. A large amount (300 mL) of absolute

methanol was added to the liquid residue and the resulting solution

place in a refrigerator to precipitate a white solid. The solid was

collected and dried to give 20.10 g (38%) of the product as a white

solid with mp 73-74 oc (lit[51] mp 74-76 oC). IR (deposit): 1211,

1163 (C-0) cm-l. IH NMR (CDCI3): 5 4.47-(s, 4H), 7.20-7.36 (m, 4H),

7.50 (s, IH).

General Procedure for the Preparation of svm-(Hvdroxv)(methyn dibenzocrown Ethers 87 and 9 5

To 0.39 g (16,2 mmol) of magnesium turnings in 140 mL of

anhydrous Et20 under nitrogen was added dropwise 4.59 g (32.4

mmol) of methyl iodide. The reaction mixture was stirred in an ice

bath until the magnesium disappeared and white emulsion formed. A

solution of the sym-ketocrown ether (32.4 mmol) in 210 mL of THF

was added dropwise at 0 oc. Reaction was continued for 10 hr at

room temperature. To the reaction mixture, 80 mL of 5% aqueous

ammonium chloride solution was added, and the mixture was stirred

for 5 hr. The solvent was evaporated and extracted with CH2CI2 (2 x

100 mL). The CH2CI2 solution was washed with water, dried over

magnesium sulfate and evaporated in vacuo. The crude product was

chromatographed on alumina with EtOAc as eluent.

94

s y m - ( H y d r o x y ) ( m e t h y I ) d i b e n z o - 1 6 - c r o w n - 5 (87). A

white solid with mp 109-111 oc (lit[55] mp 110-111 oc) was obtained

in 72% yield. IR (deposit from dichloromethane on a NaCl plate):

3410 (OH), 1130 (C-0) cm-l . I H NMR(CDCl3): 5 1.43 (s, 3H), 4.17-3.69

(m, 12H), 6.93 (s, 8H).

sym- (Hydroxy) (me thy l )d ibenzo -14 -c rown .4 (95). A

white solid with mp 140-142 oc (lit[57] mp 142.5-143 oC) was


plate): 3490 (OH), 1124 (C-0) cm-l . I H NMR (CDCI3): 5 1.34 (s, 3H),

2.49 (m, 2H), 3.72 (s, OH), 4,45-4.83 (m, 8H), 6.91 (s, 8H).

General Procedure for the Preparation of Pvridvl-Subsntuted Crown Ethers Using Sodium Hvdride

Procedure A. Under nitrogen, svm-hydroxydibenzo-16-

crown-5 (4.00 g, 11.0 mmol) and 0.48 g (11.0 mmol) of a 60%

dispersion of NaH in mineral oil were added to 120 mL of dry DMF.

The reaction mixture was stirred for 1 h at room temperature. A

solution of 2-picolyl chloride hydrochloride (0.95 g, 5.8 mmol)

dissolved in 50 mL of dry DMF was added dropwise during a 10-min

period and the reaction mixture was stirred for 24 h and quenched

with 20 mL of H2O. The DMF was removed in vacuo and the

remaining aqueous mixture was extracted with CH2CI2 (2 X 50 mL).

The combined CH2CI2 extracts were dried over MgS04 and evaporated

in vacuo. The residue was chromatographed on alumina with EtOAc

as a eluent.

95

Procedure B. Under nitrogen, 2-picolyl chloride

hydrochloride (0.26 g, 1.58 mmol) and 0.06 g (1.58 mmol) of a 60%

dispersion of NaH in mineral oil were added to 80 mL of dry THF.

The reaction mixture was stirred for 2 h at room temperature. The

precipitate was removed by filtration through a bed of Celite on a

sintered glass funnel. The filtrate was added dropwise to a solution

of sxi!l-hydroxydibenzo-16-crown-5 (0.55 g, 1.58 mmol) and 60%

dispersion of NaH ( 0.12 g, 3.16 mmol) in 60 mL of dry THF. The

reaction mixture was stirred for 24 h at room temperature and

quenched with 20 mL of water. The THF was removed in vacuo and

the remaining aqueous mixture was extracted with CH2CI2 (2 X 50

mL) and dried over MgS04. After evaporation of the solvent in,

vacuo, the crude product was chromatographed on alumina with

EtOAc as a eluent.

svm-(2-Picolvloxv)dibenzo-13-crown-4 (82). A white

solid with mp 72-73 oC was obtained in a 18% yield by procedure A

and in a 36% yield by procedure B. IR (deposit from chloroform on a

NaCl plate): 1114 (C-0) cm-l. IH NMR (CDCI3): 5 3.78-3.83 (m, IH),

4.01-4,45 (m, 8H), 4.84 (s, 2H), 6.85-7.25 (m, 8H), 7.49-7.52 (m, IH),

7.62-7.69 (m, 2H), 8.51-8.53 (d, IH). Anal. Calcd. for C23H23NO5: C,

70.21; H, 5.89. Found: C, 70.06; H, 5.83.

sym-(2-Picolvloxv)dibenzo-14-crown-4 (83). A white



NaCl plate): 1107 (C-0) cm-l. IH NMR (CDCI3): 5 1.94-2.54 (m, 2H),

96

3.90-4.46 (m, 4H), 4.86 (s, 2H), 6.68-7.05 (m, 8H), 7.10-7.35 (m, IH),

7.52-7.80 (m, 2H), 8.48-8.72 (m, IH). Anal. Calcd for C24H25NO5: C,

70.74; H, 6.18. Found: C; 70.76; H, 6.14.

SXin.-(Methyl)(2-picoIyloxy)dibenzo-14-crown-4 (98 ) .

A yellowish oil was chromatographed on alumina with EtOAc-hexane

(1:2) as a eluent to give a white solid with mp 130-132 oc in a 30%

yield by procedure B. IR (deposit from chloroform on a NaCl plate):

1118 (C-0) cm-l. IH NMR (CDCI3): 5 4.12-4.38 (m,8H), 4.91 (d, 2H),

6.84-6.99 (m, 8H), 7.14-7.26 (t, IH), 7.55-7.74 (m, 2H), 8.53-8.55 (d,

IH). Anal. Calcd. for C24H25O5NO.5 H2O: C, 69.75; H, 6.56. Found: C;

69.77; H, 6.60.

&XIlL-(2-Picolyloxy)dibenzo-16-crown-5 (84). A white



NaCl plate): 1111 (C-0) cm-l. IH NMR (CDCI3): 5 3.91-4.43 (m, 13H),

5.03 (s, 2H), 6.82-7.00 (m, 8H), 7.18-7.26 (m, IH), 7.71-7.75 (q, 2H),

8.56-8.58 (d, IH). Anal. Calcd for C25H28NO6O.ICH2CI2: C, 67.43; H,

6.34. Found: C, 67.66; H, 6.00.

svm-(Prop vn(2-picolyloxv)dibenzo-16-crown-5 (91) A

reddish-colored oil was chromatographed on alumina with EtOAc-

hexane (1:2) as eluent to give a yellow sticky oil in a 22% yield by

procerue B. IR (neat): 1122 (C-0) cm-l. IH NMR (CDCI3): 5 0.91-1.04

(m, 3H), 1.50-1.62 (m, 2H), 2.00-2.08 (m, 8H), 7.11-7.17 (m, IH),

7.63-7.68 (m, 2H), 8.50-8,54 (m, IH), Anal. Calcd for

C28H33NO6O.ICH2CI2: C, 68.90; H, 6.86, Found: C, 69.10; H, 6.92.

97

2-Picolyl Dodecyl Ether (104). A colorless oil was obtained

in an 8% yield by procedure B. IR (neat): 1122 (C-0) cm-l. I H NMR

(CDCI3): 5 0.77-0.83 (m, 3H), 1.18-1.34 (m, 18H), 1.51-1.65 (m, 2H),

3.44-3.51 (t, 2H), 7.05-7.12 (m, IH), 7.34-7.39 (d, IH), 7.56-7.64 (m,

IH), 8.45-8.48 (m, IH). Anal. Calcd for C18H31NO: C, 77.92; H, 11.26.

Found: C, 78.01; H; 11.35.

General Procedure for the Preparation of Pvridvl-Substituted Crown Ethers Using Potassium Hydride

Under nitrogen, KH (3.03 g, 26.4 mmol, of a 35% dispersion in

mineral oil) was washed with pentane (2 X 20 mL) to remove the

protecting oil and 80 mL of THF was added. To the suspension,

picolyl chloride hydrochloride (1.09 g, 6.6 mmol) was added. After

stirring at room temperature for 2 h, the solid was removed by

filtration through a bed of Celite on a sintered glass funnel. The

filtrate was added dropwise to the mixture of the crown alcohol (1.20

g, 3.3 mmol) and KH (1.51 g, 13.2 mmol) in 80 mL of THF and the

mixture was stirred for 24 h at room temperature. Water (20 mL)

was added, and the reaction mixture was extracted with CH2CI2 (2 X

50 mL). The combined CH2CI2 extracts were washed with water (30

mL), dried over MgS04 and evaporated in vacuo. The crude product

was chromatographed on alumina with EtOAc-hexane (1:2) as eluent.

5jJlL-(I^ecyl)(2-picolyloxy)dibenzo-14-crown-4 ( 1 0 0 ) .

Chromatography of the crude product gave a colorless oil in a 66%

yield. IR (neat): 1118 cm-l. I H NMR (CDCI3): 5 0.84-0.90 (t, 3H),

98

1.24-2.04 (m, 18H), 2.29 (m, 2H), 4.14-4.34 (m, 8H), 4.88 (s, 2H),

6.86-6.99 (m, 8H), 7.17-7.26 (m, IH), 7.61-7.70 (m, 2H), 8.53-8.55

(m, IH). Anal. Calcd for C34H45NO5: C, 74.55; H, 8.28. Found: C,

74.66; H, 8.29.

aXIIL-(Methyl)(2-picolyloxy)dibenzo-16-crown-5 (90 ) .

A sticky oil was obtained in 17% yield. IR (neat): 1123 (C-0) cm-l.

IH NMR (CDCI3): 5 1.66 (s, 3H), 3.81-4.46 (m, 12H), 5.04 (s, 2H), 6.81-

6.98 (m, 8H), 7.14-7.26 (m, IH) 7.62-7.68 (m, 2H), 8.50-8.54 (m, IH).

Anal. Calcd. for C26H29NO6: C, 69.16; H, 6.47. Found: C, 69.65; H, 6.45.

iXJIL-(Decyl)(2-picoIyloxy)dibenzo-16-crown-5 (92). A

colorless oil was obtained in 36% yield. IR (neat): 1123 cm-l. I H

NMR (CDCI3): 5 0.84-0.90 (t, 3H), 1.00-1.68 (m, 16H), 2.00-2.08 (q,

2H), 3.91-4.47 (m, 12H), 5.08 (s, 2H), 6.79-6.97 (m, 8H), 7.10-7.17

(m, IH), 7.60-7.67 (m, 2H), 8.50-8.52 (d, IH). Anal. Calcd for

C35H47NO6: C, 72.76; H, 8.20. Found: C, 72.56; H, 8.19.

iXI!L-(Propyl) (benzyloxy)dibenzo-16-crown-5 ( 1 0 3 ) .

Under nitrogen, KH (1.75 g, 15.3 mmol, of a 35% dispersion in

mineral oil) was washed with pentane (2 X 20 mL) to remove the

protecting mineral oil and 100 mL of dry THF was added. To the

suspension, crown ether alcohol 88 (2.0 g, 5.1 mmol) in 30 mL of

THF was added slowly. After stirring at room temperature for 1 h, a

solution of benzyl bromide (0.87 g, 5.1 mmol) in 50 mL of THF was

added dropwise and the mixture was stirred for 15 h at room

temperature and quenched with 10 mL of H2O. The THF was

removed in vacuo and the remaining aqueous mixture was extracted

99

with CH2CI2 (2 X 50 mL). The combined CH2CI2 extracts were washed

with water (50 mL), dried over MgS04 and evaporated in vacuo. The

residue was chromatographed on alumina with EtOAc-hexane (1:3) as

eluent to give 1.96 g (80%) of a white solid with mp 97-98 oC. IR

(deposit from chloroform on a NaCl plate): 1139 (C-0) cm-l. I H NMR

(CDCI3): 5 0.96-1.03 (t, 3H), 1.49-1.61 (m, 2H), 1.97-2.05 (m, 2H),

3.86-4.45 (m, 12H), 4.92 (s, 2H), 6.80-6.91 (m, 8H), 7.23-7.44 (m,

4H). Anal. Calcd for C29H34O6: C, 72.78; H, 7.16. Found: C, 72.99; H,

7.21.

Sodium svm-Dibenzo-16-crown-5-oxy xanthate (105) .

The protecting mineral oil from NaH (2.16 g , 54.0 mmol of 60%

dispersion in mineral oil) was removed by washing with 50 mL of

pentane under nitrogen and 180 mL of THF was added. To the

mixture, svm-hydroxydibenzo-16-crown-5 (6.0 g, 17.4 mmol) in 50

mL of THF was added dropwise and the mixture was stirred for 1 h

at room temperature. Carbon disulfide (2.90 g, 37.5 mmol) in 40 mL

of THF was added dropwise during a 30-min. period. The reaction

mixture was stirred for 10 h at room temperature and was filtered.

To the filtrate 20 mL of water was added and the THF was

evaporated in vacuo. The remaining aqueous mixture was extracted

with CH2CI2 (2 X 50 mL). Evaporation of the CH2CI2 in vacuo gave a

yellow solid which was purified by recrystallization from absolute

ethanol to give 4.30 g (56%) of a yellow solid with mp 148-152 o c .

IR (deposit from dichloromethane on a NaCl plate): 1238 (C=S) cm-l.

100

IH NMR (CDCI3): 5 3.72-4.58 (m, 13H), 6.70-7.17 (s, 8H). Anal. Calcd

for C20H2iO6S2NaH2O: C, 51.89; H, 4.97. Found C, 52.04; H, 4.48.

Methyl ixnL-Dibenzo-16-crown-5-oxyxanthate (107 ) .

Xanthate 105 (1.33 g, 3.0 mmol) was dissolved in 50 mL of absolute

ethanol at room temperature and a solution of CH3I (0.86 g, 60

mmol) in 10 mL of EtOH was added under nitrogen. The reaction

mixture was stirred for 3 h at 50 oc. After evaporation of the

solvent in vacuo. 50 mL of water was added and the mixture was

extracted with CH2CI2 (2 X 50 mL). The organic layer was dried over

anhydrous MgS04 and the solvent was evaporated in vacuo, the

residue was chromatographed on silica gel with EtOAc as eluent to

give 0.86 g (66%) of a white solid with mp 97-100 oC. IR (deposit):

1255 (C=S) cm-l. I H NMR (CDCI3): 5 2.52 (s, 3H), 3.80-4.78 (m, 13H),

6.74-7.24 (m, 8H). Anal. Calcd for C21H24O6S2: C, 57.78; H, 5.54.

Found: C, 58.04; H, 5.64.

Methyl s v m - D i r 3 ( 4 ) - t e r t - b u t y l b e n z o l - 1 6 - c r o w D - 5 - o x y

xanthate (108). Following the synthetic procedure given for 107,

sodium xanthate 106 (0.40 g, 0.75 mmol) and CH3I (0.22 g, 1.50

mmol) in 50 mL of absolute ethanol were stirred for 3 h at 50 o c .

After addition of water (20 mL), the mixture was extracted with

CH2CI2 (2 X 30 mL). The organic layer was dried over MgS04 and

chromatographed on silica gel with EtOAc as eluent to give 0.11 g

(27%) of a red solid with mp 65-67 oC. IR (deposit from

dichloromethane on a NaCl plate): 1121 (C=S) cm-l. I H NMR (CDCI3):

5 1.27 (s, 25H), 2.54 (s, 3H), 3.93-4.61 (m, 13H), 6.87-7.06 (m, 6H).

101

Anal. Calcd for C29H40O6S2I.5H2O: C, 60.50; H, 7.61. Found: C, 60.68;

H, 7.36.

General Procedure for Preparation of svm-(Alkvn(methoxy)dibenzocrown Ethers 1 1 1 - 1 1 3

To a solution of NaH (0.60 g, 15.0 mmol), 60% dispersion in

mineral oil) in dry THF (120 mL) was added the appropriate

dibenzocrown ether alcohol (5.15 mmol) in 30 mL of THF. The

reaction mixture was stirred for 2 h at room temperature. A solution

of CH3I (1.46 g, 10.30 mmol) in 50 mL of THF was added dropwise,

and the mixture was stirred for 24 h at room temperature. Water

(50 mL) and CH2CI2 (200 mL) were added. To the inhomogeneous

solution 1 N-NaOH aqueous solution (80 mL X 2) was added and the

mixture was shaked vigorously. The organic layer was separated and

washed with brine (50 mL), water and dried over MgS04. The

residue was purified by column chromatography on alumina with

EtOAc as eluent to give the desired product.

svm-(Methvl) (methoxy)dibenzo-16-crown-5 (111). A

white solid with mp 115-117 oC was obtained in 80% yield. IR

(deposit from chloroform on a NaCl plate): 1122 (C-0) cm-l. IH NMR

(CDCI3): 5 1.51 (s, 3H), 3.53 (s, 3H), 3.85-4.27 (m, 12H), 6.81-7.26 (m,

8H). Anal. Calcd for C21H26O6: C, 67.36; H, 7.00. Found: C, 67.60; H,

7.09.

svm-(Propyn(methoxv)dibenzo-16-crown-5 (112). A

white solid with mp 91-920C was obtained in 90% yield. IR (deposit

102

from chloroform on a NaCl plate): 1122 (C-0) cm-l. I H NMR (CDCI3):

5 1.02 (t, 3H), 1.38-1.57 (m, 2H), 1.85-1.93 (m, 2H), 3.55 (s, 3H), 3.64-

4.35 (m, 12H), 6.81-7.06 (m, 8H). Anal. Calcd for C23H30O6: C, 68.63;

H, 7.51. Found: C, 68.32; H, 7.60.

SXm.-(Decyl)(methoxy)dibenzo-16-crown-5 (113). After

chromatography the crude product was recrystallized from hexane-

THF to give a white solid with mp 59-60 oc in 56% yield. IR (deposit

from chloroform on a NaCl plate): 1123 (C-0) cm-l. I H NMR (CDCI3):

5 0.88 (t, 3H), 1.26 (m, 16H), 1.89 (m, 2H), 3.55 (s, 3H), 3.83-3.95 (m,

4H), 4.13-4.18 (m, 6H), 4.33 (d, 2H), 6.81-6.98 (m, 8H). Anal. Calcd.

for C30H44O6: C, 71.97; H, 8.86. Found: C, 72.04; H, 8.77.

General Procedure for the Preparation of N-(2-Trifluoro-4.6-dinitrophenvn-4'-aminobenzocrown Ethers 114 and 116

To a solution of the 4'-aminobenzocrown ether (5.78 g, 20.4

mmol) in 250 mL of absolute methanol was added 2-chloro-3,5-

dinitrobenzotrifluoride (5.68 g, 21.0 mmol) then sodium bicarbonate

(2.3 g, 27.4 mmol). The mixture was refluxed for 24 h. The

precipitate was filtered and solvent was removed from the filtrate in

vacuo. The crude residue was chromatographed on alumina with

EtOAc as a eluent to give the desired product.

N - ( 2 - T r i f l u o r o - 4 , 6 - d i n i t r o p h e n y I ) - 4 ' - a m i n o b e n z o - 1 4 -

crown-4 (116). A red solid with mp 121-123 oC was obtained in

22% yield. IR (deposit from chloroform on a NaCl plate): 3415 (Nil);

1511 (NO2); 1132 (C-O) cm-l. I H NMR (CDCI3): 5 1.75-2.04 (m, 4H),

103

3.40-3.81 (m, 8H), 4.09-4.18 (m, 4H), 6.46-6.63 (m, 2H), 6.80-7.10 (d,

IH), 7.64 (s, NH), 8.65 (d, IH), 8.87 (d, IH). Anal. Calcd for

C21H22N3O8F3: C, 50.30; H, 4.42. Found: C, 50.73; H, 4.54.

N-(2 -Tr if luor 0 - 4 , 6 - d i n i t r o p h e n y l ) - 4 ' - a m i n o b e n z o - 1 5 -

crown-5 (114). A red solid with mp 135 oC was obtained in 54%

yield. IR (deposit from chloroform on a NaCl plate): 3416 (NH); 1597

(NO2); 1133 (C-0) cm-l. IH NMR (CDCI3): 5 3.71-3.93 (m, 12H), 4.06-

4.17 (m, 4H), 6.55-6.60 (q, 2H), 6.77-6.81 (d, IH), 7.64 (s, NH), 8.66

(d, IH), 8.85 (d, IH). Anal. Calcd. for C21 H22N3O9F3: C, 48.74; H,

4.29. Found : C, 49.15; H, 4.26.

N - ( 2 - T r i f l u o r o - 5 , 6 - d i n i t r o p h e n y l ) - 5 ' - n i t r o - 4 * -

aminobenzo-15-crown-5 (115). To a solution of aminobenzo

crown ether 114 (1.50 g, 1.9 mmol) was added acetic acid and

fuming nitric acid (2.5 mL of each). The reaction mixture was stirred

for 10 min at room temperature. The organic layer was separated

and washed with water (4 X 50 mL) and dried over MgS04. After

evaporation of the solvent in vauo. the residue was chromatographed

on silica gel with EtOAc as eluent to give 0.34 g (21%) of a sticky

reddish oil. IR (neat): 3462 (NH); 1583 (NO2); 1130 (C-0) cm-l. i n

NMR (CDCI3): 5 3.59-3.71 (m, 12H), 3.82-3.87 (m, 2H), 4.01-4.05 (m,

2H), 5.86 (d, NH), 6.65-6.70 (d, IH), 6.98-7.05 (q, IH), 8.79-8.80 (d,

IH), 9.09-9.10 (d, IH). Anal. Calcd for C14H21NO4.O.9 EtOAc: C, 46.04;

H, 4.43. Found: C, 46.38; H, 3.92.

104

General Procedure for the Preparation of Acvclic Polvether Secondary Alcohols 117 119 and 1 2 0

To 16.39 g (132 mmol) of the appropriate methoxyphenol in

1.8 L of water-THF (1: 1), 5.28 g (132 mmol) of NaOH was slowly

added. The mixture was stirred and heated for 2 h at 80 o c under

nitrogen and then cooled to 50 oc . Epichlorohydrin (6.11 g, 66 mmol)

was added during an 8-h period with a syringe pump and stirring

was continued at 50 oc for 2 days. After evaporation of the THF in

vacuo, the residue was extracted with CH2CI2 (2 X 100 mL). The

CH2CI2 extracts were washed with brine, dried over MgS04, and

evaporated in vacuo. Chromatography of the residue on alumina

with EtOAc as eluent gave the desired product.

l , 3 -Bis (o -methoxyphenoxy) -2 -propano l (117) . A white

solid with mp 69-71 oC was obtained in 66% yield. IR (deposit from

chloroform on a NaCl plate): 3428 (OH); 1253; 1124 (C-0) cm-l. I H

NMR (CDCI3): 5 3.72 (s, IH), 3.80 (s, 6H), 4.15-4.25 (m, 4H), 4.42 (pen,

IH), 6.80-7.00 (m, 8H). Anal. Calcd for C17H20O5: C, 67.09; H, 6.62.

Found: C, 67.24; H, 6.73.

l , 3 -B i s (p -me thoxyphenoxy) -2 -p ropano l (119) . After

chromatography the crude product was recrystallized from Et20 to

give white solid with mp 99-101 oC in 54% yield. IR (deposit from

chloroform on a NaCl plate): 3417 (OH); 1233; 1046 (C-0) cm-l. I H

NMR (CDCI3): 5 2.83 (s, OH), 3.58-3.86 (m, 6H), 3.96-4.24 (m, 4H),

105

4.28-4.36 (m, IH), 6.82-6.89 (m, 8H). Anal. Calcd for C17H20O5: C,

67.09; H,6.62. Found: C, 67.28; H, 6.70.

l ,3-Bis(o-methoxyphenoxy)-2-propanone (120). To 1.8

L of acetone was added 20.0 g (65.7 mmol) of 1.3-bis(ii-

methoxyphenoxy)-2-propanol (117). The solution was stirred for 2

h in an ice bath and 120 mL of Jones reagent was added during a 2 h

period. (The Jones reagent was prepared by addition of 27.6 mL of

cone H2SO4 to 32.0 g of Cr03 in 40 mL of water followed by enough

water to make 120 mL.) Stirring was continued for an additional 24

h at room temperature. The green precipitate was filtered and the

solvent was removed from the filtrate in vacuo. Water (500 mL) was

added and the mixture was extracted with CH2CI2 (2 X 100 mL). The

combined CH2CI2 extracts were washed with water (2 X 100 mL),

dried over MgS04, and evaporated in vacuo to give a brownish oil.

Recrystallization from EtOAc-hexane gave 13.0 g (65%) of a white

solid with mp 69-71 oC. IR (deposit from chloroform on a NaCl

plate): 1742 (C-0) cm-l. IH NMR (CDCI3): 5 3.86 (s, 6H), 4.96 (s,4H),

6.83-6.97 (m, 8H). Anal. Calcd. for C17H18O5; 67.54; H, 6.00. Found:

C, 67.67; H. 6.05.

General Procedure for the Preparation of Acvclic Polvether Tertiary Alcohols }2^ and 1 2 2

To 0.13 g (12.6 mmol) of magnesium turnings in 100 mL of THF

under nitrogen was added 1.55 g (12.6 mmol) of l-bromopropane,

and the mixture was refluxed until the magnesium turnings

106

disappeared. The solution was cooled to 0 oc and 1.91 g (6.3 mmol)

of ketone 120 in 20 mL of THF was added. The reaction mixture was

refluxed for 5 h and cooled to 0 oc. After slow addition of 30 mL of

5% aqueous NH4CI, the THF was evaporated in vacuo. The resulting

oil was extracted with Et20 (100 mL). The ether extract washed with

water (2 X 50 mL) and dried over MgS04. After evaporation in vacuo

the residue was chromatographed on alumina with EtOAc as eluent to

give the desired product.

2 - [ (fi.-M e t h o X y p h e n o x y) m e t h y I ] -1 - (iL-

methoxyphenoxy)-2-pentanol (121). A colorless oil was

obtained in 68% yield. IR (neat): 3482 (OH) cm-l. IH NMR (CDCI3): 5

0.92-0.99 (t, 3H), 1.42-1.63 (m, 2H), 1.71-1.80 (m, 2H), 3.17 (s, IH),

3.75-3.86 (m, 6H), 3.98-4.12 (q, 4H), 6.82-7.06 (m, 8H). Anal. Calcd

for C20H26O5O.25H2O: C, 68.49; H, 7.55. Found: C, 68.72; H, 7.83.

2- [ ( f i . -Methoxyphenoxy)methyIl - l - ( iL-

methoxyphenoxy)-2-dodecanol (122). A colorless oil was

obtained in 47% yield. IR (neat): 3482 (OH) cm-l. IH NMR (CDCI3): 5

0.84-0.90 (t, 3H), 1.22-1.29 (t, 16H), 1.72-1.60 (q, 2H), 3.79-3.84 (d,

6H), 3.98-4.16 (m, 4H), 6.82-7.05 (m, 8H). Anal. Calcd for C27H40O5:

C, 72.94; H, 9.07. Found: C, 72.36; H, 9.45.

General Procedure for the Preparation of Acvclic Polvether Carboxylic Acids 123-127

After removal of the mineral oil from 27.43 g (0.24 mol) of KH

(35% dispersion in mineral oil) with pentane under nitrogen, 0.039

mol of the acyclic polyether alcohol in 100 ml of THF was added

107

during a 1 h period. The mixture was stirred for 1 h at room

temperature and 5.42 g (0.078 mol) of bromoacetic acid in 125 mL of

THF was added during a 3-h period. The mixture was stirred for 24

h and water (5 mL) was carefully added to consume the excess KH.

The mixture was filtered and the filtrate was evaporated in vacuo.

The residue was dissolved in water (200 mL) and acidified to pH<l

with concentrated HCl. The oil which separated was decanted, and

the aqueous solution was extracted with CH2CI2 (2 X 100 mL). The oil

and CH2CI2 extracts were combined, washed with water (2 X 50 mL),

and dried over MgS04. Evaporation of the solvent gave the desired

product.

l,3-Di(iL-methoxy phenoxy)-2-(oxy ace toxy)propane

(123). The crude product was recrystallized from acetone-hexane to

give a white solid with mp 82-84 oC in 67% yield. IR (deposit from

chloroform on a NaCl plate): 3357 (OH); 1762 (C=0); 1255,1124 (C-0)

cm-l. IH NMR (CDCI3): 5 3.85 (s, 6H), 4.05-4.35 (m, 5H), 4.48 (s, 2H),

6.75-7.05 (m, 8H). Anal. Calcd for C19H22O7: C, 62.97; H, 6.12. Found

C, 62.87; H, 6.30. l ,3-Di(i iL-methoxyphenoxy)-2-(oxyacetoxy)propane

(126). A yellow liquid was obtained in 90% yield. IR (neat): 3312

(OH); 1730 (C=0); 1280, 1156 (C-0) cm-l. IR NMR (CDCI3): 5 3.78 (s,

6H), 4.14-4.21 (m, 5H), 4.43 (s, 2H), 6.48-5.58 (m, 6H), 7.15-7.25 (m,

2H). Anal. Calcd. for C19H22O7: C, 62.97; H, 6.12. Found : 62.93; H,

5.95.

108

l ,3-Di(]2.-methoxyphenoxy)-2-(oxyacetoxy)propane

(127). A yellow liquid was obtained in 84% yield. IR (neat): 3213

(OH), 1760 (C=0), 1226, 1038 (CO) cm-l. 1H NMR (CDCI3): 5 3.68 (s,

6H), 4.06 (s, 5H), 4.34 (s, 2H), 6.76-6.77 (m, 8H). Anal. Calcd for

C19H22O7: C, 62.97; H, 6.12. Found: C, 62.87; H, 6.15.

4,4-Bis[(fi .-methoxyphenoxy)methyl]-3-oxaheptanoic

acid (124). A pale yellow oil was obtained in 81% yield. IR (neat):

3354 (OH); 1733 (C=0) cm-l. I H NMR (CDCI3): 5 1.01 (m, 3H), 1.39-

1.51 (m, 2H), 1.80-1.88 (mn, 2H), 3.64 (s, 6H), 4.02-4.22 (q, 4H), 4.40

(s, 2H), 6.82-7.01 (m, 8H). Anal. Calcd for C22H28O7: C, 65.33; H, 6.98.

Found: C, 65.04; H, 7.00.

4 ,4-Bis[ (2 . -methoxyphenoxy)methyl l -3-oxat r idecanoic

acid (125). A colorless oil was obtained in 77% yield. IR (neat):

3354 (OH); 1772 (C=0) cm-l. I H NMR (CDCI3): 5 0.84-0.90 (t, 3H),

1.25-1.61 (m, 16H), 1.82-1.89 (m, 2H), 3.77-3.88 (m, 6H), 4.08-4.34

(m, 4H), 4.42 (s, 2H), 6.82-7.00 (m, 8H). Anal. Calcd for

C30H42O7O.5H2O: C, 68.81; H, 8.28. Found: C, 68.72; H, 8.49.

3,9-Dioxa-6-(N-tosylaza)-undecane-l , l l -diol (146).t73]

To a mixture of 32.25 g (0.26 mol) of 2-(2-chloroethoxy)ethanol and

69.10 g (0.50 mol) of anhydrous K2CO3 in 200 mL of dry DMF was

added 17.1 g (0.1 mol) of p-toluene-sulfonamide in 50 mL of DMF.

The reaction mixture was refluxed for 4 d with vigorous stirring.

The insoluble material was filtered and the filtrate was evaporated

in vacuo. The oily residue was chromatographed on alumina with

EtOAc as eluent to give 24.0 g (68%) of yellow oil. IR (neat): 3385

109

(OH); 1333, 1159 (SO2); 1159 (C-0) cm-l. I H NMR (CDCI3): 5 2.38 (s,

3H), 2.87 (s, IH), 3.08-3.21 (m, 2H), 3.28-3.92 (m, 6H), 6.06-6.24 (t,

IH), 7.18-7.62 (m, 4H).

l , l l - D i m e t h o x y - 3 , 9 - d i o x a - 6 - ( N - t o s y l a z a ) u n d e c a n e

(147). Under nitrogen, a solution of diol 146 (2.77 g, 8.0 mmol)

dissolved in 20 mL of dry THF was added to a suspension of 1.28 g

(32.0 mmol) of NaH (60% dispersion in mineral oil) in 20 mL of THF.

After stirring for 1 h at room temperature, a solution of methyl

iodide (4.54 g, 32.0 mmol) dissolved in 50 mL of THF was added

slowly. After 24 h, the solvent was removed and the residue was

taken up in CH2CI2 (100 mL), washed with 1 N-NaOH aqueous

solution, then water and dried over MgS04. Evaporation of the

solvent in vacuo gave 2.44 g(81%) of yellow oil. IR (neat): 1340,

1158 (SO2); 1158 (C-0) cm-l. I H NMR (CDCI3): 5 2.42 (s, 3H), 3.21-

3.67 (m, 22H), 7.27-7.33 (m, 2H), 7.65-7.73 (m, 2H). Anal. Calcd for

C17H29NO6S: C, 54.38; H, 7.78. Found: C, 54.37; H, 7.59.

l , l l - D i m e t h o x y - 3 , 9 - d i o x a - 6 - a z a u n d e c a n e (148). Under

nitrogen at room temperature. Na2HP04 (1-87 g, 13.2 mmol) and 6%

sodium amalgam (14.40 g ) were added to tosylate 147 (2.27 g , 6.0

mmol) dissolved in 200 mL of anhydrous dioxane-methanol (1:1).

The reaction mixture was refluxed for 2 d. The precipitate was

filtered and washed with methanol (50 mL). After evaporation of

the combined filtrate and washing, CHCI3 (100 mL) was added to the

residue. The mixture was filtered and the filtrate was evaporated in

vacuo. The crude product was chromatographed on silica gel with

110

EtOAc and then MeOH as eluents to give 0.80 g (60%) of yellow liquid.

IR (neat): 3504 (NH); 1199 (C-0) cm-l. I H N M R (CDCI3): 5 2.18 (s,

NH), 3.41 (s, 6H), 3.52-3.67 (m, 16H). Anal. Calcd. for C10H23NO4: C,

54.27; H, 10.47. Found: C, 53.88; H, 10.25.

N-Tosyldiethanolamine (137). Under nitrogen,

diethanolamine (28.0 g, 0.27 mol) and K2CO3 (21.0 g, 0.15 mol) were

added to 150 mL of water. The reaction mixture was stirred for 1 h

at 70 oc. p.-Toluenesulfonyl chloride (50.0 g* 0.25 mol) was added

slowly over a 30-min period. The reaction mixture was refluxed for

1 h, cooled to 50 oc , and filtered. The filtrate was placed in ice bath

and white crystals precipitated. The crystals were filtered and

washed with water. Recrystalization from water gave a white solid.

The solid was dissolved in acetone and dried over MgS04.

Evaporation of the solvent gave 45.8 g (70%) of white solid with mp

100-101 o c . IH NMR (CDCI3): S 2.56 (s, 3H), 3.11-3.47 (t, 4H), 3.65-

3.98 (t, 4H), 4.20 (s, 2H), 7.18-7.80 (q, 4H).

N-TosyImonoaza -15-c rown-5 (138). Method A: N-Tosyl

diethanolamine was added to a 60% dispersion of NaH in mineral oil

(2.60 g, 0.01 mol) suspended in 100 mL of DMF-THF (4:1). After 1 h

triethyleneglycol ditosylate (4.58 g, 0.01 mol) in 25 mL of DMF-THF

(4:1) was added at room temperature during a 5-h period. After 2 d,

the precipitate was filtered and 20 mL of water was added to the

filtrate. The THF was evaporated in vacuo and CH2CI2 (300 mL) was

added to the residual liquid. The solution was extracted repeatedly

111

with brine to remove the DMF. The organic layer was washed with

water (100 mL) and dried over MgS04. The solvent was removed in

vacVTQ. Residual DMF was removed under vacuum at 40 oc/0.04 mm.

Column chromatography of the residue on silica gel with EtOAc as

eluent gave 1.10 g (31%) of white crystals, with mp 27-290C (lit[69]

mp 29-320C). IR (deposit from dichloromethane on a NaCl plate):

1350, 1295 (SO2), 1127 (C-0) cm-l. I N M R (CDC13); 5 1.62-1.88 (m,

3H), 3.68-4.50 (m, 20H), 7.72-8.02 (d, 2H),8.18-8.42 (d, 2H).

Method B: Under nitrogen, small pieces of freshly cut sodium metal

(4.10 g, 0.180 mol) were added to a solution of diethanolamine (6.30

g, 0.60 mol) in 480 mL of dry t-butyl alcohol. The mixture was

heated (70 oC) to dissolve the sodium metal. To the reaction mixture,

a solution of triethylene glycol ditosylate (27.40 g, 0.060 mol) in p-

dioxane (300 mL) was added dropwise during a 6-h period. The

reaction was continued for 24 h at 70 oC. After cooling and filtration

of the solid material, the filtrate was evaporated in vacuo. The oily

residue was dissolved in water (100 mL) and extracted once with

hexane to remove hexane-soluble by products. The aqueous layer

was extracted with CH2CI2 (2 X 100 mL). The combined organic

layers were dried over MgS04 and evaporated in vacuo to give 14.65

g of crude oily product. To the solution of crude monoaza-15-crown-

5 (4.0 g, 18.0 mmol) in CH2CI2 (80 mL), 25% NaOH ( 20 mL) was

added dropwise during a 1 h period. To the reaction mixture, p-

toluenesulfonyl chloride was added and the mixture was refluxed for

5 h. The reaction mixture was cooled to room temperature and 30

112

mL of water was added. The CH2CI2 layer was separated, washed

with water (20 mL), and dried over MgS04. After evaporation of the

solvent in vacuo, the residue was chromatographed on alumina with

CH2CI2 as eluent to give 1.00 g (15%) of white solid.

Monoaza-15-crown-5 (130).[70] Under nitrogen, tosyl-

protected monoaza-15-crown-5 (0.72 g, 2.00 mmol) was added to

100 mL of dry MeOH-dioxane (1:1) containing Na2HP04 (0.62 g, 4.34

mmol) and 4.80 g of 6% sodium amalgam. The mixture was stirred at

reflux for 24 h and filtered. The solvent was removed from the

filtrate in vacuo and the residue was dissolved in 50 mL of CH2CI2.

The resulting solution was washed with H2O (30 mL X 2) and dried

over MgS04. Evaporation of solvent in vacuo gave 0.14 g (32%) of

colorless oil. IR (deposit from a dichloromethane on a NaCl plate):

3413 (NH), 1116 (C-0) cm-l. IH NMR (CDCI3): 5 2.54-2.95 (q, 4H),

3.02 (s, NH), 3.48-3.88 (m, 16H).

General Procedure for the Preparation of 4'-Nitrobenzocrown Ethers 139-144

Under nitrogen, benzo-12-crown-4 (2.62 g, 11.7 mmol) was

dissolved in 80 mL of CHCI3 and glacial acetic acid (50 mL) was

added. To the reaction mixture, a solution of fuming nitric acid (15

mL) in 30 mL of CHCI3 was added dropwise during a 30-min. period.

Reaction was continued for 24 h at room temperature. The organic

layer was separated and washed with saturated aqueous Na2C03 and

then with water (2 X 100 mL) and dried over MgS04. After

evaporation of the solvent in vacuo, the residue was

113

chromatographed on alumina with EtOAc as eluent to give the

desired product.

4'-Nitrobenzo-12-crown-4 (139). A yellow solid with mp

98-100 oc (litfSl] mp 96-97 oC ) was obtained in 74% yield. IR

(deposit): 1588 (NO2): 1124 (C-0) cm-l. 1H N M R (CDCI3): 5 3.74-3.93

(m, 8H). 4.25-4.30 (m, 4H), 6.98-7.02 (d, IH). 7.88-7.97 (m, 2H).

4*,5'-Dinitrobenzo-14-crown-4 (143). After

chromatography the yellowish residue was recrystallized from

EtOAc-hexane to give a yellow crystalline solid with mp 86-88 oc in a

72% yield. IR (deposit from chloroform solution on a NaCl plate):

1589,1535 (NO2); 1133 (C-0) cm-l. I H NMR (CDCI3): 5 1.70-2.18 (m,

4H), 3.73-3.78 (m, 8H), 4.10-4.46 (m, 4H), 7.32 (s, 2H). Anal. Calcd for

C14N18N2O8: C, 49.12; H, 5.30. Found: C, 49.06; H, 5.29.

4'-Nitrobenzo-14-crown-4 (144). Using a shorter reaction

time (1 h) than given in the general procedure, a yellowish crude

product was obtained. After purification by column chromatography

on alumina with EtOAc-hexane (1:2) as eluent a yellow oil was

obtained in a 79% yield. IR (neat): 1586 (NO2); 1136 (C-0) cm-l. I H

NMR (CDCI3): 5 2.00-2.12 (m, 4H), 3.61-3.67 (s, 4H), 3.72-3.82 (m, 4H),

4.18-4.32 (m, 4H), 6.93-7.07 (d, IH), 7.82-7.84 (d, IH), 7.89-7.93 (q,

IH). Anal. Calcd for C14H19NO6: C, 56.56; H, 6.44. Found: C, 56.59; H,

6.42.

4*-Nitrobenzo-15-crown-5 (140). A yellow solid with mp

85-87 oc (lit[71] mp 84-850C ) was obtained in 86% yield. IR (deposit

from chloroform on a NaCl plate): 1592 (NO2): 1121 (C-0) cm-l. I H

114

NMR (CDCI3): 5 3.67-3.76 (m, 8H), 3.92-3.96 (m, 4H), 4.18-4.24 (m,

4H), 6.86-6.90 (d, IH), 7.71-7.72 (d, IH), 7.86-7.92 (q, IH).


69-71 oc (lit[711 mp 70-72OC ) was obtained in 68% yield. IR (deposit

from chloroform on a NaCl plate): 1593 (NO2); 1124 (C-0) cm-l. 1 H

NMR (CDCI3): 5 3.65-3.79 (m, 12H), 3.69-3.98 (m, 4H), 4.21-4.27 (m,

4H), 6.87-6.91 (d, IH), 7.73-7.74 (d, IH), 7.86-7.92 (q, IH).


64-66 oc (lit[82] mp 67-68 oc ) was obtained in 83% yield. IR

(deposit from chloroform on a NaCl plate): 1587 (NO2): 1102 (C-0)

cm-l. IH NMR (CDCI3); 5 3.94-3.84 (m, 14H), 3.93-3.98 (m, 4H), 4.21-

4.28 (m, 4H), 6.88-6.93 (d, IH), 7.74-7.76 (d, IH), 7.86-7.92 (q, IH).

General Procedures for the Preparation of 4'-Aminobenzocrown Ethers 132-135 a n d l 4 5

Procedure A. To a solution of the 4'-nitrobenzocrown ether

(25.4 mmol) in 60 mL of dry DMF was added 10% palladium on

carbon (100 mg/g of crown ether). The mixture was hydrogenated

under 40 psi of hydrogen at room temperature for 24 h. The

reaction mixture was filtered through a bed of Celite on a sintered

glass funnel. The filtrate was evaporated in vauo to give the desired

product.

Procedure B. To a solution of the 4'-nitrobenzocrown ether

(8.4 mmol) in 100 mL of EtOH-THF (3:7) was added anhydrous

hydrazine (50.4 mmol) and 5% palladium on carbon (100 mg/g of

115

crown ether). The reaction mixture was refluxed for 24 h. The

reaction mixture was filtered through a bed of Celite on a sintered

glass funnel. Evaporation of the filtrate in vacuo gave the desired

product.

4*-Aminobenzo-12-crown-4 (132).[81] A yellow oil was

obtained in a 92% yield by Procedure B. IR (neat): 3344, 3213

(NH2): 1129 (C-0) cm-l. I H NMR (CDCI3): 5 3.50 (s, NH2), 3.78-3.91 (m,

8H), 4.08-4.14 (m, 4H), 6.22-6.28 (q, IH), 6.32-6.33 (d, IH), 6.81-6.84

(d, IH).

4'-Aminobenzo-14-crown-4 (145). A yellow oil was

obtained in a quantitative yield by Procedure B. IR (neat): 3425,

3354 (NH2); 1122 (C-0) cm-l. IH NMR (CDCI3): 5 1.91-2.26 (m, 4H),

3.51-3.80 (m, 8H, NH2), 4.00-4.27 (m, 4H), 6.20-6.26 (q, IH), 6.33 (d,

IH), 6.80 (d, IH). Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92. Found:

C, 62.85; H, 8.01.

4'-Aminobenzo-15-crown-5 (133).[^2] A red oil was

obtained in an 84% yield by Procedure A and in an 84% yield by

Procedure B. IR (neat): 3354, 3213 (NH2); 1125 (C-0) cm-l. I H NMR

(CDCI3): 5 3.66-3.98 (m, 12H, NH2), 4.04-4.08 (m, 4H), 6.18-6.24 (q,

IH), 6.27-6.28 (d, IH), 6.70-6.74 (d, IH).

4'-Aminobenzo-18-crown-6 (134).[72] A red oil was

obtained in a quantitative yield by Procedure A. IR (neat): 3396

(NH2); 1120 (C-0) cm-l. IH NMR (CDCI3): 5 3.66-3.94 (m, 20H, NH2),

4.06-4.10 (m, 4H), 6.24-6.28 (q, IH), 6.32-6.34 (d, IH), 6.71-6.75 (d,

IH).

116

4' -Aminobenzo-21-crown-7 (135)[82] A yellow oil was

obtained in quantitative yield by Procedure B. IR (neat): 3404

(NH2); 1106 (C-0) cm-l. IH NMR (CDCI3): 5 3.66-3.98 (m, 20H, NH2),

4.01-4.14 (m, 4H), 6.19-6.24 (q, IH), 6.28-6.29 (d, IH), 6.76-6.75 (d,

IH).

General Procedures for Modification of Nafion® 117 Membrane

Method A. A T X T piece of 0.007 inch thick Nafion® 117

membrane was immersed in 100 mL of 0.5 N NH4OH aqueous

solution for 24 h, washed with distilled water several times and

dried under vacuum. The dried membrane piece was refluxed in a

mixture of PCI5-POCI3 (30:60 g/g) for 24 h. The PCI5-POCI3 mixture

was poured off while hot and the membrane was washed by brief

refluxing with CCI4 (100 mL X 4). The resultant flexible white

colored membrane was dried under vacuum for one day and then

weighed. The resulting Nafion® sulfonyl chloride membrane was

placed in a 250 mL round bottomed flask with boiling chips.

Monoazacrown ether (2.0 equivalent), triethylamine (1.0 equivalent)

and 120 mL of dry DMF was added to the flask. The reaction

mixture was refluxed for 2 h. After cooling the reaction mixture, the

membrane was removed from the flask, washed with CH2CI2 several

times and dried under vacuum.

Method B. A 2" X 2" piece of 0.007 inch thick Nafion® 117

membrane was refluxed with PCI5-POCI3 (30:60 g/g) for a period of 3

h. The PCI5-POCI3 mixture was poured off while hot and CCI4 (100

117

mL) was added. Following a brief reflux, the CCI4 was poured off.

Twice more fresh CCI4 was added, refluxed and poured off. The

resulting membrane was dried under vacuum. The Nafion® sulfonyl

chloride membrane was placed in a 250 mL round bottomed flask

with boiling chips. To the reaction flask monoazacrown ether (2.0

equivalent), triethylamine (1.0 equivalent) and 120 mL of dry DMF

were added and the reaction mixture was heated at 50 oc for 48 h.

After cooling down the reaction mixture the membrane was taken

out of flask, washed with CH2CI2 thoroughly and immersed in

distilled water.

Hydrolysis of Nafion® Sulfonvl Chloride Membranes

A 2" X 2" Nafion® sulfonyl chloride membrane was immersed in

150 mL of 5% aqueous NaOH solution and refluxed for 24 h. After

cooling, the solution was poured out and the membrane was washed

thoroughly with distilled water. The membrane piece was immersed

in 5% aqueous HCl solution for 1 h at room temperature to convert

the sodium sulfonate form into the sulfonic acid form. The

membrane was washed several times with distilled water and dried

under vacuum for 1 day.

fiftneral Procedure for the Preparation of Dimesylates

In a salt ice bath, a solution of the diol (60 g, 0.40 mol) in 150

mL of CH2CI2 was addfcd dropwise to a stirred solution of the Et3N

118

(100.0 g, 1.0 mol) dissolved in 350 mL of CH2CI2. The solution was

cooled in an ice-salt bath and mesyl chloride (100.8 g, 0.88 mol) was

added dropwise during a period of 1 h keeping the temperature of

the reaction mixture at 0 oc or below. The reaction mixture was

allowed to warm to room temperature during 2 h and 100 mL of 5%

aqueous HCl solution was added. After an additional 30 min the

organic layer was separated and washed with saturated aqueous

NaHCOs (2 X 100 mL), brine (100 mL), water (2 X 100 mL), and dried

over MgS04. Evaporation of the solvent in vacuo gave the desired

dimesylate.

Triethyleneglycol dimesylate (34). A light yellow oil was

obtained in 95% yield. IR (neat): (SO2) cm-l. IH NMR (CDCI3): 5 3.08

(s, 6H), 3.64-3.79 (m, 8H), 4.34-4.39 (m, 4H).

Tetraethyleneglycol dimesylate (36). A light yellow oil

was obtained in 99% yield. IR (neat): (SO2) cm-l. IH NMR (CDCI3): 5

3.07 (s, 6H), 3.61-3.76 (m, 12H), 4.34-4.37 (m, 4H).

Bis[3-(mesyloxy)propyloxy)lethylene glycol (35). A

light yellow oil was obtained in 89% yield. IR (neat): 1349 (SO2);

1173 (C-0) cm-l. IH NMR (CDCI3): 5 2.00-2.08 (m, 4H), 3.02 (s, 6H),

3.56-3.61 (t, 8H), 4.32-4.38 (t, 4H).

Pentaethyleneglycol dimesylate (37). A light yellow oil

was obtained in 72% yield. IR (neat): 1352 (SO2); 1170 ( C-0) cm-l.

IH NMR: 5 3.17 (s, 6H), 3.62-3.70 (m, 12H), 3.74-3.79 (m, 4H), 4.35-

4.40 (m, 4H).

119

Hexaethyleneglycol dimesylate (38). A light yellow oil

was obtained in 82% yield. IR (neat): 1322 (SO2); 1125 (C-0) cm-l .

IH NMR (CDCI3): 5 3.10 (s, 6H), 3.61-3.69 (m, 16H), 3.74-3.79 (m, 4H),

4.35-4.40 (m, 4H).

Ethyleneglycol dimesylate (42). A light yellow oil was

obtained in 43% yield. IR (neat): 1352, 1248 (SO2); 1171 (C-0) cm-l .

IH NMR (CDCI3): 5 3.15 (s, 6H), 4.53 (s, 4H).

Propyleneglycol dimesylate (43). A light yellow oil was

obtained in 53% yield. IR (neat): 1338, 1250 (SO2); 1196 (C-0) cm-l .

IH NMR (CDCI3): 5 2.15-2.26 (m, 2H), 3.02-3.05 (s, 4H), 4.34-4.43 (m,

6H).

N-Tosyldiethanolamine dimesylate (68). A sticky colorless

oil was obtained in 85% yield. IR (neat): 1332, 1255 (SO2); 1123 ( C-

O) cm-l . iH NMR (CDCI3): 5 2.25 (s, 3H), 3.04 (s, 6H), 3,47-3.53 (t, 4H),

4.38-4.43 (t, 4H), 7.27-7.38 (d, 2H), 7.62-7.73 (d, 2H).

120

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synthesis of novel crown ether compounds and …

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