Preparation of novel heterocyclic catalysts for the hydrolysis of active phosphorus and carboxylate esters

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Title:
Preparation of novel heterocyclic catalysts for the hydrolysis of active phosphorus and carboxylate esters
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ix, 110 leaves : ill. ; 28 cm.
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English
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Duell, Bradley Lee, 1952-
Publication Date:

Subjects

Subjects / Keywords:
Catalysis   ( lcsh )
Hydrolysis   ( lcsh )
Phosphorus -- Decontamination   ( lcsh )
Phosphorus -- Toxicology   ( lcsh )
Organophosphorus compounds   ( lcsh )
Genre:
bibliography   ( marcgt )
theses   ( marcgt )
non-fiction   ( marcgt )

Notes

Thesis:
Thesis (Ph. D.)--University of Florida, 1987.
Bibliography:
Includes bibliographical references (leaves 102-108).
Statement of Responsibility:
by Bradley Lee Duell.
General Note:
Typescript.
General Note:
Vita.

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University of Florida
Rights Management:
All applicable rights reserved by the source institution and holding location.
Resource Identifier:
aleph - 001026376
notis - AFA8348
oclc - 18035251
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Full Text












PREPARATION OF NOVEL HETEROCYCLIC CATALYSTS
FOR THE HYDROLYSIS OF
ACTIVE PHOSPHORUS AND CARBOXYLATE ESTERS








BY



BRADLEY LEE DUELL


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF DOCTOR OF PHILOSOPHY







UNIVERSITY OF FLORIDA


1987




















To my parents, for supporting me in this,
to my grandmother, for living long enough to see this,
to Pete, for always believing I could do this,
to my Teachers, for guiding this,
and to the Universe, for loving me through this.

GOD BLESS YOU ALLII
















ACKNOWLEDGEMENTS


The thankfulness I feel toward all who have been a part

of this work could never be measured or expressed in words.

It is indeed remarkable that I am even here to receive this

degree. Yet I know that it is only through the grace of the

Father-Mother God that this dissertation has been written,

and only with His/Her guidance and strength that this Ph.D.

has been obtained. My greatest praise and gratitude goes to

God. I rejoice in being in God's universe and in being a

part of Her/His Great Plan.

This Power has expressed Itself through many people,

and none has been as important to me in my chemistry work as

my research professor, Dr. Alan R. Katritzky. He opened

many doors, first, to allow me to return to graduate school

to obtain this degree, second, in giving me an exciting

research project which brought me in contact with many new

and interesting people, and third, in helping me to find a

wonderful new job. He inspired me when I was down, "nudged"

me (gently, of course) when I needed to move ahead, and, by

his example, taught me many things about working with

people, writing papers, and being excited about chemistry.

My deepest gratitude goes to him.


iii










Dr. H. Dupont Durst of the U. S. Army CRDC also played

a central role in my Ph.D. program. I wish to thank him for

his helpful suggestions, his exuberance, and his friendly

collaboration, and for being almost as excited about my work

as I was.

I would also like to thank Drs. Merle Battiste and Bill

Jones for their support and helpfulness, not only in my

Ph.D. work, but also during my Masters. I would like to

thank Dr. Battiste for his belief that I would return for my

Ph.D., and Dr. Jones, for helping me to face myself during

my Master's work and for allowing me to get the help I

needed to recover from a hopeless state of mind and body.

Thanks especially go to all of the ARK group, for help-

ing my stay to be an exciting, fun-filled, and growth-pro-

ducing experience. Very special to me have been Ping Lue,

Zuoqang Wang, Charles Marson, Rick Offerman, Kathy Laurenzo,

and all of the Steward-type people who I have worked with.

Thanks go to Iaonis Gallos, for his wonderful suggestions

about working with polyvalent iodine compounds (especially

about keeping the temperature at exactly 400C). Especial

thanks, too, go to the Damn Indian (for not changing all my

"most"s to "moist"s). Jes!

I also thank the University of Florida, for giving me

the opportunity to study at a top-class institution. I have

been deeply touched by the warmth and beauty of the people

and campus at U. F., and am very, very happy to have been










able to witness the amazing growth of the University of

Florida over the past several years.

My deep gratitude also goes to several of my spiritual

companions on this earth plane. To all my friends in the

fellowship, in Gainesville and everywhere, I give thanks for

showing me a way to live that took me to a place where I

could get this Ph.D. (easy does itl). I thank Jack Boland

for believing in me and inspiring me to love myself and to

love my work where I was, and not try to escape it (yes,

Jack, the dream has come to passI). To my sweet Lindy go my

blessings for standing beside me and walking with me for the

past few years. I have always loved her support, guidance,

and companionship on the path that takes us home. Thanks to

Rene6 and Bill for helping me to enjoy a bright today and to

see all the possibilities for a brighter tomorrow. Thanks

for being such a blessing to me as I've walked through this

Ph.D. business.

Finally, I wish to thank my parents, Milton and Laura

Duell, for their continuous support, love, belief in God's

power working through me, and for standing by me (even when

they were not sure I was doing the right thing), and for

their generous donations to this (worthy, I trust) cause.

I would also like to thank my dear Grandma Mary, for living

long enough to see me to get this (and for all of her

"kernels"). God Bless all of my family, who have always

been a lot of fun to be with.
















TABLE OF CONTENTS


page
ACKNOWLEDGEMENTS ....................................... iii

ABSTRACT ...............................................viii

CHAPTERS

I. GENERAL INTRODUCTION ........................... 1

1.1 Background .................................. 1
1.2 Overview of Previous Research ............... 3
1.3 Aim and Objectives of the Work ............ 5
1.4 The Collaborative Project with the
U. S. Army CRDC ............................. 6
1.4.1 Introduction .............. ........... 6
1.4.2 Working Procedures ................... 7

II. SYNTHESIS AND CATALYTIC ACTIVITY OF SURFACTANT
ANALOGUES OF 4-(DIMETHYLAMINO)PYRIDINE ........... 8

2.1 Introduction and Rationale .................. 8
2.2 Synthesis ................................... 10
2.3 Kinetic Results ............................. 14
2.3.1 4-Nitrophenyl Hexanoate Hydrolysis ... 20
2.3.2 Fluorophosphonate Hydrolysis ......... 23
2.4 Discussion of Results ....................... 26
2.5 Experimental Section ........................ 27
2.5.1 Methods .............................. 27
2.5.2 Materials ........................... 28
2.5.3 Kinetic Measurements ................. 40

III. UNUSUAL CATALYTIC ACTIVITY OF ANIONIC SURFACTANT
ANALOGUES OF 4-(DIMETHYLAMINO)PYRIDINE IN
CARBOXYLATE ESTER HYDROLYSES ..................... 44

3.1 Introduction ................................ 44
3.2 Synthesis .. ....................... ... 45
3.3 Discussion of C-NMR Spectra .............. 47
3.4 Kinetic Results ............................ 49
3.5 Discussion of Results ....................... 51










3.6 Experimental Section ....................... 54
3.6.1 Methods .............................. 54
3.6.2 Materials ............................ 55
3.6.3 Kinetics ............................. 59

IV. SUBSTITUTED o-IODOSO- AND o-IODOXYBENZOIC ACIDS:
SYNTHESIS AND CATALYTIC ACTIVITY IN THE HYDROLYSIS
OF ACTIVE PHOSPHORUS ESTERS AND RELATED SYSTEMS... 60

4.1 Introduction .............................. 60
4.2 Synthesis ............ ........ 63
4.3 Discussion of C-NMR Spectra ............ 70
4.4 Kinetic Results ............................. 77
4.5 Discussion of Results ...................... 80
4.5.1 Hydrolyses in Micellar Media ......... 80
4.5.2 Hydrolyses in Microemulsion Media .... 84
4.6 Experimental Section ...................... 85
4.6.1 Methods ......................... 85
4.6.2 Materials .......................... 86
4.6.3 Kinetics ....................... .... 98

V. SUMMARY ............................................ 99

BIBLIOGRAPHY ........................................... 102

BIOGRAPHICAL SKETCH ................................... 109


vii










Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy


PREPARATION OF NOVEL HETEROCYCLIC CATALYSTS
FOR THE HYDROLYSIS OF
ACTIVE PHOSPHORUS AND CARBOXYLATE ESTERS

BY

BRADLEY LEE DUELL

August, 1987

Chairman: Alan R. Katritzky
Major Department: Chemistry

The hydrolysis of active phosphorus and carboxylate

esters by several novel heterocyclic catalysts has been

investigated. To this end, a series of ten surfactant cata-

lysts were synthesized, each containing a 4-(N,N-dialkyl-

amino)pyridine moiety carrying an eight- to ten-carbon chain

with an attached polar or charged group. The anionic deriv-

atives were more active than neutral, cationic, and zwitter-

ionic surfactants of the same type. The most active deriv-

ative, sodium 10-[butyl-(4-pyridinyl)amino]decyl sulfate,

catalyzed the hydrolysis of p-nitrophenyl hexanoate (PNPH)

with k2 38.0 M-sec-1 at pH 8.5 in the absence of added

cetyltrimethylammonium chloride (CTAC) and 62.2 M-1 sec1 in

0.001M CTAC, which compares favorably to catalysis by

2-iodoso- and 2-iodoxybenzoic acids (below). The rate

enhancements could result from the formation of "bolaform"

micelles in these systems. These surfactant catalysts,


viii










however, showed poor rate enhancements in the hydrolysis of

active phosphorus esters.

Several 2-iodoso- and 2-iodoxybenzoic acids containing

alkyl, alkyloxy, nitro, carboxyl, and water solubilizing

substituents were also synthesized, and their influence on

the rates of hydrolysis of p-nitrophenyl diphenyl phosphate

(PNPDPP), p-nitrophenyl isopropylphenylphosphinate (NPIPP),

and p-nitrophenyl hexanoate (PNPH) determined in the

presence of added CTAC. The effects of substituents of

variable electronic and aqua/lipophilic character upon
catalytic activity were determined and showed that lipo-

philic substituents significantly enhance the rates while

simple ring substitutions with electron-releasing, electron-

withdrawing, and water-soluble groups have only moderate

effects. Extraordinary rate enhancements were obtained with

5-alkyloxy-IBA and -IBX derivatives, giving second-order

rate constants of 400-5000 M-isec-1. The efficient catal-

ysis of the hydrolysis of active phosphorus derivatives

renders these aromatic 2-iodoso- and 2-iodoxybenzoic acids

potentially useful decontaminants.
















CHAPTER I

GENERAL INTRODUCTION



1.1 Background



Fluorophosphate, fluorophosphonate, phosphate, phospho-

nate, and phosphinate esters are persistent acetylcholine

esterase inhibitors [66BJ525] and neurotoxic agents. Many

are, or have been, used as potent pesticides or in other

applications [63B72, 74MI]. For example, phosphonothioates

Parathion and Fonofos and pyrophosphate TEPP are powerful

insecticides, and phthalimidophosphonothioate Dowco 199 is

an active fungicide (see Figure 1-1). Diisopropylfluoro-

phosphate (DFP) and isopropyl methylfluorophosphinate (GB)

have been designed for use as chemical warfare nerve agents

(see Figure 1-1). Because of their toxicity, effective

methods for the detoxification of these organophosphorus

derivatives are of great interest. Thus, their decomposi-

tion rates under various conditions are clearly of consider-

able importance.

Potentially significant applications of such detoxifi-

cation methods are the cleanup of chemical spills and, in

military circles, the decontamination of equipment which has











S
CH3CH20- -O-(p-C6H4NO2)

OCH2CH3


Parathion
(insecticide)




S
CH3CH2-P-S-C6H5

OCH2CH3



Fonofos
(soil insecticide)



0
II
(CH3)2CHO-P-F

OCH(CH3)2


Diisopropylfluorophosphate
(DFP) (nerve agent)


0 O
[I II
CH3CH2 -P-0-P-OCH2CH3

CH3CH20 OCH2CH3


Tetraethylpyrophosphate
(TEPP) (insecticide)



O
S
II
CH3CH20-P-N
CH3CH20



Dowco 199
(fungicide)



O
II
(CH3)2CHO-P-F
I
CH3


Isopropyl
methylfluorophosphonate
(Sarin, GB) (nerve agent)


Toxic Organophosphorus Compounds


FIGURE 1-1






-3-


been exposed to chemical warfare agents. Commonly used

decontamination methods are supertropical bleach (STB), a

white powder containing approximately 30% available chlorine

(used either as a solid mixture with dry earth, or as an

aqueous slurry with citric acid), and the DS2 decontaminat-

ing solution, a mixture of 70% diethylenetriamine, 28%

ethylene glycol monomethyl ether, and 2% sodium hydroxide

[79MI411. These methods suffer from a number of disadvan-

tages, however, such as being corrosive and difficult to

handle in field use [85MI]. A rapid, effective, and safe

water-based decontamination system would thus be of substan-

tial value to both civilian agencies and the armed forces.




1.2 Overview of Previous Research


The detoxification of organophosphorus compounds has

attracted the attention of numerous research groups over the

past several years [76MI494, 75MI150]. Although toxic

phosphorus compounds are effectively detoxified by hydro-

lysis (to give the less toxic phosphorus acids; see Figure

1-2), rates are slow, due either to inherently poor kinetics

or low solubility in water. Since most persistent

phosphorus derivatives are only sparingly soluble in water,

micellar and microemulsion media have often been employed to

improve rates of hydrolysis [76MI494, 75MI150, 81ACI131,







-4-


z
PII
--P--X


+ H20


-P-OH + HX








(Z 0 or S)







FIGURE 1-2 Hydrolytic Decomposition of
Organophosphorus Compounds






-5-


81JPC739]. Mechanistic investigations under these condi-

tions have demonstrated enhancements in the rates of both

solubilization and decomposition. This "micellar catalysis"

is thought to involve a local increase in the concentrations

of the reactive species at the micellar surface. The combi-

nation of micellar and related aggregate systems with a wide

variety of reactive functional moieties, including hydrox-

ide, phenoxide, imidazole, and others, have increased the

rates of the hydrolysis of active phosphate esters

[70JA7393, 73JA2912, 83JPC5491, 84JA7178, 79JA2429,

79IJC298, 84JOC426, 80JPC2607, 84TL4079, 80JOC4169,

81JA5784, 81JA5788, 77JCR(S)290, 77JOC2865, 82JOC1157,

83JOU696, 83JOU701, 83JOC2457].




1.3 Aim and Objectives of the Work


The primary goal of this work was to discover catalysts

which would provide rapid, effective, and safe water-based

decontamination systems for toxic phosphorus esters. The

goal from the user (field) standpoint was that a good decon-

tamination formulation should provide at least 10 half-lives

(t1/2) of reaction in 10 minutes under field conditions (in

other words, tl/2 < 1 minute; this standard, formulated by

Dr. R. A. Mackay of the U. S. Army Chemical Research and

Development Center (CRDC), is commonly called "Mackay's






-6-


criterion") [85MI]. The objective of this research was thus

to prepare a variety of potential catalyst systems and

examine their efficiency in phosphate hydrolysis. Addition-

ally, it was hoped that surfactants with general applic-

ability to the decontamination of areas affected by other

toxic and noxious compounds (e.g., haloesters, mustards)

might be discovered.




1.4 The Collaborative Project with the U. S. Army CRDC


1.4.1 Introduction


The present research project was initiated in 1984, and

involved collaboration between our group at the University

of Florida and the Chemistry Division of the U. S. Army

Chemical Research and Development Center (CRDC). The

research was carried out under the joint leadership of Dr.

Alan R. Katritzky (UF) and Dr. H. Dupont Durst (CRDC). At

the onset of the program, Dr. Durst, a professor at the

University of Puerto Rico, was on leave as a National

Research Council Fellow. He later accepted a permanent

position at CRDC. The project involved the free exchange of

ideas and results, including frequent telephone convers-

ations, bimonthly consultation trips by Dr. Durst to the

University of Florida, and trips by myself to CRDC and






-7-


related areas. My involvement also included presentation of

the results of my work at the 1986 CRDC Scientific Confer-

ence on Chemical Defense (November, 1986) and attendance at

the 1987 Army Research Office Workshop on Chemical Decontam-

ination (April, 1987). From this collaboration a number of

interesting publications have resulted.



1.4.2 Working Procedures



The primary responsibility of the group at the Univer-

sity of Florida was synthetic, involving the preparation and

complete characterization of the catalysts to be tested.

The Florida group determined which new catalysts should be

prepared, and suggested kinetic procedures and substrates to

be utilized for measuring the hydrolytic activities of the

catalysts. The facilities for measuring reaction rates

(diode-array UV/visible spectrometer, fluoride-detecting

reaction cells) and for handling the highly toxic substrates

(phosphate esters, phosphinate esters, fluorophosphorus

compounds) were available at CRDC, and the kinetic measure-

ments were carried out there. Results of the kinetic runs

were sent to the University of Florida and were evaluated

jointly by myself, Dr. Katritzky, and Dr. Durst.
















CHAPTER II

SYNTHESIS AND CATALYTIC ACTIVITY OF
SURFACTANT ANALOGUES OF 4-(DIMETHYLAMINO)PYRIDINE


2.1 Introduction and Rationale



We became interested in the possibility of applying

heterocyclic functionality to the area of phosphorus ester

hydrolysis, and surfactants incorporating the 4-N,N-dialkyl-

aminopyridine moiety seemed particularly promising.

4-N,N-Dimethylaminopyridine (DMAP) and related compounds

(Figure 2-1) are efficient catalysts for a wide range of

organic reactions, including hydrolysis, acylation, esteri-

fication, and polymerization [78AG(E)569, 83CSR129]. They

exhibit a much higher catalytic activity than ordinary

tertiary amines due to their greater nucleophilicity. DMAP

has been reported to catalyze various nucleophilic displace-

ment reactions of phosphate derivatives (e.g., phosphoryla-

tion of hydrazines) [78AG(E)569]. In addition, in contrast

to some tertiary amines, which are normally unreactive

toward phosphorus centers [53JCS511, 63JOC329], pyridines

are well-known to catalyze the hydrolysis of phosphates

[64CRV317]. Thus, it was envisaged that attachment of a

4-N,N-dialkylaminopyridine group to a long alkyl chain might


-8-







-9-


CH3
\


CH3


4-N,N-Dimethylaminopyridine
(DMAP)


4-Pyrrolidinopyridine


CH3


O



N


N


4-Morpholinopyridine


4-[4-Methylpiperidino]pyridine


FIGURE 2-1 4-Dialkylaminopyridines






-10-


lead to powerful agents for the hydrolytic decomposition of

toxic phosphate derivatives. In addition, we hoped to find

surfactants with general applicability to the decontamina-

tion of areas affected by other toxic and noxious compounds

(e.g., haloesters, mustards). Reported in this chapter are

the synthesis and catalytic properties of seven such surfac-

tant systems.




2.2 Synthesis


The compounds synthesized each comprise a 4-(N,N-dialk-

ylamino)pyridine moiety coupled to an eight- to ten-carbon

alkyl chain with an attached polar or charged group. Of the

seven compounds prepared, two are from the neutral charge

category, two are cationic, two zwitterionic, and one

anionic (Figures 2-2 and 2-3).

The neutral and anionic compounds synthesized are

4-(N-decyl-N-butylamino)pyridines in which the n-decyl group

carries an appropriate substituent in the 10-position.

Their preparation involved the common precursor 9, whose

synthesis is outlined in Figure 2-2. Preparation of

10-chloro-l-decanol (6) from 1,10-decanediol (5) in a two-

phase system proceeded in 96% yield [53JOC1356]. Subsequent

reaction with n-butylamine produced 10-(N-butylamino)-

1-decanol (7) (95%) [51JA3635]. Coupling of this amine to




































z~


-11-


z


cM,I
S5


Z -C /z

I *


\N


e
r-


z






-12-


the pyridine nucleus was attempted via a number of litera-

ture methods, with negative results [31CB1049, 51JCS1376,

84JMC1457]. These included reaction of the amine with

l-(4-pyridyl)pyridinium chloride hydrochloride (neat, and in

the presence of phenol) and with 4-chloropyridine hydro-

chloride, as well as reaction of the amine hydrochloride

with 4-chloropyridine hydrochloride at 2000. However, it

was found that reaction of pyridinium salt 8 (prepared in

situ from 4-cyanopyridine and 2-vinylpyridine)

[79USP4158093] at 1000C, followed by treatment with 40% NaOH

at reflux gave compound 9 in 24% yield (see Figure 2-2). It

was possible to run the reaction on a large enough scale to

obtain sufficient material for the subsequent preparations.

Acetylation of compound 9 with acetic anhydride (2 eq.) and

triethylamine (1.5 eq.) proceeded smoothly to produce the

other neutral surfactant, 10, in 92% yield. Reaction of

compound 9 with C1SO3H produced sulfate ester 11, and

neutralization with NaOH gave anionic surfactant 12 in 32%

overall yield.

Initial attempts to prepare 1-octyl- and 1-decyl-

l-methyl-4-(4-pyridyl)piperazinium iodides involved coupling

the quaternary piperazinium hydrochlorides with either

pyridinium salt 8 or 4-chloropyridine hydrochloride, but

partial or complete demethylation occurred. Monoethoxy-

carbonylation of piperazine on a large scale gave 14 (53%)

(Figure 2-3) [44JA263]. Alkylation with RBr/K2CO3 followed

by acid hydrolysis produced 1-alkylpiperazine hydrochlor-












-13-


I-.i


X.





U "


2 ... s
". / = _- X
Z ,3



C
r ~
3U
= S i


0

-Z Z--U





A








-z Z-UL


IO I


-L


- .4
-- t


a




s--


0 ei






--z z






= Z- -
2 ||









3-2Z Z z- Z


.4

zeC

U ;




V+


o- -



LN .k
JSm *


z z-
Z+ 2







i'

T.


z z-^ z-=







Z+z


-'I


n


I0


u

C







U


-4

4-1











C







.,-.
0

4-)
1-,






-I
U-






uc
0I
u-i

tS
vS






-14-


ides, 16a,b (73 and 70% overall yield, respectively), which

were converted by 4-chloropyridine hydrochloride into 17a,b

(84 and 58%, respectively). Protection of the pyridine

nitrogen with trityl chloride allowed selective methylation

of the piperazine ring with CH3I, giving 19 (usually not

isolated). Deprotection (trityl removal) occurred readily

with either EtOH in CH2C12 or moist ether, and

neutralization of the resulting hydrochloride salt with

sodium bicarbonate gave the cationic derivatives, 20a,b (56

and 91%, respectively, from 18a,b).

Alkylation of 18a,b with neat ethyl bromoacetate

proceeded readily to give 21a,b (not purified), and was

converted by hydrolysis with HCl into 22a,b (70 and 53%,

respectively). Neutralization of 22a,b with NaOH then gave

zwitterionic compounds 23a,b.

All compounds and most intermediates were characterized

by elemental analysis or high resolution mass spectrometry,

and by 13C-NMR, H-NMR, and IR. The 13C-NMR spectra of

selected derivatives are discussed in section 3-3.




2.3 Kinetic Results


The catalysts were tested against two substrates:

4-nitrophenyl hexanoate (PNPH) as a substrate for active

carbon ester hydrolysis and 0-(1,2,2-trimethylpropyl)methyl-






-15-


phosphonofluoridate (Soman) as a substrate for fluorophos-

phonate hydrolysis. Many reactions in micellar media show

maximum rates with a total surfactant concentration of

around 103 M; in the absence of CMC data for our materials,

this concentration range was chosen for study (attempts to

measure the CMC of the most active compound (12) by flow

injection analysis [87UP] did not conclusively show evidence

of micelle formation (other procedures for CMC measurement

are under consideration)), so it is possible that (a) the

runs may have been carried out at surfactant concentrations

below the CMC, and (b) the observed rate accelerations

(including the large enhancement with 12) might be

nonmicellar in origin). The decomposition of PNPH was

analyzed by UV spectroscopy based on the 4-nitrophenyl anion

chromophore at 402 nm. The decomposition of Soman was

determined using a simple water-jacketed cell connected to

an ion analyzer and followed using an ion selective

electrode by monitoring appearance of F-.

The decomposition of substrate (SUB PNPH or Soman) in

aqueous or largely aqueous media should follow a rate law of

the form:


rate khyd[SUB] + koH[OH ][SUB] + kCAT[CAT][SUB]



= {khyd + koH[OH] + kCAT[CAT]) [SUB] (1)


where the term khyd[SUB] represents the hydroxide-independ-

ent "background" reaction, the koH[OH-][SUB] represents the






-16-


second order reaction between OH and SUB, and the

kCAT[CAT][SUB] term is the rate enhancement resulting from

the addition of catalyst to the system.

The hydrolysis reactions were all run at the same

buffered pH value (borate, pH 8.5). Under these conditions

the first two terms of equation (1) (khyd + koH[OH]) are

constant. If the catalyst is in large excess over substrate

([CAT]>>[SUB]) (or if catalyst is not consumed in the reac-

tion), then the third term is also essentially constant.

Under these conditions equation (1) reduces to a description

of an experimentally first-order process:


rate kobs[SUB] (2)


where


kobs khyd + koH[OH] + k CATCAT] (3)


Equation (3) forms the basis of the kinetic analysis and the

data presented in Table 2-1. Typically, several (usually

seven) values of kobs were determined at different catalyst

concentrations and constant pH (pH was routinely measured

before and after each reaction to ensure it remained

unchanged). These data were plotted as kobs vs. [CAT]. In

all cases the plots were consistent with the linear relation

predicted by equation (3). A linear least-squares routine






-17-


was used to determine the statistically most valid slope

(kcat) and intercept (khyd + koH[OH-]) for each data set.
Figure 2-4 shows a typical plot of absorbance vs. time

data for the catalyst 12 (see Figure 2-2) in the hydrolysis

of PNPH. The line drawn through the points is a theoretical

line assuming simple first-order kinetics, as in equation

(2). Figure 2-5 shows the same data plotted as log(A.- At)

vs. time. Such linearity was normally observed for five or

more half-lives (i.e., >96% reaction). All kinetic runs

were performed utilizing this regime.

A point of interest was whether the catalysts were

consumed (or otherwise stoichiometrically degraded) as the

reaction proceeded or whether they were regenerated, and

were indeed "true" catalysts. Because of the predicted

instability of the most likely intermediate (a 1-acylpyri-

dinium ion), this question was addressed directly. A

kinetic run was performed with catalyst 12 and PNPH at the

same concentration (both at 5 x 10-5 M; [SUB]/[CAT] 1).

The reaction was allowed to go to completion. Since the

catalyst was not in large excess, the kinetics could only be

first order if the catalyst were not consumed during the

course of the reaction (i.e., [CAT] constant). The

collected data was fitted using first-order kinetic anal-

ysis, and yielded a kobs value consistent with data col-

lected at higher concentrations of catalyst (i.e., under

"enforced" pseudo first-order conditions). To further test










-18-


>4




C3t





r4.1







LO O
.I


U,




44




-o
E-


>

co---. 4

















UJ -," I- r
, _c




u_*-= r-- *& b --- r-: --- u..
























r-4
>4



z

IM







I -4

Li







0




w--4






II










*1-4 -
LL-2



^ ?


I I


-19-







-20-


this point, a second portion of PNPH was added to the same

reaction mixture after the initial reaction was complete.

The subsequent reaction which was observed could again be

fit using a first-order analysis, and yielded a kobs similar

to that from the initial reaction. Taken together, these

observations provided strong evidence that the compounds

were not consumed (i.e., "turn over") in the reaction, and

indeed functioned as catalysts.


2.3.1 4-Nitrophenyl Hexanoate Hydrolysis


Table 2-1 lists the second-order rate constants for

different catalysts against PNPH at pH 8.5 (see Figures 2-2

and 2-3 for catalyst structures). Table 2-2 lists the rate

constants for each catalyst against Soman at pH 8.5. All

the synthesized catalysts were reasonably good in the hydro-

lysis of PNPH (entries 1-6), with the anionic surfactant 12

being an order of magnitude larger than the other catalysts

(entry 1). The rate of hydrolysis of PNPH at pH 8.5 by 12

at 1 x 10-3 M represented a factor of 400 increase over

background hydrolysis of PNPH (khyd+koH[OH-1).

We also looked at the effects of adding a non-function-

alized supporting surfactant (1 mM and 5 mM CTAC) on the

catalytic rate of anionic surfactant 12, neutral surfactant

10, cationic surfactant 20b, zwitterionic surfactant 23b,

and DMAP (entries 1, 2, 4, 6, and 7, respectively). The

addition of CTAC to cationic 20b and zwitterionic 23b had







-21-


TABLE 2-1




SECOND-ORDER RATE CONSTANTS (k,.)
FOR THE HYDROLYSIS OF P-NITROPHENYL HEXN2ATE (PNPH)
AT pH 8.5 ([PNPH]-5.5 x 10 M)


Entry


Compound


1 12 (anionic)


2 10 (neutral)

3 20a cationicc)

4 20b cationicc)

5 23a (zwitterionic)

6 23b (zwitterionic)

7 DMAPb

8 Blank


kCAT (M SEC1)
No CTAC 1mM CTAC 5mM CTAC

38.0 62.2 35.8


1.25

1.12

1.18

0.81

1.51

3.68


35.6


0.97


2.79

1.96


32.0



0.29



1.31

1.32


a. Kinetics measurements were carried out at the U. S. Army
CRDC (see p. 7).
b. DMAP 4-(Dimethylamino)pyridine.
c. Hydrolysis in the absence of surfactant gave a pseudo
first-order rate constant of 6.5 x 10- sec which
represents background hydrolysis (khyd+k[OH[-]). At the
[PNPH] given above, this corresponds to an initial rate
-9
of 3.6 x 10- M/sec. In comparison, using kCAT for 10 at
a cone. of 0.001M, the initial rate was 72 x 109.






-22-


TABLE 2-2





PSEUDO FIRST-ORDER RATE CONSTANTS
FOR THE4HYDROLYSIS OF SOMAN AT pH 8.5
IN 9 x 10 M SURFACTANT ([SOMAN] 0.001M)a


Compound


k (min-1) x 102
*__.


12 (anionic)

10 (neutral)

20a cationicc)

20b cationicc)

23a (zwitterionic)

23b (zwitterionic)

Blank (no surfactant)


1.72

1.55

1.62

1.58

1.69

1.65

1.43


a. Kinetics measurements were carried out at the U. S. Army
CRDC (see p. 7).


Entry






-23-


minimal effect on increasing the hydrolysis rate. In

contrast, addition of CTAC to anionic 12 nearly doubled the

rate and, with neutral 10, increased the hydrolysis rate by

a factor of 28. Thus, it appeared that neutral surfactant

catalysts of the type 10 were efficient if formulated with

traditional supporting surfactants, a result consistent with

observations by Moss and coworkers, who discovered that

attachment of long-chain alkyl groups to the 2-iodosobenzoic

acid moiety dramatically increased rates of catalysis

[84JA2651, 86JA788].


2.3.2 Fluorophosphonate Hydrolysis



Disappointingly, all the catalysts synthesized had

minimal effect on the hydrolysis rate of Soman (measured as

rate of fluoride release). Plots of concentration vs. time

data (fluoride release) using catalyst 12 showed good agree-

ment between experimental points and the calculated line

(through the points) as well as when the data were plotted

as log([F -] (F-]t) vs. time (Figures 2-6 and 2-7). Again

note that the linear format of the second plot indicated no

significant deviation from first-order behavior. Although

the rate enhancements were poor, the kinetic data appeared

identical to that obtained above in the hydrolysis of PNPH.










-24-


(N








co



S0-4



0

>4




--o


















IMI
0-i0



































IDLO
C-H











LLI t
















o"a > r"- '*.11 Ii'" wt r"*' c.-j vl iz









-25-


N


CtJ >5





o
4-4










to
'Sl





r -




a- 0




I




i *w**
4-4




9J


















IS (11 -







'it a~l ot







-26-


2.4 Discussion of Results


The data obtained above showed that the substituted

pyridine surfactants increased the reaction rates of hydro-

lysis of carbon esters by a factor of 50-500 above back-

ground hydrolysis. Addition of a non-functionalized

surfactant (CTAC) to the neutral pyridine surfactant (10)

dramatically increased the efficiency of this class of

compounds. The data strongly suggested that these materials

functioned as true catalysts, i.e., they were not consumed

in the reaction. The data also showed that the hydrolysis

of reactive fluorophosphorus compounds by these materials

was poor, increasing hydrolysis over background by a factor

of only 1.1-1.2.

The results also indicated that the anionic surfactant

12 was a better catalyst, by one order of magnitude, than

the other synthesized materials in the hydrolysis of carbon

esters. The mechanistic reason for this increased effi-

ciency is investigated further in Chapter III.






-27-


2.5 Experimental Section


2.5.1 Methods



All melting points are uncorrected and were taken in

open glass capillary tubes with a Thomas-Hoover melting

point apparatus. IR spectra were obtained on a Perkin-Elmer

283B infrared spectrophotometer. Proton NMR spectra were

obtained at 60 MHz on a Varian EM 360L NMR spectrometer,

with TMS as internal standard. 1C-NMR spectra were

obtained at 25 MHz on a JEOL FX-100 NMR spectrometer, refer-

enced either to solvent (6CDC13 77.0; SDMSO-d6 39.5) or,

when D20 was utilized, to added DMSO (640.4) or dioxane

(867.4), as noted. With mixtures of CDC13 and DMSO-d6,

CDCl3 was used as reference. Low and high resolution mass

spectra were obtained on an AEI MS30 mass spectrometer.

Microanalyses were either performed in house, on a Carlo

Erba 1106 elemental analyzer, or by Atlantic Microlabs,

Atlanta, Georgia.

The measurement of the critical micelle concentration

of surfactant 12 was attempted by the flow injection

analysis method of Brooks, et al. [87UP].






-28-


2.5.2 Materials


Commercially available reagent grade solvents and

reagents were used without further purification. 4-Cyano-

pyridine, 4-chloropyridine hydrochloride, and 4-(dimethyl-

amino)pyridine were obtained from Reilly Tar and Chemical,

and used as received. Silica gel filtration utilized

either E.M. Merck or MCB silica gel 60 (230-400 mesh).

1-Alkylpiperazinium dihydrochlorides (16a,b) and

10-chloro-l-decanol (6) were prepared by literature methods

(references given in relevant sections below) and gave

satisfactory melting points and/or spectral data.


10-(Butylamino)-l-decanol (7) [51JA3635]. 10-Chloro-l-

butanol [53JOC1356] (50.0g, 0.260 mole) and n-butylamine

(175 ml) were refluxed for eight hours. The excess n-butyl-

amine was evaporated, the residue taken up in CH2C12 (300

ml) and washed with 2.5N NaOH (2 x 100 ml). The aqueous

phase was back extracted with CH2C12 (50 ml), and the

combined organic dried over MgSO4. Evaporation of the

solvent gave 56.5g (95%) of 7 as colorless needles: mp 41.5-

42.5 (lit. mp 85-94); 13C-NMR (CDCl3): 613.6, 20.1, 25.6,

27.0, 29.2, 29.6, 31.7, 32.6, 49.3, 49.7, 61.6.

Anal. Calcd for C14H31NO: C, 73.30, H, 13.62, N, 6.11.

Found: C, 73.38, H, 13.64, N, 6.08.






-29-


10-[Butyl-(4-pyridyl)amino]-l-decanol (9). 4-Cyanopyr-
idine (30.4g, 0.292 mole), 2-vinylpyridine (20.5g, 0.195

mole), conc. HC1 (43 ml), and water (25 ml) were stirred at

80-1000C for 3 hours. Triethylamine (55 ml) and a solution

of 7 (22.5g, 0.0983 mole) in isopropanol (60 ml) were added

and the mixture heated at 800C for 18 hours. After cooling

to room temperature, 40% NaOH (275 ml) was added and the

solution refluxed for 4 hours. The solvent was evaporated,

the residue washed with hexane, taken up in CH2Cl2 (150 ml),

and filtered through silica gel (125 g), washing with 1-2.5%
CH3OH/CH2C12 (4 1.). Removal of solvent, refiltration

through fresh silica gel (125 g) with ethyl acetate, and

evaporation gave 14.4g (24%) of 9 as a dark amber oil: 1H-

NMR (CDCl3): 80.8-1.8 (br m, 23H, H2-H9, Bu-H2, H3, H4),

3.26 (t, 4H, H10, Bu-H1), 3.60 (t, 2H, H1), 3.71 (s, 1H,

OH), 6.38 (d, 2H, Py-H3), 8.08 (d, 2H, Py-H2); C-NMR

(CDC13): 613.7 (Bu-C4), 20.0 (Bu-C3), 25.7 (C3), 26.8 (C8),

28.9 (C9), 29.3 (C4-C7), 32.7 (C2, Bu-C2), 49.7, 50.0 (C10,

Bu-C1), 62.2 (Cl), 106.1 (Py-C3), 149.2 (Py-C2), 152.4 (Py-

C4); IR (thin film): 3500-3100(s, br), 2920(s), 2850(s),

1640, 1600(s), 1505(s), 1455(s), 1405, 1360(s), 1290,

1220(s), 1100, 1050, 986(s), 795(s), 530(s) cm 1. Mass

spectrum (m/e (rel. intensity)): 306(16), 264(7), 263(39),

242(7), 164(15), 163(100), 122(8), 121(70), 107(42), 57(9),

55(17), 43(7), 41(20), 29(15).






-30-


High res. mass spectrum (m/e): Calcd, 306.2671. Found,

306.2661 (std. dev. 0.0031).


10-[Butyl-(4-pyridinyl)amino]-l-decyl acetate (10).
Compound 9 (4.33g, 0.0142 mole), acetic anhydride (2.90g,

0.0284 mole), and triethylamine (2.15g, 0.0213 mole) were

stirred at room temperature for one hour, then at 60-700 for

one hour. Water (40 ml) was added, the mixture basified (pH

9-10) with K2CO3 and extracted with CH2C12 (2 x 25 ml). The

combined organic extracts were washed with water (25 ml) and

evaporated. Filtration through silica gel (100g) with ethyl

acetate followed by evaporation gave 4.56g (92%) of 10 as a

light amber oil: 1H-NMR (CDC13): 60.8-1.8 (br m, 23H, H2-H9,

Bu-H2, H3, H4), 2.06 (s, 3H, COCH3), 3.35 (t, 4H, H10, Bu-

H1), 4.10 (t, 2H, H1), 6.57 (d, 2H, Py-H3), 8.33 (d, 2H, Py-

H2). 13C-NMR (CDC13): 613.7 (Bu-C4), 20.0 (Bu-C3), 20.8
(COCH3), 25.7 (C3), 26.8 (C8), 28.4 (Bu-C2), 28.9, 29.0 (C2,

C9), 29.2 (C4-C7), 49.8, 50.0 (C10, Bu-C1), 64.3 (C1), 106.1
(Py-C3), 148.8 (Py-C2), 152.5 (Py-C4), 171.0 (C-0); IR (thin

film): 3080(w), 2930(s), 2860(s), 1740(s), 1595(s), 1538(w),

1512, 1465, 1436(w), 1408, 1365, 1238(br,s), 1103(w), 1040,

985, 800 cm-1.

High resolution mass spec. (m/e): Calcd, 348.2777.
Found, 348.2781 (std. dev. 0.0033).






-31-


10-[Butyl-(4-pyridinyl)amino]-l-decyl sulfate (11).
Compound 9 (6.30g, 0.0206 mole) in CH2C12 (40 ml) was added

dropwise over a period of one hour to a solution of chloro-

sulfonic acid (2.50g, 0.0209 mole) in CH2Cl2 (20 ml),
keeping the temperature below 5C. The ice bath was removed

and stirring continued at room temperature for 20 hours,

then at 40C for 3 hours. Additional chlorosulfonic acid

(0.2g, 0.0017 mole) was added at 10C and the mixture

stirred at room temperature for 3 hours. Methanol (3 ml)

was added, the solution filtered through silica gel (100g)
with 3-5% CH3OH/CH2C12, and solvent evaporated. Trituration

with ethyl acetate gave 3.28g (41%) of 11 as a beige solid.

Recrystallization from ethyl acetate gave an analytical

sample, as beige needles: mp 109-112(d); 13C-NMR (CDC13):

613.3 (Bu-C4), 19.4 (Bu-C3), 25.1 (C3), 26.0 (C8), 28.1 (Bu-

C2), 28.7 (C2, C4-C7, C9), 50.5, 50.7 (C10, Bu-C1), 67.2
(Cl), 106.3 (Py-C3), 138.9 (Py-C2), 155.5 (Py-C4); IR
(CHBr3): 3700-2500(br, s), 2950(s), 2920(s), 2830(s),

1640(s), 1600, 1545(s), 1460, 1420(w), 1370(w), 1250(br),

1210(br, s), 1050, 980(br), 800 cm1.

Anal. Calcd for C19H34N204S: C, 59.04, H, 8.81, N,

7.25. Found: C, 59.19, H, 8.87, N, 7.17.


Sodium 10-[butyl-(4-pyridinyl)amino]-l-decyl sulfate

(12). Compound 11 (3.18g, 8.23mmole) and 1.00N NaOH (8.25

ml, 8.25 mmole) were shaken together for one hour, filtered,






-32-


and evaporated. Trituration of the resulting oil with ethyl

acetate gave 2.50g (75%) of 12 as white microcrystals: mp

92-94 C; 13C-NMR (D20; DMSO ref.): 615.3 (Bu-C4), 21.4 (Bu-

C3), 27.0 (C3), 28.5 (C8, Bu-C2), 30.8 (C2, C4-C7, C9), 51.8

(C10, Bu-C1), 70.2 (C1), 108.1 (Py-C3), 148.0 (Py-C2), 155.1
(Py-C4); IR (CHBr3): 2960, 2930(s), 2860, 1650, 1595(s),

1540, 1510, 1465(w), 1410(w), 1370(w), 1250(s), 1220(s),

1065, 985, 800 cm1.

Anal. Calcd for C19H33N2NaO4S-2.5H20: C, 50.31, H,
8.44. Found: C, 50.43, H, 8.24.


1-Octyl-4-(4-pyridinyl)piperazine (17a). 1-Octylpiper-

azine dihydrochloride (16a) [64FES269] (9.47g, 0.0349 mole)

and 4-chloropyridine hydrochloride (7.87g, 0.0525 mole) were

stirred neat at 2200 for 7-8 hours. 1.25N NaOH (60ml) was

added at room temperature, the mixture stirred vigorously,

and the solid collected and dried. Filtration of a CH2C12

solution of the solid through silica gel (45g) with 4%

CH3OH/CH2C12 followed by evaporation gave 8.14g (85%) of 17a

as pale brown needles. Recrystallization from hexane gave

an analytical sample: mp 31-33 C; 13C-NMR (CDCl3): 13.8

(Oct-C8), 22.3 (Oct-C7), 26.5 (Oct-C3), 27.2 (Oct-C2), 28.9,

29.2 (Oct-C4, -C5), 31.5 (Oct-C6), 45.6 (Pip-C2), 52.3

(Pip-C3), 58.3 (Oct-C1), 107.9 (Py-C3), 149.9 (Py-C2), 154.5

(Py-C4); IR (CHBr3): 2950(sh, s), 2920(s), 2850, 1593(s),

1540, 1505, 1460, 1450, 1390(w), 1295(w), 1245, 1230, 986,

930(w), 803, 740 cm1.






-33-


Anal. Calcd for C17 H29N3.1.5H20: C, 67.51, H, 10.66,

N, 13.89. Found: C, 67.54, H, 10.41, N, 13.83.


l-Decyl-4-(pyridinyl)piperazine (17b). Compound 17b

was prepared in 45% yield by the same procedure as above,

except utilizing 1-decylpiperazine dihydrochloride (16b)

[54JA1164]. Recrystallization from ethanol/water gave an

analytical sample as beige plates: mp 43-44C; 13C-NMR
(CDCl3): 613.7 (Dec-C10), 22.3 (Dec-C9), 26.5 (Dec-C3), 27.1
(Dec-C2), 28.9, 29.2 (Dec-C4, -C5, -C6, -C7), 31.5 (Dec-C8),

45.5 (Pip-C2), 52.3 (Pip-C3), 58.3 (Dec-C1), 107.9 (Py-C3),

149.7 (Py-C2), 154.6 (Py-C4); IR (CHBr3): 2930(s), 2860(s),

2820(sh), 1640(s), 1590(s), 1560(sh), 1508, 1460, 1450,

1380(br), 1250, 1230, 1190(s), 987(s), 930, 833, 803(s),
-1
740(w), 720(w) cm-1

Anal. Calcd for C9 H33 N30.75H20: C, 71.99, H, 10.97,

N, 13.26. Found: C, 71.93, H, 10.97, N, 13.05.


4-(4-Octylpiperazin-l-yl)-l-(triphenylmethyl)pyridinium

chloride (18a). Compound 17a (3.00g, 0.0109 mole), trityl

chloride (3.20g, 0.0115 mole), and CH2C12 (30 ml) were
stirred at room temperature for 15 hours. Evaporation of

solvent followed by trituration of the resulting solid with

dry ether gave, after drying, 5.99g (99%) of 18a as beige

microcrystals: mp 118-120 0C; 13C-NMR (CDCl3): 613.6 (Oct-

C8), 22.1 (Oct-C7), 26.1 (Oct-C3), 26.8 (Oct-C2), 28.7, 28.9






-34-


(Oct-C4, -C5), 31.2 (Oct-C6), 46.8 (Pip-C3), 52.1 (Pip-C2),

57.6 (Oct-C1), 83.0 (Trityl-C), 108.0 (Py-C3), 128.4 (Ph-C2,
-C4), 129.3 (Ph-C3), 139.1 (Ph-C1), 141.6 (Py-C2), 154.9

(Py-C4); IR (CHBr3): 3083, 3060, 2920(s), 2850, 2820, 2780,

1640(s), 1560, 1550, 1490, 1460, 1445, 1430, 1380(w), 1300,

1260, 1240, 1180, 1110(s), 1020, 1000, 930(w), 905(w),
-1
880(w), 830(w), 760, 750, 740, 700 cm- (s).

Anal. Calcd for C36H44N3Cl-1.0H20: C, 75.56, H, 8.10.
Found: C, 75.89, H, 8.43.


4-(4-Decylpiperazin-l-yl)-l-(triphenylmethyl)pyridinium
chloride (18b). The compound was prepared from 17b in 88%

yield by the same procedure as above, to give 18b as white

microcrystals: mp 110-112 C (d); 13C-NMR (CDC13): 613.8
(Dec-C10), 22.4 (Dec-C9), 26.0 (Dec-C3), 27.0 (Dec-C2),

29.0, 29.3 (Dec-C4, -C5, -C6, -C7), 31.6 (Dec-C8), 46.8

(Pip-C3), 52.2 (Pip-C2), 57.7 (Dec-C1), 83.5 (Trityl-C),

108.3 (Py-C3), 128.7, 128.8 (Ph-C2, -C4), 129.6 (Ph-C3),

139.3 (Ph-C1), 141.9 (Py-C2), 155.3 (Py-C4); IR (CHBr3):

2920(s), 2850, 1640, 1560, 1550, 1510, 1490, 1460, 1450,
1380(w), 1300, 1260(w), 1240, 1180, 1110, 1020, 1000, 760,

750, 740, 700(s) cm-1.

Anal. Calcd for C38H48N3Cl: C, 78.39, H, 8.31. Found:
C, 78.62, H, 7.93.






-35-


l-Methyl-l-octyl-4-(4-pyridinyl)piperazinium iodide

(20a). Compound 18a (4.27g, 0.00771 mole), CH3I (9 ml), and

CH2Cl2 (9 ml) were stirred at 30-40 C for 9 hours. Abso-

lute ethanol (10 ml) was added and the mixture stirred

overnight. Evaporation and trituration with ether gave,

after collection and drying, 3.95g of gold needles (the

hydrochloride salt of 20a). This solid was taken up in
CH2C12 (40 ml), washed with 1:1 NaHCO3(satd.)/H20 (2 x 40

ml) and dilute aqueous Nal. Evaporation of the organic

layer and trituration with ethyl acetate gave 1.81g (56%) of

20a as a yellow solid. An analytical sample was obtained by

filtering an ethanolic solution of this material, evapor-

ating, and triturating the residue with ethyl acetate to

give pale yellow microcrystals: mp 111-4 oC(d); 13C-NMR

(CDC13/DMSO-d6): 613.1 (Oct-C8), 21.0 (Oct-C2), 21.5 (Oct-

C7), 25.2 (Oct-C3), 28.0 (Oct-C4, -C5), 30.6 (Oct-C6), 39.5

(Pip-C3), 46.2 (N-CH3), 58.3 (Pip-C2), 63.6 (Oct-C1), 108.3

(Py-C3), 149.2 (Py-C2), 152.6 (Py-C4); IR (CHBr3): 2920(s),

2850, 1640(w), 1590(s), 1545(w), 1505, 1460, 1420(w), 1255,
-1
1230(w), 1020(w), 990, 920, 800, 735(w) cm-

Anal. Calcd for CH1 32N3I-1.5H20: C, 48.65, H, 7.94,

N, 9.45. Found: C, 48.54, H, 7.41, N, 10.07.


1-Decyl-l-methyl-4-(4-pyridinyl)piperazinium iodide

(20b). Compound 18b (2.00g, 0.00344 mole), CH3I (5 ml), and

CH2Cl2 (4 ml) were stirred at room temperature for 14 hours.






-36-


Addition of moist ether and filtration gave, after drying,

1.78g of gold plates (the hydrochloride salt of 20b). This

solid (1.00 g) was taken up in CH2C12 (10 ml) and washed

with 1:1 NaHCO3(satd.)/H20 (2 x 10 ml). Evaporation of the

organic layer and trituration with ethyl acetate gave 0.62g

(61%) of 20b as a pale yellow solid. An analytical sample

was obtained as for 20a, to give colorless microcrystals: mp
140-3 0C(d); 13C-NMR (CDC13/DMSO-d6): 613.2 (Dec-C10), 21.1

(Dec-C2), 21.7 (Dec-C9), 25.3 (Dec-C3), 28.3, 28.5 (Dec-C4,

-C5, -C6, -C7), 30.8 (Dec-C8), 39.6 (Pip-C3), 46.2 (N-CH3),
58.4 (Pip-C2), 63.7 (Dec-C ), 108.4 (Py-C3), 149.5 (Py-C2),

152.6 (Py-C4); IR (CHBr3): 2920(s), 2850, 1640(w), 1590(s),

1545(w), 1505, 1460, 1420(w), 1255, 1230(w), 1020(w), 990,
11
920, 800, 735 cm-1

Anal. Calcd for C20H36N31.1.5H20: C, 50.85, H, 8.32,

N, 8.89. Found: C, 50.91, H, 8.02, N, 8.82.


1-(Carboxymethyl)-l-octyl-4-(4-pyridinyl)piperazinium
chloride hydrochloride (22a). Compound 18a (14.0g, 0.0253

mole) and ethyl bromoacetate (42 ml) were stirred at room

temperature for 15 hours. Additional ethyl bromoacetate (15

ml) was added and stirring continued for 3 hours. Addition

of dry ether (200 ml), further stirring (1-2 hours), and

filtration gave 17.00g of a beige solid (21a). This

material (16.5g, 0.0229 mole) was refluxed in 9N HC1 (160

ml) for 10 hours. Extraction with ether (2 x 125 ml),






-37-


filtration, and evaporation of the aqueous layer to dryness

gave a solid, 9.00g of which were dissolved in water/meth-

anol (80 ml:20 ml). This solution was cooled in ice and

basified with 1.ON NaOH (50 ml). After warming to 10 0C,

the slurry was filtered, washed with water, the filtrate

acidified to pH 3-4 with HC1 (aq.), and evaporated to

dryness. The resulting residue was taken up in ethanol and

filtered. The filtrate was evaporated and triturated with

ether to give 5.75g (66%) of 22a as colorless microcrystals:

mp 202-204 C(d); 13C-NMR (D20; dioxane ref.): 614.6 (Oct-

C8), 22.6 (Oct-C2), 23.1 (Oct-C7), 26.6 (Oct-C3), 29.4 (Oct-
C4, -C5), 32.2 (Oct-C6), 40.7 (Pip-C3), 57.4 (CH2COOH), 59.4

(Pip-C2), 62.0 (Oct-C1), 109.2 (Py-C3), 140.6 (Py-C2), 158.3

(Py-C4), 167.0 (COOH); IR (KBr): 3500-2500(br, s), 3090,

2920(s), 2860(s), 1750(s), 1640(s), 1545(s), 1450, 1285,

1210, 1160, 1030(w), 990, 930, 880, 870, 780(s), 660 cm1.


l-(Carboxymethyl)-l-decyl-4-(4-pyridinyl)piperazinium

chloride hydrochloride (22b). Intermediate 21b was prepared

by the procedure above. Compound 21b (17.5g, 0.0234 mole)

was refluxed for 6 hours in 9N HCl (200 ml). Extraction

with ether (2 x 200 ml), filtration, and evaporation of the

aqueous solution gave a solid, which was dissolved in water

(250 ml). The solution was cooled in ice and basified with

1.ON NaOH (125 ml). After warming to room temperature, the

solids were filtered, and the filtrate acidified with HC1






-38-


and evaporated to dryness. The residue was taken up in

water (50-60 ml), filtered, and acetone (600 ml) added.

After standing a few minutes and filtering, more acetone

(400 ml) was added, the slurry cooled in ice, and the solid

collected to give 3.62g of 22b as colorless microcrystals.

A second crop (4.45g) was obtained by evaporating the

filtrate and triturating with acetone (100 ml). The overall

yield was 8.07g (66%): mp 202.5-4 C(d); 13C-NMR (D20;

dioxane ref.): 614.7 (Dec-C10), 22.9 (Dec-C2), 23.4 (Dec-

C9), 26.9 (Dec-C3), 29.8, 30.3 (Dec-C4, -C5, -C6, -C7), 32.7

(Dec-Cg), 40.8 (Pip-C3), 57.3 (CH2COOH), 59.5 (Pip-C2), 62.2
(Dec-C1), 109.2 (Py-C3), 140.6 (Py-C2), 158.3 (Py-C4), 167.2

(COOH); IR (KBr): 3500-2500(br, s), 3080, 2920(s), 2860(s),

1750(s), 1645(s), 1620, 1570, 1550(s), 1460, 1430, 1420,

1400, 1285(w), 1210, 1190, 1160(s), 1120(w), 990, 930, 875,

780(s), 660 cm1.


l-(Carboxymethyl)-l-octyl-4-(4-pyridinyl)piperazinium
hydroxide, inner salt (23a). Compound 22a (5.25g, 0.0129

mole) in water (50 ml) was titrated at 0C to pH 9.2 with

1.00N NaOH (19.00 ml). After filtration and evaporation,

the residue was taken up in absolute ethanol (28 ml),

filtered, evaporated, and dried in vacuo to give 4.32g

(100%) of 23a as a beige glass. An analytical sample was

obtained by taking up the glass in 2:1 CH2C12/MeOH, washing

with NaHCO3(satd.), filtering and evaporating the organic






-39-


layer, washing the resulting solid with ether, and drying to

give colorless microcrystals: mp 176-8 oC(d); 13C-NMR (D20;

dioxane ref.): 614.6 (Oct-C8), 22.2 (Oct-C2), 23.1 (Oct-C7),

26.8 (Oct-C3), 29.3, 29.5 (Oct-C4, -C5), 32.2 (Oct-C6), 40.5
(Pip-C3), 58.6 (Pip-C2), 59.5 (CH2COO-), 60.2 (Oct-C1),

109.8 (Py-C3), 149.3 (Py-C2), 155.3 (Py-C4), 168.8 (COO);

IR (CHBr3): 3500-3300(br(H20)), 2950(s), 2920(s), 2860,

1630(br, s), 1595(s), 1542, 1530, 1465, 1390(br), 1270,

1220, 1170, 1025(w), 990, 925, 890(w), 875(w), 805, 740(w),
-i
705 cm-1

Anal. Calcd for C19H31N302*0.25H20: C, 67.52, H, 9.39,
N, 12.43. Found: C, 67.55, H, 9.45, N, 12.40.


l-(Carboxymethyl)-l-decyl-4-(4-pyridinyl)piperazinium
hydroxide, inner salt (23b). Compound 22b (0.55g, 0.00127

mole) in water (7 ml) was titrated at 0C to pH 11.6 with
1.00N NaOH (2.50 ml). The solid was collected and dried to

give 0.27g (59%) of 23b as colorless microcrystals: mp 177-9

C(d); 13C-NMR (CDC13): 613.3 (Dec-C10), 21.1 (Dec-C2), 21.7
(Dec-C9), 25.7 (Dec-C3), 28.4-28.6 (Dec-C4, -C5, -C6, -C7),

31.0 (Dec-C8), 39.1 (Pip-C3), 56.6 (Pip-C2), 57.9 (CH2COO-),

58.7 (Dec-C1), 108.1 (Py-C3), 149.3 (Py-C2), 153.0 (Py-C4),

164.8 (COO-); IR (CHBr3): 3500-3300(br(H20)), 2950, 2920(s),

2850, 1750(w), 1640(br,s), 1590, 1542, 1535, 1464, 1385,
-1
1270, 1220, 1030(w), 990, 820, 800, 770 cm-1

Anal. Calcd for C21H35N302.1.5H20: C, 64.92, H, 9.86,
N, 10.81. Found: C, 65.04, H, 9.84, N, 10.77.






-40-


2.5.3 Kinetic Measurements


All kinetics measurements were performed by Dr. H. D.

Durst at the U. S. Army CRDC (see p. 7).

Reagents and Stock Solutions. Cetyltrimethylammonium

chloride (CTAC) was purchased from Eastman Kodak. Micellar

solutions prepared from this material as received gave

kinetic data indistinguishable from those prepared from CTAC

recrystallized from methanol. Micelle solutions were

prepared by weighing the appropriate amount of catalyst into

the aqueous buffer so that the final solution of surfactant

was 0.001 M. New surfactants were synthesized as described

in the synthesis section, and surfactant solutions for

kinetics prepared from analytical materials. The concentra-

tion of catalyst in all kinetic runs ranged between 0.1-1.0

mM, with the exception of the turnover experiment where

[CAT] 0.05 mM. After generation of the "stock" catalyst

solution, subsequent dilutions were performed in the ratio

8:7:6:5:4:3:2 giving, under normal conditions, seven

different catalyst concentrations to be used in the calcula-

tion of the second-order rate constant (kCAT). 4-Nitro-

phenyl hexanoate (PNPH) was purchased from Sigma and used as
-3
received. A 5.5 x 10-3 M stock solution of PNPH (UV sub-

strate) was prepared in anhydrous acetonitrile and 0.020 ml

added to the cell to initiate the reaction, the final con-

centration being always 5.5 X 10- M. 0-(1,2,2-Trimethyl-
centration being always 5.5 X 10 M. O-(l,2,2-Trimethyl-






-41-


propyl)methylphosphonofluoridate was prepared by standard

methods at CRDEC and supplied as a distilled, water-white

liquid. A stock solution was prepared from this material in

anhydrous acetonitrile and 0.050 ml added to the fluoride

cell to initiate the reaction. The final total volume in

the UV experiments was 2 mL and in the fluoride ion release

experiments, 3.380 ml.

Aqueous Phase. The aqueous phase at pH 8.5 was a

borate buffer prepared using sodium tetraborate decahydrate

(Na2B407'10H20, Baker Reagent, 4.76g, F.W. 381.4) and

dissolving in 500 ml deionized, glass-distilled water. To

this solution was added sodium chloride (3.21g, F.W. 58.50)

and 0.1 M HC1 (152 ml). This entire mixture was then

diluted to 1 liter. All pH measurements were performed

using a glass electrode with an Orion 940 or Fisher Accumet

Model 825 MD pH meter, calibrated using Fisher standard

buffers at pH values of 4.00, 7.00, and 10.00. The pH of

the prepared buffers was checked before each kinetic run to

ensure no variation from run to run. In the PNPH hydro-

lyses, the pH of the reaction mixture was checked at the

conclusion of each run as well.

UV Kinetic Measurements. UV reactions were followed by

monitoring the absorbance of the product, 4-nitrophenoxide

ion, at 402 nm (estimated e in a CTAC micellar medium 1.88

X 104M-1cm-1) using either a 1) Hewlett-Packard 8450A Photo-

diode Array Spectrophotometer equipped with a single sample






-42-


station and interfaced to an HP-85 computer, or 2) Gilford

2400S Spectrophotometer equipped with a thermostatted 4-cell

carriage, a cell positioning programmer, and interfaced to

an Apple IIe computer via an Adalab Interface card. Both

instruments were set up for "real time" data acquisition

through their respective computers. The HP-8450A was

generally used for "fast" kinetic runs (tl/2 on the order of

5-120 sec) and the Gilford 2400S for "slow" kinetic runs

(tl/2 > 120 sec). Temperature control (25 + 0.1C) was
achieved by use of an HP-2437 Programmed Temperature

Controller system on the HP-8450A and with a water circu-

lating Endocal RTE-8DD Controlled Bath for the Gilford

2400S.

Ion Selective Electrode Measurements. The method for

measuring agent (Soman) hydrolysis data (fluoride appear-

ance) has been reported elsewhere [87JPC861].

Calculation of Rate Constants. Rate constants from

both UV and ion selective electrode data were generated on a

HP-85 or Apple IIe microcomputer, using a weighted least-

squares technique applied to the data in the ln(A, At) vs.

time format. Individual weights were calculated using a

linear-to-log transform procedure and second-order rate

constants calculated using at least seven different

concentrations. Reactions were followed to >90% completion

and showed good overall first-order kinetics (r > 0.99).







-43-



Reproducibilities of the rate constants were less than + 5%.

Rate constants for individual runs are given in Tables 2-1

and 2-2 above.


















CHAPTER III

UNUSUAL CATALYTIC ACTIVITY OF
ANIONIC SURFACTANT ANALOGUES OF 4-(DIMETHYLAMINO)PYRIDINE
IN CARBOXYLATE ESTER HYDROLYSES


3.1 Introduction


In Chapter II, a series of surfactants incorporating

the 4-(N,N-dialkylamino)pyridine moiety as catalysts for

fluorophosphate and carboxylate ester hydrolyses was

studied. All the compounds catalyzed the hydrolysis of

p-nitrophenyl hexanoate, although none efficiently catalyzed

that of fluorophosphate. The most surprising finding was

that the single anionic derivative, sodium 10-[butyl-(4-pyr-

idinyl)amino]decyl sulfate (2) (Figure 3-1), was more active

by an order of magnitude over neutral, cationic, and

zwitterionic analogues. Compound 2 catalyzed the hydrolysis

of 4-nitrophenyl hexanoate with k2 38.0 M1 sec-1 (at pH

8.5), which compared favorably to hydrolyses utilizing the

active o-iodosobenzoate catalysts developed by Moss and

coworkers [83JA681, 84JA2651, 86JA788]. The superior acti-

vity of 2 compared to its analogues of different charge type

was unexpected, since ester hydrolyses under basic condi


-44-






-45-


tions, although readily enhanced by cationic surfactants

(e.g., cetyltrimethylammonium chloride (CTAC)), are normally

retarded by anionic surfactants (e.g., sodium dodecyl

sulfate) [75MI98].

In an effort to clarify this situation, three addi-

tional related anionic 4-(N,N-dialkylamino)pyridine surfac-

tants (3, 5, 7; Figure 3-1) were prepared. In this chapter

is discussed their synthesis and catalytic activity in the

hydrolysis of PNPH.




3.2 Synthesis


The anionic 4-(N,N-dialkylamino)pyridine surfactants

were all synthesized from 10-[butyl-(4-pyridyl)amino]-

1-decanol (see Chapter II for synthesis) according to the

plan outlined in Figure 3-1 (all compounds in this chapter

are numbered according to Figure 3-1).

In Chapter II, the synthesis of sulfate 2 from alcohol

1 by reaction with chlorosulfonic acid was reported.

Attempts to synthesize phosphate derivative 3 by analogous

one-step processes failed. Alcohol 1 did not react with

P205/H3PO4 and treatment with phosphoryl chloride gave the
alkyl chloride. However, utilizing the method of Tener

[61JA159], DCC-catalyzed cyanoethylphosphorylation of 1,

followed by removal of the cyanoethyl protecting group with

sodium hydroxide gave 3 in 45% yield.








-46-


n-Bu-N-(CH2) 100H




N


CISO3H

(41%)


1. DCC/NCCH2CH20PO3H2

2. NaOH (45%)

MsCl/
NEt3

(95%)


n-Bu-N-( CH2)10OSO3H




N

2





n-Bu-N-(CH2)10 OPO3H


-HCI


3

3


n-Bu-N-(CH2) 10OMs



N -.HC1


K2SO3/KI

(50%)


n-Bu-N-(CH2 )10 SO H


->
SHC1


5


KCN/
KI
(63%)
v


n-Bu-N-(CH2)10CN



N HC1
N


HCl(aq.)

(87%)


n-Bu-N-(CH2 ) COOH



7 -HC1

7


FIGURE 3-1 Synthetic Scheme for Anionic Surfactants


->






-47-


Sulfonate 5 and carboxylate 7 were prepared via

mesylate 4, itself synthesized in 95% yield by reaction of 1

with mesyl chloride in the presence of triethylamine.

Treatment of 4 with K2SO3/KI in refluxing ethanol gave 5 in

50% yield, as the hydrochloride salt. Carboxylate 7 was

synthesized by reaction of 4 with KCN/KI in refluxing

ethanol to give 6 (63%) followed by acidic hydrolysis (87%

yield).

All final compounds and intermediates gave satisfactory
13C-NMR, IR, and analytical data.





3.3 Discussion of C-NMR Spectra


13C-NMR data for intermediates and final compounds are

shown in Table 3-1 (alcohol 1 and DMAP are included for

comparison purposes). Assignments were based upon compar-

ison to known systems.

The chemical shifts were consistent with the structure

shown in Table 3-1. Chemical shifts for pyridine carbons

C-2', C-3', and C-4' of 1 were essentially the same as those

for DMAP. However, compounds 2-7 were hydrochloride salts,

and this difference was reflected in the 1C chemical shifts

of the pyridine nucleus. Carbon C-2' was shielded by

approximately 10 ppm, whereas C-4' was deshielded (by 1-3












-48-


I..
-y u.


- S
C-

-i s
U
CM


CM z
N/


0 -





C'. S
CN





U, S3
CM












-S
CM L
Nn u


CM





-t O





X


Un



'a

O





























o c


















I
0 e
































0, <
-
E


CIf
-













.0 =
r- L -i -




C 8 ^ C










.0 1.0 V)
14 CN am




CN CM Cm

ra ra
-> in CM

0" o
CN in
(B B;


g\ r s

oo co c

NCM C C
CO C 0

\o o i
CM CM C

dc B
-I r^ T

C' O C
CN C h


m
E-4
z


)





P-



z
U



z




0








E-4
to



u)
1-:






L)





z
n
0-
z:
















1-
El


SC-



~ 0 0

- M


Un Ln -17 -4r
CM CM C14 CM

M o co


~u~ru
CM C, M

CM CM C C


CM r- reo 0
'0 '.0 '.0 r

- (- 0 -U

U U Ufn


o2 me
-< (


C N

N



,, n .0
,.,j






rr:





rJ --.er
e3 -






01
-" a)















or,
r- rC
v=s



'-I


& s)





S ) C

.0
M

u = a^
'-!
r^


- -


U U







0 Z

'.0U







-49-


ppm) and C-3' was relatively unchanged compared to 1.

Similar effects have been reported for other pyridinium ions

[80MI118].

Chemical shifts for the alkyl carbons were also as

expected. Carbon C-1 resonated at 662.2 in 1, at slightly

higher values in 2-4, and farther upfield (at 633) in 5 and

7. In nitrile 6, C-1 occurred at 615.7 which, in combin-

ation with the CN resonance at 6118.5, was useful as a

diagnostic tool for confirming the presence or disappearance

of 6. Carbons C-1 and C-2 of phosphate 3 were both split

into doublets, with 2J-5.8 Hz and 3J-7.3 Hz, respectively,

due to 13 C31 coupling.




3.4 Kinetic Results



The procedures utilized for the kinetics measurements

were described in Chapter II. The anionic surfactants were

tested for catalytic activity in the hydrolysis of 4-nitro-

phenyl hexanoate (PNPH). Catalysts 2 and 7 were utilized as

free bases, and 3 as its hydrochloride salt. Limited

solubility precluded the testing of sulfonate 5. The

results are reported in Table 3-2, in which rate constants

for DMAP and alcohol 1 are included for the purpose of

comparison.







-50-


TABLE 3-2




SECOND-ORDER RATE CONSTANTS (k )
FOR THE HYDROLYSIS OF P-NITROPHENYL HE M.bATE (PNPH)
AT pH 8.5 ([PNPH]-5.5 x 10 M)



Entry Compound kCAT (M SEC-1

No CTAC 1mM CTAC 5mM CTAC

1 1 (ROH) 1.25 35.6 32.0

2 2 (ROSO3H) 38.0 62.2 35.8

3 3 (ROPO3H2) 2.36

4 7 (RCOOH) 2.69

5 DMAPb 3.68 1.96 1.32

6 Blank (no surfactant) c





a. Kinetics measurements were carried out at the U. S. Army
CRDC (see p. 7).
b. DMAP 4-(Dimethylamino)pyridine.
c. Hydrolysis in the absence of surfactant gave a pseudo
first-order rate constant of 6.5 x 10- sec- which
represents background hydrolysis (khyd+kOH[OH- ). At the
[PNPH] given above, this corresponds to an initial rate
_q
99
of 3.6 x 10 M/sec. n comparison, using kCAT for 3 at
a cone. of 0.001M, the initial rate was 130 x 10-9.







-51-


3.5 Discussion of Results


Surfactant 2 remained the most effective catalyst in

this whole series, and was some 15 times better than 3 or 7.

However, k2 values for 3 and 7 (2.36 and 2.69 M-1sec-,

respectively) were still about twice those for neutral

surfactant 1 and for the analogous cationic and zwitterionic

surfactants, synthesized previously. The anionic head group

thus appeared to play a significant role in the catalytic

activity of these systems.

The relatively high efficiency of the anionic compounds

at first glance appeared anomalous since, as mentioned

above, for electrostatic reasons, anionic surfactants

normally retard basic hydrolyses. However, other factors

can be invoked. Thus, anchimeric assistance of hydrolysis

of the 1-acylpyridinium intermediate by the anionic head

group could account for the observed enhancements. Electro-

static stabilization of the acylpyridinium intermediate may

also be taking place (Figure 3-2). Formation of the acyl-

pyridinium 8 is known to be the rate-determining step in

hydrolyses of the type RCOX ----> RCOOH + HX [83CSR129].

Electrostatic stabilization of the positive charge in 8 by

the anionic group could lower the transition state energy

for its formation and thus increase the rate of formation of

8.







-52-


R-N-(CH2)10-A

R'COX


N


R-N



N A
I
O-C
R'


R-N-(CH2 10-A

H20 >

.N

+

R'COOH


R-N-(CH2) 10-A






9


R-N



N
H


FIGURE 3-2 Electrostatic Stabilization of Acylpyridinium
and Bolaform Micelle Formation with Anionic Surfactants






-53-


Another important factor is the pKa of the various
groups involved. At the pH of the reaction medium (pH 8.5),

the 4-(dialkylamino)pyridine group (pKa 9.4 [83CSR129]) is

approximately 90% in the protonated form (Py-H+) (the
percentage of protonated pyridine (Py-H+) in a solution of

Py is given by: %Py-H {[Py-H+]/([Py-H+]+[Pyl))xl00 -

(1+1OPH-PKa)-xlOO (1+108.5-94) -1x100 89%). The OSO3H
and COOH groups (pKa approximately -3 and 4.8, respectively

[72MI58]) should both be 100% ionized and the OP03H2 moiety

(pKa values -2.1 and 7.2 [72MI58]) approximately 96% in the
OPO3" form (the percentage of A- in a solution of HA is

given by: %A- {[A-]/([A-]+[HA]))xl00 (1+10PKa-pH)-
x100). Thus, the dominant species present in solution are

zwitterionic (9; Figure 3-2). Hence, 2, 3, and 7 could act

as zwitterionic "bolaform" surfactants (Figure 3-2)

[51JA949, 74JPC1387]. The surface activity of dicationic
bolaforms has been interpreted by the formation of "wicket-

like" structures at the air-water interface (74JPC1387].

Such bolaforms can form micelles if the connecting carbon

chain length equals or exceeds 12 (Figure 3-2) which are

capable of increasing the rate of p-nitrophenyl dodecanoate

hydrolysis (by 28-fold at pH 12) [74JPC1387].

This reasoning carries with it significant implications
for the surfactants synthesized in this study. The chain

lengths in compounds 2, 3, and 7 connecting the anionic to

the cationic (PyH+) groups are roughly 15 atoms (including






-54-


N, 0, and S, and counting the pyridine ring as 2 atoms) and

this would allow the chains to form bolaform micelles. The

formation of "wicket-like" species is perhaps even more

likely than with the dicationic bolaforms because of the

oppositely charged head groups involved. This would account

for the higher catalytic activity of the "anionic" surfac-

tants, since the other surfactants prepared are incapable of

forming such micelles. In solution, the "neutral" and

"zwitterionic" surfactants would actually have a net

positive charge (+1), whereas the "cationics" would possess

an overall double positive charge (+2).

At the present time, the reason for the high activity

of surfactant 2 (ROSO3H) relative to 3 (ROPO3H2) and 7

(RCOOH) remains unclear. A further investigation of the

precise structures of the species present in solution is

necessary to determine the cause of this phenomenon.




3.6 Experimental Section


3.6.1 Methods


The methods used were the same as described in section

2.5.1., except that a Varian XL-200 spectrometer was also

used to obtain 13C-NMR spectra. 1C-NMR spectra of all

compounds are listed in Table 3-1.






-55-


3.6.2 Materials


Commercially available reagent grade solvents and

reagents were used without further purification. Silica gel

filtrations utilized either E.M. Merck or MCB silica gel 60

(230-400 mesh). 10-[Butyl-(4-pyridinyl)amino]-l-decanol (1)

and 10-[butyl-(4-pyridinyl)amino]-l-decyl sulfate (2) were

prepared as described in Chapter II.


10-[Butyl-(4-pyridinyl)amino]-l-decyl phosphate (3).

Barium (2-cyanoethyl)phosphate dihydrate (0.58g ;1.73 mmole)

and Amberlite IR-120 H.C.P. cation exchange resin sulfonicc

acid; 3g) were stirred in water (5 mL) until the barium salt

dissolved. The solution was passed through a column of the

same resin (5g), washing with water (15 mL). The water was

removed by adding dry pyridine (10 mL), evaporating, and

repeating the process, giving a yellow oil. To this was

added 1 (0.51g; 1.67 mmole) in dry pyridine (10 mL), fol-

lowed by dicyclohexylcarbodiimide (1.38g; 6.70 mmole) and

the mixture stirred at room temperature for 17 hrs. Water

(2 mL) was added, stirring continued for 1 hour, then 10%

HOAc (50 mL) added and the mixture heated on a steam bath

for 2 hrs. The solvent was evaporated and the residue

heated on the steam bath with 0.5N NaOH (70 mL) for 2 hours.

After cooling to room temperature, the solid was filtered






-56-


and the filtrate acidified and evaporated (via ethanol

azeotrope). The semisolid was taken up in absolute ethanol

(50 mL), filtered and evaporated. To the resulting oil was

added water (20 mL). The mixture was basified (pH 10) with

2.5N NaOH, then extracted with EtOAc (2 x 10 mL). After

acidification of the aqueous layer, NaCl was added and the

solution extracted with 3:2 CH2C12/EtOH (3 x 10 mL). The

combined extracts were dried over MgSO4 and evaporated to

give 0.32g (45%) of 3 hydrochloride, as an amber oil. IR

(thin film): 3500-2000(br), 3300(br), 2930(s), 2850(s),

2200, 2060, 1730, 1650(s), 1545(s), 1465, 1370, 1210 (br,

s), 1080-950(br, s), 910, 730(s) cm-1.
Anal. calcd for. C19H36CIN204P-H20: C, 51.75, H, 8.69.

Found: C, 51.43, H, 8.62.


10-[Butyl-(4-pyridinyl)amino]-l-decyl methanesulfonate

hydrochloride (4). A solution of methanesulfonyl chloride

(0.48g; 4.20 mmole) in CH2C12 (4 mL) was added dropwise over

a period of ten minutes to a solution of 1 (1.24g; 4.06

mmole) in CH2Cl2 (12 mL) at room temperature. After

stirring 3 hours, the solution was cooled in ice, triethyl-

amine (0.78g; 7.72 mmole) and additional methanesulfonyl

chloride (0.48g) were added in one portion, and stirring

continued at room temperature for 24 hours. After addition

of CH2C12 (20 mL), the mixture was washed with water (20

mL), 1N HC1 (20 mL), dried over MgSO4, and evaporated to






-57-


give 1.63g 4 (95%) as an amber oil (4 was stored in CH2C12
in the refrigerator to prevent decomposition). IR (thin

film): 3100-2300(br), 2930(s), 2860(s), 1640(s), 1590(w),

1545(s), 1460, 1420(w), 1345(s), 1210, 1170(s), 1100(w),

1040, 970, 940, 930, 810, 730 cm1.

High res. mass spectrum (m/e)(for free base): Calcd,

384.2447. Found, 384.2469 (std. dev. 0.0053).


10-[Butyl-(4-pyridinyl)amino]decanesulfonic acid hydro-

chloride (5). Compound 4 was taken up in CH2C12, washed

with lN NaOH, filtered through silica gel, and evaporated to

give the free base. The free base (0.24g; 0.63 mmole),

K2SO3 (0.36g; 2.28 mmole), KI (0.32g; 1,93 mmole), and EtOH

(95%; 1.5 mL) were refluxed for 17 hrs. Water (10 mL) was

added and the ethanol evaporated. The solution was acidi-

fied to pH 3-4 and extracted with CH2C12 (1 x 15 mL). The

organic layer was washed with 1N HC1 (10 mL), dried over

MgSO4, and evaporated to give 0.13g (50%) of 5 as a yellow

glass. IR (thin film): 3400(br), 3100-2300(br), 2920(s),

2860(s), 1645(s), 1550(s), 1465, 1420, 1370, 1230, 1190(s),

1110, 1030, 825, 720, 520(br)cm-1

Anal. calcd for C19H35CIN203S.2H20: C, 51.51, H, 8.87.

Found: C, 51.89, H, 8.87.






-58-


11-[Butyl-(4-pyridinyl)amino]undecanenitrile
hydrochloride (6). Compound 4 (0.90g; 2.13 mmole), KCN

(0.56g; 8.62 mmole), KI (1.20g; 7.23 mmole), and EtOH (abs.;

9 mL) were refluxed for 17 hours, at which point more EtOH

(5 mL) was added and refluxing continued for 2 hours. Water

(20 mL) was added and the ethanol evaporated. The mixture
basified with 2.5N NaOH and extracted with CH2C12 (1 x 25

mL). The organic layer was evaporated, the resulting oil

taken up in CH2C12 (7 mL), washed with 1N HC1 (7 mL), and

passed through a pad of silica gel (5 g), washing with 2-6%

MeOH in CH2C12. Evaporation of the eluate gave 0.47g 6

(63%) as an amber oil. IR (thin film): 3420(br), 2920(s),

2850(s), 2230(w), 1640(s), 1550(s), 1460, 1420, 1365, 1185,

1100(w), 915(w), 820, 725cm-1.

Anal. calcd for C20H34CIN3*3H20: C, 59.17, H, 9.93.

Found: C, 59.29, H, 8.93.


ll-[Butyl-(4-pyridinyl)amino]undecanoic acid

hydrochloride (7). Nitrile 6 (0.42g; 1.19 mmole) and cone.

HCl (4mL) were refluxed for 15 hours, then more cone. HCl (2

mL) was added and refluxing continued for 2 hours more.

After cooling to room temperature, the mixture was extracted

with 3:1 CH2C12/MeOH (3 x 4mL), the extracts dried over

MgSO4 and passed through a pad of silica gel (2 g), washing

with 3:1 CH2Cl2/MeOH (40 mL). Evaporation of the eluate

gave 0.37g (87%) 7 as an amber glass. IR (thin film): 3600-







-59-


2500(br), 3400(br), 2960(s), 2930(s), 1720(s), 1650(s),

1550(s), 1465, 1425, 1370, 1190(s), 1100(w), 1030(w), 820,

730 cm1.

Anal. calcd for C20 H35CN2 022H20: C, 59.02, H, 9.66.

Found: C, 59.61, H, 9.22.

The free base (zwitterion) of 7 was utilized for rate

measurements, and was prepared by washing a chloroform

solution of 7 with 1N NaOH, boiling with charcoal, filtering

through silica gel with 5-15% MeOH/CH2Cl2, and evaporating

to give a thick, colorless oil, which slowly crystallized to

colorless needles. Spectra were identical to those for 7,

except that the 13C-NMR lacked the resonance at 6175.1, and

the IR lacked the broad absorption at 3100-2300cm-1, and

possessed an additional band at 920cm-1

Anal. calcd for C20H34N202*2H20: C, 64.83, H, 10.34.

Found: C, 64.74, H, 10.16.


3.6.3 Kinetics


Rate measurements were carried out utilizing p-nitro-

phenyl hexanoate (PNPH) as substrate. The procedures

utilized for the kinetics measurements were described in

Chapter II. All kinetics measurements were performed by Dr.

H. D. Durst at the U. S. Army CRDC (see p. 7).
















CHAPTER IV
SUBSTITUTED o-IODOSO- AND o-IODOXYBENZOIC ACIDS:
SYNTHESIS AND CATALYTIC ACTIVITY IN THE HYDROLYSIS OF
ACTIVE PHOSPHORUS ESTERS AND RELATED SYSTEMS


4.1 Introduction


A particularly significant advance in the micellar

approach to phosphate ester decomposition was the introduc-

tion by Moss and coworkers of 2-iodosobenzoic acid (IBA)

and its derivatives as nucleophilic catalysts. o-Iodoso-

benzoic acids 1, 2, and 3 (see Figure 4-1) exist predomi-

nantly in the l-hydroxy-l,2-benziodoxolin-3-one (alterna-

tively denoted l-hydroxy-1,2-benziodoxol-3(3H)-one) (4b)

tautomeric form. They were shown to be powerful reagents

for the cleavage of phosphates in an aqueous cetyltrimethyl-

ammonium chloride (CTAC) micellar medium [83JA681, 84JA2651,

86JA788]. o-Iodosobenzoic acid (1) itself cleaved p-nitro-

phenyldiphenylphosphate (PNPDPP) with k2 645 1/mole-sec at

pH 8 in aqueous CTAC [84JA2651]. 2-Iodoso-5-octyloxybenzoic

acid (2) was more efficient, displaying k2 14,400 1/mole-

sec [84JA2651], and the fully-functionalized (dimethylhexa-

decylammonium)ethoxy surfactant (3) was still better, with

k2 28,500 1/mole-sec [86JA788]. Moss recently studied


-60-








-61-


O-- ,


OC
O c I



U



Ol
0 0 "
O co

0

'
o
o



0 0






-11
o 4

o


a



o ___/ --
.ii.ri ^






-62-


five further analogues of IBA, 5-methoxy-IBA, 5-nitro-IBA,

and three compounds with modified iodoxole rings

[86JOC4303], but all were less active than IBA itself.

Significantly, all of the Moss IBA compounds accelerated the

rate of ester decomposition without being consumed, at least

in the CTAC micellar medium studied.

The structure of IBA undoubtedly contributes to its

catalytic activity. X-ray and infrared studies [64JPS104,

64NA512, 65JCS3721] indicate that IBA exists in the bicyclic

forms 4b and 4c (Figure 4-1). The pKa of IBA is 7.02 (in

our hands, by titrimetry). As the iodoso substituent is

electron withdrawing (a 0.88) [78MI521] (this is the a

value for the p-I(OAc)2 group; to the best of our knowledge,

the a for I-0 has not been measured, but since the I-0 group

likely exists as the hydrated species I(OH)2 in aqueous

solution (to some extent), a for the diacetate should

approximate that for I-0), monocyclic IBA (4a), should have

a pK of approximately 3.3 (the pKa of unsubstituted benzoic

acid is 4.2). Hence, the tautomeric equilibrium between 4a

and 4b favors the cyclic form 4b by a factor of greater than

1000.

The only serious disadvantage to the widespread use of

iodosobenzoic acids in decontamination appears to be their

potential instability. In this respect, our attention was

drawn to the related 2-iodoxybenzoic acid (IBX), which also

exists in a cyclic form [81CSC489], and is considerably more






-63-


stable and easier to synthesize. Moss reported that

2-iodoxybenzoic acid was less active as a catalyst than the

iodoso by a factor of 3.8, but analogues have apparently not

been tested [84JA2651]. Indeed, the iodosobenzoate and

iodoxybenzoate functionalities, although known in the

literature for almost 100 years, have not been investigated

synthetically with any vigor. Although a plethora of

information exists in the literature concerning hydrolyses

catalyzed by IBA, IBX, and the derivatives reported by Moss,

data for other IBA and IBX analogues is lacking. In view of

the great interest in these compounds and their derivatives

as decontamination catalysts, a variety of IBA and IBX

derivatives were synthesized and their catalytic activity

versus a number of standard simulants and fluoride-releasing

substrates measured.




4.2 Synthesis


The IBA and IBX analogues prepared in this study are

shown in Figure 4-2. The alkyloxy derivatives (compounds 2,

2x, 5, 5x, 6, and 6x) were studied to examine the effect of

altering the chain length upon catalytic activity. Although

Moss suggested that the octyl chain in 2 was responsible for

an increased solubility in the micelles, and therefore a

higher activity [84JA2651], no published comparative work

















1







0 o
00
02Z


U) U)
w a

> g

S



0 0
.5 .5
N N

0 >
(0) X
0 0


C C


-64-


CN x
II XXX X X
C ) IO(O CO Oi

II M 1 ) ^ I 1 0









I 1 1K
0o
0 0 0 0 0 U Z







-65-


was previously available to examine that hypothesis. The

compounds were synthesized following the general procedure

developed by Moss (Figure 4-3), and gave the IBA compounds

(2, 5, 6) in reasonable yields. The analogous IBX deriva-

tives 2x and 5x were isolated from preparations of the

corresponding IBA, whereas 6x (5-dodecyloxy-IBX) was

prepared directly from the iodo compound using Ac2O/H202.

Although the alkyloxy compounds have a high catalytic

activity, their solubility in water is rather low.

Increased water solubility was considered likely lead to

increased activity, and greater convenience for practical

use. We therefore prepared compounds with a glycol chain

attached to the IBA (IBX) nucleus (compounds 7 and 8x).

The route shown in Figure 4-3, utilizing the mesylate of

diethylene glycol monomethyl ether [83CCT245] (prepared by

standard methods from the alcohol) as alkylating agent, gave

7. Several attempts to prepare the analogous hydroxy

derivative (X OCH2CH2OCH2CH2OH) by the same methodology

failed, therefore 5-hydroxy-2-iodobenzoic acid (15) was

esterified and then alkylated with 1,2-dibromoethane, as

described by Moss [86JA788], to give 21, which, upon

hydrolysis and oxidation, gave hydroxyethoxy IBX 8x (Figure

4-4).

To improve the water solubility, we also synthesized

compounds in which a charged group was attached to the

aromatic nucleus. With ammonium salt 9x, this was simply










-66-


x




04


o0 0


0











0
z
0
0 _









0




z

z





z 0
Im0"



O

1^


0 o- /







So
z
z 0

* ('1


0

0
us
O


0
*4





0-


*f)





LO

$4 -4
00
O4
4-1



uw
c) 0





10

fn0
4J




in





u-4
0 0)









-67-


0

o _





0 0 8,
SoQ0 4M
0






SOu






$O 2cu
C7aU
w -0

0 m -





0
0D 0
0 \ o
W |\
0
0 \






0,
\

O
ff ,_(\
o.

\<^ sz(






-68-


accomplished by treatment of 21 with triethylamine, followed

by chlorination and hydrolysis (Figure 4-4). An alternative

approach involved synthesis of terephthalic IBA derivative

12 from toluic acid, via iodination, followed by oxidation,

first with permanganate (to produce 27), then with fuming

nitric acid to afford 12 (Figure 4-5). At the pH commonly

used in the hydrolytic runs (8.5), one of the carboxylic

acid groups in 12 would be ionized, which should lead to

increased water solubility.

A further approach to the solubility problem involved

shortening the alkyl tail attached to the IBA (or IBX)

nucleus. Thus, 5-methyl-IBA (10) was prepared from

5-methyl-2-aminobenzoic acid (30) by diazotization, iodina-

tion (to give 31), and oxidation with Ac20/H202. 5-Methyl-

IBX (10x) was made from 31 via chlorination-hydrolysis

(Figure 4-5).

To determine the effect of an electron withdrawing

group on catalytic activity, nitro derivatives 11, 11x, 13,

and 13x were synthesized (Figure 4-5). Compound 13 was

prepared from 2-amino-4-nitrobenzoic acid (28) by diazotiza-

tion, iodination (to give 29), and oxidation with fuming

nitric acid. Iodoxy analog 13x was prepared by chlorina-

tion-hydrolysis of 29. Synthesis of 13 was easily accom-

plished by treatment of 2-iodobenzoic acid (32) with fuming

nitric acid by the method of Morrison and Hooz [70JOC1196].

Iodoxy derivative 13x was synthesized from 13 by oxidation

with hypochlorite solution [32HCA1102].























o
z
II

x
C.
I-


o -
o z
II II
0





I"
00
o o
II II

t',. o


0
z
0 -






SZ 4

o
z
,t z


0
z 4

0
__0"1
" o t


-69-


m
0


0 0
oa


- 4
I O
oz


x x
0 "




fo
II II

o0 1


0
o
0 04
uo
C4 c


0
r





z


\ 0


:c0Z


0
0







-70-


Aside from determining the effects of methyl and nitro

groups on catalytic activity, 10(10x), 11(llx), and 13(13x)

were also of interest because of their relatively straight-

forward syntheses. The anthranilic acid precursors for

these compounds are commercially available (Aldrich), thus

large-scale synthesis of each should be easy.




4.3 Discussion of C-NMR Spectra


Although the chemistry and use of polyvalent iodine

compounds has developed significantly during the past two

decades, no systematic study of their 1C-NMR spectra has

been undertaken. The 1C spectra of some iodobenzene

dicarboxylates and a few iodonium ylids have been reported

[78CB2099, 85JCS(P1)757], but overall the data is rather

sparse. In particular, to the best of our knowledge, no
C-NMR data has been reported for iodoxy and iodoso

compounds (for reviews, see 790MR499 and 80MI). Having a

number of IBA and IBX derivatives in hand, a thorough

examination of their 13C-NMR spectra was carried out.

The aromatic carbon-13 assignments for selected

2-iodoso- and 2-iodoxybenzoic acids are shown in Table 4-1.

The corresponding 2-iodobenzoic acids are included for

comparison. A variety of standard techniques were utilized

to assign spectra, including 13C substituent chemical shifts








-71-


TABLE 4-1



AROMATIC 1C-NMR ASSIGNMENTS FOR SELECTED
2-IODO-, 2-IODOSO-, AND 2-IODOXYBENZOIC ACIDS





S-COOH

IOn

n = 0 (iodo)
1 (IBA)
2 (IBX)


Compound Solvent C-1


2-IC6H4COOH
IBA


5-OC8-Iodo
5-OC8-IBA
5-OC8-IBX


5-CH3-Iodo
5-CH3-IBA
5-CH3-IBX


4-NO2-Iodo
4-NO2-IBA
4-NO2-IBX


5-NO2-IBA
5-NO2-IBX


DMSO-d6
(1) DMSO-d6


(16)
(2)
(2x)


(31)
(10)
(10x)


(29)
(13)
(13x)


(11)
(llx)


CDC13
DMSO-d6
DMSO-d6


CDC13
DMSO-d6
CDC13/
CD OD/
DMSO-d6
DMSO-d6

DMSO-d6
DMSO-d6

DMSO-d6

DMSO-d6
DMSO-d6


136.6
131.4


133.5
133.0
137.7


138.2
131.5
137.7


C-2 C-3


93.9
120.4


82.8
108.9
82.1


90.6
116.7
89.5


143.2 93.9
136.6 122.1
143.7 93.8


133.4 127.7
138.1 104.1


140.4
134.3


142.3
127.1
141.2


141.7
126.0
140.6


134.4
125.9
134.8


128.1
142.5


C-4 C-5


132.3
131.0


120.7
121.7
119.1


134.6
135.2
133.2


148.1
151.5
148.6


128.1
126.1


128.0
126.2


158.9
160.9
158.5


132.8
140.5
134.9


123.0
121.7
123.4


149.7
147.3


C-6


130.1
130.2


117.9
115.4
116.3


132.8
131.5
131.4


130.2
137.1
130.6


124.8
124.2






-72-


(SCS) [80MI111], INEPT, proton-coupled gated NOE experi-
ments, relaxation times, and 2-D heteronuclear correlation

spectroscopy cosyY). Carbon assignments for 2-iodobenzoic

acids could sometimes be obtained by calculation of the

expected chemical shifts from known SCS values [80MI109].

IBA, IBX, and some iodobenzoic acid derivatives required

2D-COSY experiments for unequivocal assignments.

5-Octyloxy-2-iodobenzoic acid (16) exemplifies the

process utilized to make more complex assignments. Figures

4-6 and 4-7 show the 13C- and 1H-NMR spectra for 16. The

quaternary carbons, C-l, C-2, and C-5, were readily identi-

fied as the less intense peaks (i.e., longer relaxation

times) at 682.1, 137.7, and 158.5. The only reasonable

assignment for the resonance at 682.1 was C-2, the upfield

shift resulting from the iodine heavy-atom effect [80MI68].

The 6158.5 peak was assigned to C-5, the large downfield

shift resulting from the large ipso SCS value for alkyloxy

groups (-+30) [80MI111]. By elimination, the resonance at

6137.7 was assigned to C-1.

Methine carbons C-3, C-4, and C-6 could not be

unequivocally assigned by the above method. However, the

corresponding protons could be readily identified in the
H-NMR spectrum as H-3 at 67.7 (d, J 9Hz; ortho coupling

to H-4), H-6 at 67.3 (d, J 3Hz; meta coupling to H-4), and

H-4 at 66.7 (dxd, J 9Hz, 3Hz; ortho coupling to H-3, meta

coupling to H-6). A two-dimensional C-H COSY experiment









-73-


-C


Cl

LO


O
-co


0
-0
E4


O








-74-


ZZ

a_


-0



























rD



























CD









-75-


A 0Z Ob~
I I l I 11


09 OE 001
I I I, I I I


UOZ1 O' UI


-a -=3 ,
-. '. -. 1
I ~ C ~ -, 4j.
r :, n
ZJ =-4 ,. C

C Il-r U 3
S.--~~1l fl *S. S. S
-5 .5t. t ~ r I




-r r -.. ...: -. 1


I- CL
I /

U *- 0
<
a




( _

_rj







iif
ii


~i


rIl


(i-
1,_








SI
eU:
/i-




i'L







I \;[


v-'


___ r 03
$ ---~


I-'
I :

3
U
i-


SII


r\J
U-
LU








C
LL



zL
0 M



< C
icl
- LO
I-eC




on
L r'


\ -
U iT


u
0
0
N
C





I
0


.0
x



U
O





0
'0
a)
O











ul
u





0


1-I
L,
0



o
o
N



co

0






-76-


(proton decoupled) was then carried out, and is shown in

Figure 4-8. The results clearly correlated H-3 with the

carbon resonance at 6141.2 (C-3), H-6 with the peak at

6116.3 (C-6), and H-4 with that at 6119.1 (C-4), thus

completing the carbon assignments.

The most striking general feature of the spectra listed

in Table 4-1 was the strong deshielding of C-2 in the iodoso

compounds, approximately 25 ppm, relative to the

corresponding iodo derivatives. This deshielding was of the

same magnitude as that observed in other trivalent aryl

iodides, such as iodobenzene diacetate, iodine (III) ylids,

and oxo-bridged iodine (III) compounds [78CB2099,

85JCS(P1)757]. In contrast, C-3 was shielded by about 15

ppm, whereas other carbons remained relatively unaffected.

Since oxidation of iodine (I) to iodine (III) causes a

downfield shift at C-2, it was expected that further oxida-

tion to iodine (V) would be accompanied by a greater shift.

Surprisingly, the opposite effect was observed. In fact,

the 1C chemical shifts for the iodoxy acids appeared

essentially identical to those of the iodo compounds.

However, closer examination of this phenomenon showed that,

in the NMR solvent used (usually DMSO-d6), the iodoxy

compounds decomposed to the corresponding iodo derivatives.

For example, after standing at room temperature for twenty

minutes, a DMSO solution of 5-octyloxy-2-iodoxybenzoic acid

(2x) clearly showed, by thin-layer chromatography (silica






-77-


gel; 10:3 CHC13/EtOH), the absence of 2x and the appearance

of a spot with the same Rf as the iodo acid, 16. Other IBX

derivatives gave identical results.




4.4 Kinetic Results


The procedures utilized for the kinetics measurements

were described in Chapter II. p-Nitrophenyl diphenyl phos-

phate (PNPDPP) and p-nitrophenyl isopropylphenylphosphinate

(NPIPP) were utilized as phosphorus substrates for the

kinetic measurement. p-Nitrophenyl hexanoate (PNPH) was

similarly used as a carboxylate ester substrate (Figure

4-9). PNPDPP and PNPH have been used extensively as

standard reference substrates for the kinetic evaluation of

phosphate hydrolysis catalysts, and thus provided a good

data base for comparing our compounds to other systems.

NPIPP, a new p-nitrophenolate-releasing simulant introduced

in this study, was utilized because the effects of catalysts

on its rate of hydrolysis correlate well with those for

fluoride-releasing agents.

Kinetics were carried out in both 0.001M and 0.005M

CTAC at pH 8.5 (borate buffer) and were monitored spectro-

photometrically for the appearance of p-nitrophenolate anion

at 402 nm. Substrate concentration in all runs was 5.0 x
10-5M, and the concentration of catalyst ranged between 0.1-
10 14, and the concentration of catalyst ranged between 0.1-








-78-


fl) m


0 0 C
S. O 4



S1 o. Qt0 0
4-J



SI U)
0)


0
a 8 o 1


6N = 0



U)U


0 00

0..
o


z.z
CLa
o o =- 1


0 > 0

o ki V x
0 c c u
o |L
g "^






-79-


1.0 mM, with the exception of the turnover experiment where

[CAT] 0.05 mM. Second-order rate constants were deter-

mined from rate measurements at several (usually seven)

concentrations of catalyst (IBA or IBX). Plots of log(A, -

At) vs. time were linear over five or more half-lives (i.e.,

>96% reaction). All kinetic runs were performed utilizing

this regime.

A point of interest was whether the catalysts were

consumed (or otherwise stoichiometrically degraded) as the

reaction proceeded or whether they were regenerated, and

were indeed "true" catalysts. Because of the predicted

instability of the most likely intermediate (a 1-acyloxy-

1,2-benziodoxol-3(3H)-one), this question was addressed

directly. Several kinetic runs were performed with

5-alkyloxy-IBAs 2, 5, and 6 vs. PNPDPP in 0.001M CTAC where

the substrate was in large excess ([PNPDPP] 5 x 10-5 M;

[PNPDPP]/[IBA] 50-100). The reactions were allowed to go

to completion. With such a small proportion of the cata-

lyst, the kinetics could only be first order if the catalyst

was not consumed during the course of the reaction (i.e.,

[IBA] constant). The experimental data fitted first-order

kinetic analysis, and yielded a kobs value consistent with

data collected at higher concentrations of catalyst (i.e.,

under "enforced" pseudo first-order conditions). These

observations provided strong evidence that the substituted

IBA compounds are not consumed (i.e., "turn over") in the

reaction, and indeed functioned as true catalysts.






-80-


4.5 Discussion of Results


4.5.1 Hydrolyses in Micellar Media


The results are summarized in Table 4-2. In absolute

terms, the most efficient catalyst vs. NPIPP at 0.001M CTAC

was 2 (5-octyloxy-IBA; k2 461), with 5-butoxy-IBX (Sx)

nearly as effective (k2 433). Hydrolysis of PNPDPP was

best catalyzed by 5-dodecyloxy-IBA (6; k2 4864) followed

by 5-butoxy-IBA (k2 4575) and 5-octyloxy-IBA (k2 4526).

5-Octyloxy-IBX was also quite effective, giving k2 4494.

The alkyloxy derivatives were also the most effective vs.

PNPH, in the order 5-octyloxy-IBA, 5-dodecyloxy-IBA, and

5-butoxy-IBX (k2 3611, 3176, and 2805, respectively). The

high activity of the alkyloxy compounds verifies Moss'

earlier work with 5-octyloxy- and other iodosobenzoic acids,

which indicated that substrates possessing groups that

increase solubility in the micelles should increase the

reactivity [84JA2651, 86JOC43031. However, lengthening the

tail did not markedly increase the rate, and thus would

appear to be of limited value in these systems.

The other derivatives were significantly less effective

than the alkyloxys in hydrolyzing any of the substrates

tested. Of these, the 4-nitro and 5-methyl compounds were








-81-


TABLE 4-2

SECOND-ORDER RATE CONSTANTS (M SEC ) FOR
2-IODOXYBENZOIC ACID VS. 2-IODOSOBENZOIC ACID CLEAVAGES
IN ImM AND 5 mM CTAC AT pH 8.5


Catalystb



5-H
(1)

5-butoxydc
(5,5x)

5-octyloxyd,d
(2,2x)

5-dodecyloxycd
(6,6x)

4-nitrod,e
(13,13x)

5-nitrof
(11,11x)

5-methyld,c
(10,10x)

4-COOHe
(12)

5-DEG-0Med
(7)

5-OCH CH20Hd
(8xi 2

5-0CHCH 2NEt 3+d
(9x)


vs. NPIPP
kx k k /kI


31
----- (66)

433 406
(245) (257)

256 461
(186) (200)

300 361
(138) (156)


vs. PNPDPP
kX kI k/kI


----- 260
----- (277)

1.07 4450 4575
(0.95) (976) (1089)

0.56 4494 4526
(0.93) (953) (966)

0.83 4012 4864
(0.88) (913) (1007)


0.97
(0.90)

0.99
(0.99)

0.82
(0.91)


66 66 1.00 1089 1032 1.06
(75) (92) (0.82) (538) (647) (0.83)


vs. PNPH
kx kI k/kI


--- --- 182
---- -- (238)


2805 2504 1.12
(804) (917) (0.88)
2794 3611 0.77
(807) (807) (1.00)

1777 3176 0.56
(743) (887) (0.84)

1056 416 2.54
(225) (304) (0.74)


33 34 0.97 612 588 1.04 424 212 2.00
(40) (49) (0.82) (305) (381) (0.80) (110) (157) (0.70)


64 90
(67) (138)

4
(7)

--- 28
----- (92)

40 ----
(125) ----

60 ----
(70) ----


0.71
(0.49)


564 774 0.73 381 579 0.66
(307) (583) (0.53) (221) (516) (0.43)


--- --- 146
-- ------ (110)

-- ------ 463
-- ------ (380)

--- 575
---- (404) ------

---- 552
--- (300) ------


-- ------ 89
-- ------ (92)

-- ------ 246
-- ------ (272)

---- 310 ----
--- (355) ------

--- 350
---- (210) ------


a. Kinetics measurements were carried out at the U. S. Army CRDC (see p. 7).
b. Footnotes denote the synthetic procedures used to prepare the IBX or IBA
compounds, resp., from the corresponding 2-iodobenzoic acid. The quantity
"k2[IBXl/k2IIBA]" represents the kinetic advantage of the IBX over the IBA
derivative. Unparenthesized values were obtained at 1mM CTAC; values in
parentheses are for 5mM CTAC. c. (1) Ac20/H202, (2) H20. d. Chlorination-
hydrolysis. e. Fuming nitric acid. f. 11 prepared from 2-iodobenzoic acid with
fuming nitric acid; llx prepared from 11 with NaOCl.






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the best, being 2-3 times more active than IBA itself, but

5-7 times less active than the alkyloxy analogs (Table 4-2).

Although presumably more water soluble, 4-carboxy-IBA (12)

and diethylene glycol IBA 7 were less effective than IBA,

probably because of a low solubility in the micelle.

Most surprising was the high activity of the IBX deriv-

atives tested (relative to the IBAs). These possessed from

56% (5-octyloxy-IBX) to 107% (5-butoxy-IBX) of the catalytic

efficiency of the corresponding IBA compounds in the hydro-

lysis of NPIPP and PNPDPP. 5-Octyloxy-IBX had k2 4494 vs.

PNPDPP, which was 99% of the iodoso activity. 5-Butoxy-IBX
was nearly as efficient, with k2 4450, and 97% of the

iodoso activity. However, 4-nitro-IBX showed the greatest

kinetic advantage vs. PNPDPP compared to the iodoso, at

106%. In the hydrolysis of NPIPP, 5-butoxy-IBX was the most

efficient, both in overall rate (k2 433) and in advantage

over the iodoso (107%). 5-Dodecyloxy- and 5-octyloxy-IBX

possessed the next highest efficiencies (k2 300 and 256,

respectively), but with significantly lower activity than

the IBA derivatives (83 and 56%, respectively). 4-Nitro-

IBX, although about four times less active than the 5-octyl-

oxy, possessed 100% of the activity of the corresponding
iodoso compound. 5-Methyl-IBX was equally as good, although

with somewhat lower activity than 5-methyl-IBA (71%).

Interestingly, increasing the concentration of CTAC

from ImM to 5mM markedly improved the catalytic efficiency







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of the nitro and methyl derivatives vs. NPIPP. The alkyloxy

compounds, on the other hand, decreased in efficiency. Rate

vs. [CTAC] profiles typically increase rapidly to a maximum

as the CMC is approached, then decrease slowly with increas-

ing surfactant concentration (for examples, see 83JA681,

84JA2651, and 86JA788). 5-Octyloxy-IBA, for example,

possesses a maximum rate at 0.20mM, and IBA, at 1.00mM CTAC

in the hydrolysis of PNPDPP [84JA2651]. The rate-

[surfactant] profiles for the nitro and methyl derivatives

probably increase more gradually, so that the measurements

at 1mM and 5mM both fall on the upward portion of the curve.

Practically, this would be advantageous, because, by

increasing surfactant concentration, one could increase the

capacity of the system without a concomitant decrease in

catalyst reactivity.

The surprising catalytic efficiency of the iodoxy

analogues of iodoso compounds previously found to be

effective catalysts, in addition to its theoretical signif-

icance, is of considerable practical importance because the

stability of the iodoxy derivatives is far higher than that

of their iodoso analogs [66CRV243]. Moss reported that IBX

possessed only 28% of the activity of IBA [84JA2651]. One

of the iodoso derivatives prepared by Moss lost activity

over a period of time, and it is likely that other iodoso-

benzoates present similar stability problems [86JA788].

Comparable decreases of catalytic activity in other substi-






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tuted IBAs have been observed in CTAC microemulsions [87PC].

Moreover, iodoxy compounds are often simpler to prepare than

the iodoso derivatives.

Selected results of hydrolyses of fluoride-releasing

substrates under micellar conditions demonstrated that

5-octyloxy-IBA was the most efficient (at both 0.001M and

0.005M CTAC), with 4-nitro- and 5-methyl-IBA being compar-

able in activity in the 0.005M solutions.


4.5.2 Hydrolyses in Microemulsion Media


Although k2 values for hydrolyses of fluorophosphates

under micellar conditions were high, one cannot load signif-

icant amounts of substrate into the system to achieve an

effective decontamination formulation. Thus, selected cata-

lysts were tested in a microemulsion medium. Utilizing a

high concentration of CTAC (approximately 20% (1M)) with a

cosurfactant such as Bu4NBr or 1-butanol in aqueous

bicarbonate, excellent rates of reaction were obtained. At

concentrations of 1-10mM, 5-nitro-IBA (11) hydrolyzed

fluoride-releasing agents with k2-50, corresponding to

t1/2 1.4 sec. (with 10mM catalyst), which far exceeds
Mackay's criterion (tl/2 4 1 minute; section 1.3) and

provides a system which gives essentially instantaneous

decomposition of these toxic compounds.






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4.6 Experimental Section


4.6.1 Methods


All melting points are uncorrected and were taken in

open glass capillary tubes with a Thomas-Hoover melting

point apparatus. IR spectra were obtained on a Perkin-Elmer

283B infrared spectrophotometer. Proton NMR spectra were

obtained at 60 MHz on a Varian EM 360L NMR spectrometer,

with TMS as internal standard. 13C-NMR spectra were

obtained at 25 MHz on a JEOL FX-100 NMR spectrometer,

referenced either to solvent (6CDCl3 77.0; 6DMSO-d6 -

39.5) or, when D20 was utilized, to added DMSO (640.4) or

dioxane (667.4), as noted. With mixtures of CDC13 and DMSO-

d6, CDCl3 was used as reference. The two-dimensional COSY

spectrum of 16 was obtained at the University of Florida on

a Nicolet NT-300 spectrometer, and those of 2-iodobenzoic

acid, 1, 11, and 29, at the U. S. Army Chemical Research and

Development Center, on a Varian XL-200. Low and high

resolution mass spectra were obtained on an AEI MS30 mass

spectrometer. Microanalyses were either performed in house,

on a Carlo Erba 1106 elemental analyzer, or by Atlantic

Microlabs, Atlanta, Georgia.






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4.6.2 Materials


Commercially available reagent grade solvents and

reagents were used without further purification. Silica gel

filtrations utilized either E.M. Merck or MCB silica gel 60

(230-400 mesh). 5-Octyloxy-2-iodosylbenzoic acid (2)

[84JA2651] and 2-iodoxy-5-nitrobenzoic acid (llx)

[32HCA1102] were prepared according to literature methods.

2-Iodoxybenzoic acid (Ix) [36AJP17], 2-iodosyl-5-nitro-

benzoic acid (11) [70JOC1196], 2-iodo-4-nitrobenzoic acid

(29) [49ACS131, and 2-iodosyl-l,4-benzenedicarboxylic acid

(12) [65JCS3721] were synthesized at the U. S. Army Chemical

Research and Development Center, following literature proce-

dures. 2-Iodosylbenzoic acid (1) was purchased from Sigma

Chemical Company and used as received.


5-Butoxy-2-iodobenzoic acid (17). 5-hydroxy-2-iodo-

benzoic acid (15) (1.50g, 5.68 mmole) [84JA26511, NaOEt

(11.7 mmole; prepared in situ from 0.27g Na), 1-iodobutane

(1.15g, 6.25 mmole), and absolute ethanol (15 mL) were

refluxed for 23 hours. The ethanol was evaporated, water

(30 mL) added, and the mixture made basic (pH 10) with 2.5N

NaOH. After extracting with ether (2 x 20 mL), the aqueous

layer was acidified (4N HCl), and extracted with CH2C12 (2 x

20 mL). The combined organic extracts were dried over






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MgSO4, passed through silica gel (8g) and washed with CH2Cl2
(200 mL). Evaporation of the solvent gave 1.21g (67%) of 17
as beige microcrystals: mp 88-91; 13C-NMR (CDC13): 613.7

(Bu-C4), 19.1 (Bu-C3), 31.0 (Bu-C2), 68.0 (Bu-C1), 82.8

(Ar-C2), 117.9 (Ar-C6), 120.8 (Ar-C4), 133.7 (Ar-C1), 142.4

(Ar-C3), 159.0 (Ar-C5), 171.3 (C-0); IR (CHBr3): 3300-2500

(br,s), 2950(s), 2920(s), 2860, 1690(s), 1580, 1565, 1460,
1420, 1410, 1380, 1270(br,s), 1220(s), 1060(w), 1025(w),

1005, 865(w), 820, 755, 720cm-1

Anal. Calcd for CH11 1303: C, 41.27, H, 4.09. Found:

C, 41.69, H, 4.09.


5-Dodecyloxy-2-iodobenzoic acid (18). Prepared in 81%
yield via the same procedure as above, except using 1-iodo-
dodecane as alkylating agent. Obtained light brown micro-

crystals: mp 54-8; 13C-NMR (CDC13): 814.6 (Dod-C12), 22.7

(Dod-C11), 25.9 (Dod-C3), 29.0-29.6 (Dod-C2, -C49), 31.9

(Dod-C10), 68.4 (Dod-C1), 82.8 (Ar-C2), 117.9 (Ar-C6), 120.9

(Ar-C4), 133.7 (Ar-C ), 142.4 (Ar-C3), 159.1 (Ar-C5), 171.5

(C-O); IR (CHBr3): 3300-2500 (br,s), 2920(s), 2850(s),

1695(s), 1585, 1560, 1460, 1420, 1410, 1380(w), 1275(br,s),

1230, 1190(s), 1060(w), 1005, 865(w), 820(w), 785, 755,
11
720cm-1

Anal. Calcd for C19H29103: C, 52.78, H, 6.76. Found:

C, 53.09, H, 6.84.






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5-Butoxy-2-iodosylbenzoic acid (5). Cl2 gas (dried by
passing through anhydrous CaSO4) was bubbled into an ice-

cooled solution of 17 (0.90g, 2.81 mmole) in CHCl3 (7 mL)

for 30 minutes. The solvent was evaporated with a stream of

dry argon, and the resulting solid transferred to a mortar.

Ice (5g) and Na2CO3 (1.3g) were added, and the mixture
crushed to a paste. 1.ON NaOH (14 mL) was added, the slurry

stirred at 15-20C for 2 hours, diluted with water (10 mL),

and filtered. The filtrate was acidified with 4N HC1, the

solid collected, washed with water, and dried. The result-

ing material was washed with two small portions of EtOAc,

once with ether, and dried in vacuo to give 0.62g (66%) of

5 as beige microcrystals: mp 200-200.5 (d); 13C-NMR (DMSO-

d6): 813.6 (Bu-C4), 18.6 (Bu-C3), 30.5 (Bu-C2), 68.0

(Bu-C1), 108.8 (Ar-C2), 115.4 (Ar-C6), 121.9 (Ar-C4), 127.1

(Ar-C3), 132.9 (Ar-C1), 160.9 (Ar-C5), 167.5 (C-O); IR

(CHBr3): 3200-2500(br,s), 2960(s), 2940(s), 2880, 1600(s),

1555(br,s), 1450(s), 1420, 1330, 1260, 1220, 1110, 1065,

1040, 1030, 1010, 790(s), 725cm-1.

Analysis calcd for C11H13104: C, 39.31, H, 3.90.

Found: C, 39.58, H, 3.66.


5-Dodecyloxy-2-iodosylbenzoic acid (6). Prepared in

33% yield from 18 via the same procedure as for 5. An

analytical sample was obtained by recrystallization from






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acetone, as colorless microcrystals: mp 121-3 (d); 1C-NMR

(CDC13/CD3OD): 614.0 (Dod-C12), 22.6 (Dod-C11), 25.8

(Dod-C3), 28.8-29.5 (Dod-C2, C4-9), 31.8 (Dod-C10), 69.2

(Dod-C1), 104.7 (Ar-C2), 116.7 (Ar-C6), 124.8 (Ar-C4), 127.4

(Ar-C3), 129.9 (Ar-C1), 162.6 (Ar-C5) 167.5 (C-O); IR

(CHBr3): 3080, 3070, 2960, 2940, 2920(s), 2890, 2850(s),

1650(s), 1580, 1550, 1455(s), 1420, 1410, 1390(w), 1325(s),

1310, 1290, 1280(s), 1240, 1130(s), 1110(s), 1090, 1020(s),

1000, 920, 880, 820, 790, 775, 725cm-1

Anal. calcd for C19H29I04-1.0H20: C, 48.93, H, 6.70.

Found: C, 48.57, H, 6.32.


5-Butoxy-2-iodoxybenzoic acid (5x). 4-Butoxy-
2-iodosylbenzoic acid was prepared via chlorination/hydro-

lysis of the iodo compound (17). The crude solid thus

obtained was washed with ethyl acetate and ether. The

combined washes were evaporated and recrystallized from

acetone to give 5x (6%). A second recrystallization gave

an analytical sample, as colorless needles: mp 190-190.5;
13C-NMR (DMSO-d6): 13.7 (Bu-C4), 18.6 (Bu-C3), 30.5 (Bu-C2),

67.6 (Bu-C1), 82.1 (Ar-C2), 116.2 (Ar-C6), 119.2 (Ar-C4),

137.8 (Ar-C1), 141.2 (Ar-C3), 158.5 (Ar-C5), 167.8 (C-O); IR

(CHBr3): 3060, 2960, 2930, 2870, 1670(s), 1580, 1450, 1320,

1280(s), 1240, 1110, 1000(w), 880, 830, 780, 770cm1.

Anal. calcd for C11H13105: C, 37.52, H, 3.72. Found:

C, 37.43, H, 3.37.






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5-Octyloxy-2-iodoxybenzoic acid (2x). Obtained in 26%

yield from 16 by the procedure above. Recrystallization

from acetone gave an analytical sample, as colorless plates:

mp 113-5; 13C-NMR (DMSO-d6): 613.9 (Oct-C8), 22.1 (Oct-C7),

25.4 (Oct-C3), 28.4-28.6 (Oct-C2, -C4, -C5), 31.3 (Oct-C6),

67.9 (Oct-C1), 82.1 (Ar-C2), 116.3 (Ar-C6), 119.1 (Ar-C4),

137.7 (Ar-C ), 141.2 (Ar-C3), 158.5 (Ar-C5), 167.7 (C-O); IR

(CHBr3): 3080, 3065, 2950, 2940(s), 2920(s), 2850(s),

1670(s), 1650(s), 1580, 1460(s), 1420, 1390(w), 1325(s),

1280(s), 1240(s), 1110(s), 1030, 1000, 920, 880, 820, 790,

775, 720(w)cm-1
Anal. calcd for C15H21105: C, 44.13, H, 5.18. Found:

C, 44.03, H, 4.94.


5-Dodecyloxy-2-iodoxybenzoic acid (6x). Acetic

anhydride (1 mL), and 30% H202 (0.25 mL) were stirred at

exactly 40C for 4 hours, then 5-dodecyloxy-2-iodobenzoic

acid (0.22g; 0.50 mmole) added and the mixture stirred at

exactly 400 for 20 hours. The slurry was poured into water

(10 mL) and stirred at room temperature for 1 hour. The

solid was collected, washed, and dried to give 0.19g (85%)

of 6x, as colorless microcrystals: mp 172-5 (d); C-NMR
(CDC13/CD3OD): 612.7 (Dod-C12), 21.0 (Dod-C11), 24.3
(Dod-C3), 27.4-27.9 (Dod-C2, C4-C9), 30.2 (Dod-C10), 66.7

(Dod-C1), 80.4 (Ar-C2), 115.4 (Ar-C6), 117.7 (Ar-C4), 135.7

(Ar-C1), 140.0 (Ar-C3), 157.4 (Ar-C5), 166.4 (C-O); IR






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(CHBr3): 2920(s), 2850(s), 1685, 1570(br), 1450(s), 1420,

1320, 1280(s), 1235, 1100, 1010(w), 870, 820, 790, 720cm-1.

Anal. calcd for C19H29105: C, 49.15, H, 6.29. Found:

C, 50.39, H, 6.32.


2-Iodo-5-(2-(2-methoxyethoxy)ethoxy)benzoic acid (19).
Prepared in 45% yield via the same procedure utilized for

17, except using a 1:1 molar mixture of 2-(2-methoxyethoxy)-

ethyl methanesulfonate [83CCT245] and sodium iodide as

alkylating agent. Purification was accomplished by two

filtrations through silica gel utilizing, as eluant systems,

first, ethyl acetate, then 2% MeOH/CH2C12, to give a yellow

oil which slowly crystallized on standing. 13C-NMR (CDC1):

658.8 (CH3), 67.5, 69.3, 70.4, 71.6 (CH2), 83.0 (Ar-C2),

117.6 (Ar-C6), 120.2 (Ar-C4), 134.3 (Ar-C1), 142.1 (Ar-C3),

158.4 (Ar-C5), 169.0 (C-O). IR (thin film): 3600-

2300(br,s), 2920(s), 2880(s), 1710(br,s), 1590(s), 1560(s),

1465(s), 1455(s), 1420(s), 1280(br,s), 1230(br,s), 1130(s),

1100(s), 1060(s), 1010, 960, 925, 870, 820, 780, 755, 740
-1
cm .


2-Iodosyl-5-(2-(2-methoxyethoxy)ethoxy)benzoic acid

(7). Prepared in 38% yield via the same procedure utilized

for 5. Obtained yellow microcrystals: mp 104-6. 1C-NMR

(CDC13): 658.8 (CH3), 68.5, 69.2, 70.5, 71.7 (CH2), 105.3

(Ar-C2), 116.7 (Ar-C6), 124.6 (Ar-C4), 127.5 (Ar-C3), 130.0

(Ar-C1), 162.0 (Ar-C5), 167.1 (C-0).