SYNTHESIS OF LIPOPHILIC MONOAZA CROWN CARBOXYLIC ACIDS by HOLLIS JOSEPH BOSS, B.A. A THESIS IN CHEMISTRY
Submitted to the Graduate Faculty of Texas Tech University in Partial Fulfillment of the Requirements for the Degree of MASTER OF SCIENCE

Approved

Accepted

May, 1985

ACKNOWLEDGEMENTS

Several would like to

people thank

have Dr.

c o n t r i b u t e d to t h i s d e g r e e.

The a u t h o r this

Richard B a r t s c h for h i s d i r e c t i o n of

research

work; Dr. John Marx for h i s very h e l p f u l s u g g e s t i o n s during of this thesis; D r. Kenneth Coskran, my u n d e r g r a d u a t e
my w r i t i n g research to
a d v i s o r at Potsdam S t a t e C o l l e g e , for g i v i n g rae the d e s i r e for
p u r s u e t h i s d e g r e e ; and f i n a l l y , e s p e c i a l thanks to my p a r e n t s support.

t h e i r never-ending

TABLE OF CONTENTS
Page ACKNOWLEDGEMENTS LIST OF TABLES LIST OF FIGURES I. INTRODUCTION General Background of Crown Ethers Cation Complexation and the Template Effect Crown Ether Carboxylic Acids lonophore Carboxylic Acids Lipid Bilayer Membrane and lon Transport Previous Syntheses of Crown Carboxylic Acids Azacrown with a Pendant lonizable Group Statement of Research Goals II. RESULTS AND DISCUSSION Preparation of the Lipophilic, lonizable Synthetic Intermediate _ Synthesis of the Monoaza Crown Ethers 76, 77, and 2 Coupling of the Lipophilic, lonizable Synthetic Interraediate with the Monoaza Crown Ethers

ii vi vii 1

Conclusion III. EXPERIMENTAL General 2-Methyl-2-undecanol (^) 2-Methyl-2-undecyl Chloride (62^) 4-(1,1-DimethyIdecyl)-l,2dimethylbenzene (65) 4(5)-(1,1-Dimethyldecyl)-2-methylbenzoic Acid (69) Methyl 4(5)-(1,1-Dimethyldecyl)-2methylbenzoate ( O ) ^^ Methyl 4(5)-(1,1-Dimethyldecyl)-2(bromomethyl)benzoate (5^) Triethylene Glycol Ditosylate (^) Tetraethylene Glycol Ditosylate (84) Pentaethylene Glycol Ditosylate (^).
l-Aza-4,7,10,13-tetraoxacyclopentadecane (7^) l-Aza-4,7,10,13,16-pentaoxacyclooctadecane (^Z^ l-Aza-4,7,10,13,16,19-hexaoxacycloheneicosane (IS) N-[4(5)-(1,1-Dimethyldecyl)-2carbomethoxybenzyl]monoaza-15crown-5 (89^) N-[4(5)-(l,l-Dimethyldecyl)-2carbomethoxybenzy1]monoaza-18crown-6 (90) N-[4(5)-(l,l-Diraethyldecyl)-2carbomethoxybenzyl]monoaza-21crown-7 (91)

44 ^^ 45

A General Procedure for the Preparation of Compounds 92^, ^ , and 94. N-[4(5)-(l,l-Dimethyldecyl)-2carboxybenzyl]monoaza-15crown-5 (2) N-[4(5)-(l,l-Dimethyldecyl)-2carboxybenzyl]monoaza-18crown-6 (9^) N-[4(5)-(l,l-Dimethyldecyl)-2carboxybenzyl]monoaza-21crown-7 (94^) REFERENCES APPENDIXES APPENDIX A. PROTON NUCLEAR MAGNETIC RESONANCE SPECTRA APPENDIX B. INFRARED SPECTRA

LIST OF TABLES

1. 2. 3.
Diameters of the Cavities Alkaline and Alkaline Earth Atomic Radii Naturally occurring, Monocarboxylic Acidcontaining Antibiotics Binaphthyl-containing Crown Ethers with a Pendant Carboxylic Acid Group Crown Ether Carboxylic Acids with Two Benzene Subunits

LIST OF FIGURES

15-Crown-5 Monensin Complex pH Sensitivity of the N-substituted, Diaza-18Crown-6 Carboxylic Acid 5^ A Schematic Representation of Cation Transport by an AzaCrown Versus a Crown
Hydrochlorination Apparatus The Monocarboxylic Acid Isomers

CHAPTER I INTRODUCTION

General
Background prepared 1967 that 2 by of Crown Ethers. Cyclic p o l y e t h e r s were first until

Luttringhaus field

and Z i e g l e r.

However, i t was not

the first
of "crown e t h e r c h e r a i s t r y " was r e a l l y b o r n when the ability of these In an materials attempt to to

Pedersen complex

recognized of

a variety

cationic

substrates. 1),

synthesize crystals"

bis-phenol which

_1. ( E q u a t i o n
Pedersen isolated solubility

"white

showed a d r a m a t i c a l l y d i f f e r e n t

behavior

1. (CICH^CH^^^O, NaOH 2. H^O"^

R=THP,H

methanol

than In

expected
an u n c h a r a c t e r i s t i c

ultraviolet slightly

t h e i o n i c diaraeter of the c a t i o n , complexes may occur with r a t i o s 1:1, 2:1, 3:1, values of or 3:2 (crown ether:ion). and raetal ion Tables 1 and 2 give

accepted

cavity
d i a m e t e r s from which a
d e s i r e d " b e s t f i t " approximation can be made. The accounts the are template effect i s an unusual f e a t u r e of crown e t h e r s which
f o r the remarkably high y i e l d s o b t a i n e d in the s y n t h e s i s of p o l y e t h e r s , e s p e c i a l l y the l a r g e r i n g s. without using high dilution The high y i e l d s

cyclic

achieved
c o n d i t i o n s and can be
TABLE 1 Diameters of the Cavities

Crown Echer

12-Crown-4 I4-Crown-4 15-Crown-5 18-Crown-6 21-Crown-7

Diameter,

1.2 1.2-1.5 1.7-2.2 2.6-3.2 3.4-4.3
TABLE 2 3,6 Alkaline and Alkaline Earth Atomic Radii
Alkaline Cation Li"^ Na"^ K"^ Rb"^ Cs Fr"*"
Diameter, A 1.20 1.90 2.66 2.96 3.34 3.52
Alkaline Earth Cation Be^"^ Mg^* Ca^* Sr^"^ Ba Ra^"^
Diameter, X 0.62 1.30 1.98 2.26 2.70 2.80
7 attributed to this s p e c i a l effect. Evidence by Greene and Cook
c o r r o b o r a t e Pedersen's o r i g i n a l suggestion that this effect of a metal ion being used to direct the steric

consists

c o u r s e of the

synthesis in the

of a s p e c i e s which would o t h e r w i s e not be r e a d i l y o b t a i n e d of t h e metal ion. Moreover, many crown e t h e r s a r e

absence

i s o l a t e d in t h e i r complexed form with the template i o n. Crown E t h e r Carboxylic Acids Crowns lipophilic raake tends on t h e ionic t o b e h y d r o p h i l i c on the i n s i d e of the c a v i t y and outside. Their l i p o p h i l i c e x t e r i o r s allow thera to in o r g a n i c s o l v e n t s and in n o n - p o l a r

soluble

substances

raembrane the

media. of
The c o u n t e r a n i o n , however, has a g r e a t i n f l u e n c e on the crown e t h e r s to s o l u b i l i z e i o n i c s u b s t a n c e s. complex neutral solely t o o c c u r , an anion must accorapany the crown from ethers, the availability of 9 For raetal the

ability

a stable cation.

crown With is

counteranion however,

the extracting solvent.

Unfortunately
t h o s e anions t h a t a r e normally encountered in p r o c e s s s o l v e n t
e x t r a c t i o n s a r e c h l o r i d e s , n i t r a t e s , and s u l f a t e s and have d i s t r i b u t i o n coefficients ^ , between the aqueous and the organic phase t h a t a r e too low

-. 10-14

to be u s e f u l. I n v e s t i g a t i o n was b e g u n complexing not depend agents upon into t h e design of new macrocyclic
i n which the p r o c e s s of metal ion e x t r a c t i o n did concomitant t r a n s f e r of the c o u n t e r a n i o n s frora
t h e a q u e o u s t o t h e organize phase. Thus, P e d e r s e n ' s developraent 2 of n e u t r a l c r o w n e t h e r s was soon followed by Cram's a d d i t i o n of a pendant c a r b o x y l i c a c i d group t h a t , when d e p r o t o n a t e d , could a c t as
own " i n t e r n a l "

coun t er a n i o n.

crown e t h e r compounds
r e s e r a b l e the a c y c l i c , c a r b o x y l i c acid i o n o p h o r e s , monensin and
n i g e r i c i n (Figure 2 ).
lonophore occur.ring, carboxylic complexes the

Carboxylic

Acids.

The a b i l i t y

of the n a t u r a l l y
n i g e r i c i n - 1 y pe a n t i b i o t i c s , acid group, 18 to form
which c o n t a i n a pendant alkali raetal ion

lipi-soluble

was known. acid

Further

evidence supported the idea t h a t in i t s deprotonated forra for raigration studies, carry

carboxylic

moiety

mu s t b e

coraplex Pressraan alkali
f o r m a t i o n to o c c u r. 19 reported that earth

Using bulk phase ion the

n i g e r i c i n - t y pe a n t i b i o t i c s ions

and a l k a l i n e

a c r o s s l i p i d b a r r i e r s and
suggested He a l s o dipole raetal
the d e s i g n a t i o n " i o n o p h o r e s " for such compounds (Table 3 ).
r e p o r t e d t h a t metal c a t i o n complex fonnation i s via induced i n t e r a c t i o n s with the oxygen atoras and t h a t t r a n s p o r t of the

ions 2).

a n t i b i o t i c s i s in an e l e c t r i c a l l y n e u t r a l Lardy 20 showed that the

(Figure

In a d d i t i o n , monocarboxy1ic

naturally

occurring,

acid-type

antibiotics

cause l o s s of

potassium from mitochondria. Lipid Blayer Membrane and lon T r a n s p o r t. The b a r r i e r to ion
moveraent a c r o s s e i t h e r a b i o l o g i c a l or a model l i p i d b i l a y e r membrane is the organic i n t e r i o r through which the cation-complex raust raove.

Therefore, of the

the composition of the b a r r i e r i s important for the design e t h e r c a r b o x y l i c a c i d s and for the design of the model raerabrane for testing. Studies 22 have identified

crown bilayer

TABLE 3 Naturally Occurring, Monocarboxylic Acid Containing, Macrocyclic Antibiotics '
Antibiotic Dianemycin Monensin Nigericin X-206 X-537
lon Best Selected Na Na' K

Figure 2.

Monensin Complex
8 this interior t o b e an approximately 12:1 raolar r a t i o of decane to This a c c o u n t s for the very n o n p o l a r , low d i e l e c t r i c ( C) ). F u r t h e r m o r e , the araount of
p h o s pho 1 i p i d. raedia ion (D (decane, extracted = 9.08

D = 1.99

i s g r e a t l y reduced in changing from a dichloromethane to a toluene (D = 2. ( C ) ^ ^ ) model

(20C)^^) but

interior,

a more a c c u r a t e '

i n d i c a t i o n of c a t i o n s t a b i l i t y and
selectivity is obtained. The with is
t r a n s p o r t of metal c a t i o n s through a l i p i d b i l a y e r merabrane
the a i d of a monocarboxylic a c i d - t y p e a n t i b i o t i c or crown e t h e r , to occur by c a t i o n c o m p l e x a t i o n a t the b a s i c pH through

envisioned

aqueous-organic the the
i n t e r f a c e , followed by f a c i l i t a t e d d i f f u s i o n
n o n p o l a r o r g a n i c i n t e r i o r , and f i n a l l y , r e l e a s e of the c a t i o n at acidic pH a q u e o u s - o r g a n i c that and proton results interface. 25 In a d d i t i o n , i t is

c h l o r i d e can be c o n s i d e r a b l y
An I R s p e c t r u r a of t h e c r u d e p r o d u c t showed no OH s t r e t c h 100% y i e l d ). was i s o l a t e d The ferric After w o r k - u p to reraove s o l u b i l i z e d HCl, t h e

(i.e., product

i n 98% y i e l d. chloride then 62^ and a c a t a l y t i c amount of used to anhydrous

64 w a s

a l k y l a t e o - x y l e n e 63 u s i n g

o u e o

II u C u z. ^ -J

u <U

03 C H M O r-l
25 the was high procedure shown yield to of be Nightengale. clean, (The 43 From t h e GC a n a l y s i s raonoalkylated for the the reaction in
g i v i n g only the reported

product ^

(88%).

yield )

a l k y l a t i o n of
o - x y l e n e w i t h j t - b u t y l c h l o r i d e was 70%. Nightengale buty 1-benzene butylbenzoic product, and 71 acid did 43 by reported the the

o x i d a t i o n of in

1,2-dimethyl-4-_t2-raethyl-4-_t-

raethod

E q u a t i o n 18 to She

73 in not

34% y i e l d.
r e p o r t e d o n l y t h e one

report

f o r m a t i o n of e i t h e r t h e m o n o o x i d a t i o n

Py. H^o

J i ^X^

t-Bu^\^CH,

* 80^, 6 h

"CHi

isomer,
2-me t h y l-5-_t-butyIbenzoic phthalic acid. 46 ) (The
a c i d , or t h e d i o x i d a t i o n

product, is

4-_^-butyI inert
t e r t i a r y a l k y l group ( _ t - b u t y l )
t o o x i d a t i o n by KMnO,. In the by synthesis
4 ( 5 ) - ( l , 1-dimethyldecyl )-2-methylbenzoic i t was d e t e r m i n e d t h a t GC identify the oxidation the
N igh t enga 1 e ' s p r o c e d u r e , not be directly used to
analysis products gas the

could of

6_5_ s i n c e
t h e c a r b o x y l i c a c i d s would not e l u t e from

chromatograph. yield in of an

Therefore, effort

to d e t e r m i n e t h e t y p e of o x i d a t i o n and condirions, to t h e
to a c h i e v e t h e optimum r e a c t i o n acid

conversion

(or diacid bv-product)

methyl

was n e c e s s a r y.
Gas chromatography then i d e n t i f i e d
type of o x i d a t i o n product (mono-, mono-, d i - ) and the product r a t i o. Second, very used. easily After o ver-ox ida t ion if of 65 t o the d i a c i d can be achieved t o o long of a r e a c t i o n time is

t o o much KMnO, o r

careful the
s t u d i e s i n v o l v i n g a v a r i a t i o n of the r a t i o of t e m p e r a t u r e , and the r e a c t i o n time, it
65 t o KMnO, , was c o n c l u d e d hydrocarbon

reaction the

GC r e s u l t s
t h a t a 1:3 molar r a t i o of the t e r a p e r a t u r e of 80C, and a

6_5_ t o

KMnO, , a r e a c t i o n
t o t a l r e a c t i o n time of 7-8 hours gave the b e s t y i e l d of 69. The r e l a t i v e amounts of the two isomeric raonoacids (Figure 6 ) , by GC a n a l y s i s of the e s t e r s , showed very l i t t l e v a r i a t i o n under a l l oxidation c o n d i t i o n s surveyed and v a r i e d from a low of 1.5:1.0 to a
high of 2. 0 : 1. 0 for the c o n d i t i o n s l i s t e d above.

H3CH.)^-| CH3 H , 68

Figure 6.
The Monocarboxylic Acid Isomers
Although the two monoacids were not separated, and the spectrum is complex, the low field aromatic region can best be interpreted as
27 the partial overlap is of t w o s i g n a l s i n an a p p r o x i m a t e l y 2:1 to H^ 6 ^ , which shows a d o u b l e t in structure ratio. at

The m a j o r 8.1, J

product Hz.

assigned fits

= 9-10

6_7, which should

show o n l y proton of

coupling. at Hz.

The minor isomer i s a s s i g n e d as , w i t h 8.15 This ( o v e r l a p p i n g one l e g of t h e d o u b l e t fits t h e isomer which should show too
H^ a p p e a r i n g J = 2-3

6_7_) w i t h meta

coupling.
The o t h e r a r o r a a t i c hydrogen s i g n a l s o v e r l a p analysis. i s t h e lowest of the
severely for f u r t h e r This, encountered material made to
t h e low y i e l d (17%) of t h i s r e a c t i o n , in the preparation of 5_6_. Much

starting

6_5_ i s

recovered the

unoxidized.
However, when a t t e m p t s were raore

increase

by making t h e r e a c t i o n c o n d i t i o n s
v i g o r o u s , t h e d i a c i d b y - p r o d u c t becarae e v i d e n t. Lastly, benzoic acid of unlike in 65 N i g h t e n g a l e ' s s y n t h e s i s of 2-raethyl-4-_t-butylthe is

w h i c h o n l y one isoraer was r e p o r t e d l y i s o l a t e d , is not exclusive for one not isomer a l t h o u g h i t be obtained
oxidation selective. effecting

Better

without isomeric

diacid formation.

The monoacids were used as t h e thera. 6^
m i x t u r e and no a t t e m p t s were made t o s e p a r a t e The product ( vide facile necessity isomers of e s t e r i f i ca t i o n of
f o r e l u c i d a t i o n of
and r a t i o s by gas chromatography has been d i s c u s s e d E s t e r i f i c a t i on forraation after of the acid a l s o p r o t e c t s 47-49 against 19).
supra ). lactone 70 w a s

bromination

(Equation
Compound catalytic 78% y i e l d.

synthesized

by r e f l u x i n g ^
in dry methanol and a I t was o b t a i n e d in
amount of s u l f u r i c
a c i d for four d a y s.

CH^CH^^gC

> -

"3

CH3(CH^)^C
The f i n a l synthetic equivalent using
in the p r e p a r a t i o n of the l i p o p h i l i c

interraediate of

was the a l l y l i c broraination of _70 with one P h o t o i r r a d i a t i o n for one hour

N-bromo s ucc in imide.

a W T u n g s t e n based on
larap afforded the brominated product ^6. in the NMR i n t e g r a t i o n s. I n c r e a s i n g the

75-85% y i e l d s

p h o t o i r r a d i a t i o n time did not give h i g h e r y i e l d s. Synthesis of the Monoaza Crown E t h e r s 76. 77, and 78 The 78 al. synthetic 2 ) was this route adapted to t h e monoaza crown e t h e r s 26., XZ ^^^ frora the procedure of O k a h a r a e_t_

(Scherae ' In were

synthesis, in
the N - s u b s t i t u t e d frora the

monoaza crown

ethers

obtained

good y i e l d s
r e a c t i o n of the This

unprotected two-step

d i e thanolamine with the corresponding d i t o s y l a t e.

procedure

e l i m i n a t e s the a d d i t i o n a l two s t e p s of n i t r o g e n

protection

and d e p r o t e c t i o n (to prevent the p o s s i b i l i t y of undesired that

t o H,

n=I,2,3

n-1,2,3
The isolated afforded carboxylate as
raonoaza-18-crown-6 the the pure crude
a d d i t i o n product ^
was a l s o function the pure The

corapound. 9J_) , b u t

Hydrolysis of the e s t e r atterapts to isolate

92_ by c o l u r a n

c h r oma t o g r aphy were u n s u c c e s s f u l.
n u c l e a r magnetic resonance s p e c t r a showed an impurity at 2.32 ppm and an anoraalous u p f i e l d s h i f t for the aromatic p r o t o n s.
34 Conclusion A new carboxylic unique ethers. atom series acid of lipophilic, crown e t h e r s c o n t a i n i n g a pendant This s e r i e s p r e s e n t s a
group h a s been s y n t h e s i z e d. route to three

synthetic Most

n o v e l l i p o p h i l i c , monoaza crown incorporates a nitrogen acid

significantly,

this synthesis
i n t o a crown r i n g , which is
in a s s o c i a t i o n with a pendant c a r b o x y l i c to s i g n i f i c a n t l y enhance c a t i o n

group,

abilities.
CHAPTER III EXPERIMENTAL General
Melting apparatus ( H NMR) and p o i n t s were d e t e r m i n e d on a F i s h e r - J o h n s m e l t i n g are uncorrected. were either obtained CDCl^ 3 reported reported in as units follows: downfield cheraical or Proton nuclear magnetic with point

resonance

spectra in
a V a r i a n EM-360 or EM-360A A l l cheraical s h i f t s are

spectrometer

CCl,. 4
frora t e t r a m e t h y l s i l a n e. shift (mul t i p l i c i t y ,

Data a r e integrated

intensity, either
peak a s s i g n m e n t ).

Infrared

(IR) s p e c t r a were o b t a i n e d on

a Beckman

A c c u l a b 8 o r a N i c o l e t MX-S FT-IR s p e c t r o m e t e r on ).
KCl p l a t e s and a r e g i v e n in wavenumbers (cra All as
s t a r t i n g m a t e r i a l s and s o l v e n t s were r e a g e n t g r a d e and used u n l e s s otherwise stated. Dry s o l v e n t s were p r e p a r e d as N,N-dimethylforraamide (THF) and

received

follows: (DMF) w a s tert-butyl Gas
p y r i d i n e was d r i e d o v e r KOH p e l l e t s , dried
o v e r 4A m o l e c u l a r s i e v e s , t e t r a h y d r o f u r a n from c a l c i u r a h y d r i d e.
a l c o h o l were d i s t i l l e d chromatography capillary
(GC) was performed w i t h a V a r i a n Aerograph

Model-3700 and mm

gas c h r o r a a t o g r a p h e q u i p p e d w i t h a FID d e t e c t o r The column used was a 0.20 SE-30 column from SGE from

temperature X 25 ra

programming c a p a b i l i t y. silica capillary

iodoraethane/diethyl

37 reaction of ethyl flask was t h e n p l a c e d i n a c o l d w a t e r b a t h , and a s o l u t i o n anhydrous diethyl refluxed reaction
c a p r a t e 6 ( 4 3. 1 g, 0. 5 mol) in f r e s h , mL) was added
a t such a r a t e t h a t t h e m i x t u r e the grayish

gently. mixture placed

Upon c o m p l e t i o n of t h e e s t e r a d d i t i o n , was refluxed in an was The clear had f o r an a d d i t i o n a l h o u r. and a
The r e a c t i o n f l a s k was

ice-bath,

s a t u r a t e d aqueous amraonium c h l o r i d e to e f f e c t a
solution reflux. finally solution
a d d e d d r o p w i s e t h r o u g h t h e a d d i t i o n funnel grayish after been
s o l u t i o n became c l o u d y , t h e n opaque w h i t e , and sufficient The s a t u r a t e d aqueous ammonium c h l o r i d e r e a c t i o n m i x t u r e was s t i r r e d After s e t t l i n g , the organic well layer

added.

(mechanically) was with decanted
f o r 15-20 m i n u t e s. into a 1-L
s e p a r a t o r y funnel and washed

successively

saturated
a q u e o u s amraoniura c h l o r i d e , water. It
s a t u r a t e d aqueous sodium raagnesium sulfate and
bicarbonate, evaporated solution in

was d r i e d over

vacuo then
to a c l o u d y , p a l e y e l l o w s o l u t i o n.

The yellow solution

refluxed
in 5% aqueous sodium h y d r o x i d e m i x t u r e was t r a n s f e r r e d

overnight. funnel and

reaction
to a s e p a r a t o r y grayish,

allowed

t o s e p a r a t e i n t o two l a y e r s : colorless, top l a y e r.

a cloudy,

b o t t o r a l a y e r and a c l e a r , separated with dried then of

The bottom l a y e r was

and e x t r a c t e d w i t h d i e t h y l e t h e r. The r e s u l t i n g e t h e r - s o l u b l e raagnesiura sulfate.
The top l a y e r was washed

water. with vacuum

f r a c t i o n s were corabined and solvent,
R o t a r y e v a p o r a t i o n of the

distiUation 6_1_ a s

( 7 2. 5 - C / 0. mm) a f f o r d e d colorless liquid: 5)

( 3 6. 9 g, 92%) )

alcohol 1143

a clear,

IR Cneat, cm (m, 1-66

(C-0);

^H NMR ( C D C I 3 , (m, 22 H,

0.57-0.97

3 H, (s.

CH2CJL3),

0.97-1.63
( C H ^ ) gC ( CH3 ) ^ ) ,
38 IH, OH). Elemental Found: Analysis. C a l c u l a t e d for C H 0: C 77.35-

H, 1 4. 0 6.

C, 7 7. ; H, 1 3. 8 9.

2-Methyl-2-undecyl H. C. Brown 44 for used. the
The g e n e r a l p r o c e d u r e by their
c o n v e r s i o n of t e r t i a r y a l c o h o l s i n t o

chlorides was the

I n t h i s p r o c e d u r e , anhydrous hydrogen in the a p p a r a t u s i l l u s t r a t e d

generated reaction acid.

in situ, of
in F i g u r e 5, by concentrated
h y d r o c h l o r i c acid with

sulfuric The

apparatus

assembled

tight. buret, fitted,

Concentrated and

hydrochloric sulfuric flask. in
a c i d was p l a c e d i n t o t h e g r a d u a t e d a c i d was p l a c e d i n t o t h e s p e c i a l l y
500-raL E r l e n r a e y e r coluran of raercury drop
The a c i d i n t h e b u r e t was s u p p o r t e d by a An i n t e r n a l caused
the s p e c i a l l y adapted buret t i p.

pressure the seal

o f a p p r o x i m a t e l y 10 t o 20 m below a t m o s p h e r i c m hydrochloric
concentrated of the buret
a c i d to be drawn t h r o u g h the mercury
a n d t o drop i n t o t h e s t i r r e d E r l e n m e y e r f l a s k of acid. T h i s caused t h e g e n e r a t i o n of hydrogen (A c l o u d y , white is
concentrated chloride gas
i n r e s p o n s e to r e s t o r e t h e p r e s s u r e.
v a p o r was e v i d e n c e of a n h y d r o u s HCl f o r r a a t i o n. ) caused by the injection of the alcohol

The p r e s s u r e drop

into the r e a c t i o n

flask.

Therefore, which buret. was

injection

of t h e a l c o h o l 62^ (10 raL, 8.2 g) was a t a r a t e the

enabled

a d r o p w i s e a d d i t i o n of t h e h y d r o c h l o r i c a c i d from the
F o l l o w i n g c o m p l e t i o n of a d d i t i o n of t h e a l c o h o l , for an a d d i t i o n a l

reaction A

continued with vigorous s t i r r i n g change frora a c l e a r , colorless

15 m i n u t e s.

to a c l o u d y , y e l l o w i s h

solution

39 was evident. The reaction s o l u t i o n was reraoved from t h e reaction
w i t h a s y r i n g e and p l a c e d i n t o a s e p a r a t o r y f u n n e l. top layer was r e m o v e d , d i s s o l v e d in m e t h y l e n e filtered,

The c l e a r , chloride,
colorless dried afford 720 with

magnesiura pale

sulfate,
and e v a p o r a t e d i n vacuo to IR ( n e a t , cm~ ) 3 H, CH^CH^ ) ,

yellow liquid 5)

( 8. 0 g, 98%): (m, 8 H,

(C-CI); (ra,

^H NMR ( C D C I 3 , 14 H, CH^ ) ,

0.73-1.07 (m,

1.07-1.50

1.50-1.89

CH^C(CH3)^Cl).

GLC a n a l y s i s :

> 99% p u r i t y ( 1 9. 8 m i n u t e r e t e n t i o n

tirae).

4 - ( l , 1 - D i r a e t h y l d e c y l ) - 1 , 2 - d i r a e thy Ibenzene (65). 63 (198.3 g, 1.867 mol) was weighed directly into

-Xylene a 1-L ,

thr ee-necked , (18.1 an was the g, 0.112
r o u n d - b o 11 omed f l a s k.
Anhydrous f e r r i c c h l o r i d e 6U^ in
m o l ) was a d d e d , and t h e r e a c t i o n f l a s k was p l a c e d

ice-bath. then

2-Me t h y 1 - 2 - u n d e c y 1 c h l o r i d e ^2 ( 7 3. 4 g, 0.358 mol) i n a 250 mL a d d i t i o n f u n n e l and added dropwise when was 0 C. Upon c o r a p l e t i o n of t h e a d d i t i o n , the

placed

raixture
solution stirring reaction resulting
c h a n g e d frora a d a r k brown to a l i g h t brown c o l o r. was continued for an additional 4 h at

Vigorous

0 C, and the The
was t h e n p l a c e d in t h e r e f r i g e r a t o r solution raL) and was poured into The

horaogeneous acid (500

ice-cold, 6 N was then
hydrochloric transferred with

stirred.

t o a 1-L s e p a r a t o r y f u n n e l. ether
The top l a y e r was e x t r a c t e d aqueous
petroleum chloride, well with
( - C ) , t h e n washed w i t h s a t u r a t e d

sodium dried

and w a t e r. calcium mm)
The r e s u l t i n g c l e a r y e l l o w s o l u t i o n was chloride. 87.8 Vacuum d i s t i U a t i o n g (88%) o f 65. a s a (118.5clear.

119.5C/0.05

afforded
40 colorless (CDCI3, ArCH^), liquid: 6) 6.95 IR (neat, (m, cm"-^) (C=C), 815 (C-H); ^H N R M H, CH^CH^), 2.18 (s, 6 H,

N-bromosucc inimide was then placed was

7_1_ ( 2. g, 0. 3

a p p r ox iraa t e l y applied for
2. 5 cra frora t h e r e a c t i o n f l a s k and hour. Upon c o r a p l e t i o n of the from carbon
irradiation reaction, the
t h e y e l l o w - w h i t e s u c c i n i r a i d e p r e c i p i t a t e was f i l t e r e d mixture and rinsed using a sraall araount of

te trachloride. with

The r e s u l t i n g y e l l o w f i l t r a t e was washed

successively raagnesium

5% aqueous sodium h y d r o x i d e and w a t e r , Rotary was

t h e n d r i e d over

sulfate. oil which
e v a p o r a t i o n of t h e s o l v e n t a f f o r d e d _56^ as a yellow imraediately H NMR d a t a yields: (m, (s, and in t h e next step without the product further

used The in 6)

purification. consistently NMR (s, (CCl^, 0.7 H,

showed IR

was formed H

75-85%

( C C l ^ , cm" ) CH^ a n d COOCH3), (d, 1 H,
1720 (C=0); CH^iH.^), 4.91 ArH, (s,
0.80-1.96 imp), 2 H, 3.83 ArH)

25 H, 3 H, 7.85

ArCH^ (m,

CH^Br),

J=9Hz).

Unreacted 6 2.58.

material
6_9_ a c c o u n t e d for t h e N R i m p u r i t y at M
Triethylene (36.04 g, 0.240

Glycol raol) was

Ditosylate added

(83.).^^

Triethylene

glycol round-

to a 500-raL, t h r e e - n e c k e d ,
43 bottoraed flask which was equipped with a t h e r m o m e t e r , a 500-mL After
pressure-equalizing flushing and the the

addition funnel,

and a m a g n e t i c s t i r r e r.

apparatus flask

with n i t r o g e n , pyridine
(250 mL) was added, bath.

reaction of

w a s c o o l e d to -3C i n an a c e t o n e - i c e
A solution in not pyridine to

p_-toluenesulfonyl

c h l o r i d e 8^ (100.66 g, 0.528 mol)

(150 the

mL) was t h e n added d r o p w i s e over 4.25 h a t a r a t e reaction raixture to e x c e e d 5C. The r e a c t i o n
m i x t u r e was t h e n p o u r e d i n t o a b e a k e r c o n t a i n i n g 700 raL of i c e w a t e r , and the ditosylate product was collected by filtration.
Recry s t a l I i z a t ion as w h i t e crystals: 1100
from a b s o l u t e e t h a n o l a f f o r d e d mp - C , (C-0); (ra, 8 H, ^H IR (KBr,
104 g (95%) of 4 and 1163.2.H, (s, 6 H, 7.30

cra"^) )

(S^^O)^), ArCH^), and 7.76