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Decomposition of 1,4 3,6-Dianhydrohexitol Dinitrates
Decomposition of 1,4 3,6-Dianhydrohexitol Dinitrates
by
MICHAEL JACKSON
B.Sc, Manchester University, 1965
U.Sc, Manchester University, 1957
DOCTOR OF PHILOSOPHY
in the Department
of
Chemistry
shown that none of the parent isohexides were formed i n the reaction
differed from the rapid and selective removal of one nitrate group
tion for the three isohexide dinitrates and activation energies were
determined.
the pyridine reaction and independent of the solvent and isomer used.
their derivatives.
Faculty of Graduate Studies
PROGRAMME OF T H E
DOCTOR OF PHILOSOPHY
°t
MICHAEL JACKSON
B. Sc., University of Manchester, 1955
M. Sc., University of Manchester, 1956
COMMITTEE IN CHARGE
D E A N G. M. SHRUM: Chairman
c. A. M C D O W E L L M. D A R R A C H
L. D. HAYWARD A. M. CROOKER
A. ROSENTHAL T. M . C. TAYLOR
R. STEWART S. A. JENNINGS
External Examiner: Professor C. H. E . Bawn, C. B. E . , F. R. S.
University of Liverpool
THE DECOMPOSITION OF 1,4;3,6-DIANHYDROHEXITOL DINITRATES
Abstract
PUBLICATION
Other Studies:
Department or by h i s r e p r e s e n t a t i v e s . I t i s understood
that copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l
Department of Chemistry
The U n i v e r s i t y of B r i t i s h Columbia,
Vancouver $, Canada.
Page
INTRODUCTION 1
HISTORICAL INTRODUCTION
Chapter II Stereochemistry 11
EXPERIMENTAL
Materials 110
APPENDIX I
APPENDIX II
REFERENCES 154
FIGURES
Page
VI C Conformation of Cyclopentane 17
Reaction at 115°C. 83
Water Added 89
Page
Separations 62
in Acetonitrile 103
Council.
INTEOAUCTION
and the pentanitrates are stable to further attack under the same
molecule. The nitrate esters of two of these have been prepared and
isohexides and their acetate and sulphonate esters which forms a back-
reaction with those of other nitrate esters and with those of other
HISTORICAL INTRODUCTION
CHAPTER I
obtained a compound with the same molecular formula from the dry
mannide. Fauconnier found that isomannide had two free hydroxyl groups
which he thougM were primary and thus proposed formula (IV) f o r the
H0.CH . CH . CH . CH . CH . CH 0H
o o
2
\ / \ / 2
0 0
(iv)
was later supported by Van Romburgh and Van Der Burg (5) who also
and on the basis of this and. the easy formation of isomannide from
intervening years the compound was used several times, but no further
(6). They assumed that the benzoyl groups had not migrated and this
the tosyl groups were primary (Oldham and Rutherford Rule (8)).
The tosylate and iodo compounds also have physical constants identical
have occurred but was overlooked due to the fact that tosyloxy groups
The only other major work on the isohexides before 1945, apart
from Some patents on the use of these compounds and their esters as
on the conductivity of boric acid solutions and found they caused very
-6-
of the two anhydrides and their dinitrates, the former were found to
rings.
dehydration.
-7-
making models of the latter and the fact that four-membered rings are
this structure. They showed that the hydroxy1 groups are secondary
acid showed the origin of one anhydride ring, although i t was recog-
this reaction.
tosylation
3,6-anhydro-B-manni to 1 > l-0_-t osy 1-3,6-anhydro-
1 mole D-mannitol
tosyl chloride
complete
acetylation
v
sodium
isomannide ^ — l-0-tosyl-2,4,5-tri-0-acetyl-
;
methoxide 3,6-anhydro-D-mannitol
sulphuric acid as catalyst also gives higher yields than the corres-
2. Mild hydrolytic agents did not bring about ring opening. The
atoms•
secondary.
5. 1 , 4 - a n h y d r o s o r b i t o l and 3 , 6 - a n h y d r o s o r b i t o l b o t h y i e l d e d
a c i d whereas 1 , 5 - a n h y d r o s o r b i t o l d i d n o t *
F u r t h e r p r o o f o f t h e a n h y d r o r i n g s t r u c t u r e was g i v e n by W i g g i n s
were u s e d f o r t h e s y n t h e s i s o f i s o m a n n i d e f r o m 3,6-dianhydro-D-mannitol.
methyl-3,6-anhydro—oC-methyl-D-glucofuranoside p r e v i o u s l y prepared by
E a w o r t h e t a l * (19), t h u s g i v i n g f i n a l p r o o f o f t h e r i n g structure.
I s o i d i d e was t h e l a s t o f t h e known i s o h e x i d e s t o be p r e p a r e d ,
p r o b a b l y due t o t h e r a r i t y o f i t s p a r e n t h e x i t o l - L - i d i t o l . I t can
be f o r m e d by s i m i l a r methods t o t h e o t h e r i s o h e x i d e s b u t t h e y i e l d s
u r a t i o n i s more s t a b l e t h a n t h a t o f i s o m a n n i d e (21), a c c o u n t i n g f o r
the higher y i e l d s .
P r o o f o f t h e s t r u c t u r e o f i s o i d i d e was o b t a i n e d by c o m p a r i s o n
w i t h i s o s o r b i d e and i s o m a n n i d e w h i c h i t r e s e m b l e s c l o s e l y and b y t h e
f o l l o w i n g s y n t h e s e s o f t h e compound -
1. The a c t i o n o f s o d i u m m e t h o x i d e on 3,4-di-O-tosyl-D-mannitol
or 3 , 4 - d i - 0 - t o s y l - l , 2 , 5 , 6 - t e t r a - 0 - a c e t y l - D - a i a n n i t o l gave
i n v e r s i o n s a t b o t h t h e Cg and p o s i t i o n s o f D-mannitol t o
2. Treatment o f e i t h e r i s o m a n n i d e o r i s o a o r t t d e w i t h Raney
-10
readily.
from the other three hexitols. Models indicate that their ring struc-
ture would be more strained than that of the three isohexides described.
CHAPTER II
STEREOCHEMISTRY
formulae (25) are excellent for configurational analysis but not for
-12-
conformation work. The newer Newman formulae (26) i n which the molecule
and lower while the backward ones are drawn to the right and higher.
present i n this compound by the X-ray work of Bijuoet and co-workers (27).
(28) i n connection with the study of the ring form of the sugars.
bond, the results vere poor. Kemp and Fitzer (29) postulated a
the hydrogen atoms are closer together and therefore the molecule i s
are quite small and therefore any position may be taken up during the
thermal energies (ca. 600 cal./mole) and a barrier which would prevent
w i l l be disregarded.
A 8 c 3> £ F
Ring Systems
basis of planar structures, but Sachse (32) and Mohr (33) recognized
that strain free (bond angles not altered from the tetrahedral angle)
possible theoretically. These are most commonly called the chair and
boat chair
types.
molecule. There are three axial bonds on each side of the molecule
in the chair form* The six other carbon-hydrogen bonds are directed
there are two chair and s i x boat forms possible, depending upon the
The C„ conformation (Figure VI) has four atoms i n a plane and one
The other (Figure VII), called the C„ conformation, has three atoms
only the C. conformation. This was also confirmed with the mono-
tinually.
Various saturated fused ring systems are known, the most common
each system. These isomers arise from the configurations at the ring
junctions. I f the two hydrogen atoms at the ring junctions are on the
same side of the rings then the compound i s designated " c i s " , i f they
vv
trans C I S
f i r s t i t was assumed that the trans isomer would take up the double
the double boat form (Figure IX). Later i t was found that a double
Hassel (43) which showed that this was the actual conformation taken
c i s and trans forms agree quite well with experimental values f o r the
-19-
rings. I t has been seen that cyclopentane rings are very close to
This was shown i n the combustion data of Barrett and Linstead (45),
related carbonyl compound (IV) i t was found that only the c i s compound
.9c
/ \ CM,
CH, /
© (iv)
operation causes strain i n the case of the trans isomer (47) but not
i n the c i s isomer*
The l,4;3,6-Dianhydrohexitols
furan type which i t has been seen have a very similar steric form to
the cyclopentane ring. In actual fact the bond angle of the oxygen
compared to the C-G-C angle.will probably tend to make the ring more
that the fused tetrahydrofuran ring system could exist i n two forms
A 8
CIS
H.OH
1
&
X
3
H
5" S
4 4
0(« C p
CHgOH CHgOH CH 0H o CH 0H o
CH-OH CH 0Ho
I I 1 I I *
2
2
2
CHgOH CH OH
I
Dulcitol D-Altritol Allitol D-Mannitol Sorbitol L-Iditol
and 4 (formulae A, C and E, Figure X). The c i s form would stem from
give a trans form. Isohexides have been formed from the f i r s t three
hexitols while the second group have not been reported to give i s o -
hexides rests upon the assumption that the configuration of the parent
hexides possess the c i s ring form. We can now go further into the
-23-
system.
positions each have two bondsnot involved i n the rings. One pair of
of the rings. These are called the endo bonds. The other pair are
the V and are called exo bonds. The relative positions of these
bonds are best seen when the molecule i s viewed along the bond of the
ring j u n c t i o n - the
7 c
3 " c
4 bond. The rings are seen as lines being the
possible.
bridges.
-24-
direction along the bond to be broken and from the opposite side of
the carbon atom from the group being displaced. For this type of
position, the nucleophile must pass close to the face of the second
i s less than 1A* between the van der Waals r a d i i of the carbon atoms
in the second ring and the line along which attack must be made to be
of the ring away from the second ring and thus there i s no hindrance.
has been assumed i n the f i r s t two cases that these derivatives must
anhydro and imide bridges have only one atom between the two carbons
ments, from models, show that the distances between the centres of the
exo-exo bridge.
In the methylene bridge system the CH<> group joins the two oxygen
atoms. Thus the bridge is composed of three atoms and can span a
larger distance. These derivatives have been prepared for both iso-
CHAPTER III
f
Chemical Reactivity
opening have been recorded. These cases have involved the use of
was inferred from this that the 1,4-ring (the isoidide type) was the
acid does not affect the rings, however phosphorous tribromide reacts
hexitols (21).
normally involves the two carbon atoms bearing the free hydroxyl
tion of the products shows that i n some cases the reactions are ex-
(B) When the carbon atom i s not attacked and the reaction site
The group (Al) reactions are found to occur only when the sub-
uration i s observed and both positions react with equal ease, although
A and C-B).
observed.
reacting only when the substituent i s i n the endo position are thought
for this reaction (53, 54) and recently a l l the reactions of this
type i n the isohexides have been reviewed by Cope and Shen (55).
back of the carbon atom and i t i s this requirement which causes the
group to approach from the inside of the V of the rings. This mode
an endo group the attack i s from the outside of the V and i s not
hindered.
^C-OH + S0Cl o
, i
-c-o-so-ci
v / \ 4 ^ a b
- x
-c SO CI ^C-OSOCl
* ' —* 4.
x J, cl
ci-cj + SO + Cl"
^c-ci + so 2
retention inversion
These workers proposed the SN2 mechanism for the reaction and
-32-
About the same time Wiggins and Wood carried out reactions v i t h
which removed the mesyl group and gave a chloro compound identical
their mechanisms.
primary group and probably i s the same for secondary groups when
these react.
ditosylate.
anism.
From measurement of models this could only occur with the endo-
Only one example i n this group has been reported (63). Isomannide
parent compounds.
The mechanism of this reaction has been reviewed and the following
mechanism proposed
OH
-» ROH
(64).
the carbonium ion intermediate but that only the dimesylate of iso-
idide c r y s t a l l i s e d out.
the present work when the iodo derivatives of the isohexides were
ion i s formed.
In both the latter reactions and probably i n the former the iso-
the exo side of the molecule being more readily attacked than the
endo rather than the fact that a group i n the exo position i s more
In this group of reactions the bond between the carbon and the
derivatives but there are only a few examples of these and this d i s -
in reaction rate, as seen with the SN2 reactions at the earbon atom,
methanol (7). In the present work the three isohexide dinitrates were
charcoal.
of reaction of the endo and exo groups i n the case of isosorbide when
ation of isosorbide carried out by Cope and Shen (66). These workers,
barium methoxide (0.3 Normal) for eight hours reflux gave a 52$ y i e l d
lov yield of isosorbide vas obtained, the main product being trianhydro-
for a comparison to be made but the endo group has been shown to be
TABLE I
2-0-Acetyl-5-0j-tosyl isosorbide
m.p. 64-65°C.
[**] +50.5°
D
(66)
-41-
TABLE I (cont'd.)
2,5-methy1ene-
isomannide m.p. 84-85° C , +133.2°, (51)
t
2,5—methylene-
isoidide m.p. 83-84° C , -152.1°, (51)
l,4;2,5j3,6-tri-
anhydro-D-mann i t o1 m.p. 66.5-67.2°C, +128.4°, (66)
2,5-imido-2,5-
deoxyisomannide m.p. 99-100°C, t^3 e
+90.5°, (61)
-42-
CHAPTER IV
Hydrolytic Decomposition
Baker and Easty (70-72) have made a kinetic study of the alkaline
with the carboxylic esters. In these compounds there are two modes
alkyl-oxy f i s s i o n
i
i i
R'.CO'O.R and 0 N'0.R
9
! * \
acyl-oxy f i s s i o n alkoxy-nitro fission
the series methyl* ethyl, isopropyl and t-butyl nitrate the change-
the isopropyl and lQfi of the t-butyl nitrate reactions being of the
are added. The hydroxyl ion exchanges with the thiophenol, the t h i o -
reaction.
that the nucleophilic attack occurs anywhere but on the carbon atom*
However Anbar et aJU (73) have obtained evidence that i n primary alkyl
(74) have carried out kinetic and other work on optically active 2-
octyl n i t r a t e . With this compound they have shown that about 70$ of
rather than the oxygen-carbon one which would be the case i n attack
that t h i s was due to the attack of the neutral water molecule on the
anhydro ring (76)* On the other hand a single isolated nitrate group
tetranitrates has been studied and was found to be rapid i n 0.1 Normal
were not isolated but i t was suggested that the reaction proceeded
(72) found that there was no acid catalysis of the hydrolysis reac-
Reductive Cleavage
aluminum hydride, acid plus metal and alkaline sulphides (79). The
and rapid. One mole of hydrazine was consumed for each mole of nitrate
group to y i e l d the parent alcohol and 1.5 moles of gas, of which one
mole was nitrogen and 0.5 moles nitrous oxide. Merrow and Dolah (81)
to the parent alcohol. The gas evolved was at a maximum of 1.35 moles
B: + R.G.N0 2 ) RO" + B: N 0 g
+
make i t the more l i k e l y site for the nucleophilic attack than the
oxygen. Rate studies were made on benzyl nitrate which give predom-
former attacking the nitrogen atom and the latter the carbon ( c f .
boiling with hydrazine (85). This reaction does not affect tosyl
groups.
Trans-nitration
Several types of this reaction have been recorded and are reviewed
been used to induce ethyl nitrate to nitrate benzene and toluene (88).
Nitration under alkaline conditions was noted with ethyl nitrate and
H
1
+
R.ONOg + H S0 2 4 > [R-0-N0 ] 2 + HS<> 4
H
1
+ +
[R-0-N0 ]2 * ROH + NOg
This scheme explains the observations that the nitrates were not r e -
generated when the sulphuric acid solution was poured into water and
(96). The acetates formed i n this reaction have the same configura-
Thermal Decomposition
has been carried out on the thermal decomposition of solid and liquid
hand the simple alkyl nitrates, i . e . methyl, ethyl and propyl nitrates,
have been used for thermal decomposition studies i n the gaseous state.
This has caused some variation i n the value of the activation energy
obtained from these plots. One group of workers (97) used the latter
results are thought to be the more accurate and to represent the truer
values. The kinetic results are put further in doubt due to the
R.0.N0 2 ^ R.O* + N0 2
As both these products are very reactive the secondary reactions are
nitrate, together with those of other alkyl nitrates, have been summar-
ised by Gray (101) and by Luft (102). They f a l l i n the general range
of 35-40 kcals. per mole, the higher values being thought to be the
more accurate.
balance.
between two heated copper plates (103) or dropping the sample into a
Cook (105), using the quartz spring method, has studied the de-
tetranitrate. This method can only be used for materials which have
values f a l l f a i r l y well into a line with the results from the decompo-
s i t i o n of alkyl nitrates.
have been shown to undergo a rapid and selective reaction with pyridine
108).
Bi + C ^ B* C-~ + N0_
I 3
0N0 2
Ryan and Cassey (109) have studied the reactions of several alkyl
amine nitrate when heated with primary nitrates for periods of eight
in these reactions shoved that the comparative rates for the nitrates
-53-
cotton 9.4.
reaction in the case of primary nitrates i s of the SN2 type, with the
B: H - C —
I S-
-C 0N0 o
i -A
The SN2 reaction i s not possible in the neopentyls due to the steric
Emmons and Freeman (106) have shown that nitrate ester groups
found that the yields vere improved by the use of pyridine as reagent.
mately two nitrate groups per glucose unit (114). The hydroxylamine
the number of oxine groups i n the f i n a l product vas lov and i t vas
found that the nitrate groups removed had been replaced by hydroxyl
the 4—position; the 2-nitrate group was also removed to some extent.
between the various members and between the individual nitrate groups.
formed in mole to mole ratio with the nitrate group removed (114).
When the reagent is simply pyridine the gaseous products are more
+
NH .OH + R.ONO > NO - NH .OH + RO
2 2 2 2
It has been seen that a similar reaction has been proposed for the
-56-
this type have been noted vith alkyl nitrates under basic conditions.
CHAPTER V
Materials
idide was from isomannide ditosylate (55). This compound was treated
catalyst and the syrupy product from this reaction was dehydrated
melting points and specific rotations and those of their acetate and
-58-
were used - the sulphuric a c i d / n i t r i c acid (68) and the acetic acid/
acetic anhydride/nitric acid (119). The former method was that used
with chloroform or ether. The total yields were then generally about
90J& of theoretical.
also prepared by Goldberg (121) who reported melting point and specific
of water.
nitrate groups, shoved no-hydroxyl peak, and had bands vhich could be
The pyridine used in these reactions vas reagent grade and vas
Preliminary Investigation
tion of the solutions did not change over a period of several veeks.
Hovever vhen the solutions vere heated to about 50°C. colour developed
water (10 x volume of pyridine solution) and from the resulting mix-
Figure XII -
Pyridine solution
i
Poured into water
(10 x volume)
I
Extracted with ether
i
Filtered
j J 1
The separation of the nitrate into organic and inorganic fractions was
r e a c t i o n would, be p r e s e n t i n t h e aqueous s o l u t i o n .
TABLE I I I
Chromatography o f F r a c t i o n s i n
Preliminary Separations
Reaction mixture + ++
Aqueous s o l u t i o n + zero
The u n r e a c t e d i s o h e x i d e d i n i t r a t e s were i s o l a t e d f r o m t h e r e a c t i o n
p r o d u c t s i n v a r i o u s r e a c t i o n s i n v o l v i n g 10 t o 90$ d e c o m p o s i t i o n a t
and m e l t i n g p o i n t s a n d m i x e d m e l t i n g p o i n t s t a k e n f o r i d e n t i f i c a t i o n .
were r u n on s e v e r a l o f t h e s e s a m p l e s a n d f o u n d t o be i d e n t i c a l with
o u t t h e e t h e r f r a c t i o n s were i n v e s t i g a t e d b y p a p e r c h r o m a t o g r a p h y
a c t e r i s e d b y r u n n i n g known s a m p l e s i n p a r a l l e l lanes.
-63-
ducts are possible from this type of denitration, either the mono-
reaction mixture was treated with tosyl chloride after cooling, but
alcohol and therefore the alcohol extract from one separation was
dinitrate and 500 mg. of the isohexide vere refluxed in pyridine for
this time the reaction mixtures vere vorked up and the alcohol
one half to constant melting point vhen melting points and mixed
i t vas found that very fev of the available developing agents could
hexides contain few functional groups. The ring systems are very
The only other active groups i n the molecule are the tvo non-vicinal
solvent systems for the separation of the isohexides but the means of
before treatment with iodine and after this treatment the brown spots
has been published but very few details were given (123). A favour-
able report (124) on the use of Celite columns for partition chroma-
packed into the column and that the prepared columns have a rapid
the isohexides were separated completely from each other when run
-66-
Oft]
0-3 g- >s*>so«.s<oe
Z 02-
O
o 01.
O 0.3
FAon A /$*>** A *N'•>€
©a PimmAre REACTION.
o
o-i
0\ Of A AtfAcr|©tf Win*
The optically active material flowing with the front was not i s o -
immediately after the solvent front and the other i n the correct posi-
tion for the isohexide, showing that the f i r s t peak was not isohexide.
reading produced when known amounts of isohexide were eluted from the
been about 10 mg., this represents a bf> yield from the decomposed
P a r t i a l l y Denitrated Products
hexane/methanol system the spot moved off the starting line (indicating
i t was not inorganic nitrate) but was well behind the isohexide d i -
of hydroxyl compounds.
acid and the isohexide but only low yieldsof product, consisting mainly
nitrated derivatives.
anhydride were found to be complete i n less than one hour and when the
nitration was carried out in acetic acid alone no nitrate ester was
products.
those from the ether solution of the pyridine reactions. As the paper
cyclohexane 1,2-diols (126). The separation was good but the columns
them were determined (Table IV). I t can be seen that the acid washing
TABLE IV
only change in conditions was the method of drying the pyridine. The
the later reactions calcium hydride was used as drying agent. The
The effect of the presence of water on the products and the rate of
were carried out on the syrup obtained from evaporation of the frac-
tions from the column. Nitrogen content was 5.4$ whereas an isohexide
mononitrate required 7.32$. The low result indicated that some impurity
was present, and this was probably residual solvent since the high
methanol) was nitrated in the usual way and the nitrate ester thus
Pyridinium Nitrate
reaction vessel above the pyridine solution when the reaction mixture
noted inside the condenser when no drying tube was used to seal the
reaction mixture. Samples of these crystals were taken and had the
from the oxides of nitrogen given off from the reaction. A solution
deposit i n the condenser so that the n i t r i c acid must have been formed
formed i n the reaction was present i n the aqueous solution after the
pyridine was a black solid ("Insoluble Material A") and was recovered
TABLE V
A - Time (hours)
B - Concentration (moles/litre)
C - Percentage of nitrate decomposed
Isoidide dinitrate
A 7 22.2 11.3 27
B 0.089 0.064 0.068 0.043
C 57 19 40 13.5
Isosorbide dinitrate
A 3 12 26 3 11 33
B 0.018 0.11 0.125 0.014 0.075 0.13
C 33 64 40 36 50 44
but the aqueous solution was dark brown. Evaporation of the latter
results were obtained. The material "A" burned only very slowly i n
a Bunsen flame while "B" was combusted rather more quickly. Both
due to the basic character of this mixture as "B" was readily soluble
The material from the latter process was readily soluble in water.
"A" and "B", did not represent major products of the reaction. The
this procedure and to test for such products tvo experiments vere
The former was zero and the latter correct for pyridine i n a l l cases.
weeks the liquid became brown i n colour. In the second experiment the
no optical a c t i v i t y .
mono and dinitrate accounted for 80-95$ of the material in the ether
and was not eluted from the alumina columns i n a definite peak and was
The aqueous solution was investigated and divided into two frac-
inium nitrate from the other material and from these experiments i t
was concluded that the material was optically active and of an acidic
ated to dryness and several portions of water added and evaporated off
column gave two different end points when phenol phthalein and methyl
acid ( n i t r i c acid) and a weak acid. No method was found to isolate the
latter component.
Nitrogen Balance
were t r i e d but only very low yields of an acidic substance were obtained
keto compound exists to a large extent i n the enol form and forms
pyridine reaction.
Conclusion
reaction were the insoluble materials, "A" and "B", which appeared
of the parent diol was formed in the reaction and only a very small
nitrated material indicated that when one nitrate group was removed
the molecule was activated to cause a rapid loss of the second group.
-81-
CHAPTER VI
activation energies.
tubes. The latter were used when the reactions had half lives of
longer than about twenty four hours; i n these cases the open system
various times and diluted with water. The aqueous solution was
extracted with ether and the nitrate i n the ether extract was deter-
TABLE VI
1st extraction . 90 89 90
2nd extraction 9 7 6
3rd extraction 2 3 2
It i s seen from these results that 90$ of the nitrate ester vas
ether extracts vere pooled and made up to 10 ml. and three 1 ml.
The method vas not highly accurate but vas more rapid than precise
ones.
The plots vere confirmed by large scale reactions i n vhich the un-
o.
3
O
or_ 4
UJ • 9^. ISOMANNIDE DINITRATE
$ x3
<r
t ui
z or
t
z -i 0 ^ ISOSORBIDE DINITRATE
2 v. 2
z
2
u
z ISOIDIDE DINITRATE
o
u s
JL
8 12
e •
16
L
20
TIME (HOURS)
0 00258
(Figure XV).
constants for the reactions are shovn i n Figure XVI. From the straight
isohexide dinitrates.
TABLE VII
Frequency
—1 —6
Temp. k (sec."" x 10~ ) H (kcals.) factor
dine required a higher temperature than did that of the hexitol hexa-
various solvents.
above 115°C. for these experiments. Zane found that the cyclohexane-
or 100°C. for a given period. The solution was then cooled, diluted
with ether and loaded directly onto an alumina column from which the
decomposition vas more rapid but proceeded at the same rate i n each
-86-
isoso^Binfc T>\u\Tkfrre.
position.
-87-
the other tvo solvents became yellow to orange in colour during the
tion. However when the reactions were run on larger scales this
ditions was the method of drying the pyridine and i t was thought that
in the later reactions the pyridine was drier than i n the e a r l i e r ones.
dried pyridine to which small portions of water had been added. The
products of the reaction were separated and the material i n the ether
TABLE VIII
nitrate nitrate
1 - 1:2 1.5:1
2 - 1:2 1:1
carried out i n the same way as for the studies i n dry pyridine. Three
different amounts of water vere added equivalent to one. two and four
moles of water per nitrate group i n the original solution and a temp-
cating that the rate of the reaction increased with time (Figure XVIII)
R [Kitrate Ester]
K a t e
" k' + k" [HO]
TIM e ( M O*At)
brown colour developed at the same rate and an insoluble black material
was deposited during the latter stages of the reaction. In the course
of the nitrate esters were analysed for nitrate (,see page 74).
TABLE IX
—1 —5
Rate constants expressed i n sec. x 10
Moles H^O per mole isohexide dinitrate
0 1 2 4
one of trans-nitration (see page 47). It has been seen that nitrate
proceed via the nitronium ion. NO*, formed i n the ionisation of the
nitrate ester. No mechanism has been put forward for the trans-
were heated at reflux or 100°C. for some time and then diluted with
water and excess sulphuric acid added. The resulting solutions were
position of several alkyl nitrates (see page 50) and f a l l i n the range
10
35-40 kcal. with frequency factors about 10 . Solid nitrates were
found to have an activation of about 39 kcal. and frequency factor
12
nitrate were well outside the experimental error and indicated that
some reaction occurred with these compounds which was different from
the thermal decomposition of nitrate esters and the reaction vhich
of -
Ratio nitrate-pyridine to
thermal decomposition
Isomannide dinitrate 3
Isosorbide dinitrate 6
Isoidide dinitrate 10
to the other tvo nitrates. This could be due to tvo factors. Firstly
the other two nitrates and may interact to deactivate the reaction
with the pyridine. Secondly the reaction with pyridine may only occur
readily with groups i n the exo position and slowly with endo groups.
have similar activation energies and similar water effects due to the
-93-
reaction of the exo group masking that of the endo group. It was
that when one nitrate group was removed the second one was lost very
rapidly. This would also account for the fact that isoidide and iso-
isomannide.
may play the major part i n the reaction of isomannide dinitrate. The
pyridine.
rate studies was rather laborious and a more rapid method would aid
to remove the coloured material from the alcohol fractions and would
probably remove the colour from the pyridine solution. The results
obtained here using the direct estimation of the nitrate ester could
In t h i s type of reaction the endo and exo groups vere quite different
the endo and exo positions. I t was hoped that i n t h i s way further
reasonable rate plots were obtained (Figure XIX). The method used
96
" i — i •
1 0
1* ?0 1*9
Tine (secoNM)
was to prepare a sulphuric acid solution of the xylenol and then add
lines. The half lives obtained from these plots, however, proved to
be the same for each of the isohexide dinitrates within the estimated
experimental error. It would appear from these results that the rate
and not the carbon atom i t i s joined to. The benzyl ether of iso-
mannide has been reacted with sulphuric acid i n acetic anhydride and
dride containing 10$ sulphuric acid and the change i n optical rotation
[•«JD +89.6).
a<
. *o ixo
(60). In the isohexides the tosyl groups are secondary and isolated
(except i n the special case of isosorbide). Cope and Shen (66) have
Cope and Shen (66) have stated that the tosyl groups i n isomannide
the conditions used by Cope and Shen for the reaction of isoidide
had used 50$ of the theoretical and the isomannide derivative 100$ of
These results shoved that the group i n the endo position vas
had been hydrolysed f i r s t this reaction could not have taken place.
study of the reaction vas carried out when i t vas found that the
and eight hours and, after cooling, the precipitated sodium p-toluene-
1-0 "
whereas i t was vastly different from those of the exo tosyloxy groups
toluenesulphonylisosorbide.
Its infrared spectrum confirmed the presence of the acetyl group and
i s 2-0-acetyl-5-iodo-5-deoxy-L-isoidide.
alkyl halide alone or with some solvent. Better yields are obtained
alkyl halides and s i l v e r ion and even third order for the reaction of
the halide gave changes i n rate consistent with an SN1 type mechanism
(134, 135). This mechanism was supported by the work involving the
butanol n i t r a t e .
-102-
attack of the incoming group and the removal of the halogen by the
s i l v e r ion are involved. One part without the other would cause a
pounds were a l l assumed to have the iodo group i n the exo position
and isosorbide are also known, these too are expected to have the exo
configuration.
and dried over phosphorous pentoxide. When calcium hydride was used
TABLE X
Yield s i l v e r
Compound Temp. Time iodide by v t .
TABLE XI
Yield
points.
attack on the two faces of the ring system. Thus in this particular
case the reaction involved the removal of the iodine atom to form a
tion out on the corresponding iodo derivative having the endo config-
would expect very much increased rates of reaction and a single product
Conclusions
latter. The alkaline hydrolysis of the tosylate esters has been shown
sulphuric acid appears to have the reverse order for the rates but
the endo position. Thus for this reaction, also in group B, the endo
as a whole rules out the SN2 mechanism at the carbon atom for this
pyridine on the carbon atom of the nitrate (see page 52). In the iso-
hexides this could only occur with isomannide or with the 5-position
attacks the carbon atom, and i n the reaction of hydrazine with nitrate
in the nitrate group, most probably the nitrogen atom. This occurs in
?«
B: >N > B:N0o + 0
• * i
0 C
I
C
oxide which were observed. In the case of the reaction with pyridine
mannitol hexanitrate.
these reactions two nucleophiles exist, one being neutral - the water
and hydrazine molecule, and the other being negatively charged - the
hydroxyl and the hydrazide ion. The neutral species, attack at the
r
carbon atom and the charged species at the nitrogen. The above mech-
hydrolysis and the action of hydrazine, does not explain the high
necessarily be i n group B.
nitrate was produced i n the reaction* thus this mechanism could not
steric requirements of this type of reaction are not known. The form-
i s not known, neither the reaction products nor the rate studies gave
probably s t e r i c i n nature.
-110-
EXPERIMENTAL
Materials
TABLE XII
and the solution saturated with dry hydrogen chloride gas. The result-
ing solution was refluxed for twenty hours and the excess hydrochloric
acetic anhydride (2:1, 15 ml.) at 0°C. was added, dropwise and with
below 5°C. The reaction mixture was kept below 5"C. during the addi-
tion and then allowed to stand at 5°C. for two hours. After this time
the mixture was poured into ice-water (400 ml.). Part of the nitrate
hours, this was f i l t e r e d off and washed well with water. Yield -
The f i l t r a t e was extracted with ether (3 x 100 ml.) and the ether
product. Yield syrup - 0.6 g., total yield - 2.8 g. (86$). Itecrystal-
ate. The residue was treated with water (50 ml.), allowed to stand
5-0-T
—• osylisosorbide-2-nitrate
m.p. 98-100°C.
t r i a l runs on one gram samples the bulk (16.5 g.) was dissolved in
Part (2.55 g.) was acetylated by the method of Cope and Shen (66)
at 0°C. for two hours the mixture was poured into water (100 ml.) and
bicarbonate solution and water then dried over sodium sulphate and
onto an alumina column (7.5 mm. x 20 cm.) and eluted with chloroform.
lised on scratching. Seed crystals from this caused the bulk of the
(5 mm. x 30 cm.) eluted with benzene (5 ml.) and ether (50 ml.). Frac-
tions were collected and samples from them subjected to paper chroma-
v i t h Rf 0.35 and showing both nitrate and tosylate colour tests vere
hexane/methanol solvent (Rf 0.35) and gave the tosylate and nitrate
reactions.
with ethyl iodide (45 g.) i n ethanol (25 ml.) for four hours. The
mixture was allowed to cool and the resulting crystals were collected
ion exchange resin i n the hydroxyl form and neutralising the eluate
Isomannide (4.6 g.) was dissolved i n acetic acid (20 ml.) and
was added slowly at 0°C. After standing at 0°C. for three hours the
mixture was poured into water and extracted with ether after twenty
four hours. The ether solution was washed with water and sodium
(1.6 g.) showed two spots on paper chromatographs and was subjected
by methanol.
(0.17 g.) and isoidide (0.9 g.) gave syrupy mononitrate (0.17 g.).
TABLE XIII
Analyses of Derivatives
in ether, was added to 10-15 ml* 70$ (v/v) sulphuric acid and 1 ml. of
taper flask, washing i n with 150 ml. water. Boiling chips were added
and the flask was f i t t e d with an inverted U-shaped take-off tube which
a digestion flask was added 2 ml. concentrated sulphuric acid and 0.1 g.
added and heated for five minutes. Powdered potassium sulphate (0.6 g.)
G3
and a trace of selenium catalyst vas added and the mixture gently
Then 8 ml. 30$ sodium hydroxide solution vas added and the steam d i s -
250 ml. Iodine flask. A drop of methyl red indicator vas added and
paper (Whatman No. 41) having a 3 mm. x 2 cm. vick projecting from
one corner. The f i l t e r paper vas then folded tvice lengthways and
rolled into a tight cylinder vhich vas inserted into the centre of a
The sample, i n the platinum holder, vas hung belov the stopper of the
Iodine flask. Holding the stopper v i t h sample i n one hand the flask
then the vick vas lighted and the stopper quickly introduced into the
flask and held firmly down u n t i l the combustion was completed. The
opened. The stopper and walls were washed down with 100 ml. of d i s -
when a further 100 ml. of water were added and the volume again
reduced to 25 ml.
indicator. The end point was again compared to the colour of the
(2) As above, but treated with 50$ hydrochloric acid for eighteen
The alumina was poured into glass columns dry, with light tapping,
u n t i l the alumina would not pack down any further* No pre-wash was
given, the mixture was loaded d i r e c t l y onto the dry column i n a small
A column height of 20-30 cm. was used and about 0.5 g. of material was
The solvents used for elution were i n order of increasing eluting power
A l l the organic solvents used were "Reagent Grade" and were dried
TABLE XIV
So1vent Compound
Petroleum ether
Ether diiodoisoidide
Acetone monotosylisosorbide
Methanol
Water
optical rotation vas measured then the vhole solution vas evaporated
loaded onto a column (5.5 mm. diameter, 25 cm. high), and vashed on
v i t h more ether. After standing for three hours the column vas eluted
-123-
Celite No. 535 (Johns-Manvilie) was acid washed (147) then dried
with water) and poured into the column. The Celite was compressed by
suction at the bottom of the column and by tamping down at the top.
dry Celite at the bottom of the tube before adding the wet C e l i t e ,
this absorbed any water which separated out of the butanol with a f a l l
in the temperature.
(1) A layer of dry Celite was placed at the top of the column, the
dry Celite and was then introduced onto the top of the column.
(2) The material was dissolved i n a small amount of water then mixed
well with dry Celite (weight equal to the water present). This
mixture was added to the top of the column i n a slurry with the
124-
developing agent.
The l a t t e r method vas used i n most cases. A rate of about 1 ml. per
Paper Chromatography
Solvent Systems
esters 0.98.
vas set up v i t h tvo dishes in the bottom, one containing hexane saturated
-125-
f i l t e r paper was led up from each of the dishes and fastened to the
the solvent and the vapour in the tank. The paper was spotted with
material i n the usual way, attached to a glass rod, and placed i n the
tank suspended from the rod with cotton thread through a hole in the
lid. The paper was equilibrated i n this way for a period of four to
methanol at the top of the tank. The solvent ran at a rate of about
paper from the tank quickly enough to mark the solvent front before
determine the distance the front had travelled. One was to draw a
line on the paper at a suitable distance and allow the solvent to reach
this front before removing the paper. The other was to observe the
boiling i n range 65-70°G. and with n^2 1.3755 this was used as n-
22
were used with success for chromatography; the Rf values were lowered
-126-
use. After mixing the hydrocarbon and methanol with shaking the
mixture was allowed to separate into two layers. The top one was used
For isohexides -
for a short period then placed i n a chamber of iodine vapour for about
background.
For nitrates -
in ethanol (95$) was sprayed onto the paper. After drying the treated
in Figure XXIII, this was used i n most cases with various modifica-
the table.
TABLE XV
Summary of Separations
the residue of this ether solution was zero. The original ether solu-
and tosyl chloride (0.150 g.) was added. The mixture was allowed to
stand for twenty four hours and was then poured into water and
-130-
ised by melting point and mixed melting point. The alcohol extract
0°C. and tosyl chloride (0.200 g.) was added. After standing for twenty
four hours the solution was worked up as before. Yield - 0.015 g.,
not c r y s t a l l i n e .
detected. The alcohol extract was dissolved i n water (30 ml.) and
IR 120, OH*" form - both columns 7 mm. x 50 cm.). The eluate was evap-
XIII).
tions. The alcohol extract was separated and yielded 0.550 g. and
second half was tosylated as described above and gave 0.60 g. (90$)
them* Samples (0.10 g.) were heated with concentrated sulphuric acid
these fractions.
132-
solvents).
mixture, then fractions were collected and their refractive index was
measured. The residue was divided into the ether and aqueous solu-
methanol (20 ml.) and passed through a charcoal column (15 cm. x 9.5
residue was divided into ether and aqueous solutions. The aqueous
methyl red indicator were used. Part of the eluate was passed through
-133-
retained and was not eluted with 2 Normal acetic acid. The ether
nitrate (0.101 g.) and isosorbide mononitrate (0.080 g.) were isolated.
as used i n the rate studies. The solutions were refluxed for various
times after which they were poured into sulphuric acid (3 Normal,
nitroxylenol.
d i s t i l l a t i o n procedure.
134-
The reactions vere carried out i n glass bulbs with long stems.
A water jacket was f i t t e d over the stem and the top enclosed by a
for lower temperatures. Samples were removed directly from the bulb
nitrate ester was extracted with ether (3 x 1 ml.) and the combined
reproducable results using the bulb method described above. This was
reaction was carried out.in sealed tubes (11 x 50 mm.). Pyrex test
water was prepared i n bulk and portions taken for the reactions. For
reactions at 100°C. the bulbs or sealed tubes were placed above boiling
water. For 87°C. the vapour above a boiling, two layer, mixture of
Other Reactions
with a long stem and 1 ml. of the solvent added. The top of the
stem was well plugged with glass wool and enclosed with a drying
tube. The bulb was then heated in a vapour bath (diethyl carbinol,
bulb then adding 3 ml. ether and introducing the solution onto the
top of an alumina column (7.5 mm. by 20 cm.). The bulb was washed
out with two 2 ml. portions of ether which were added to the column.
A further 15 ml. of ether was passed through the column and then 50 ml.
Solvents Used
(reduced pressure).
tilled.
-136-
Sulphuric acid containing 100 mg. xylenol i n 100 ml. (10 ml.)
was placed i n a 250 ml. standard taper round bottomed flask and stirred
(or heated in a water bath) for a given time under anhydrous condi-
to small volume then water and chloroform added and the mixture shaken.
The layers were separated and the aqueous one re-extracted with a
-137-
onto alumina columns and the elution carried out with portions of
pooled and evaporated. The intermediate fractions were also pooled and
or 0.0124 moles) added. The mixture was refluxed for two hours, cooled
precipitate was washed with acetic anhydride (10 ml.) and dried at
refluxed for a further two hours and the precipitate collected as before.
The solution from this stage was refluxed for four hours before i s o l a -
reduced pressure. The mixture was shaken with water and chloroform,
separated, and the aqueous layer washed with further chloroform. The
rubbing at 0°C.
solution (100 ml.) was refluxed for three hours. The mixture was then
and water (50 ml.) and chloroform were.added and the mixture shaken.
Yield - 0.284 g. syrup. This syrup crystallised on seeding and was re-
88-90°C.
Isoidide ditosylate (0.502 g.) was reacted i n the same way. The
104-105.5°C.
been reached* The solution was then poured into water (20 ml*) and
manner.
Dulcitol (3.6 g.) was dried under vacuum then placed i n a Dean-
(0.12 g.). The mixture was refluxed and the water which was removed
-140-
was measured at various times (Figure XXIV). After four hours the
Mannitol was reacted under the same conditions and gave a 40$
y i e l d of isomannide
I *• 3 *• fi 6
TIMS (HOURS)
(I4l) (1 ml. alcoholic sludge) were heated at 150°C. under water pump
pressure for two hours. After this time the mixture was dissolved i n
for four hours. Samples were removed, centrifuged and their optical
The addition of acid was over one hour and s t i r r i n g was con-
3. Reaction (2) was repeated but with 30 ml. water and 50 ml. of
and barium nitrate (18 g.). The mixture was stirred for s i x
hours at 24° G.
Action of A l k a l i on Diiodoisoidide
potassium hydroxide (30$, 0.5 ml.) for two hours. After this time the
added and the mixture was extracted with ether (2 x 3 ml.). The ether
solution was washed with acid and base then dried over sodium sulphate.
-142-
(extractable by carbontetrachloride).
-143-
APPENDIX I
nitration reaction which occurs when nitrate esters are treated with
the nitrate ester, giving nitronium ions which are available for the
spectrum.
these are formed in constant proportions (1:6). The former has low
nitrate ions. Halogen ions are stated to interfere (140) but only at
solution i f more than 0.2 ml. was present. Up to 3 ml. of ether had
80$ (v/w) sulphuric acid has been used generally for the trans-
the results of some tests conducted to test this variation. The reac-
tion was rapid but the rate dropped off rapidly at about 70$ sulphuric
Tests were conducted to show that the nitroxylenol was not de-
TABLE XVI
TABLE XVII
TABLE XVIII
0-5 ml. 62 57
5-10 ml. 24 29
10-15 ml. 9 10
15-20 ml. 3 3
20-25 ml. 1 1
Total 99 100
-147-
APPENDIX II
Paper Chromatography
graphy are only suitable for substances which are more or less hydro-
which the compound travels) which are i n the range 0.1 to 0.9 for the
materials being used. The lower limit of this range can be extended
substances generally are not. There have been many attempts to increase
These can be divided into two groups - one where f i l t e r paper i s used
as a base and the other where various other materials are used. The
-148-
latter method has only been used recently and there i s not very much
strength, especially when wet. Among the materials used are asbestos,
be done without breaking down the basic fibres and so the strength of
for i r r i g a t i o n and the system has been called "reverse phase" chroma-
one.
solvent. Bush (151) working with steroid compounds also reported the
tank containing the solvent system i n dishes at the bottom and was
cation. Hexane saturated with methanol was used most frequently but
i t was shown (Table XIX) that the hydrocarbon used does not have very
constant than those normally obtained here. Por the purposes of this
known material along parallel lanes. The Rf values were constant for
various steroids (151) i t was noted that the Rf values increased with
The above results show that with increasing water content of the
city. It was noted however that the presence of one or two parts of
more easily handled, the methanol i n these systems did not separate
readily soluble i n benzene and were found to run quite well i n solvent
From the results the solvent systems D and £ are recommended for
be seen that the systems can be varied readily to suit the particular
to dry and then exposing to ultraviolet light for five minutes. The
Solvent Systems
TABLE XIX
Isomannide
dinitrate 0.12 0.20 0.12 0.07
Isosorbide
dinitrate 0.19 0.26 0.175 0.10
Isoidide
dinitrate 0.355 0.42 0.31 0.20
-153-
TABLE XX
Isomannide
dinitrate 0.20 0.18 0.25 0.50
Isosorbide
dinitrate 0.26 0.26 0.34 0.59
Isoidide
dinitrate 0.42 0.43 0.54 0.72
TABLE XXI
Dinitrates Ditosylates
G II I G H I
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