Novel process for synthesis of a liquid irritant, 1-methoxycycloheptratriene

An improved multi-step process for synthesizing the liquid irritant 1-metycycloheptatriene from tropylium tetrafluoborate the improvement comprising the step of using a polymerization/condensation inhibitor or retarder to minimize impurities and increase yield of the irritant product. Phenothiazine is the preferred polymerization inhibitor.

BACKGROUND OF THE INVENTION 
This invention relates to an improved process for preparing the liquid 
irritant agent 1-methoxycycloheptatriene. 
The invention further relates to an improved process for preparing the 
irritant agent 1-methoxycycloheptatriene from tropylium tetrafluoborate 
through use of a polymerization/condensation inhibitor to increase the 
yield and purity of the agent. 
The invention still further relates to a more rapid and efficient method 
for isomerization of 7-methoxycycloheptatriene to its isomer 
1-methoxycycloheptatriene. 
The existing processes for preparing 1-methoxycycloheptatriene basically 
consists of a three step synthesis wherein an aqueous solution of 
cycloheptatrienyl tetrafluoroborate (tropylium tetrafluoroborate) in 
methanol is first converted to the 7-methoxycyclohepta 1,3,5-triene isomer 
by reaction with sodium bicarbonate; the resulting 7-isomer is thermally 
isomerized to 3-methoxycyclohepta-1,3,5-triene and this 3-isomer is in 
turn is either thermally isomerized to 1-methoxycyclohepta-1,3,5-triene or 
isomerized in a methanol solution, under acid catalysis, to the 
1-methoxycyclohepta-1,3,5-triene isomer. The prior art process which had 
given the best yield of 1-methoxycylohepta-1,3,5-triene, i.e, 
approximately 43% with a purity of 85-89 mole % is best illustrated 
schematically in the following series of three reaction equations; 
##STR1## 
In the first step of the above synthesis, warm water is used to dissolve 
the cycloheptatrienyl tetrafluoborate (tropylium tetrafluoborate) (I) salt 
under a nitrogen atmosphere. Methanol is added to the resulting aqueous 
solution of (I), followed by the addition of solid sodium bicarbonate to 
give the reaction product 7-methoxycycloheptatriene (II). The 
7-methoxycycloheptatriene (II) is isomerized by heating at 150.degree. C. 
for two hours to produce 3-methoxycycloheptatriene (III). In the third 
step, 3-methoxycycloheptatriene (III) is isomerized in an acid catalyzed 
rearrangement utilizing hydrogen chloride in methanol at room temperature 
for two hours, followed by neutralization with sodium bicarbonate, 
filtration and fractional distillation to give the product 
1-methoxycycloheptatriene (IV). 
The prior art processes described above have resulted from numerous studies 
of the isomerization reaction of alkoxycycloheptatriene. The production of 
cycloheptatrienylium bromide, its hydrogenation to cycloheptane, its 
subsequent conversion by phenyllithium to 7-phenylcycloheptatriene and the 
synthesis of 7-methoxycyclohepta (1,3,5) triene was first disclosed in The 
Cycloheptatrienyl (Tropylium) Ion., J. Am. Chem. Soc. 76, 3202 (1954) by 
W. Von E. Doering et al. Synthesis of 1-ethoxy-1,3,5-cycloheptatriene by 
reaction of 1-ethoxycyclohexene with dichlorocarbene and hot quinoline 
rearrangement is shown in A Synthesis of 3,5-Cycloheptadienone by W. E. 
Parham et al, J. Am. Chem. Soc. 84, 1755 (1962). Irradiation of 
7-methoxycyclohepta-1,3,5-triene in the vapor phase has given a 40% yield 
of 1-methoxycyclohepta-1,3,5 triene by the process of O. L. Chapman et al, 
An Anomalous Photoisomerization in the Cycloheptatriene Series, Proc. 
Chem. Soc. at 221, July 1963. 
Thermal isomerization of 7-methoxycycloheptatriene at 150.degree. C. by 
irreversible reaction into 3-methoxycycloheptatriene and subsequent 
reversible isomerization of the 3-isomer to 1-methoxycycloheptatriene 
under the same conditions is disclosed in Thermal Isomerization of 
Alkoxycycloheptatriene, Proc. Chem. Soc., February 1964, 59 by E. Weth et 
al, and A. Piter Borg et al, The Chemistry of Cycloheptatriene Part XII: 
The Thermal Behaviour of Substituted Cycloheptatrienes, Rec. Trav. Chim. 
84, 1230 (1965). Thermal isomerization of alkoxycycloheptatrienes, e.g., 
7-methoxycycloheptatriene in sealed tubes at temperatures in the range of 
75.degree.-220.degree. C., i.e., under pressure to give a mixture of 
3-methoxy-1-methoxy and 2-methoxy-cycloheptatriene is disclosed in T. 
Nozoe et al, The Thermal Isomerization of Alkoxycycloheptatrienes and Some 
Reactions of its Product, Bull Chem. Soc. of Japan, 38, 665-674, April 
1965. T. Tezuka et al disclosed in Thermal Reactions of 
Alkoxycycloheptatriene at 300.degree.-800.degree. C., Chem. Lett. Japan, 
pp 1341-1346 (Chemical Society of Japan), 1974, that 
7-methoxycycloheptatriene is completely consumed at 
300.degree.-400.degree. C. to form 3-methoxy and 1 
-methoxycycloheptatrienes when pyrolyzed by passing through a quartz 
column containing heated quartz tips. Heating at 450.degree. gave 
1-methoxycycloheptatriene as the sole isomer product. 
Finally, the prior art has recognized the benefit of excluding moisture 
from the thermal isomerization reaction of 7-methoxycycloheptatriene to 
the 3-methoxy and subsequently rearrangement to the 1-methoxy isomer by 
conducting the reaction at 150.degree. C. for 2.5 hr in a nitrogen 
atmosphere. 
In all the above described methods of preparing the irritant 
1-methoxycycloheptatriene, yields at each step are adversely effected by 
high-boiling polymeric or condensation-type material recovered as pot 
residue after distillation of the crude product. The overall yield of 
product and the purity of the product 1-isomer has been limited. 
Applicant's process has succeeded in obtaining significantly better yields 
of higher purity product through elimination of the adverse effects of 
these high boiling polymeric materials. 
SUMMARY OF THE INVENTION 
An improved multi-step process for synthesizing the liquid irritant 
1-methoxycycloheptatriene through the steps of reacting cycloheptatrienyl 
tetrafluoroborate in aqueous solution with methanol and sodium bicarbonate 
to produce 7-methoxycycloheptatriene, thermally isomerizing the 
7-methoxycycloheptatriene to 3-methoxycycloheptatriene by heating at 
150.degree. C. for 2 hours and isomerizing the 3-methoxycycloheptatriene 
to 1-methoxycycloheptatriene by acid, catalyzed rearrangement employing 
methanolic hydrogen chloride followed by neutralization with sodium 
bicarbonate, filtration and fractional distillation to give the final 
product the improvement comprising the step of utilizing a 
polymerization/condensation inhibitor to increase the overall yield and 
purity of the 1-methoxycycloheptatriene product. The overall yield and 
purity of the product can further be increased through the step of 
conducting the thermal isomerization of 7-methoxy to 3- and 
1-methoxycycloheptatriene at 180.degree. C. under reduced pressure, e.g., 
by heating in a sealed reactor. 
It is the principal object of this invention to provide an improved process 
for synthesizing the liquid irritant 1-methoxycycloheptatriene through use 
of a high-boiling polymerization/condensation material inhibitor. 
It is a further object of this invention to provide an improved process for 
synthesizing an alkoxycycloheptatriene isomer product of increased overall 
yield and purity. 
It is a still further object of this invention to provide an improved 
process for more rapidly synthesizing a 1-alkoxycycloheptatriene, e.g., 
1-methoxycycloheptatriene in increased overall yield and purity through 
the step of increasing the thermal isomerization of the 7-isomer to the 
1-isomer by heating at 180.degree. C. under reduced pressure. 
These and other objects of this invention will become apparent from the 
following detailed description of the invention. 
DESCRIPTION OF THE INVENTION 
The improved process of this invention for synthesizing the liquid irritant 
1-methoxycycloheptatriene in substantially increased yields and purity 
involves the novel use of a polymerization inhibitor/retarder in the prior 
art process described above. The polymerization inhibitor/retarder of this 
invention minimizes formation of high-boiling polymeric or 
condensation-type material, which had previously remained as impurities in 
the crude product and pot residue. This minimization of high-boiling 
polymeric material has resulted in substantially increased yields of 
1-methoxycycloheptatriene, i.e., from approximately 43% yield without 
inhibitor to 62%-69% with the inhibitor and a purity increase from the 
range 85-89 mole % to the range of 92-93.6 mole % with the instant 
improved process. 
The polymerization inhibitor/retarders that have been found to have utility 
in the process of this invention include phenothiazine, hydroquinone, 
nitrobenzene and L-ascorbyl palmitate, with phenothiazine being preferred 
as producing the greatest increase in product yield and purity. A more 
complete discussion of the scope of compounds which are recognized in the 
art as polymerization inhibitor/retarder, together with a detailed 
discussion of the mechanism by which polymerization is suppressed, can be 
found in the text Principles of Polymerization by George Odian, 
McGraw-Hill, Inc., 1970 at pp. 221-231. 
The polymerization inhibitor has produced increased yields and purity of 
the final 1-methoxycycloheptatriene product when added during the first 
step of the process, but optimum results are obtained when the inhibitor 
is present during each reaction step in the multi-step synthesis process, 
e.g., by addition prior to each reaction step. 
The improved process of this invention also includes other modifications of 
the prior art process which increase yield and purity of the instant 
product, particularly when used with the polymerization inhibitor of this 
invention. In particular, it has been found that by heating the water, 
which is added to the cycloheptatrienyl tetrafluoroborate salt in step 1 
of the process, to approximately 52.degree. C. under nitrogen atmosphere 
and purging the water with nitrogen for 30 minutes prior to addition of 
said tetrafluoroborate salt, a significant increase in yield of the 
7-isomer is achieved and consequently, a greater yield of 1-iosmer product 
results at increased reaction rates. Replacement of the sodium bicarbonate 
with triethylamine in the acid catalyzed rearrangement of step 3 also 
decrease overall reaction time by instantaneous neutralization of the 
acid. 
The preferred embodiment of the improved process of this invention involves 
the use of the above mentioned process modifications of the prior art 
process, particularly the use of the polymerization inhibitor 
phenothiazine, with the additional process improvement of heating the 
7-methoxycycloheptatriene in the second step of the process to an elevated 
temperature, e.g., 180.degree. C. at reduced pressure to give a final 
product 1-methoxycycloheptatriene of increased mole percent yield and 
purity. More specifically, it has been found that when 
7-methoxycycloheptatriene is heated at 180.degree. C. under reduced 
pressure, a substantial quantity of the order of 80 mole % of 7-isomer is 
isomerized to 1-methoxycycloheptatriene with complete consumption of the 
7-isomer whereas heating at 150.degree. C. (atmosphere pressure), as in 
the prior art process, yields the 3-methoxycycloheptatriene as a major 
component with only approximately 12-13 mole % 1-methoxycycloheptatriene 
product. Subsequent acid catalyzed rearrangement (step 3 of the synthesis) 
of the product in the preferred process yields a final product containing 
approximately 92 mole % of the 1-methoxy isomer and a purity of methoxy 
isomers of 99 mole % versus a yield of 90 mole % 1-methoxy isomer (96% 
purity of methoxy isomer) obtained when the improved process of this 
invention utilizes the atmospheric heating at 150.degree. C. of the prior 
art process. 
The improved process of this invention can be best illustrated by reference 
to the reaction equation for the preferred embodiment of the instant 
improved process. 
##STR2## 
In the above process, water was heated to 52.degree. C. and purged with 
nitrogen to expel any dissolved oxygen. Phenothiazine was added, followed 
by addition of cycloheptatrienyl tetrafluoborate (I), methyl alcohol and 
solid sodium bicarbonate to give a crude product, 
7-methoxycycloheptatriene (II), which was distilled in the presence of 
phenothiazine to give a yield of approximately 59%. The 
7-methoxycycloheptatriene with added phenothiazine inhibitor, is then 
thermally isomerized by heating at 180.degree. C. under pressure, e.g., in 
a sealed reaction vessel, to give a 100% conversion to a product, 
containing 1-methoxycycloheptatriene (IV) as its major component, e.g., 82 
mole % and minor amounts of 3-methoxy isomer, e.g., 16 mole % and 
2-methoxycycloheptatriene isomer, with added phenothiazine, is treated 
with methanolic hydrogen chloride for 2 hours at room temperature, 
followed by neutralization with triethylamine, filtration, and fractional 
distillation to effect acid catalyzed rearrangement of the 3-methoxy 
isomer to 1-methoxycycloheptatriene. The final product contained 
approximately 92 mole % 1-methoxycycloheptatriene, 2 mole % 3-isomer and 5 
mole % of 2-methoxycycloheptatriene, with an overall methoxy isomer purity 
of 99%. The preferred process exhibited at approximate 70-75% yield of 
1-methoxycycloheptatriene from the initial 7-isomer, which is 
significantly greater than the best prior art yield of approximately 43% 
and an improvement over the instant process of using phenothiazine with 
atmospheric heating of the 7-isomer at 150.degree. C. (approximately 
62-67%).

The improved process of this invention can be best shown by the following 
detailed examples, which are meant to be merely illustrative and not 
limiting upon the invention. 
EXAMPLE 1 
Preparation of 1-methoxycyclohepta-1,3,5-triene utilizing phenothiazine as 
a polymerization inhibitor 
Step A. Preparation of 7-methoxycyclohepta-1,3,5-triene 
In a 3-liter, 3-neck, round-bottom flask equipped with a stirring bar, 
thermometer, and gas inlet tube, 1200 ml of water was heated to 52.degree. 
C. and purged with nitrogen to expel any dissolved oxygen. A solution of 
0.53 gm of phenothiazine (0.1% by weight of reactant cycloheptatrienyl 
tetrafluoroborate) in 25 ml of benzene was added, followed by addition of 
534 grams (3 moles) of cycloheptatrienyl tetrafluoroborate, during which 
time heat was reapplied until a temperature of 50.degree. C. was attained. 
To the resulting solution was added 300 ml of methyl alcohol and stirring 
was discontinued. A resulting dark green solution was cooled to 
approximately 35.degree. C., and 325 grams (3 moles) of solid sodium 
carbonate were added rapidly but cautiously in order to avoid excessive 
frothing. 
The reaction mixture was transferred to a 2-liter separatory funnel, the 
upper oily layer separated, and the aqueous layer was extracted with five 
200 ml portions of ethyl ether. The oily layer and combined ethereal 
extracts were dried over anhydrous magnesium sulfate and the solvent was 
removed in vacuo on a rotary evaporator. The crude yield of 332.4 grams 
(90.7% of theoretical yield) contained 76 mole % of 
7-methoxycyclohepta-1,3,5-triene according to NMR analysis. Vacuum 
distillation of the crude product through a 6-inch, air-jacketed Vigreux 
column in the presence of 0.33 gram of phenothiazine (0.1% of crude 
product weight) at 15 mm Hg under a nitrogen atmosphere gave the four 
fractions listed below, with a combined weight of 216.2 gm representing a 
59.0% yield. 
______________________________________ 
Mole % Purity 
7- 
Boiling Frac- Methoxycyclohepta- 
Cyclohepta- 
Point tion Weight 1,3,5-triene 
1,3,5-triene 
______________________________________ 
(.degree.C./torr) 
(gm) 
25-56 1 20.0 73.0 27 
56-60 2 85.3 98.5 1.5 
59.5-60.5 
3 66.2 99 plus trace 
60.5-48 4 44.7 99 plus trace 
______________________________________ 
Step B. Preparation of 3-methoxycyclohepta-1,3,5-triene 
Phenothiazine (1.4 gm=0.1% by weight of 7-methoxycycloheptatriene) was 
dissolved in 1381.9 gm of distilled 7-methoxycycloheptatriene. The 
solution was then heated under nitroen at ambient pressure for 2 hours at 
150.degree. C., during which time low-boiling materials were removed by a 
condenser set for downward distillation. Upon cooling, the residual 
material weighed 1345.2 grams, representing a crude yield of 97.3% (based 
on initial 7-methoxy isomer). NMR analysis indicated a product composition 
of 76 mole % 3-methoxycyclohepta-1,3,5-triene, 12 mole % 
1-methoxycyclohepta-1,3,5-triene and 4 mole % unconverted 7-methoxy 
isomer. The product was of sufficiently good quality to be utilized for 
conversion to 1-methoxycycloheptatriene without prior distillation. 
Step C. Preparation of 1-methoxycyclohepta-1,3,5-triene 
A solution of 360 ml (353.8 gm) of the crude 3-methoxycycloheptatriene from 
the above step, 0.35 gm of phenothiazine, 1750 ml of methyl alcohol, and 
36.4 ml of methanolic hydrogen chloride (98.1 mg HCl/ml methyl alcohol 
solution) was stirred for 2 hr. 15 min. at ambient temperature under a 
nitrogen atmosphere. The clear, red-colored acidic solution was 
neutralized with 9.9 gm of triethylamine, the solvent was removed in vacuo 
on a rotary evaporator, and the residue was filtered through a 
fritted-glass funnel containing a layer of Celite filter aid. The 
resulting 342.4 gm (96.8% crude yield) of reddish-colored filtrate was 
indicated by NMR analysis to contain 60 mole % purity of 
1-methoxycycloheptatriene. 
Vacuum fractional distillation of the crude product at 5 mm Hg under a 
nitrogen atmosphere afforded a main fraction of 204.5 gm (57.8% yield, bp 
43.degree.-46.5.degree.) of colorless distillate. NMR analysis indicated 
the distillate was 96.1 mole % in combined 1-methoxy and 3-methoxy 
isomers, and indicated a 90.7 mole % content of 1-methoxycycloheptatriene 
in the sample. A second fraction afforded 42.1 gm (11.9% yield) of 
colorless product which was 90.4 mole % pure in 1-, 2-, and 3-methoxy 
isomers and contained 51.2 mole % 1-methoxycycloheptatriene. The total 
yield of both fractions was 69.7% (based on crude reactant 3-methoxy 
isomer). 
EXAMPLE 2 
(A) Former process of preparing 7-methoxycyclohepta-1,3,5-triene and (B) 
said former process modified by addition of phenothiazine prior to 
distillation of crude 7-methoxy isomer 
(A) The procedure of Example 1, Step A, was repeated using one-third molar 
proportions but without the use of an inhibitor (phenothiazine in benzene 
solution). A crude 7-methoxy isomer (75.5% yield) was indicated by NMR 
analysis to contain 9 mole % cycloheptatriene, 9 mole % aromatic 
impurities, 3 mole % ethyl ether and 79 mole % 7-methoxy isomer. 
Distillation under a nitrogen atmosphere at 10 mm Hg afforded two 
fractions (47.2% yield based on the fluoborate reactant) which NMR 
indicated to contain 3 mole % cycloheptatriene and 97 mole % 
7-methoxycycloheptatriene. 
(B) A three-fold scale-up of the above procedure was conducted (80.6% yield 
of crude 7-methoxy isomer). Vacuum distillation at 10 mm Hg under a 
nitrogen atmosphere and with 0.29 gm of phenothiazine (0.1% of crude 
product weight) gave 183.9 gm (50.2% yield) of 7-methoxycycloheptatriene. 
EXAMPLE 3 
Acid catalyzed rearrangement of 3-methoxycyclohepta-1,3,5-triene to 
1-methoxycycloheptatriene (A) without phenothiazine and (B) with 
phenothiazine added prior to distillation 
(A) 3-Methoxycycloheptatriene (56.0 gm) in a 1-liter 2 neck flask was 
diluted with 280 ml of methanol while under a nitrogen atmosphere. 
Methanolic hydrogen chloride (4.0 ml) containing 142.8 mg HCl/ml methanol 
was added and after stirring for 2 hr. 20 min., the resulting clear red 
colored solution was neutralized with 1.6 gm triethylamine, the solvents 
evaporated in vacuo on a rotating film evaporator, and filtered through a 
fritted glass funnel containing a layer of Celite yielding 45.3 gm (80.7% 
yield) of medium brown colored solution. NMR analysis revealed 50 mole % 
purity of 1-methoxycycloheptatriene. Distillation of this crude product at 
5 mm Hg under a nitrogen atmosphere afforded 26.0 gm (46.4% yield) of 
1-methoxycycloheptatriene (89.2 mole %, 97.1 mole % pure 1- and 3-methoxy 
isomers by NMR). 
(B) The above reaction was repeated with 72 ml (69.6 gm) of distilled 
3-methoxy isomer, 350 ml of methanol, 5 ml of methanolic hydrogen 
chloride, and neutralized with 2 gm of triethylamine. The resulting 64.9 
gm of crude product was distilled with 0.06 gm of phenothiazine (0.1% of 
crude product weight) at 5 mm Hg under a nitrogen atmosphere to give 40.5 
gm (58.2% yield) of colorless 1-methoxycycloheptatriene. NMR analysis of 
the product (2 fractions) indicated 97.0 and 98.2 mole % pure in 1- and 
3-methoxy isomers containing 85.0 and 91.7 mole % 
1-methoxycycloheptatriene, respectively. Redistillation in the presence of 
phenothiazine gave a 53.7% yield (37.4 gm, 94.9% recovery) of colorless 
1-methoxy isomer (98.2 mole % pure in 1- and 3-methoxy isomers, 89.6 mole 
% 1-methoxycycloheptatriene by NMR analysis). 
EXAMPLE 4 
Preparation of 1-methoxycyclohepta-1,3,5-triene by Thermal Isomerization of 
7-methoxycycloheptatriene under pressure 
Separately, 88.3 and 63.1 grams of 7-methoxycycloheptatriene with purities 
of 97.4 and 98.2 mole %, respectively, were transferred to a pear-shaped, 
heavy-walled, glass flask of 200 ml capacity. The void was filled with 
nitrogen, and the flasks were sealed with a neoprene gasket and glass 
stopper held in place with a fitted heavy-gauge wire brace. The flasks 
were then heated for 3 hours in an oil bath maintained at 180.degree. C. 
After cooling, the flasks were opened and the product analyzed by NMR. The 
results are shown in the table below. 
______________________________________ 
Isomer Ratio 
Weight Total Isomers 
Run (gm) 1-Isomer 3-Isomer 
2-Isomer 
(mole %) 
______________________________________ 
1 88.3 77.0 18.6 4.4 97.0 
2 63.1 81.2 13.2 5.5 95.8 
______________________________________ 
A solution of methanol (1521 ml) containing 0.31 gm phenothiazine, 15 ml 
anhydrous methanolic hydrogen chloride (178.7 mg/ml), and 304.6 gms of 
1-methoxycycloheptatriene (80 mole % pure), was stirred for 2 hours 20 
minutes at ambient temperature. The acidic solution was then neutralized 
with 7.5 gm of triethylamine, the solvent was removed in vacuo on a rotary 
evaporator, and the residual liquid was filtered through a fritted-glass 
funnel (coarse porosity) containing a layer of Celite filter aid to give 
269.0 grams of crude product. Washing of the filter cake with ether 
followed by removal of solvent from the filtrate gave an additional 20.7 
grams of crude product. Both products were combined to give a crude yield 
of 95.1% containing 62 mole % of 1-, 2-, and 3-methoxy isomer. Vacuum 
fractional distillation of this product through a 6 inch, air-jacketed 
Vigreux column gave the fractions shown in the table below. 
______________________________________ 
Total 
Boiling 1-,2-3- 
Point Weight Yield 1-Methoxy 
Methoxy 
Fraction 
.degree.C./5 torr 
(gm) (%) Isomer Isomer 
______________________________________ 
1 36-37 111.5 36.6 88.0 95.1 
2 37-40 91.2 29.9 90.8 96.4 
3 40-33 24.2 7.9 81.0 91.2 
______________________________________ 
EXAMPLE 5 
Preparation of 1-methoxycyclohepta-1,3,5-triene by thermal isomerization 
under pressure 
Five thermal-pressure reactions of distilled 7-methoxycycloheptatriene 
(132.8-136.7 gm of 83.7-100% purity) were carried out at 180.degree. C. 
for 3 hours in the presence of 1% phenothiazine and over a nitrogen 
atmosphere in a 200 ml pear-shaped heavy walled glass bomb. NMR analysis 
indicated the mole percent purity of the 1-, 2-, 3-methoxy isomers was 
90-96.5 and the mole percent purity of the 1-methoxy isomer was 66-77. 
Upgrading of the above products by acid catalyzation gave 
1-methoxycycloheptatriene of exceptionally high yield and purity. Thus, 
0.36 gm of phenothiazine was added to 365 ml (358.0 gm) of 
methoxycycloheptatriene (ca. 94 mole % 1-, 2-, 3-methoxy isomer; 77 mole % 
1-methoxy isomer) stirred in a nitrogen atmosphere, followed by 730 ml of 
A. C. S. certified methanol (2 ml methanol/ml methoxycycloheptatriene), 
and 18.3 ml of methanolic hydrogen chloride containing 121 mg HCl/ml 
methanol solution. After the solution was stirred for 2 hours 20 minutes, 
it was neutralized with 6.1 gm of triethylamine and the methanol was 
evaporated in vacuo from a rotating film evaporator. The product 
containing solid triethylamine hydrochloride was diluted with 250 ml 
ether, the mixture filtered through a fritted glass funnel, a layer of 
Celite filter acid, and the filter cake washed with ether. The ethereal 
solution was evaporated in vacuo again until a net weight of 364.2 gm was 
attained. High vacuum distillation of the medium red colored clear 
solution containing 0.36 gm of phenothiazine gave two fractions as shown 
below. 
______________________________________ 
Weight Mole % Purity 
Methoxycycloheptatriene 
Fraction 
(gm) 1-Isomer Total 1-, 2-, 3-Isomer 
______________________________________ 
I 218.2 93.6 98.6 
II 29.8 62.6 94.4 
______________________________________ 
One percent BHA and BHT (butylated hydroxyanisole and toluene, 
respectively) were added to fraction I as light stabilizers. The combined 
weight of fractions I and II represent a yield of 69.2%. 
Another upgrading of 353 ml (348.8 gm) of thermal-pressure reaction product 
as above by acid catalyzed rearrangement gave the following: 
______________________________________ 
Mole % Purity 
Fraction Weight (gm) 1-Isomer 1-, 2-, 3-Isomer 
______________________________________ 
I 195.3 93.1 98.3 
II 37.9 72.5 94.9 
______________________________________ 
which represented a total yield of 66.9%. 
EXAMPLE 6 
In a study of the thermal-pressure reaction of 7-methoxycycloheptatriene in 
an aluminum bomb (61.7 mm.times.19 mm cavity, 5 mm wall thickness, and 19 
ml capacity), it was found that the pressure increased gradually and was 
dependent upon time and temperature. After 4 hours at 
180.degree.-188.degree. C., the final pressure was 58 psig, after 1 hour 
at 220.degree. C., the final pressure was 80 psig. The mole percent purity 
in each preparation was ca. 85 for 1-, 2-, 3-methoxy isomers and ca. 72 
for 1-methoxycycloheptatriene. When heating at 220.degree. C. was 
continued for an additional three hours, the pressure reached 118 psig and 
the product obtained, when analyzed by NMR, had a decreased mole percent 
purity of 1-, 2-, 3-methoxy isomers (ca. 64). 
EXAMPLE 7 
Comparison of thermal isomerization of 7-methoxycyclohepta-1,3,5-triene 
with phenothiazine inhibitor at 150.degree. C. (atmosphere pressure) and 
180.degree. C. (greater than atmospheric pressure) 
Heating 7-methoxycycloheptatriene at 150.degree. C. and atmospheric 
pressure affords 3-methoxy isomer as the principal product whereas heating 
at 180.degree. C. under pressure affords 1-methoxy isomer as the major 
component, as shown below. 
______________________________________ 
Method 7-Isomer 2-Isomer 3-Isomer 
1-Isomer 
______________________________________ 
I 150.degree. C. (atmo) 
3.5 -- 83.7 12.8 
II 180.degree. C. (under 
0 5.5 13.2 81.2 
pressure) 
______________________________________ 
Separate treatment of the products with methanolic hydrogen chloride 
(phenothiazine present during reaction and fractional distillation) gave 
the following results: 
______________________________________ 
% Yield 
Source of 90% Less Pure 
Starting Material 
(1-Isomer) (1-Isomer) Total 
______________________________________ 
I (150.degree. C., atm.) 
54.8 12.0 66.8 
II (180.degree. C., press.) 
66.6 7.9 74.5 
______________________________________ 
EXAMPLE 8 
Comparison of thermal isomerization of 7-methoxycyclohepta-1,3,5-triene by 
heating in a sealed NMR tube at 180.degree. C. with and without 
phenothiazine inhibitor 
One to two milliliters of a solution prepared by dissolving 0.32 gm of 
phenothiazine in 32.1 gm of 94 mole % purity 7-methoxy isomer were 
transferred to six NMR tubes over a nitrogen atmosphere and immersed in a 
pre-heated oil bath at 180.degree. C. for the time indicated below, cooled 
to room temperature, and the NMR observed 
______________________________________ 
MOLE PERCENT 
Methoxy Isomer Ratio 
Time 1-Isomer 2-Isomer 3-Isomer 
7-Isomer 
1-,2-,3-Isomer 
______________________________________ 
3 min 2.5 -- 56.2 41.3 
5 min 5.4 -- 72.8 21.7 
10 min 
14.3 -- 78.6 7.1 
30 min 
36.9 none 60.9 2.2 
1 hr 55.6 2.2 40.2 2.0 
2 hr 69.9 6.8 23.3 -- 
3 hr 76.3 6.8 16.9 -- 
4 hr 76.3 8.4 15.3 -- 87.6 
5 hr 77.4 7.3 15.4 -- 89.0 
______________________________________ 
The reaction was then carried out without an inhibitor in a pear-shaped 
heavy walled glass bomb of 200 ml capacity. In a first synthesis without 
an inhibitor, 88.3 gm of 97.4 mole % purity 7-methoxy isomer was employed. 
A 63.1 gm sample of 98.2 mole % 7-methoxy isomer was used in a second 
synthesis. The glass bombs were secured with a neoprene gasket and glass 
stopper held in place with a fritted heavy gauge wire brace. 
______________________________________ 
Mole Percent 
Methoxy Isomer Ratio 
Purity 
Run Time 1-Isomer 2-Isomer 
3-Isomer 
1-, 2-, 3-Isomer 
______________________________________ 
1 3 hr 77.0 4.4 18.6 97.0 
2 3 hr 81.2 5.5 13.2 95.8 
______________________________________ 
As shown in the above examples, the instant process yields 
7-methoxycycloheptatriene, 3-methoxycycloheptatriene and final product 
1-methoxycycloheptatriene, respectively, in significantly increased 
amounts and purity over that obtained in prior art processes through use 
of "catalytic" amounts, i.e., 0.1-1.0% by weight of reactant mixture of 
phenothiazine polymerization condensation inhibitor. In particular, the 
addition of phenothiazine to crude 7-methoxycycloheptatriene prior to 
distillation increased the yield from 43.2% to 50.2%. When phenothiazine 
was added to water heated to 52.degree. C. under nitrogen followed by 
addition of cycloheptatriene tetrafluoroborate, methanol and solid sodium 
bicarbonate, the yield of distilled 7-methoxycycloheptatriene was 59.0%. 
The conversion of 7-methoxy isomer to the 3-methoxy isomer by thermal 
isomerization at 150.degree. C. (atmospheric pressure) with phenothiazine 
inhibitor added prior to distillation gave an 86.6% yield of 3-methoxy 
isomer, whereas addition of phenothiazine prior to heat isomerization gave 
97.3% yield of 3-methoxy isomer. 
The initial conversion of 3-methoxy isomer to the 1-methoxy isomer without 
phenothiazine inhibitor gave a yield of approximately 46.4%. The yield was 
increased by use of phenothiazine during fractional distillation to 58.2% 
and the use of phenothiazine during the neutralization reaction and during 
fractional distillation gave a further increase in yield to 62.1%. 
Finally, the conversion of 7-methoxy isomer to 1-methoxycycloheptatriene by 
thermal isomerization at 180.degree. C. (under pressure) with use of 
phenothiazine as a polymerization inhibitor gave an increased final yield 
of 1-methoxycycloheptatriene of the order of 74.5%. 
The methoxycycloheptatriene isomers used in the process of this invention 
are known to be susceptible to autoxidation, particularly the 
1-methoxycycloheptatriene product which has customarily been stabilized 
with anti-oxidants. It is therefore essential that a nitrogen atmosphere 
be maintained during all steps of the instant process. 
The most significant improvement in the improved process of this invention 
is the use of a polymerization inhibitor/retarder during all reaction and 
distillation steps of the instant process for minimizing the presence of 
impurities and extraneous materials in the crude methoxycycloheptatriene 
products and thereby increasing the final yield of 
1-methoxycycloheptatriene product. Use of a concentration of approximately 
0.1% w/w of the preferred phenothiazine inhibitor in all reaction steps 
has been found to give significantly improved yields, but this amount of 
phenothiazine inhibitor is not critical and can be varied within the skill 
of one in the art. As a practical matter, however, yields of 1-methoxy 
isomer have not been significantly improved by use of phenothiazine in 
amounts in excess of the present 0.1% w/w concentration. 
The temperature of the fluoroborate solution is critical in the sense that 
when the temperature exceeds 60.degree. C., product yield decreases. 
Further decreases in yield were noted if the crude 7-methoxy isomer 
product was allowed to stand for an extended period of time, e.g., 
overnight prior to distillation. 
The reaction temperature used in the thermal isomerization of 
7-methoxycycloheptatriene to 3-methoxycycloheptatriene at atmospheric 
pressure should not substantially exceed 150.degree. C., since at higher 
temperatures, there is a potential for loss of material due to charring. 
When the thermal isomerization was carried out under pressure in a sealed 
container at 180.degree. C., all of the 7-methoxy isomer was thermally 
isomerized to give 1-methoxycycloheptatriene as its principal product. The 
temperature used in the sealed container thermal isomerization can be 
increased above 180.degree. C., e.g., 220.degree. for one hour or 
250.degree. C. for 5 minutes without adversely affecting product yield, 
but continued heating at higher temperatures may result in decreased 
purity of the methoxycycloheptatriene isomer product. 
The time requirement for the acid-catalyzed isomerization of 
3-methoxycycloheptatriene to 1-methoxycycloheptatriene has been found to 
be 2 hours for optimum conversion, with shorter periods giving less 
conversion and larger periods resulting in increased impurity content in 
the final product. The ambient temperature conditions used in this 
acid-catalyzed rearrangement process step can be varied to give faster or 
slower reaction rates with higher or lower temperatures, but the overall 
yield and purity will not be significantly effected. 
The acid-catalyzed isomerization reaction has been found to be sensitive to 
substantial reduction in the amount of acid catalyst used (almost no 
conversion with an 80% reduction in catalyst); but increasing the amount 
of catalyst, e.g., 100% increase, has no effect on the yield. 
The use of triethylamine as a neutralizing agent in the acid catalyzed 
isomerization reaction has resulted in a more rapid and convenient 
reaction than that obtained with the anhydrous sodium bicarbonate of the 
prior art process. 
With the above reaction condition limitations in mind, the reaction 
conditions and amounts of reactants used in the present process may be 
varied within the scope of the invention to achieve optimum yield and 
purity of product 1-methoxycycloheptatriene irritant agent. 
The particular materials and apparatus used in the practice of this 
invention are conventional in the art and most are readily available from 
commercial suppliers. The particular apparatus used in the practice of 
this invention such as the 6 inch by 22-mm OD Vigreux columns used in 
distillation, are conventional and can be replaced with longer columns or 
high-efficiency spinning band columns, though these have not materially 
increased product purity. The particular solvents used in the process of 
this invention can also be varied, as for example, by replacement of the 
preferred methanol solvent with diethyl ether, with consequential increase 
in yield and decrease in product purity. 
The improved process of this invention has succeeded in producing 
1-methoxycycloheptatriene in substantially increased yields and purity at 
an increased reaction rate through use of a polymerization 
inhibitor/retarder for minimizing impurities and extraneous materials in 
the reaction product. 
The improved process of this invention can further be used for synthesizing 
analogous alkoxycycloheptatriene isomers by substitution of the 
appropriate corresponding reactants in the novel process steps of this 
invention. 
The particular polymerization inhibitor used can be selected from 
conventional polymerization inhibitors such as hydroquinone, nitrobenzene 
and L-ascorbyl palmitate, though phenothiazine has been found to give far 
better results in the process of this invention. 
Finally, the 1-methoxycycloheptatriene synthesized by the improved process 
of this invention has been known in the art as an effective irritant agent 
which can be disseminated in liquid or vapor form by conventional 
dissemination means. The use of 1-methoxycycloheptatriene as an irritant 
agent and the method of disseminating this agent is therefore not 
considered a part of this invention. 
Applicant having disclosed his invention, obvious modification will become 
apparent to those skilled in the related chemical art. Applicant therefore 
wishes to be limited only by the scope of the appended claims.