Vinyl ether
Encyclopedia
Vinyl ether, also known as divinyl ether, divinyl oxide, Vinethene (pharmaceutical trade name) and ethenoxyethene (IUPAC), is a clear, nearly colorless, volatile liquid which was briefly used as an inhalation anesthetic. It can be cyclopolymerized by itself and serves as a cross-linker in copolymerizations.
Much to the dismay of some pharmacologists, the synthesis and isolation of pure vinyl ether proved to be a difficult challenge for chemists; vinyl ether was suspected to be a nearly ideal anesthetic as its structure was the combination of an alkene
and an ether
. In practice, vinyl ether proved to have favorable properties that allowed its brief usage as an anesthetic; on the other hand, it left many unimpressed. Aggravated by the issue of potentially toxic degradation over long-term storage and possible hepatic toxicity, vinyl ether began to leave the operating theater. Today, vinyl ether is a relic in the field of anesthesiology; however, the analytical techniques used to study its pharmacology laid the groundwork for the testing of new anesthetic agents.
In 1899, Knorr and Matthes attempted a synthesis of vinyl ether by exhaustive methylation
of morpholine. (Major, 1935) They attained such a small quantity of product that no characterization was possible.
Cretcher et al. reported, in 1925, what would become the foundation for one industrial method used to produce vinyl ether. It was stated that the action of heated sodium hydroxide upon β,β`-dichlorodiethyl ether produced a liquid boiling at 39°C (among other identified products). (Major, 1935) However, in a subtly modified process Hibbert et al. reported the isolation of a product boiling at 34-35°C, "divinyl ether". Finally, in 1929, a patent issued to Merck & Co reported isolation of vinyl ether boiling ca. 28°C. The currently accepted boiling point of vinyl ether is 28.3°C; the Merck patent, therefore, was the first to report the isolation of a pure product.
. (Mazurek, 2007)
As an anesthetic ethylene has many favorable properties, although its very low potency often requires hypoxic
conditions to achieve full anesthesia. Ethyl Ether on the other hand is a fairly potent anesthetic but falls short of ethylene in some respects. In comparison to ether, ethylene has a much lower occurrence of post operative nausea; additionally, ethylene has faster induction and recovery times than ether. (McIntosch, 1925)
Solely guided by predictions based upon structure, Leake perused the usage of vinyl ether as an inhalation anesthetic. (The Science News Letter, 1934) As vinyl ether was unknown in its pure form, Leake approached organic chemists at Berkeley asking them to synthesize this novel anesthetic. (Mazurek, 2007) Leake’s colleagues however, were unable to prepare vinyl ether; later though, Leake received help from two Princeton chemists, Randolph Major and W. T. Ruigh. Using samples received from Princeton, in 1930, Leake and fellow researcher Mei-Yu Chen published a brief study characterizing the anesthetic effects of vinyl ether upon mice. In the conclusion of this study, they cordially invited further research of this drug. (Mazurek, 2007)
This invitation was accepted; in 1933 Samuel Gelfan and Irving Bell of the University of Alberta
published the first human trials of vinyl ether. They reported the experience of Gelfan himself as he was anesthetized with vinyl ether via the open drop technique. (The Science News Letter, 1934) Although, according to Leake, anesthesiologist
Mary Botsford at the University of California
was the first to clinically administer vinyl ether for a hysterectomy in early 1932. (Mazurek, 2007)
Thenceforth, vinyl ether was studied extensively at other institutions, though political climate at Berkeley hindered further study by Leake. Vinyl ether had some success but its usage was limited by aforementioned concerns of liver toxicity and degradation upon long term storage. (Mazurek, 2007)
Vinyl Ether is a rather unstable compound which with exposure to light or acid fumes decomposes to acetaldehyde
and polymerizes into a glassy solid. Like many other ethers vinyl ether is also liable to form peroxides upon exposure to air and light. For these reasons vinyl ether is sold with inhibitors such as poly-phenols and amines to quell polymerization and peroxide formation. (Major, 1937) The anesthetic product was inhibited with .01% phenyl-α-napthylamine which gave it a faint violet fluorescence. (Finer, 1965)
Vinyl Ether rapidly decolorizes a solution of bromine in carbon tetrachloride
; it is also rapidly oxidized by aqueous potassium permanganate
; sulfuric acid
reacts with vinyl ether producing a black tarry resin and some acetaldehyde. (Major, 1935)
Vinyl ether has a rapid onset with little excitement upon induction. Induction causes little coughing however produces increased salivation. (Finer, 1965) During anesthesia vinyl ether can cause some patients to twitch. In rare cases this twitching can lead to convulsions; these convulsions are treatable. (Martin, 1941) Additionally, morphine-atropine pre-medication usually prevents this problem. (Finer, 1965) The recovery from vinyl ether is rapid with only rare cases of post operative nausea and vomiting, although headache after anesthesia sometimes occurs. (Finer, 1965)
Short operations pose little danger to the patient. Longer operations which use greater than 200ml of anesthetic can be dangerous due to hepatic and renal toxicity. In an attempt to circumvent the toxicity of vinyl ether while maintaining its favorable properties it was mixed 1:4 with ethyl ether producing ‘Vinethene Anesthetic Mixture’ (V.A.M.). V.A.M. shows smoother induction and recovery than ethyl ether alone yet is relatively non-toxic for longer procedures. (Finer, 1965) Though compared to ethyl ether V.A.M is less suitable for cases requiring deep anesthesia. (Martin, 1941)
Vinyl ether is a potent anesthetic giving it a large safety margin; the ratio of the anesthetic to lethal does for vinyl ether is 1 to 2.4 (ethyl ether: 1:1.5). (Anderson, 1937) However, this potency is hard to control with simplistic equipment. While anesthetic machines were numerous during the years of vinyl ether’s popularity, the simplistic ‘open drop technique’ also maintained its prevalence. Anesthetic machines of the time could suitably contain vinyl ether’s potency, however, via the open drop technique smooth anesthesia for long procedures was hard to sustain. (Martin, 1941) Further aggravating this problem, warm temperatures increase the volatility of vinyl ether making it even harder to regulate via the open drop technique. (Stumpf, 1935)
Overall, vinyl ether’s only strengths compared to ethyl ether are favorable induction and recovery. During anesthesia vinyl ether has no particularly wonderful properties and is harder to control than other agents. Therefore, vinyl ether was commonly used as a preliminary anesthetic before administration of diethyl ether. Additionally, vinyl ether was only used for short operations or analgesia, e.g. dentistry and obstetrics. Vinyl ether was used infrequently for long operations because of toxicity, cost, and superior alternatives.
Much to the dismay of some pharmacologists, the synthesis and isolation of pure vinyl ether proved to be a difficult challenge for chemists; vinyl ether was suspected to be a nearly ideal anesthetic as its structure was the combination of an alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
and an ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
. In practice, vinyl ether proved to have favorable properties that allowed its brief usage as an anesthetic; on the other hand, it left many unimpressed. Aggravated by the issue of potentially toxic degradation over long-term storage and possible hepatic toxicity, vinyl ether began to leave the operating theater. Today, vinyl ether is a relic in the field of anesthesiology; however, the analytical techniques used to study its pharmacology laid the groundwork for the testing of new anesthetic agents.
Synthetic
The first preparation of vinyl ether was reported in 1887 by Semmler. (Major, 1935) This chemist reported the production of vinyl ether from its sulfur substituted analogue, divinyl sulfide (obtained from the essential oil of Allium Ursinum L.), by reaction with silver oxide. Semmler's product which boiled at 39°C was found to be sulfur free and molecular weight determinations were theoretically in accordance with vinyl ether.In 1899, Knorr and Matthes attempted a synthesis of vinyl ether by exhaustive methylation
Hofmann elimination
Hofmann elimination is a process where an amine is reacted to create a tertiary amine and an alkene by treatment with excess methyl iodide followed by treatment with silver oxide, water, and heat.After the first step, a quaternary ammonium iodide salt is created...
of morpholine. (Major, 1935) They attained such a small quantity of product that no characterization was possible.
Cretcher et al. reported, in 1925, what would become the foundation for one industrial method used to produce vinyl ether. It was stated that the action of heated sodium hydroxide upon β,β`-dichlorodiethyl ether produced a liquid boiling at 39°C (among other identified products). (Major, 1935) However, in a subtly modified process Hibbert et al. reported the isolation of a product boiling at 34-35°C, "divinyl ether". Finally, in 1929, a patent issued to Merck & Co reported isolation of vinyl ether boiling ca. 28°C. The currently accepted boiling point of vinyl ether is 28.3°C; the Merck patent, therefore, was the first to report the isolation of a pure product.
Anesthetic
Even before its isolation and characterization, the application of an unsaturated ether as an anesthetic interested some pharmacologists. One such pharmacologist, Chauncey Leake, was particularly captivated by the then theoretical vinyl ether. Leake predicted that vinyl ether would combine the properties of two anesthetic agents, ethyl ether, and ethyleneEthylene
Ethylene is a gaseous organic compound with the formula . It is the simplest alkene . Because it contains a carbon-carbon double bond, ethylene is classified as an unsaturated hydrocarbon. Ethylene is widely used in industry and is also a plant hormone...
. (Mazurek, 2007)
As an anesthetic ethylene has many favorable properties, although its very low potency often requires hypoxic
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
conditions to achieve full anesthesia. Ethyl Ether on the other hand is a fairly potent anesthetic but falls short of ethylene in some respects. In comparison to ether, ethylene has a much lower occurrence of post operative nausea; additionally, ethylene has faster induction and recovery times than ether. (McIntosch, 1925)
Solely guided by predictions based upon structure, Leake perused the usage of vinyl ether as an inhalation anesthetic. (The Science News Letter, 1934) As vinyl ether was unknown in its pure form, Leake approached organic chemists at Berkeley asking them to synthesize this novel anesthetic. (Mazurek, 2007) Leake’s colleagues however, were unable to prepare vinyl ether; later though, Leake received help from two Princeton chemists, Randolph Major and W. T. Ruigh. Using samples received from Princeton, in 1930, Leake and fellow researcher Mei-Yu Chen published a brief study characterizing the anesthetic effects of vinyl ether upon mice. In the conclusion of this study, they cordially invited further research of this drug. (Mazurek, 2007)
This invitation was accepted; in 1933 Samuel Gelfan and Irving Bell of the University of Alberta
University of Alberta
The University of Alberta is a public research university located in Edmonton, Alberta, Canada. Founded in 1908 by Alexander Cameron Rutherford, the first premier of Alberta and Henry Marshall Tory, its first president, it is widely recognized as one of the best universities in Canada...
published the first human trials of vinyl ether. They reported the experience of Gelfan himself as he was anesthetized with vinyl ether via the open drop technique. (The Science News Letter, 1934) Although, according to Leake, anesthesiologist
Anesthesiologist
An anesthesiologist or anaesthetist is a physician trained in anesthesia and peri-operative medicine....
Mary Botsford at the University of California
University of California
The University of California is a public university system in the U.S. state of California. Under the California Master Plan for Higher Education, the University of California is a part of the state's three-tier public higher education system, which also includes the California State University...
was the first to clinically administer vinyl ether for a hysterectomy in early 1932. (Mazurek, 2007)
Thenceforth, vinyl ether was studied extensively at other institutions, though political climate at Berkeley hindered further study by Leake. Vinyl ether had some success but its usage was limited by aforementioned concerns of liver toxicity and degradation upon long term storage. (Mazurek, 2007)
Chemical
Vinyl Ether is a volatile, flammable liquid with a sweet, ethereal non-irritating odor (described to be similar to ethyl chloride). It is practically insoluble in water (.53g/100g water at 37°C) but miscible with ethanol, ethyl ether, oils and other organic solvents.Vinyl Ether is a rather unstable compound which with exposure to light or acid fumes decomposes to acetaldehyde
Acetaldehyde
Acetaldehyde is an organic chemical compound with the formula CH3CHO or MeCHO. It is one of the most important aldehydes, occurring widely in nature and being produced on a large scale industrially. Acetaldehyde occurs naturally in coffee, bread, and ripe fruit, and is produced by plants as part...
and polymerizes into a glassy solid. Like many other ethers vinyl ether is also liable to form peroxides upon exposure to air and light. For these reasons vinyl ether is sold with inhibitors such as poly-phenols and amines to quell polymerization and peroxide formation. (Major, 1937) The anesthetic product was inhibited with .01% phenyl-α-napthylamine which gave it a faint violet fluorescence. (Finer, 1965)
Vinyl Ether rapidly decolorizes a solution of bromine in carbon tetrachloride
Carbon tetrachloride
Carbon tetrachloride, also known by many other names is the organic compound with the formula CCl4. It was formerly widely used in fire extinguishers, as a precursor to refrigerants, and as a cleaning agent...
; it is also rapidly oxidized by aqueous potassium permanganate
Potassium permanganate
Potassium permanganate is an inorganic chemical compound with the formula KMnO4. It is a salt consisting of K+ and MnO4− ions. Formerly known as permanganate of potash or Condy's crystals, it is a strong oxidizing agent. It dissolves in water to give intensely purple solutions, the...
; sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...
reacts with vinyl ether producing a black tarry resin and some acetaldehyde. (Major, 1935)
Anesthetic
In the United States, vinyl ether was sold under the trade name Vinethene. In addition to the normal inhibitors, vinyl ether intended for anesthetic use contained some ethanol (1.5-5%) to prevent frosting of the anesthetic mask. (Major, 1937) Despite inhibitors manufacturers warned that once opened vinyl ether should be used quickly. (Stumpf, 1935)Vinyl ether has a rapid onset with little excitement upon induction. Induction causes little coughing however produces increased salivation. (Finer, 1965) During anesthesia vinyl ether can cause some patients to twitch. In rare cases this twitching can lead to convulsions; these convulsions are treatable. (Martin, 1941) Additionally, morphine-atropine pre-medication usually prevents this problem. (Finer, 1965) The recovery from vinyl ether is rapid with only rare cases of post operative nausea and vomiting, although headache after anesthesia sometimes occurs. (Finer, 1965)
Short operations pose little danger to the patient. Longer operations which use greater than 200ml of anesthetic can be dangerous due to hepatic and renal toxicity. In an attempt to circumvent the toxicity of vinyl ether while maintaining its favorable properties it was mixed 1:4 with ethyl ether producing ‘Vinethene Anesthetic Mixture’ (V.A.M.). V.A.M. shows smoother induction and recovery than ethyl ether alone yet is relatively non-toxic for longer procedures. (Finer, 1965) Though compared to ethyl ether V.A.M is less suitable for cases requiring deep anesthesia. (Martin, 1941)
Vinyl ether is a potent anesthetic giving it a large safety margin; the ratio of the anesthetic to lethal does for vinyl ether is 1 to 2.4 (ethyl ether: 1:1.5). (Anderson, 1937) However, this potency is hard to control with simplistic equipment. While anesthetic machines were numerous during the years of vinyl ether’s popularity, the simplistic ‘open drop technique’ also maintained its prevalence. Anesthetic machines of the time could suitably contain vinyl ether’s potency, however, via the open drop technique smooth anesthesia for long procedures was hard to sustain. (Martin, 1941) Further aggravating this problem, warm temperatures increase the volatility of vinyl ether making it even harder to regulate via the open drop technique. (Stumpf, 1935)
Overall, vinyl ether’s only strengths compared to ethyl ether are favorable induction and recovery. During anesthesia vinyl ether has no particularly wonderful properties and is harder to control than other agents. Therefore, vinyl ether was commonly used as a preliminary anesthetic before administration of diethyl ether. Additionally, vinyl ether was only used for short operations or analgesia, e.g. dentistry and obstetrics. Vinyl ether was used infrequently for long operations because of toxicity, cost, and superior alternatives.