Vinyl ether

Vinyl ether

Systematic (IUPAC) name
ethenoxyethene
Clinical data
Routes of administration	inhalation
Pharmacokinetic data
Excretion	pulmonary
Identifiers
CAS Number	109-93-3 N
ATC code	N01AA02 (WHO)
PubChem	CID 8024
ChemSpider	7733 Y
Chemical data
Formula	C4H6O
Molar mass	70.0898 g/mol
3D model (Jmol)	Interactive image
SMILES O(\C=C)\C=C
InChI InChI=1S/C4H6O/c1-3-5-4-2/h3-4H,1-2H2 Y Key:QYKIQEUNHZKYBP-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

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.

History

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 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 ethylene. (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)

Properties

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 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)

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.

Also, experiments were conducted with ethyl vinyl ether, a compound with one vinyl and one ethyl group. This substance produced results placing it between diethyl ether and divinyl ether both in terms of toxicity and speed of induction and recovery, producing promising results similar to V.A.M. (Grosskreutz, Davis 1956) Despite much simpler synthesis (vinylization of ethanol with acetylene) ethyl vinyl ether didn't enter widespread use in anasthetics, as superior halogenated ethers replaced it shortly after its first trials.

References

1. R. Major, et al. U.S. Patent 2,021,872, 1935.
2. Mazurek, M J. California Society of Anesthesiologists Bulletin 2007, 55(4), 86-9.
3. O. McIntosch. The American Journal of Nursing 1925, 25(4), 290-93.
4. The Science News-Letter, Vol. 26, No. 709. (Nov. 10, 1934), pp. 293–294.
5. R. Major, et al. U.S. Patent 2,099,695, 1937.
6. Finer, Basil. Brit. J. Anaesth. 1965, 37, 661-66.
7. Stumpf, E H. The Journal of American Institute of Homeopathy 1935, 28(9), **.
8. Martin, Stevens. Anesthesiology 1941, 2(3), 285-299.
9. Anderson L. F. The American Journal of Nursing 1937, 37(2), 276-280.

October 1956, Volume 3, Issue 4, pp 316–325

1. Grosskreutz D. C., Davis D. A. "Use of ethyl vinyl ether for general and thoracic surgery", Canadian Anaesthetists’ Society Journal 1956