Address correspondence to Raymond C. Roy, MD, PhD, Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009. Address e-mail to [email protected].
The title is an homage to the novel The Spy Who Came in from the Cold published in 1963, the year that enflurane was discovered. It is also meant to introduce the strong historical and chemical connections shared by refrigerants and inhaled anesthetic agents. Before diethyl ether was an anesthetic, it was the refrigerant described in the 1834 patent for the first vapor compression machine for making ice.
Modern refrigerants and inhaled agents contain carbon-fluorine bonds synthesized by the Swarts reaction, developed in the 1890s. It remained a laboratory curiosity until the 1930s when it was applied on an industrial scale to produce chlorofluorocarbon (CFC) refrigerants, trademarked as Freons (DuPont), Arctons (Imperial Chemical Industries [ICI]), and Genetrons (Honeywell). Terrell and Croix né Speers synthesized the modern agents using the Swarts reaction. The industrial processes yielding enflurane, isoflurane, desflurane, and sevoflurane in sufficient quantity to meet the world's needs, a 1.46-billion-dollar industry in 2022, are modeled after the CFC production methods.
I argue that the modern agents are a legacy of the refrigeration industry and not, as often claimed, of the Manhattan Project (Table). Industrial production has always been critical to the availability of inhaled anesthetics from ether and chloroform to modern agents.
During the Scottish Enlightenment medical school lectures were open to the public. Professorial appointments were unsalaried, so lecturers charged fees for their presentations that included memorable demonstrations. The notes of the charismatic William Cullen (1710-1790; Glasgow 1743-1755; Edinburgh 1755-1790) were widely circulated throughout Europe. He lectured in English rather than Latin. From 1748, he demonstrated ice production by using a vacuum pump to lower boiling point of ether and enhance its evaporation, which cooled the atmospheric water vapor enough to create ice on the vessel surface. Thus, ether was first demonstrated as a refrigerant almost 100 years before its use as an anesthetic. Benjamin Franklin in 1757 discussed with the English physician-scientist John Hadley the decrease in temperature and appearance of ice when ether evaporated from the mercury bulb of a thermometer.
Early Applications of Ether As a Refrigerant
The icebox, as a container for ice to keep contents cold, was invented in 1802 by Thomas Moore (1760-1822). Early applications of artificial refrigeration used ether to produce ice to compete with natural lake and river ice that was harvested in blocks in colder regions and shipped to warmer locations. Initially, natural ice wastage was 66%, but with better-insulated ships, it was 8%. Several individuals became wealthy "ice kings." Natural ice was the second most lucrative export from the United States after cotton in 1870. Supplemental Digital Content 1, Supplement S1, https://links.lww.com/AA/E825, details some of the key work of innovators producing artificial ice using ether, like Jacob Perkins (1766-1849), the "father of the mechanical refrigerator," Alexander Catlin Twining (1801-1884), and James Harrison (1816-1893).
Chlorofluorocarbon Refrigerants
As the industry moved from making ice for ice boxes to keeping things cold with cooling coils, refrigerants entered the home. Fred William Wolf, Jr (1879-1954) invented the first electric refrigerator for the home, the Domelre (domestic electric refrigerator) in 1913. By then ammonia, butane, methyl bromide, methyl chloride, sulfur dioxide, and others had replaced ether, although it was still listed as a refrigerant in the 1930 American Medical Association Committee on Poisonous Gases report on the health risks of these chemicals.
In 1928, Thomas Midgley, Jr (1889-1944) and Albert Leon Henne (1901-1967) presented dichlorodifluoromethane as a nontoxic, noncorrosive, and nonflammable refrigerant. It was the first chemical with a carbon-fluorine bond to be produced industrially. This and other molecules containing both carbon-chlorine and carbon-fluorine bonds were called CFCs. They are considered first-generation refrigerants by carbon-fluorine chemists with diethyl ether belonging to the zero-generation. Studies in the 1970s demonstrated a climate impact by CFCs. Second-generation refrigerants (hydrochlorofluorocarbons) were developed with lower ozone-depleting potential (ODP). Then third-generation refrigerants (hydrofluorocarbons) appeared with no ODP, but unfortunately were shown to have significant global warming potential (GWP). Fourth-generation refrigerants (hydrofluoroolefins with olefin meaning a carbon-carbon double bond) have low ODP and GWP, but added a degree of flammability Modern anesthetic agents, scavenged and expelled into the atmosphere above hospitals, also have significant ODP and GWP. The return of ether as a refrigerant has recently been suggested because of its minimal ODP and GWP.
Fluorinated Refrigerants As Anesthetic Agents
The drive to develop nonflammable anesthetic agents increased after October 1, 1926, when Harvey Williams Cushing (1869-1939) first used William Tecumseh Bovie's (1882-1958) electrosurgical unit in an anesthetized patient. Since refrigerants and anesthetic agents share similar physical properties, for example, liquid at room temperature and easily vaporized, new refrigerants and related compounds were tested as potentially inflammable anesthetics. Fluorination of existing anesthetic agents was also attempted. Booth and Bixby and Henne studied the fluorine derivatives of chloroform for anesthetic activity and found them lacking. Earl Thurston McBee (1906-1973) sought to fluorinate cyclopropane but was unsuccessful.
The refrigerant 2-chloro-1,1,1-trifluoroethane (CF3CH2Cl), or Freon 133a, was prepared by McBee and sent to Benjamin Howard Robbins (1904-1960) as one of 46 compounds for pharmacologic testing. Robbins studied all 46 and suggested that CF3CHBr2 had potential but the above CF3CH2Cl did not. However, Charles Walter Suckling (1920-2013) substituted a bromine for a hydrogen in Freon 133a, which was an Arcton in the ICI system, to make 2-bromo-2-chloro-1,1,1-trifluoroethane (CF3CHBrCl), or halothane. Suckling was working for the General Chemicals Division of ICI which had experience in producing pesticides and CFC refrigerants. He had the reversibility of halothane anesthesia tested first on grain weevils by Frank Bradbury using the ICI model from their pesticide research before asking Raventos and Johnstone to do the mammal and human testing.
Several authors have assumed, perhaps because Robbins recommended CF3CHBr2 for further investigation, that Suckling replaced a bromine with a chlorine in this molecule. However, the chemical reaction to do this was too difficult to commercialize. Suckling started with a fluorinated molecule, readily available from the refrigeration industry, and substituted a bromine for a hydrogen using a well-established bromination process.
Carbon-Fluorine Chemistry -- the Swarts Reaction
Fluorine occurs relatively commonly in the earth's crust (fluorspar). But carbon-fluorine bonds occur rarely in living things. The first carbon-fluorine bond was synthesized in 1835 by Jean-Baptiste André Dumas (1800-1884) and Eugène-Melchior Péligot (1811-1890) who heated dimethyl sulfate (produced by the reaction of sulfuric acid with methanol) with dry potassium fluoride to produce monofluoromethane. Importantly this reaction did not require elemental fluorine as the fluorine source. Fluorine was isolated in 1886 by Nobel Laureate Ferdinand Frédéric Henri Moissan (1852-1907) but his attempts to produce carbon-fluorine compounds by direct reaction of hydrocarbons with elemental fluorine all led to fires or explosions.
The breakthrough came with the Belgian chemist Frédéric Jean Edmond Swarts (1866-1940), who replaced some of the hydrogens in methane and ethane by direct reaction with chlorine or bromine gas. Next, he replaced the chlorine or bromine with fluorine derived from antimony fluoride. His first published reaction was between SbF3Br2 and carbon tetrachloride to produce CFCl3 (Freon 11). The use of heavy metal fluorides as the source of fluorine is called the Swarts reaction.
Because Swarts published in Belgian journals, the details of his work were not widely distributed. Fortunately, Henne was also Belgian and with Midgely applied the Swarts reaction to produce Freons. Booth then applied the Swarts reaction to make fluorine derivatives of chloroform to study as anesthetics. He and Henne in separate publications also described the syntheses of fluorochloroethanes, a derivative of which would subsequently lead to halothane. Henne introduced the Swarts reaction to McBee, whose earlier work had enabled the commercial production of cyclopropane by Mallinckrodt. They fluorinated chloropropanes in Henne's laboratory. Then, McBee in his own laboratories produced the 46 compounds containing fluorine using the Swarts reaction that were sent to Robbins. Finally, the Swarts reaction is also cited by Ross Clark Terrrell (1925-2010) and Louise Speers Croix (1920-1992) in their syntheses of the modern agents.
The Manhattan Project (1941-1946)
The work of the Project was intensely focused on the creation of an atomic bomb. Its chemical engineering efforts were divided into 2 major areas. One was the separation of fissile uranium-235 from uranium ore, predominately nonfissile uranium-238. The other area was the development of coolants, lubricants, pressure seals, valve packings, gaskets, and tubing inert to fluorine and uranium hexafluoride for the equipment required. In 1941, Aristid von Grosse (1905-1985) established that molecules containing only carbon and fluorine fit the requirements. Fluorine chemists, including McBee and William Taylor Miller, Jr (1911-1998) were recruited to develop the required compounds. McBee was responsible for the preparation of the alkane coolant perfluoroheptane and the aromatic precursor bis(trifluoromethyl)benzenes. Miller studied the reactions involving methyl alcohol fluoroethylenes, which produced ethers that included methoxyflurane and developed poly (chlorotrifluoroethylene) polymers for lubricating oils, greases, and waxes.
The Table summarizes quotations from the anesthesia literature that suggest modern anesthetics emerged from the Manhattan Project. Medical historians are challenged with dating this work accurately because Project scientists were forbidden from publishing their work. McBee started with the Project in late 1941 and only published in 1947 work appearing in doctoral dissertations from 1941 and 1942 describing the synthesis of the 46 carbon-hydrogen-fluorine compounds sent to Robbins. In a 1970 interview McBee stated, "...we did carry on an extensive research program for years making fluorine-containing anesthetics..." Then, "... we changed our research program in 1941 from organic chemistry (carbon-hydrogen-halogen molecules) to inorganic chemistry (carbon-fluorine and uranium hexafluoride)." Thus, McBee's preparation of the compounds sent to Robbins by Mallinckrodt occurred before his involvement with the Project. Robbins' paper on the 46 compounds was received by the journal in 1945, describing work performed "during the past two years." Moreover, those working on the Manhattan Project were not seeking anesthetic agents (Supplemental Digital Content 2, Supplement 2, https://links.lww.com/AA/E826). Although Miller did prepare methoxyflurane in 1944 while working for the Project, its synthesis was previously patented in 1940 by Gowland using the Swarts reaction.
The fluorination processes developed for the Project were either too dangerous, too expensive, or both for the industrial production of anesthetic agents. When Terrell and Croix created the new carbon-fluorine bonds in the modern agents, they used the Swarts reaction.
Modern agents are a legacy of the industrialization of the Swarts reaction by the refrigeration industry in the 1930s.
Importance of Industrialization
Industrialization yielded high-quality agents in large volumes. Quality, as defined by purity, was an issue with diethyl ether and chloroform. Charles Thomas Jackson (1805-1880) noted that ether "should be free from Sulphurous acid, Aldehyde and Alcohol." James Young Simpson (1811-1870) complained in 1847 of the impure chloroform he purchased (specific gravity "1.130 instead of 1.480. There was little or no chloroform in it.") Yet, initially not everyone appreciated the purity of Eward Robinson Squibb's ether (Supplemental Digital Content 3, Supplement S3, https://links.lww.com/AA/E827).
The production of modern agents is far more complex than that for ether and chloroform. There are many steps between the discovery chemical reaction to the actual production of an anesthetic agent: (1) original reaction with low yield of desired product; (2) improved reaction with higher yield; (3) product purification by distillation, crystallization, column separation, etc; (4) pharmacologic testing with pure product; (5) pilot plant production; and then (6) full production. The commercial production of the Freons is a good example. Midgeley and Henne translated a laboratory curiosity into an industrial process. "Frigidaire (General Motors) and Du Pont founded a joint company (Kinetic Chemicals) which began manufacture of the new materials under the trade name Freons. Following the originators' patents, and using large-scale processes worked out by Daudt and Youker, Freons 11 (CFCl3), 12 (CF2Cl2), 113 (CF2ClCFCl2), and 114 (CF2ClCF2Cl) were introduced early in the decade followed later by Freon 22 (CHF2Cl) as a result of process improvements by Benning."
The genius of Terrell and Croix was to focus on compounds with an ether linkage and always to consider the industrialization component. For any new agent they required "a synthesis that could be used to manufacture relatively large quantities [tons]" "... much of the work was done with readily available starting materials, such as CF2=CFCl, the starting material for enflurane; CF3CH2OH and CF2HCl (Freon 22), the starting materials for isoflurane and desflurane; and (CF3)2CH-OH, the starting material for sevoflurane." Isoflurane is a great example of the issue of transition from original synthesis to industrial production. "The first synthesis of isoflurane was a three-step process starting from trifluoroethanol... Although this method was suitable for preparation of experimental quantities, the yields were too low for commercial manufacture, the major problem being low yields in the chlorination step." "Difficulties in purifying the final chlorination product almost led to the abandonment of the compound." Croix salvaged the process by introducing "difluorocarbene into a process where it was used to manufacture hundreds of tonnes of isoflurane during its patent life time and even greater amounts when it became a generic drug. Croix' second breakthrough came when it was necessary to remove the contaminant..."
In summary, the refrigeration industry owes a debt to what was later discovered to be an anesthetic, diethyl ether. It "repaid the debt" by introducing chemical compounds with carbon-fluorine bonds and industrializing their production. Modern anesthetic agents emerged as derivatives of carbon-fluorine refrigerants (halothane) or from the industrial application of the Swarts fluorination reaction first applied in the refrigeration industry. Modern inhaled agents are not legacies of the Manhattan Project. They came in from the cold of the refrigeration industry.
ACKNOWLEDGMENTS
The author acknowledges and sincerely thanks Judith Robins of the Wood Library-Museum for her assistance in utilizing the resources of the Wood Library Museum of Anesthesiology, Schaumberg, IL. Administrative support was provided Addie Larimore in the Department of Anesthesiology of Wake Forest University School of Medicine, Winston-Salem, NC.