Bis(trichloromethyl)carbonate (BTC, Triphosgene): A Safer Alternative

Communication pubs.acs.org/OPRD

Bis(trichloromethyl)carbonate (BTC, Triphosgene): A Safer Alternative to Phosgene? Livius Cotarca,†,* Thomas Geller,‡ and József Répási§ †

LC Consulting, 33052 Cervignano del Friuli (UD), Italy Product Supply, Crop Science Division, Bayer AG, 41539 Dormagen, Germany § SONEAS Hungary, Illatos út 33, Budapest, H-1097, Hungary ‡

(vapor pressure at ambient temperature appr. 0.4 mbar), and commercial availability. In addition, BTC is currently not as tightly regulated as phosgene, and its reputation is, without wellfounded reasons, much better than that of phosgene. Because of the stability of BTC at ambient temperature and its solid-state handling, the transportation, storage, handling, and processing of BTC appear to be more convenient than for phosgene. On small and medium scales (laboratories and pilot plants), BTC provides substantial operational convenience because exact amounts can be weighed easily. Furthermore, no facilities for carbon monoxide or chlorine (or phosgene cylinder) handling are necessary. This ease of handling helps pharmaceutical and fine chemicals producers perform “phosgenations” in pilot plants and kilo laboratories, which are normally not adequately equipped to use phosgene directly. Because of the setup of these facilities, phosgene is normally replaced with BTC or another phosgene substitute/equivalent during the process research and development phases. For various reasons, including commercial aspects, suppliers and most published literature brand BTC as “safe phosgene”, or “safer phosgene,” or “green phosgene.” The branding as “safe phosgene” is particularly misleading. New research results clearly show that BTC is at least as dangerous as phosgene.4,5 Its toxicity is only partly related to phosgene, which is released as a byproduct in the off-gas phases during reactions; BTC has a distinctive toxicity profile that differs substantially from that of phosgene.4 Although BTC is a solid, it has a low but significant vapor pressure and sublimes. At room temperature, the BTC concentration of a saturated atmosphere is 4.2 g/m 3 , approximately 100 times higher than the LC50 value for rats (41.5 mg/m3), (see Toxicology section, infra). Ubichem reports an even higher value (11.6 g/m3) for the calculated BTC concentration in a saturated atmosphere.6 Because of the high lipophilicity of BTC, it does not react directly with water. Under certain conditions, BTC vapor can even pass a sodium hydroxide scrubber unchanged and may be found as a deposit behind the scrubber. This problem must be solved individually for each process. In industrial environments, handling is critical because no detector calibrated for BTC is commercially available; thus, discrimination between phosgene and BTC is not yet possible, meaning that relevant concentrations of BTC may remain undetected.

ABSTRACT: Bis(trichloromethyl)carbonate (BTC, triphosgene) is a versatile compound that enables highly efficient syntheses. In addition, because of its solid state, it is a very convenient compound for small-scale phosgenations. Consequently, this compound is favored as a phosgene substitute in research and development and in small-scale production. Although BTC is highly toxic, safe handling is possible as long as the properties and chemical reactivity of this compound are understood and considered. However, branding as “safe phosgene” or “safer phosgene” is misleading. The solid state of BTC leads to the misconception that there is no significant exposure. However, the vapor pressure is sufficiently high to easily result in toxic concentrations. In addition, proper monitoring is not yet possible. Proper use of BTC could be more complex than the handling of phosgene itself. However, handling of BTC is normally always associated with phosgene and has its own toxicity. Therefore, the use of BTC will become more regulated in the future, which will directly increase responsibility in route selection during process development. A stringent safety concept for phosgenations using BTC is necessary. Because of the interconnection with phosgene, the safety concept for BTC will likely be an extended version of the safety concept for phosgene.

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INTRODUCTION Bis(trichloromethyl) carbonate (BTC, also known as triphosgene) was first described as early as 1880,1 and a patent using BTC was filed in 1900.2 Surprisingly, the compound remained almost unknown for the next 100 years.

BTC was “re-discovered” in the last decades of the 20th century and is now the most commonly used phosgene substitute.3a−f It is widely used in research, development, and industry, for example, for the production of active pharmaceutical ingredients (APIs) but also for agrochemicals, polymers, and fine chemicals on small-to-medium scales (Figure 1). The popularity of BTC is directly related to its physical properties, that is, its solid form, its low tendency to evaporate © 2017 American Chemical Society

Received: June 26, 2017 Published: August 11, 2017 1439

DOI: 10.1021/acs.oprd.7b00220 Org. Process Res. Dev. 2017, 21, 1439−1446

Organic Process Research & Development

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Figure 1. Triphosgene applications.

The misconception of a “safer phosgene” is dramatically underscored by the fact that, within the last 10 years, several significant incidents with phosgene were de facto incidents with BTC (Table 1).

not available, OECD is the abbreviation of The Organization for Economic Co-operation and Development (OECD Guidelines for the Testing of Chemicals)]. Other toxicological data are rare. Because of the lack of additional data, a conservative risk assessment is necessary!

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Table 1. Recent Incidents with BTC (Including Incidents from BTC Generated Phosgene) 2004 Fuzhou City (China)

561 people (1 fatality, 2 severe poisonings, 1 moderate poisoning, 18 mild poisoning, 24 irritations, of which 14 were members of the medical staff) 24 people (acute poisoning)

2007 unknown location (China) 2008 Munich 40 people (2 severe poisoning, 40 hospitalized) (Germany) 2009 Union 16 people (13 hospitalized) (USA) 2011 Suzhou 82 people (1 fatality, 23 severe poisonings, 81 (China) hospitalized)

SOURCES OF BTC AND QUALITY Most BTC is produced via photochlorination of dimethyl carbonate in China (Table 2); few BTC producers operate

ref 7

Table 2. BTC Producers in China (2013)

ref 8

company name

BTC capacity (kT/y)

SX Shanxi Wuchan Fine Chemical Co., Ltd. SD Shandong Zhongyuan Chengwu Chemical Co., Ltd. SX Shanxi Shanhe Chemical Co., Ltd. ZJ Zhejiang Lishui Youbang New Materials Co., Ltd. JS Jiangsu Lianyungang Chaofan Chemical Co., Ltd. SD Shandong Dezhou Lvbang Chemical Co., Ltd.

10 10 8 6a 6 1

ref 9 ref 10 ref 11

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a

ZJ Zhejiang Lishui Youbang New Materials Co. (= Upchem) claims to have increased capacity to 20 kT/y.

TOXICOLOGY As a solid, BTC is assumed to be an unproblematic compound. However, recent publications describe an aggressive attack of the mucosa, a significant vapor pressure and sublimation.4,5 The vapor pressure of approximately 0.4 mbar at ambient temperature is sufficiently high to result in toxicologically critical concentrations. It does not immediately decompose to phosgene; however, the BTC molecule itself interacts with biological systems. Studies with rats have clearly shown that the toxicological profile of BTC and phosgene are remarkably different.4,12,13 Whereas phosgene is only acutely toxic, BTC exhibits a biphasic mortality pattern typical for irritant gases, causing injuries in both the lower respiratory tract and the airways. After an acute toxic effect, a second mortality peak occurs after 11−14 days. In inhalation studies the LC50 (acute median lethal toxic concentration) value of BTC was determined to be 41.5 mg/m3 or 3.4 ppm (LC50 of phosgene: 7.2 mg/m3 or 1.8 ppm). Thus, the vapor saturation concentration of BTC at ambient temperature is approximately 100 times its LC50.4 A calculation of the preliminary estimated occupational exposure level (OEL) would result in an OEL of 1 μg/m3 [8 h, no TLVSTEL - short-term exposure limit conditional value because a long-term OECD TG#412 and/or TG#413-inhalation study is

outside of China, and these products usually manufacture BTC for internal use only. Currently, more than 500 T/y of this material is exported to India. The quality of BTC on the market differs dramatically. One quality indicator might be the appearance of the BTC. Lowquality BTC can contain amorphous material, whereas better quality BTC is fully crystalline. BTC of lower quality typically has a lower stability and contains more volatile toxic compounds.4 Most of the impurities are derived from the manufacturing process, as the photochlorination is a consecutive substitution process, with partially chlorinated dimethyl carbonates (all are liquids, see structures shown below) as intermediates:

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(CCl4 solution) appear at 1832 cm−1 for CO stretching and at 1178, 967, and 945 cm−1 for C−O stretching. Various physical data for BTC are available in the literature. Some data are summarized in Table 3 and Figure 3.

Other impurities such as phosgene and diphosgene are generated by degradation.14,15 BTC of industrial quality can contain more than 20 different impurities at concentrations greater than 0.1%; the concentrations of some of these impurities can even exceed 1% (e.g., carbon tetrachloride). Carbon tetrachloride and partially chlorinated dimethyl carbonates are toxic.16 Although impurities might be acceptable for the production of fine chemicals, they are surely not acceptable for APIs or their direct precursors. For these purposes, purified or recrystallized BTC is required, which could profoundly affect the process economics as well as the safety requirements. BTC, which is available at less than 2 USD/kg when purchased in ton quantities, can easily cost 100 USD/kg if needed in high quality. Quality is typically controlled using argentometric titration methods (with or without pretreatment). However, the content determined by these methods may be misleading because they do not appropriately discriminate between BTC and the aforementioned impurities. For example, BTC (Cl content 71.68%) containing 10% pentachlorodimethyl carbonate (an intermediate in the production process; Cl content 67.58%) would show a content of 99.4% in the assay. Inaccurate purity may result in numerous problems because partially chlorinated impurities can affect the stability of the product, result in the formation of unexpected impurities during reactions, and cause lower or variable yields. If the impurity profile of the product must be controlled (e.g., in the manufacture of APIs or advanced intermediates), other analytical methods must be used. The best method for purity control is likely quantitative 1H NMR. Chromatographic methods can be used to map impurities and evaluate their carry-over into the subsequent steps of the process.

Table 3. Physical and Toxicity Properties of Phosgene and BTC phosgene

BTC

formula CAS Reg. No. MW (g/mol) phase @ ambient conditionsa bp (°C)/760 Torr mp (°C) density of melted BTC (g/cm3) density of bulk solid (g/cm3) solubility

parameter

COCl2 75-44-5 98.916 colorless gas 7.4−8.2 −128 to −118

vapor pressure (mm Hg @ 20 °C) LC50, rat, inhalation, 4 h (mg/m3 air)b

1170−1215 7.2

C3O3Cl6 32315-10-9 296.748 crystalline solid 203−206 79−83 1.629 (80 °C) 1.723c soluble in ether, tetrahydrofuran, hexane, chloroform, dioxane, ethyl acetate 0.263 (25 °C) 41.5

Temperature (20 °C) and pressure (1 atm). bSee also ref 12. cSee also refs 20 and 21.

a

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STRUCTURE AND PHYSICAL PROPERTIES Hales was first to draw attention to the inappropriate term “triphosgene” because the compound is not derived from carbonyl chloride (structure A).17 The two trichloromethoxy groups of BTC (structure B) are almost electronically equivalent to the chlorine atoms in phosgene, which explains these compounds’ similar nucleophilic reactivity patterns. A cyclic unstable “trioxomethylene” structure (structure C) has been proposed but has never been observed in the solid state at standard temperature and pressure (Figure 2).18 The structure of BTC was predicted by Hales et al. on the basis of IR spectra, with special reference to CO and C−O stretching vibrations.17 The importance of this work resides in the first confirmation of a planar structure for BTC before X-ray data were available.19 The main bands in the IR spectrum of BTC

Figure 3. BTC vapor pressure data.

BTC is currently not listed in the DIPPR 801 database (American Institute of Chemical Engineers) of physical properties of industrial chemicals. More research is required to close the information gaps on triphosgene. Vapor pressure data for BTC in the literature are very rare. To our knowledge, only Ubichem has provided experimental vapor pressure data,.6 A particularly important but widely unknown behavior of BTC is that it sublimes even at room temperature. This fact is of utmost importance for the handling of BTC including safety procedures (Figure 4)

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STABILITY BTC can be regarded as a “diester” of carbonic acid with trichloromethanol. However, when solid crystalline BTC is immersed in water at ambient temperature, no significant change in pH (following hydrogen chloride release) occurs; hence, no decomposition into phosgene is observed. This behavior is due to the very low solubility of BTC in water (log Pow = 2.94, calc.22). Notably, the decomposition is kinetically hampered. If accessibility is increased, e.g., in the presence of a water-miscible solvent such as tetrahydrofuran or dioxane, the expected reaction is observed. BTC is then dissolved and forms a homogeneous liquid−liquid system with the solvent and water. Higher

Figure 2. Structures of phosgene and triphosgene. 1441



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Figure 4. BTC sublimation: photos of BTC on a watchglass taken after 0, 35, and 200 min at ambient temperature and sublimed BTC.

with an onset temperature of ca. 170 °C and a reaction enthalpy of ca. +110 J/g. This behavior can be interpreted as decomposition of BTC into gaseous products (CO2, CCl4, COCl2), thus balancing the negative decomposition enthalpy with the endothermic evaporation enthalpy of the decomposition products. When an accelerating rate calorimeter (ARC) is used, the onset is observed at ca. 130 °C (ca. −280 J/g), and a second decomposition is observed beginning ca. 180 °C; the results show no evidence of decomposition at temperatures less than 130 °C. To identify the gases developed from the decomposition of BTC, an experiment was performed on a thermogravimetric analyzer coupled to an FT infrared spectrometer.15 The simultaneous presence of COCl2, diphosgene, CO2, and CCl4 between the thermal decomposition products suggests a decomposition mechanism that proceeds through a six-membered transition state:

temperatures (and catalysts) can further accelerate decomposition. When BTC reacts with nucleophiles, it liberates phosgene, which can react further.23 Nucleophilic catalysts, for example, ammonium chloride, quaternary ammonium, and phosphonium halides, can be used to decompose BTC into phosgene. Several studies on the mechanism revealed numerous details. Solvation processes and the stability of the intermediates play an important role in the catalytic cycle.24,25 Several molecules of the nucleophile are associated with BTC at the beginning of a nucleophilic attack.3d,e The solvent nature, catalyst, and temperature strongly affect the reaction rate. For example, Eckert et al. designed a “phosgene-on-demand” process in which nucleophilic catalysis employing a solid catalyst is used to decompose BTC to phosgene.26,27 The thermal stability of BTC has been controversial for many years. However, no systematic and comprehensive investigation on its stability is available. The available data indicate that its stability is particularly influenced by impurities; however, the purity of BTC is not easy to determine. Early studies claimed that BTC exhibits high thermal stability, that is, that BTC is stable at temperatures greater than 200 °C and as high as 300 °C.18,28,29 However, several newer studies have reported substantially lower thermal stability. Differential scanning calorimetry (DSC) measurements in closed systems showed melting started at approximately 82 °C and the onset of exothermal decomposition around 160 °C (−200 J/g).15 Eckert assumed that this discrepancy could be explained by the experimental conditions employed. Aluminum crucibles are typically used for DSC measurements. Traces of phosgene and BTC can react with the aluminum to form AlCl3 and CO via a well-known exothermic reaction. The generated AlCl 3 can further catalyze the decomposition of BTC:30

Recently, some TGA (termogravimetric analysis) data indicated that, at 130 °C and atmospheric pressure, BTC is completely volatilized. The spectra of BTC vapors have been measured/determined by passage through a gas-phase IR cell heated at 120 and 230 °C. Under these experimental conditions, no decomposition was evident, but high volatility was obvious.33 In summary, three decomposition pathways are identified in the literature: (i) BTC decomposes into three molecules of phosgene below the boiling point (206 °C) in the presence of initiators;24−26 (ii) At lower temperatures (e.g., during distillation), BTC decomposes into phosgene and diphosgene. Upon heating, rapid decomposition to phosgene occurs when BTC is mixed with powdered activated carbon or Lewis acids;17,34 (iii) Decomposition to carbon dioxide, carbon tetrachloride and phosgene can occur; the off-gases were analyzed through thermogravimetric analysis−Fourier transform infrared (TGAFTIR) analysis.15

When the crucible material was changed, this effect was eliminated, and no decomposition was observed ca. 160 °C. DSC characterization of commercially available BTC (Aldrich, “saltfree”) indicated that it is thermally stable to 200 °C. The thermal decomposition of BTC is moderately exothermic (ca. −240 J/ g).31 Thus, the results of the aforementioned previous investigations underscore that salts (especially chlorides) significantly influence the stability of BTC, consistent with the results of Hood who reported the decomposition of BTC into diphosgene and phosgene upon distillation.32

Extensive tests were performed to determine the stability of BTC in the presence of various impurities.16 BTC was found to indeed be unstable in the presence of partially chlorinated intermediates, metal ions, activated carbon, and nucleophiles.

Naturally, data on decomposition depend on the method of analysis. In open crucibles, BTC shows an endothermic reaction 1442



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BTC DETERMINATION AND MONITORING The odor of BTC or phosgene is definitely inappropriate as a warning signal; toxicologically relevant amounts of these compounds remain undetected and can accumulate over time (e.g., phosgene: >0.13 ppm odor perception, >1.5 ppm recognition of odor, >3 ppm irritations; 50−150 ppm·min subclinical effects; >150 ppm·min pulmonary edema likely; example: 1 ppm phosgene in air results after >2.5 h in a lung edema). Methods for analyzing BTC have been published using a Förster resonance energy transfer (FRET) method35 and a reaction system consisting of pyridine and dimethylbarbituric acid for in situ detection and estimation, allowing selective detection in nanomolar quantities of analyte.36 However, because of the instability of the analyte under the given circumstances, the GLP-compliant validation of this method failed.4 OSHA derivatization method no. 61 for phosgene was used for BTC-containing atmosphere characterization, meaning that BTC was analyzed as equivalents of phosgene.4,37 The required analytical range of concentrations for quantitative determination may vary from the ppb level to virtually 100%. For quantitative determination, the recommended methods are those for phosgene, for example, colorimetric methods or titrations (especially the liberation of iodine from acetone sodium iodide or argentometric chloride determination after hydrolysis).38,39 13C NMR could be a helpful tool because the chemical shifts of the BTC peaks are easy to recognize (108.0 and 140.9 ppm). Although phosgene can be easily monitored in ambient air, the monitoring of BTC or mixtures of BTC and phosgene is not yet possible. Neither chromogenic methods (e.g., Harrison’s reagenta nonaqueous solution of diphenylamine and 4(N,N-dimethylamino)benzaldehyde in ethanol, phosgene indicator badges, medical phosgene indicator badges, or Draeger tubes) nor electrochemical detectors can distinguish between phosgene and BTC. In addition, the absence of official occupational exposure limits for BTC (only preliminary OEL calculated, 1 μg/m3) would make BTC measurement results almost meaningless. Problematically, the reading of the different monitoring methods might be misleading in the presence of BTC and phosgene. However, no monitoring alternatives exist.

material is usually a single polyethylene (PE) bag, which is packed into PE-, fiber-board- or metal drums. BTC is sometimes also shipped in simple (double) polyethylene bags only, possibly with an outer cardboard box. The drums/bags are then shipped inside containers. BTC diffuses through PE or high-density PE (HDPE) bags quite readily.42 Particularly in the case of low-quality PE, the diffusion of BTC, its byproducts, and its decomposition products might be so extensive that, in some cases, the secondary packaging material becomes pressurized (phosgene). Therefore, these systems are not suitable for long-term storage. Because the typical transit time for sea transport from Asia to Europe or the USA is 4−8 weeks, BTC and its decomposition products (including phosgene) could likely be found between the airspace of the primary and secondary packaging materials. In this scenario, BTC might affect the integrity of the outer package (e.g., metal drum) and could pose a serious health risk for workers opening the secondary packaging material while assuming that the primary packaging material will protect them from exposure. Researchers have found that diffusion can be reduced by a factor of 50−100 if fluorinated polymers are used as a barrier [Ubichem]. To our knowledge, none of the current manufacturers use such a packaging material because it is substantially more expensive than standard PE and HDPE packaging materials. In addition, no manufacturers request refrigerated or cooled shipment of the product; therefore, during long transport in a sea container, the product might be exposed to extreme temperatures. Thus, logistics, storage, and handling must be considered explicitly in the process safety analysis for BTC.

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COMMENTS ON THE USE OF BTC ON THE INDUSTRIAL SCALE Because BTC itself is highly toxic and because its use is normally connected with phosgene (storing, reaction, off-gas), rules and precautions that are at least as strict as those for phosgene must be applied. Unfortunately, the currently available MSDSs for BTC are incomplete and might not provide correct physical data. Relevant data (e.g., vapor pressure, sublimation, LC50 data, and inhalation) are often missing. Although safety aspects must be individually evaluated for each process, some aspects important to the authors are outlined below: • An appropriate employee training program should be in place. Personnel should be informed about potentially delayed effects after exposure to BTC/phosgene, which might be lethal. An emergency response and evacuation plan should be established and frequent drills executed. • Proper personal protective equipment, including phosgene dosimeter badges (medical badges) should be used. Breathing protection is mandatory where contact with BTC/phosgene is possible. For minor operations (e.g., opening of flushed equipment), full-face filter masks might be acceptable. For all other operations, the use of self-contained breathing apparatus (SCBA) is highly recommended. • Monitoring for phosgene is mandatory for all plant areas, including the storage area. Alarms (audible and visual) should be automated (and calibrated for phosgene). • BTC should be stored in a remote area of the site and segregated from other materials. Only the currently required BTC quantities should be stored. The storage area should be ventilated to a sodium hydroxide scrubber (on demand).

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TRANSPORTATION, PACKAGING, STORAGE, AND HANDLING BTC is shipped in quantities ranging from research quantities to full container loads worldwide by sea and by air. Most companies label BTC with the hazard statements H314 (“causes severe skin burns and eye damage”) and H330 (“fatal if inhaled”). The European Chemicals Agency (ECHA) database indicates a lack of data for human health hazards and environmental hazards. According to the ECHA Web site (May 2017),40 the compound is likely to meet the criteria of Annex III to the REACH RegulationSubstance of Very High Concern.41 Notably, in several material safety data sheets (MSDS), the hazard statements for BTC are incomplete or wrong. No common practice exists for packing BTC. Quantities for laboratories are usually well-packed (normally glass bottles in addition to outer break-resistant packages); however, packing for larger quantities might be problematic. Bulk BTC is typically packed into 20−25 kg drums/units. The primary packaging 1443



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• Pipes containing BTC/phosgene should be distinctively marked; plant hardware exposed to BTC should be made from the proper material (caution: BTC slowly penetrates through PTFE!). A proper preventative maintenance program should be in place. • Accumulation of BTC and/or phosgene should be avoided as much as possible. • The preparation of solutions of BTC only in clean, anhydrous solvents is recommended, and these solutions should be used in reactions. Bases, Lewis acids (e.g., FeCl3 or AlCl3), or porous substances should not be added to a concentrated solution of BTC because doing so might result in uncontrolled decomposition, releasing large amounts of phosgene. • Depending on the decontamination concept, the water/ moisture content of the nitrogen flow should also be checked. The scrubber system should also be considered a potential source of water (vapor). • During and after reaction with BTC (homogeneous phase or biphasic systems), phosgene can usually be detected in the offgases and all of the layers (i.e., organic and aqueous); this possibility should also be considered in cases of reactor cleaning, and so forth. The organic phase can contain significant amounts of phosgene and BTC. • All off-gases (also from vacuum pumps) should be passed through a sodium hydroxide scrubber or be hydrolyzed in a washing tower filled with activated carbon before being released into the atmosphere. Particularly at higher temperatures, BTC decomposes violently, releasing phosgene. However, an excessively low temperature can result in breakthrough of the scrubber. A high pH does not guarantee the destruction of BTC and phosgene in the off-gases. Therefore, the off-gas released to the atmosphere should be monitored for phosgene to ensure virtually no phosgene release. • The diffusion of BTC and/or phosgene into the packaging material during storing is substantial (see above). This “dissolved” material in the PE or HDPE matrix cannot be removed by washing the surfaces. The BTC and/or phosgene will slowly diffuse out of the polymer matrix. Therefore, hazardous concentrations of these compounds might build up in areas where empty packaging material is stored. Empty packaging material should be enclosed (e.g., packed into PE bags or drums), labeled as hazardous waste, and incinerated as soon as possible. • Before equipment is removed from service, all lines must be purged and tested for residual BTC/phosgene (e.g., using indicator paper or a mobile phosgene detector). The diffusion problem is also relevant for PTFE-lined pipes and pumps. Thus, any polymer parts that contact BTC/phosgene could contain relevant amounts of these compounds.

SCBA (self-contained breathing apparatus) and protective clothing is highly recommended. A supply of decontamination solution (25% aqueous ammonia, isopropanol and water, 1:1:1) should be available. All joints should be checked for tightness. The use of indicator tapes for tightness tests (e.g., commercially available indicator paper or filter papers impregnated with ethanolic solution of 5% 4-(dimethylamino)benzaldehyde and 5% N,N-diethylaniline, which exhibit a characteristic color change from yellow to blue) is advisible. Alternatively, ammonia (25%), which generates visible “smoke” upon phosgene contact, might be helpful for leak testing. Flow rates of nitrogen containing BTC/phosgene gases should be kept to the minimum practical amount. A particular warning is dedicated to operations targeting phosgene formation from BTC. A wide variety of methods have been developed for catalytically controlling BTC decomposition into phosgene. If in situ phosgene production and consumption (“phosgene-ondemand” methods) are targeted, the process should be appropriately designed to determine and control the kinetics of the consumption phase and manage the minimum possible stationary concentration of phosgene in the reaction mixture and in the reactor head space. Any operational procedure with BTC generating uncontrolled amount of phosgene should be avoided. As previously described, all off-gas (also from vacuum pumps) from the experiments should pass through a sodium hydroxide scrubber or be hydrolyzed in a washing tower filled with activated carbon. The temperature of the scrubber is important. BTC can easily pass a lab scrubber filled with sodium hydroxide and even resolidify in cool areas in and downstream of the scrubber. BTC should be stored in a cool, well-ventilated area separate from incompatible materials (e.g., protic/acidic solvents or materials, Lewis acids, bases, nucleophiles, metals, solid impurities like carbon). Storing BTC in a closed, nonventilated refrigerator is not advised because, over time, substantial amounts of BTC/phosgene can accumulate, creating a scenario where opening the refrigerator might result in exposure of the employee. Excess BTC and waste materials containing this substance should immediately be deactivated in a fume hood by treatment with a decomposition solution (see above). Rubber tubing should be decontaminated by immersion into a decomposition solution. For disposal, the tubing should be sealed in plastic bags.

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CONCLUSIONS AND OUTLOOK BTC is a versatile compound that enables highly efficient syntheses. In addition, because of its solid state, it is a very convenient compound for small-scale phosgenations. Consequently, this compound is favored as a phosgene substitute in research and development and in small-scale production. Although BTC is highly toxic, safe handling is possible as long as the properties and chemical reactivity of this compound are understood and considered. However, branding as “safer phosgene” or “safe phosgene” is misleading. The solid state of BTC leads to the misconception that there is no significant exposure. However, the vapor pressure is sufficiently high to easily result in toxic concentrations. In addition, proper monitoring is not yet possible. Proper use of BTC could be more complex than the handling of phosgene itself. Currently, handling of BTC is not as tightly regulated as phosgene. However, handling of BTC is normally always associated with phosgene and has its own toxicity. Therefore, the use of BTC may become more regulated in the future, which

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COMMENTS ON THE USE OF BTC IN THE LABORATORY AND KILO LABORATORIES Handling of BTC in small quantities is unproblematic in the lab as long as standard precautions for handling of highly toxic compounds are in place. Work with BTC/phosgene should be indicated with proper warning signs. Safety goggles, a suitable lab suit, and impermeable gloves should be worn (for pure BTC, nitrile rubber gloves, >1 mm, are recommended in most MSDSs). As long as BTC is handled exclusively in a fume hood, special breathing protection may not be necessary. However, for emergency cases, at least a full-face filter mask should be available. In the case of release of larger amounts of BTC outside the fume hood (solutions or solids), the use of a 1444



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(11) China Daily, Jan 10, 2011. http://usa.chinadaily.com.cn/epaper/ 2011-01/10/content_11818984.htm (accessed July 24, 2017). Zhang, L. L.; Zhou, S. S.; Liu, B.; Sun, Z. M.; Yang, T. J.; Zhu, S. J.; Fan, H. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2012, 24, 116. (12) Pauluhn, J. Inhalation Toxicol. 2006, 18, 423. (13) Pauluhn, J.; Mohr, U. Toxicol. Pathol. 2000, 28, 734. (14) Cotarca, L.; Eckert, H. Phosgenations: A Handbook; Wiley: Germany, 2004. (15) Cotarca, L.; Delogu, P.; Nardelli, A.; Sunjic, V. Synthesis 1996, 5, 553. (16) McDonald, R. Chem. Eng. News 2001, 79, 7. (17) Hales, J. L.; Jones, J. I.; Kynaston, W. J. Chem. Soc. 1957, 0, 618. (18) Marotta, D. Gazz. Chim. Ital. 1929, 59, 955. (19) Sorensen, A. M. Acta Chem. Scand. 1971, 25, 169. (20) Andraos, J. Pure Appl. Chem. 2011, 84, 827. (21) Su, W.; Zhong, W.; Bian, G.; Shi, X.; Zhang, J. Org. Prep. Proced. Int. 2004, 36, 499. (22) MSDS Merck Millipore, issued May 4, 2015. (23) Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 26, 894. (24) Pasquato, L.; Modena, G.; Cotarca, L.; Delogu, P.; Mantovani, S. J. Org. Chem. 2000, 65, 8224. (25) Simon, M.; Csunderlik, C. Rev. Chim. (Bucharest) 2006, 57, 193. (26) Eckert, H.; Gruber, B.; Dirsch, N. DE 197405770 (to Dr. Eckert GmbH), 1997; WO9914159 and EP0005693 (to Dr. Eckert GmbH), 1998. (27) Eckert, H.; Auerweck, J. Org. Process Res. Dev. 2010, 14, 1501. (28) Kling, A.; Florentin, D.; Jacob, E. Ann. Chim., 9th Series 1920, XIV, 189. (29) Grignard, V.; Rivat, G.; Urbain, E. Ann. Chim. 1920, XIII, 263. (30) Eckert, H.; Lei, L. Chimica Oggi-Chemistry Today 2014, 32, 32. (31) Eckert, H. Chimica Oggi-Chemistry Today 2011, 29, 40. (32) Hood, H.; Murdock, H. J. Phys. Chem. 1918, 23, 498. (33) Cotarca, L. Unpublished data. (34) Gmelin, Handbook der Anorganischen Chemie, 8th ed.; Kohlenstoff, Teil D3: Kohlenstoff-Halogen-Verbindungen (Forsetzung); Springer-Verlag: Berlin, 1976. (35) Zhang, H. X.; Rudkevich, D. M. Chem. Commun. 2007, 1238. (36) Joy, A.; Anim-Danso, E.; Kohn, J. Talanta 2009, 80, 231 BTC produces an intensely colored purple pentamethine oxonol dye when reacted with 1,3-dimethylbarbituric acid (DBA) and pyridine (or a pyridine derivative). Phosgene precursors react with 1,3-dimethylbarbituric acid (DBA) in pyridine−H2O (9:1, v/v) to produce an intense blue colored solution (λmax = 598 nm) with red fluorescence. Two quantitative methods are recommended on the basis of either UV absorbance or fluorescence of the oxonol dye. Detection limits are ∼4 mmol/L by UV and

Bis(trichloromethyl)carbonate (BTC, Triphosgene): A Safer Alternative

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