Highlights from the Literature pubs.acs.org/OPRD
Safety Notables: Information from the Literature In an effort to assist smaller companies such as T2 to avoid similar catastrophes as described in this article, the Center for Chemical Process Safety (CCPS) in collaboration with the EPA, OSHA, SOCMA, and the American Chemistry Council have made the book Essential Practices for Managing Chemical Reactivity Hazards (Johnson, R. W.; Rudy, S. W.; Unwin, S. D. Essential Practices for Managing Chemical Reactivity Hazards, Center for Chemical Process Safety/AIChE: New York, 2003, ISBN 978-0-8169-0896-7) available free online. Explosion in Waste Liquid from Formation of Nitrogen Trichloride. Okada et al. report (J. Hazard. Mater. 2014, 278, 75) that an explosion occurred a couple minutes after 5 L of sodium hypochlorite solution (12% in water) was poured into 300 L of liquid waste containing ammonium ion (∼2 mol/L). The tank cover, fluorescent lamps, and air duct were broken by the blast wave. Fortunately, there were no injuries resulting from this explosion. It was determined by ICP spectroscopy after the explosion that the waste solution contained 5 mg/L platinum (Pt) ion, although the ionic state was not measured (suspected that Pt black may have been present). The authors concluded that the explosion of the waste liquid was caused by the formation of nitrogen trichloride (NCl3). This root cause was investigated by a series of gram-scale explosion tests along with corresponding FT-IR and GC/MS analyses. During testing, an explosion resulted under similar conditions (NH4+ = 2.0 mol/L, pH = 1, w/Pt black), even in the absence of heat or static electricity. It was additionally confirmed that a small amount of Pt black functions as a catalyst for the explosion, while other Pt species do not. The authors stated that, in the case where liquid waste containing hypochlorite ion needs to be mixed with waste containing ammonium ion, there are certain conditions that would reduce the probability of explosion. Per the authors, the initial concentration of NH4+ solution should be less than 3 mol/L and the pH should be higher than 6. Also, the hypochlorite solution should be added at room temperature, should be less than 1/10th of the volume of the ammonia solution, and should be less than 0.6 mol/L in concentration. While the authors have suggested conditions in which this waste combination could be performed with a reduced risk of explosion, it would be our suggestion to investigate a safer alternative for the neutralization of each stream. Azidotrimethylsilane Explosion. An explosion that occurred during a 200 g scale synthesis of azidotrimethylsilane (TMS-N3, 2) from chlorotrimethylsilane and sodium azide in
This is the twelfth annual literature overview on safety issues that are of interest to process chemists and engineers to appear in Organic Process Research & Development. As in the previous years, this review will cover recent articles from the literature that address safety issues, common safety mistakes which seem to be repeated all too often, and present solutions to long known hazards. This paper is not intended to be all inclusive of the safety literature nor should the information presented be used to make decisions regarding safety without reading the full text of the appropriate article and conducting the appropriate hazard analyses/hazard reviews. The intent is to give a flavor of the issues facing other chemists and engineers and reveal how they are solving these problems.
■
ACCIDENTS Metalation Reaction Explosion. A tragic explosion resulting from a runaway chemical reaction occurred at the T2
Laboratories, Inc. facility in December 2007 during the 175th batch of methylcyclopentadienyl manganese tricarbonyl (MCMT, 1). The U.S. Chemical Safety Board (CSB) completed an incident investigation of the T2 explosion, summarizing their findings in an investigation report (U.S. Chemical Safety and Hazard Investigation Board, T2 Laboratories, Inc. Runaway Reaction, Report No. 2008-3-I-FL, 2009). The report identifies the root cause as a failure to recognize the runaway reaction hazard potential of the metalation step. The fact that so many batches were run without incident illustrates clearly that just because a process has been run successfully at scale does not render it intrinsically safe, especially in the absence of a full process hazard assessment (PHA). Understanding the consequences of potential process upset conditions is critical to allowing an accurate determination of risk. In this instance, a loss of adequate cooling during the metalation most likely contributed to the runaway exotherm. This in turn led to an uncontrollable pressure and temperature rise within the associated reactor and finally culminated in a huge explosion. A paper by Theis (J. Loss Prev. Process Ind. 2014, 30, 296) describes lessons learned from this incident, including the criticality of conducting a comprehensive PHA for reactive chemicals as well as ensuring the proper collection and application of adiabatic calorimetry data to characterize the chemical reaction and determine appropriate mitigation strategies. © XXXX American Chemical Society
Special Issue: Safety of Chemical Processes 14
A
dx.doi.org/10.1021/op500371s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
■
poly(ethylene glycol) (PEG) as solvent was reported (Chem. Eng. News 2014, 92 (43), 4). The Chem. Eng. News article reports that the accident significantly damaged a fume hood at the University of Minnesota and caused injuries to the student researcher involved. The article also reports that a definite root cause has yet to be confirmed, but it is postulated that hydrazoic acid may have been generated which subsequently exploded within the flask. The explosion hazards of azidecontaining compounds are well-established, particularly where there is the potential to generate hydrazoic acid in the presence of proton sources. The authors speculate that the PEG solvent employed (PEG, Mn = 300) itself may have acted as a proton source. As suggested in the article, it is also possible that the explosion was caused by the failure of the magnetic stirring during the distillation step to purify 2, causing unreacted azide salts to settle at the bottom of the flask and overheat, eventually leading to an explosion. The incident serves as a warning that following a previously published procedure does not guarantee that an experiment is intrinsically safe, even after numerous experiments have been run without incident. It is critical to recognize the inherent hazards associated with certain chemical reactions and to carry out a complete and thorough hazard assessment before committing to any experiment runs. Importantly, the assessment should be revisited whenever any significant process or equipment changes are introduced. Investigation of an Accident in a Resins Manufacturing Site. A paper (J. Hazard. Mater. 2014, 270, 45) from Casson
Highlights from the Literature
HAZARD ASSESSMENT METHODOLOGY
Predicting ADT 24 and ADT 8 for Low-Temperature Reactions Using the RC1e. The probability for triggering a secondary decomposition reaction is considered low if running at or below the temperature at which the time to maximum rate under adiabatic conditions is 24 h. This temperature, known as the 24 h adiabatic decomposition temperature (ADT 24), is the temperature at which the reaction mass has acceptable thermal stability. The ADT 24 (or also ADT 8, for 8 h time to maximum rate) can be determined by kinetic analysis of self-heating data generated from adiabatic calorimeters (i.e., ARC), by running a series of isothermal experiments at different temperatures in a differential scanning calorimeter (DSC) or by predictions using heat data from dynamic DSC runs (AKTS software). However, in the case of low-temperature reactions (−50 °C or less), this approach is limited by the lower end of the operating temperature range of most calorimeters. Lakshminarasimhan has demonstrated that nonisothermal heat data from a single experiment in a reaction calorimeter (such as the RC1e) can be used to fit the kinetics of low temperature reactions and predict the ADT 24 and ADT 8 (Org. Process Res. Dev. 2014, 18, 315). The main advantage of this approach was that the heat and kinetic data of the desired reaction and secondary decomposition reaction were determined from a single experiment (in the RC1e), avoiding the need to transfer the mixture into a separate test cell and potentially introducing variation in the temperature of the reaction mixture. This approach was used to study an o-lithiation reaction at low temperature, and the process was successfully scaled up to 10 kg batch size. Flash Point Estimation: Contribution of Functional Groups. Flash point estimation has become increasingly important in recent years due to the design of new compounds and also due to limited data available for many classes of organic compounds. This was noted last year with the presentation of a novel, reliable, and facile method for estimation of the flash point of a structurally diverse variety of flammable amines and nitrogen heterocycles (J. Loss Prev. Process Ind. 2013, 26, 650). Reliable predictions for flash point may be obtained from relationships involving experimental properties (i.e., boiling point, heat of vaporization, etc.), but these are restrictive due to the need for experimental data. An article by Mathieu and Alaime (J. Hazard. Mater. 2014, 267, 169) presents a flash point prediction model based on only the compound molecular formula. The rationale is based on two considerations: for small compounds, that the flash point must increase with molecular size as larger molecules require higher temperatures to vaporize; and for large molecules, that the flash point is less dependent on molecular size because compounds are likely to decompose before entering the vapor phase. Calculated and observed values for the test set of compounds (1170 total) yielded an average absolution error (AAE) of 13.3 K. The method is highly dependent on compound type and functional groups, and more detail is presented to describe these dependencies in the article. The authors conclude that, while there may be methods described in the literature that can yield an AAE < 10 K, the main advantage of this method is its simplicity and ability to provide immediate insight into the contributions of individual functional groups to flash point values.
et al. analyzes the effect of an accelerator on the polymerization of methyl methacrylate (MMA, 3). The study is based on the results of an investigation of an accident in a manufacturing site for resins located in the UK. The following sequence of events was presented for the accident: during an unattended batch process, a runaway undesired polymerization of 3 occurred, generating rapid vaporization of monomer, which in contact with an ignition source led to an explosion and subsequent fire. Since no initiator for the polymerization had been added, it was thought that an accelerator contributed to the onset of the undesired polymerization. As a result, the accelerator involved in the accident (N,N-diisopropyl-para-toluidine, DIPPT, 4) was tested by differential scanning calorimetry (DSC) and adiabatic calorimetry (using the ARC). The DSC and ARC testing revealed that 4 produced significant increases in the initial rate and extent of polymerization of 3, which would reduce the minimum process temperature that can lead to a runaway polymerization and increase the likelihood of this occurring in large process vessels (which have a decreased rate of heat transfer per unit volume). The isothermal and adiabatic data support the conclusion that the explosion at the factory was due to the ignition of a large volume of a fuel−air mixture formed from the discharge of flammable vapor from the mixing vessel when the contents became overheated due to a runaway exothermic reaction. The authors conclude that this work pointed out the need for more experimental studies on this type of chemical process before scale-up for industrial applications. B
dx.doi.org/10.1021/op500371s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
■
Highlights from the Literature
ALTERNATIVE REAGENTS New Reactive Chlorinating Reagent. A novel guanidine based chlorinating reagent, 2-chloro-1,3-bis(methoxycarbonyl)guanidine
autocatalytic behavior. The authors suggest that the use of solutions of 6 in these solvents should be avoided, particularly in high concentration/elevated temperature or if prepared ahead of time. It was recommended to consider the solvent quality in those scenarios, as 6-solvent incompatibility is caused by a radical cascade and the risk is increased by mixing in impurities, such as a radical initiator. The authors also concluded that 7 showed the same behavior as 6 during testing, and therefore, the same incompatibility considerations would be recommended. This was an important conclusion because 7 is regularly substituted for 6 in industrial applications due to its low cost and high bromine content. Formation of Nitro Heteroaromatics Using Oxone in Water. The oxidation of nitrogen-rich heterocyclic amines 8
(CBMG, 5) or “Palau’-chlor”, has been introduced as a mild, direct, and operationally safe means of direct chlorination for a range of nitrogen-containing heterocycles as well as select classes of arenes, sulfonamides, and silyl enol ethers. Aryl C−H chlorination is a classical method to prepare aromatic chlorides and can be generalized into two main classes: reactive and practical. Reactive methods utilize traditional chlorinating reagents (Cl2 or SO2Cl2), which generally have safety liabilities that limit their application at scale because of their aggressive reactivity. Milder methods use substantially less reactive reagents [N-chlorosuccinimide (NCS) and 1,3dichloro-5,5-dimethylhydantoin (DCDMH)], which although generally inexpensive, easy to handle, and therefore practical, suffer from the fact that their reduced reactivity can limit their application. Often operating with radical-based mechanisms, t-BuOCl serves as a valuable chlorinating reagent, but its reactivity is variable on arenes, and it is dangerously lightsensitive (releasing MeCl), heat-sensitive (releasing Cl2), and moisture-sensitive (ignition). Other chlorinating reagents exist, but many of these are toxic (e.g., PhSeCl), explosive (e.g., TiCl4/CF3CO3H), hygroscopic (e.g., NCS/ZrCl4), or strongly acidic (e.g., SbCl5, N-chloramines in neat acids); hence, many chlorination reagents and methods have significant liabilities that may limit their application in organic chemistry. Baran et al. (J. Am. Chem. Soc. 2014, 136, 6908) discovered 5 to be an air-stable solid with good thermal stability below 100 °C. It exhibits a reactivity profile equivalent or better than those of more aggressive reagents that are more difficult to use at scale. Moreover, this reactivity was achieved without sacrificing functional group tolerance and at a comparable cost to the classic reagent NCS. Incompatibilities between Brominating Agents and Solvents. Shimizu et al. have measured the heat of reaction between
provides a highly attractive alternative route for the synthesis of nitro derivatives 9 since it can selectively introduce nitro groups into the ring. Various oxidants and conditions have been employed, but those methods typically suffer from harsh conditions, dangerous reagents, expensive metal catalysts, or toxic organic solvents. Pang et al. present an operationally simple, inherently safe, environmentally benign, and chemoselective conversion of a wide range of amines 8 to the corresponding nitro derivatives 9 using potassium peroxymonosulfate (oxone, 10) as the oxidant in water (Org. Process Res. Dev. 2014, 18, 886). 10 was chosen as the oxidant because it is cheap, commercially available, can be used with water, can be quenched with a mild reducing agent such as sodium bisulfate, its byproducts are not harmful to the environment, and it does not emit pungent vapors or pose a serious inhalation riskmaking 10 attractive for large-scale applications. The utility of the method was demonstrated by the synthesis of two important energetic compounds, 3,4,5-trinitro-1H-pyrazole (TNP) and 5-amino-3-nitro-1H-1,2,4-triazole (ANTA). As stated in the article, further expansion of the substrate scope is currently underway in the authors’ laboratory. Fluoroform as a Difluorocarbene Source. Dolbier and Thomoson demonstrate that fluoroform (CHF3, 11) can be
N-bromosuccinimide (NBS, 6) and various solvents using the Advanced Reactive System Screening Tool (ARSST) and the RC1e reaction calorimeter to gain insight into potential incompatibilities. Similar experiments were performed with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 7), and the results have been reported (Org. Process Res. Dev. 2014, 18, 354). The authors concluded that acetonitrile, dichloromethane, and ethyl acetate could be recommended as solvents for use with 6, as those did not show significant incompatibility during testing. However, amides (DMF, DMA, NMP, etc.), THF, and toluene did show significant incompatibility with 6 with
used as the difluorocarbene source in a convenient process for conversion of phenols and thiophenols to their difluoromethoxy and difluorothiomethoxy derivatives (J. Org. Chem. 2013, 78, 8904). The authors state that 11, which is non-ozone depleting, non-toxic, and an inexpensive gas, is a byproduct of Teflon manufacture, but that it could be readily manufactured as a commodity chemical by fluorine/chlorine exchange of chloroform if desired. This is considered a replacement of chlorodifluoromethane (CHF2Cl), which was a favored reagent for generating C
dx.doi.org/10.1021/op500371s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Highlights from the Literature
and ease of recyclability, in addition to its apparent complete retention of stereochemistry and applicability to both solution and solid-phase synthesis of certain large peptides with difficult sequences. This corresponds to an article presented in 2012, presenting a new derivative of Oxyma as a peptide-coupling additive for peptide-forming reactions in water (Org. Lett. 2012, 14 (13), 3372). DABSO-Based Sulfone Syntheses. DABSO (14), formed from DABCO and sulfur dioxide, has previously been
difluorocarbene in the past but is no longer used as much as it is a significant ozone-depleter. The reactions proposed by the authors are two-phase, very clean, carried out at moderate temperatures and atmospheric pressure, and provide moderate-to-good yields. As a result, the proposed process should be very competitive with other methods for preparing these important compounds. Sodium Chlorodifluoroacetate as a Difluorocarbene Source. Sodium chlorodifluoroacetate (SCDA, 12) is a versatile
introduced as a replacement for gaseous sulfur dioxide in many applications, due to the difficulty of handling a toxic gaseous reagent (Org. Lett. 2011, 13 (18), 4876). Willis et al. have developed a simple, versatile one-pot sulfone synthesis based on the in situ electrophilic trapping of metal sulfinates generated from organometallic reagents and 14 (Org. Lett. 2014, 16, 150). The authors state that a broad class of sulfones can be synthesized in moderate to excellent yields using this method due to the use of a wide range of organometallic substrates and electrophiles. In addition, Rocke et al. have demonstrated that organozinc reagents react with 14 to give zinc sulfinate salts, which can be alkylated in situ to afford sulfones (Org. Lett. 2014, 16, 154). The authors state that the transformation has a broad scope and is compatible with a wide range of structures, including nitriles, secondary carbamates, and nitrogen-containing heterocycles.
reagent for introducing CF2 and CF3 groups into organic compounds. Unlike many common perfluoromethylating agents, 12 is an inexpensive, crystalline solid which is stable at ambient temperature and in air. The reagent undergoes decarboxylation at moderate temperatures (ca. 90 °C) to form difluorocarbene, which can be used in situ for di- and trifluoromethylations. Greaney and Williams have developed a simple method for the chlorodifluoroacylation of N-methylindoles using 12 (Org. Lett. 2014, 16, 4024). The method is mild and does not require activation with anhydrides, acyl chlorides, or strong Lewis acids. Mechanistic investigations indicate that the active ester formation occurs via difluorocarbene, which is generated from 12. According to the article, the authors are currently exploring the utility of this reaction in the development of biologically relevant molecules. New and Efficient Coupling Reagent. Mandal et al. describe a new coupling reagent, ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxy-
■
SURVEY OF RESEARCHERS REGARDING LABORATORY SAFETY Jon Evans addressed the topic of laboratory safety in a recent article published in Chemistry World (May 2014). A 2012 survey of US academic laboratories reported that 86% of around 2400 researchers judged that their laboratories were safe places to work. However, further analysis of the report highlighted a difference in levels of safety comfort between senior (94%) and junior researchers (69%), and furthermore, around 80% of the researchers reported they indulged in “risky” working practices with serious accidents such as chemical burns and chemical inhalation occurring fairly often. Academic lab safety was compared with safety in industrial laboratories, which are considered much safer places to work with better training and hazard management. The article then discussed some past incidents and how the safety culture has changed (and is continuing to change) as a result. Finally, the situation in laboratories in the UK is discussed, and the author concludes that those working in laboratories cannot afford to be complacent, even though they are helped greatly by the COSHH (Control of Substances Hazardous to Health) regulations.
imino)acetate (o-NosylOXY, 13), which has a similar efficiency to existing popular coupling reagents (HOBt-based as well as Oxyma-based coupling reagents) but is devoid of major drawbacks (J. Org. Chem. 2014, 79, 5420). According to the authors, those drawbacks are the generation of a large amount of chemical waste, the use of harsh conditions and toxic reagents, and a cumbersome recycling process (not environmentally friendly or cost-effective). The synthesis of 13 was completed by the reaction between ortho-nitrobenzenesulfonyl chloride and Oxyma in the presence of DIPEA under nitrogen atmosphere. Reagent 13 is stable at room temperature and did not show any change on timedependent HPLC and 1H NMR for 20 days. The reagent was tested in a variety of different synthesis reactions, namely, for the synthesis of amides, hydroxamates, peptides, and esters. The authors concluded that this was a useful reagent due to ease of preparation, use under ambient and milder conditions,
■
LABORATORY HAZARDS SPECIAL ISSUE A recent issue of the Loss Prevention Bulletin (No. 238, August 2014) focused on laboratory safety with a number of relevant articles and case studies. There were a couple articles discussing safety management in a university laboratory and an article describing tools to prevent process safety events at university research facilities. The major tools described in the process safety article were forms developed to assess the hazards of the D
dx.doi.org/10.1021/op500371s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Highlights from the Literature
This process also eliminates the need for additional recrystallization at the final stage, thereby increasing the yield. As stated in the article, further DoE optimization led to a more robust process, which was scaled up to 70 kg in the plant without any safety or quality issues.
chemicals intended for use in the experiments and the hazards involved in performing the experiments using the experimental setup. Emergency procedures were also discussed in case of an unexpected incident during an experiment. Another article from this special issue summarized the laboratory explosion that occurred at Texas Tech University in January 2010, which was further investigated by the US Chemical Safety Board (CSB). The CSB investigated and found systemic deficiencies at Texas Tech that contributed to the incident, which were summarized in a case study report (U.S. Chemical Safety and Hazard Investigation Board. Texas Tech University Laboratory Explosion, Report No. 2010-06-I-TX, 2011). As reported, those deficiencies include a lack of physical hazard assessment, planning, and mitigation; a lack of safety management accountability and oversight; and a lack of documentation, tracking, and communication surrounding previous incidents. The lessons learned from the incident provide all academic institutions (as well as external companies/ organizations) with an opportunity to compare and improve their own policies and practices. Additional articles in the issue discuss specific equipment management and safety, various laboratory incidents highlighting the importance of process hazard analysis, and some basic guidance on safety issues raised by the scale-up of chemical reactions from laboratory scale to a commercial plant.
■
CONTINUOUS PROCESSING Continuous Process Technology: A Tool for Sustainable Production. A review article on continuous flow reactors and their applications was presented by Wiles (Green Chem. 2014, 16, 55). The obvious advantages over stirred reactor vessels are highlighted including improved thermal management, enhanced mixing control, and access to larger operating windows. All of these factors enable the development of safer and more sustainable processes. The safety section of the Wiles article points out the increased activity in the literature related to evaluation of the formation and reactions of azides and other highly energetic intermediates under flow conditions. Value of Continuous Manufacturing in Design of Greener Processes. The American Chemical Society (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable conducted a study regarding the value of continuous processing, which was defined as a key research area for green engineering. Poechlauer et al. present the findings from this roundtable (Org. Process Res. Dev. 2013, 17, 1472) as they took this study a step further and tried to elucidate the value that member companies had drawn from continuous processing in their efforts to develop greener routes. The group set out to develop the business case for continuous manufacturing and 12 drivers for continuous processing were identified, belonging to one of 3 groups: logistics/quality, chemistry/process, and safety. Some of these drivers are to improve throughput or avoid overproduction (logistics), to run a reaction below −40 °C/above 200 °C or avoid an unstable intermediate (chemistry/process), and to perform a highly exothermic reaction or run a reaction at high pressure/with hazardous gases (safety). Finally, the group investigated the relationships between a “green process” as defined by the 12 principles of green chemistry and the major benefits associated with continuous processing, including investment savings, yield/quality improvement, safety, and speed. The final analysis shows that, even in cases where making a process “greener” was not the primary goal, operation in continuous flow mode (in most cases) allows a process to become “greener” according to the 12 principles. Safe Synthesis of 2-Substituted 1,2,3-Triazoles via Flow Synthesis. The regioselective formation of 2-substituted 1,2,3triazoles is synthetically challenging, with main approaches requiring condensation with aryl hydrazines or N-2 arylation. The latter strategy is complicated by competitive N-1 substitution. Workers at UCB Pharma (Chem. Eur. J. 2014, 20, 12223) describe a multistep synthetic approach to 5-amino-2-aryl-2H[1,2,3]-triazole-4-carbonitriles, which are known antifungal agents. An obvious drawback in this procedure is the generation (and isolation) of highly reactive and sensitive aryl diazonium species, which would represent a major safety concern at scale. The paper describes the use of flow chemistry to safely generate the reactive diazonium species by mixing solutions of an aniline and tert-butyl nitrite, followed by immediate capture of the reactive intermediate with malonitrile under precisely controlled conditions. The safety and efficiency of the protocol
■
EVAPORATIVE COOLING TO CONTROL REACTION EXOTHERM Although fluoxetine hydrochloride (“Prozac”, 15) has been off patent since 2001, it continues to have good commercial value, and thus, optimization of the process also has value. Mohanty et al. have presented a strategy for optimization of the O-arylation step of the synthesis of 15 (Org. Process Res. Dev. 2014, 18, 875), stating this is the most critical step that dictates the yield and quality of the product.
The highlight of the optimized process is the concept of evaporative cooling that was employed in manipulating the highly exothermic O-arylation reaction by introducing toluene as the cosolvent. The heat of reaction and rate of energy release were measured using the RC1e reaction calorimeter and using that information (along with other experimental data), it was determined that using more than 3 volumes of toluene could control the temperature of the reaction mass below 110 °C (also the approximate boiling point of toluene). This approach was adopted for improved process safety, considering the worst-case scenario of an uncontrolled reaction exotherm with DMSO as a solvent, which could lead to further reaction runaway and explosion due to decomposition at high temperatures. E
dx.doi.org/10.1021/op500371s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Highlights from the Literature
several occasions, with the data presented corresponding to a 240 h run at a throughput of 41 g/h of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temperature, achieving high yields and avoiding solid handling and a long residence time (due to much higher concentrations than batch conditions). The resulting stream was worked-up inline using liquid−liquid extraction with membrane-based separators scaled-up from microfluidic designs. The second reaction involved a Boc-deprotection, using aqueous HCl that was rapidly quenched with aqueous NaOH using an inline pH measurement to control NaOH addition. The reaction maintained high yields under closedloop control despite process disturbances. The authors suggest the process could be improved to adjust pressure control for the membrane separators and to reduce instances of clogging due to slurry streams, which are necessary after crystallization and filtration steps. It is also noted that scaling up the process to production scale would require an evaluation of the change from laminar to turbulent flows for most streams and some reoptimization of parameters for multiphase streams. Finally, this plant demonstrated the necessity of re-evaluating the entire pharmaceutical manufacturing process with the intent to perform the synthesis in flow, as none of the steps are the same as the batch process.
allowed its rapid scale up to generate a series of antifungal derivatives. Rapid Wolff−Kishner Reductions in a Silicon Carbide Microreactor. Jensen et al. (Green Chem. 2014, 16, 176)
describe the execution of Wolff−Kishner reductions in a novel silicon carbide micro reactor. Greatly reduced reaction times and safer operation were achieved, affording high yields without requiring the use of a large hazardous excess of hydrazine. The corrosion resistance of silicon carbide avoids the problematic reactor compatibility issues that typically arise when Wolff− Kishner reductions are done in glass or stainless steel reactors. With only nitrogen gas and water as byproducts, this technique opens the possibility of performing selective, large-scale ketone reductions without the generation of hazardous waste streams. Generation and Reactions of Anhydrous Diazomethane in Continuous Flow. Diazomethane (CH2N2, 16) is a highly versatile building block in organic chemistry, but working with 16 presents several serious safety hazards. Those hazards include severe toxicity, high volatility, friction/shock-sensitivity, light sensitivity, and thermal instability. For those reasons, 16 is not often used in synthetic organic chemistry processes but has been used industrially in continuous flow to minimize the total amount of stored material. Kappe et al. demonstrated the continuous generation, separation, and reaction of 16 in a tubein-tube continuous flow reactor (Org. Lett. 2013, 15 (21), 5590). 16 is generated in the inner tube of the reactor from a feed of Diazald and a feed of potassium hydroxide. Dry 16 diffuses through a hydrophobic membrane into an outer tube where it dissolves and reacts in the solution carried within. The authors conclude this eliminates the concern of exposure to 16 and drastically reduces the risk of explosive decomposition. An Advanced Peristaltic Pumping System for Processing Organometallic Reagents. A paper by Ley et al. presents a new technology for the pumping of organometallic reagents, which utilizes a newly developed, chemically resistant, peristaltic pumping system (Org. Process Res. Dev. 2013, 17, 1192). Several examples of its use in common transformations using these reagents are reported, along with examples of telescoping the anionic reaction products. This platform allows for continuous pumping of these highly reactive substances (some examples demonstrated over periods of several hours) to generate multigram quantities of products. The authors conclude the work with an example of the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations. Multi-Step Synthesis for an Integrated, Continuous Manufacturing Process. The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented by Jensen et al. (Org. Process Res. Dev. 2014, 18, 402). The plant started with advanced intermediates, two synthetic steps away from the final API, and ended with finished tablets. The entire process was run on
■
DUST HAZARDS Model To Assess Dust Explosion Occurrence Probability. Dust explosion hazards are an ongoing threat to process facilities that deal with powders or combustible materials. In recent years, there have been a number of safety methods proposed and presented with case studies to make process plants safer. However, dust explosions continue to occur with serious consequences at a variety of dust processing facilities. A paper by Hassan et al. (J. Hazard. Mater. 2014, 268, 140) discusses a newly proposed model to estimate dust explosion probability. The paper consists of three parts: data monitoring, data analysis and probability estimation, and presentation of a nomograph for a quick assessment of dust explosion occurrence. The parameters studied for impact on dust explosions are particle diameter (PD), minimum explosible concentration (MEC), minimum ignition temperature (MIT), minimum ignition energy (MIE), and limiting oxygen concentration (LOC). For each parameter, the individual conditional probability is assessed, and the total probability of a dust explosion is calculated. The nomograph then shows the conditional probability for each parameter and also the total probability (of dust explosion) in a closed region. The authors admit that there are further considerations that could lead to an improved probability model. These include classification of dust on the basis of chemical composition and consideration of multiple parameters together rather than each individually. Some Myths and Realities about Dust Explosions. The necessary conditions for a dust explosion to occur are wellexpressed by the explosion pentagon: (i) fuel, (ii) oxidant, (iii) ignition source, (iv) mixing of the fuel and oxidant, and (v) confinement of the resulting mixture. While it might seem relatively straightforward to prevent or mitigate a dust explosion by simply removing one of the pentagon elements, the field of dust explosion risk reduction is more complex. The latest in a series of papers by Amyotte (Process Saf. Environ. 2014, 92, 292) notes that this complexity is partially rooted in several erroneous beliefs. These beliefs ignore the F
dx.doi.org/10.1021/op500371s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Highlights from the Literature
realities found with full consideration of appropriate scientific and engineering principles. Several such myths and their factual counterparts are presented with an illustrative example. The Amyotte article clearly flags the dangers associated with handling of any solids at large scale and the need to be vigilant during planning and execution of charging and drying operations. A more extensive overview is also presented by Amyotte in his book An Introduction to Dust Explosions: Understanding the Myths and Realities of Dust Explosions for a Safer Workplace (Amyotte, P. An Introduction to Dust Explosions: Understanding the Myths and Realities of Dust Explosions for a Safer Workplace; Elsevier/Butterworth-Heinemann: Oxford, United Kingdom, 2013, 280 pages; ISBN 978-0-12-397007-7). MIE and MIT of Nano- and Microtitanium Powder with Inert Nano TiO2 Powder. Recent advancements in materials science and engineering technology have resulted in a corresponding increase in the number of nanoscale products. The safety of nanoproducts, in particular nanometal powders, has become increasingly important due to the history of metal dust explosions, as the unique physical and chemical properties of nanosized metal powders can cause increased explosion potential. Mixing an inert solid compound with a combustible dust is an application of the moderation principle, as the mixing can decrease the ignition sensitivity of microsized metallic powders and permit use of the hazardous material in a less hazardous form. Yuan et al. investigated the inerting effect of nanotitanium dioxide (TiO2) powders on ignition of micro and nanotitanium (Ti) powders by gathering minimum ignition energy (MIE; J. Hazard. Mater. 2014, 274, 322) and minimum ignition temperature (MIT; J. Hazard. Mater. 2014, 275, 1) comparison data. The authors concluded that nano-Ti is much more sensitive than micro-Ti to electric sparking, even at low quantities of nano-Ti. Adding nano-TiO2 to nano-Ti powder had almost no effect on the MIE of the nano-Ti powder, as the mixture was still highly sensitive with 90% nano-TiO2 powder. This suggests that solid inertants might not be suitable for nano-Ti particles. The addition of nano-TiO2 to micro-Ti powder had a greater effect on the MIE of the micro-Ti powder. Similarly, the authors concluded that nano-Ti powder was much more sensitive to contact with a hot surface (MIT determination) than was micro-Ti powder, even when mixed with 90% nano-TiO2 powder. Again, this suggests that solid inertant technology is not able to reduce the ignition hazard of the nano-Ti powder. However, solid inertant did effectively decrease ignition sensitivity of micro-Ti powder in contact with hot surfaces, as a mixture with 70% TiO2 could not be ignited in a BAM oven. An additional finding was that the MIT of micro-Ti powder was sharply reduced with a small amount of nano-Ti powder, thus suggesting possible application of such mixtures as a solid fuel.
To overcome these limitations, Chawla et al. disclose a proline-catalyzed synthesis of imines 17 from aldehydes and chloramine-T 18 in aqueous medium (Tetrahedron Lett. 2014, 55, 3553). The authors state that this is the first organocatalytic route to aldimines using 18 reported in the literature. The synthetic procedure is considered more environmentally friendly due to operational simplicity, metal-free conditions, and taking place in an aqueous medium at ambient temperature. Non-Phosgene Route to Unsymmetrical Ureas. The classical literature methods devised for the preparation of
urea-containing compounds employ hazardous reagents such as phosgene gas, phosgene substitutes, or isocyanates, whose production and storage impose toxicological and environmental issues. Milder catalytic processes using CO and CO2 have also been used, but these usually demand high pressures (10 MPa) at elevated temperatures (∼200 °C) to generate the reactive isocyanate intermediates. In order to limit the use of these reagents, Ghazvini Zadeh et al. introduce a convenient synthesis of unsymmetrical ureas 20 by rearrangement of N-Cbz-α-amino acid amides 19 (Tetrahedron Lett. 2013, 54, 5467). In addition to avoiding hazardous reagents, this method may also lead to the minimization of waste production, avoidance of unstable intermediates, shorter reaction times, simple workup procedures, and higher yields. A Survey of Solvent Selection Guides. A group of industrial chemists have undertaken the task of reviewing a range of published solvent selection guides and producing an overarching ranking comparison (Green Chem. 2014, 16, 4546). A total of 51 solvents were considered and ranked into four categories: recommended, problematic, hazardous, and highly hazardous. It should be noted that a third of the solvents under consideration were unable to be classified unequivocally, reflective of some differences in how the source data was treated by the institutions involved. The Green Chem. paper provides an excellent summary of solvent classification and a quick reference guide to process chemists seeking a useful list of potential process solvents along with their pros and cons. On the topic of process solvents, an interesting article (Chem. Eng. News 2014, 92 (12), 30) highlights the conundrum facing
■
GREEN CHEMISTRY Organocatalytic Synthesis of N-Sulfonyl Imines in Aqueous Medium. In recent years, advances in organocatalysis have led to easier experimental procedures, more cost-effective procedures, and large reductions in chemical waste. N-sulfonyl imines 17 have been targets of this work as previously reported synthetic methods generally require harsh acidic conditions, high temperatures, use of expensive and difficult to remove metal catalysts, nongreen solvents, and extremely dry conditions. G
dx.doi.org/10.1021/op500371s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Highlights from the Literature
of incidents could have been avoided since sufficient information on the potential hazard existed. The article is a timely reminder that, when evaluating the hazards of any new process, we need to pay close attention to how the process waste streams are treated, stored, and ultimately disposed. The full paper is available as an early view in the 2014 Process Safety Progress journal.
process chemists who may be unable to utilize some potentially useful solvents at scale because they have not been classified yet by the ICH. The example of cyclopentyl methyl ether (CPME, 21) was used as an illustration. CPME is a preferred alternative to methyl tert-butyl ether, 1,4-dioxane, and tetrahydrofuran, which are popular ether solvents but rate poorly because of health, safety, or environmental concerns. Compared with these traditional ether solvents, 21 has higher hydrophobicity and, therefore, is easier to separate from water. The solvent also forms explosive peroxides at a slower rate and has better stability under acidic and basic conditions. The utility of this solvent is further underlined in an article presented last year, demonstrating that 21 was an effective solvent for radical additions and reductions (Tetrahedron 2013, 69, 2251). However, some organizations developing new drugs are reluctant to use solvents that are not listed in the ICH guidelines, principally due to the time and resource that would be required to justify residual levels of such solvents in an active pharmaceutical ingredient. Prat et al. present a solvent selection guide from SanofiAventis that helps chemists in early development select sustainable solvents that will be accepted in all production sites as the project moves through the phases of development (Org. Process Res. Dev. 2013, 17, 1517). Solvents are divided into four classes, from “recommended” to “substitution advisible” to “substitution recommended” to “banned”. The ranking is derived from Safety, Health, Environmental, Quality, and Industrial constraints. Each solvent has its own ID card that indicates its overall ranking, EH&S hazard bands, as well as its ICH limit, physical properties, cost, and substitution advice (among others). The guide is advantageous because it can be used in a very simple way, to check if a solvent is recommended, or more thoroughly, in order to get data and advice on a solvent. Another advantage is the categorization of “banned” solvents, even in the laboratory, which is aligned with the policy of OPR&D to discourage scientists’ use of “strongly undesirable solvents” (Laird, T. Org. Process Res. Dev. 2012, 16, 1). The authors make a point to mention that the guide is in alignment with the European regulations and Global Harmonized System (GHS).
David Dale Process Safety, SciMed/Fauske, Unit B4, The Embankment Business Park, Stockport, Cheshire, SK4 3GN, U.K. E-mail:
[email protected] Michael D. Ironside Hovione, East Windsor, New Jersey 08520, United States. E-mail:
[email protected] Stephen M. Shaw*
■
Chemical R&D, Arena Pharmaceuticals, Inc., San Diego, California 92121, United States
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected].
■
LESSONS LEARNED FROM CASE STUDIES OF HAZARDOUS WASTE/CHEMICAL REACTIVITY INCIDENTS Hazardous waste in the USA is regulated by the Resource Conservation and Recovery Act (RCRA) with a focus on environmental and health hazards. However, it is widely recognized that hazardous waste can be prone to chemical reactivity hazards under certain circumstances. Material that is stable under standard storage conditions can be reactive upon exposure to heat or upon mixing with other chemicals. In an article by Cox et al. originally presented at the 10th Global Congress on Process Safety, New Orleans, LA, March 31−April 2, 2014, the authors discuss the history of incidents indicating that chemical hazards with waste streams are routinely overlooked. The article focuses mainly on those incidents where inadvertent heating led to an unintended and unforeseen chemical reaction and determines that the majority H
dx.doi.org/10.1021/op500371s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
