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Article Cite This: Org. Process Res. Dev. 2017, 21, 1501-1508

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Potential Safety Hazards Associated with Using Acetonitrile and a Strong Aqueous Base Zhe Wang,* Steven M. Richter, Michael J. Rozema, Adam Schellinger, Kimberly Smith, and José G. Napolitano† Process Research and Development, †Discovery Chemistry and Technology, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States S Supporting Information *

ABSTRACT: Acetonitrile, a common solvent in organic synthesis, can be hydrolyzed in the presence of a strong aqueous base, such as NaOH or KOH, which can propagate into a runaway reaction. For a process recently reviewed in our laboratory, a possible loss of cooling incident during the desired reaction was found to have the potential to self-heat to the onset temperature of this hydrolysis reaction. This base-catalyzed acetonitrile hydrolysis was determined to potentially escalate into a runaway reaction, where it could lead to secondary exothermic runaway reactions of the reaction mixture. The use of acetonitrile was preferred for the initial cyclization step. Thus, adequate removal of acetonitrile prior to the following step avoided the process safety hazard posed by the hydrolysis of the acetonitrile solvent. The findings presented in this work serve as an alert to chemists and engineers for the potential safety hazards when scaling up a process in which the solvent becomes a reactant.

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INTRODUCTION Acetonitrile is widely used as a solvent in organic synthesis because it affords high solubility of many organic compounds, miscibility with water and many organic solvents, and modest relative toxicity. Acetonitrile can also be used as a reagent and can be catalyzed by a strong base or strong acid to undergo hydrolysis to form an amide, which can then be further hydrolyzed to a carboxylic acid.1,2 In fact, hydrolysis of nitriles is commonly used to synthesize carboxylic acids. The yield of amide formation may be reduced due to the formation of carboxylic acids3,4 because the hydrolysis of amides is faster than the hydrolysis of nitriles under basic conditions.5 Under certain conditions, deprotonation of acetonitrile affords the nitrile-stabilized anion,6 which can add to other nitrile molecules to produce dimers or trimers.7 To suppress the hydrolysis, which is competitive with trimer formation, all reactants needed to be dried with molecular sieves prior to heating.8 Acetonitrile under very high pressure and in the presence of a weak base can form trimers.9,10 Neat nitriles have also been trimerized using potassium tert-butoxide as catalyst in a focused microwave reactor.11 To safely scale up a pharmaceutical manufacturing process, a process safety evaluation must be performed. This includes evaluating heats of reaction and the thermal stability of process samples, identifying the process hazards, and defining safe operating conditions. The heat of reaction can be used to determine the adiabatic temperature rise (ATR) of a reaction, whereas the thermal stability of samples can be used to determine the onset temperatures of exothermic events and their severities. The process temperature (Tp), the maximum temperature rise of the synthesis reaction (MTSR = Tp + ATR), the boiling point of solvent (Tb), and the temperature at which the reaction will reach a maximum self-heating rate under adiabatic conditions in 24 h (TD24) are used to determine the Criticality Index, introduced by Stoessel12 and shown in Figure © 2017 American Chemical Society

1. This is used to characterize the process hazards into Classes 1 (least critical) to 5 (most critical). The processes in Classes

Figure 1. Criticality classification of chemical processes.

1−3 do not have the thermal potential to reach decomposition, and the processes in Classes 4 and 5 can potentially self-heat to the onset temperature of decomposition. In the course of a process safety evaluation for a large-scale cyclization reaction, we identified process risks and subsequent mitigation methods because the desired reaction has sufficient energy to self-heat to the onset temperature of an exothermic Received: April 27, 2017 Published: August 30, 2017 1501

DOI: 10.1021/acs.oprd.7b00158 Org. Process Res. Dev. 2017, 21, 1501−1508

Organic Process Research & Development

Article

Scheme 1

ARC was used to determine a more accurate onset temperature. As shown in Figures 4 and 5, an exothermic event was detected near 40 °C and a second exothermic event was detected near 210 °C with temperature rises of 89 and 146 °C, after correcting for thermal inertia. This is in reasonable agreement with the DSC screening. The sodium hydroxide quench and deprotection has an ATR of 66 °C and a MTSR of 89 °C, which is above Tonset, Tb, and TD24. This means that the reaction has the thermal potential to self-heat to the onset temperature of the exothermic event without the benefit of evaporative cooling. The NaOH quench and the deprotection reaction fall into criticality Class 5 in the Stoessel Criticality Index. This is undesired, as there are no inherent safety measures available to mitigate the safety concerns for a Class 5 process. To examine the severity of the runaway reaction in the event of loss of cooling, the quench was performed with a closed cell VSP2 test. The VSP2 has low thermal inertia to simulate runaway behavior in a larger reactor. The test was performed in adiabatic mode, i.e., instead of performing heat−wait−search steps to look for exothermic events, the sample was not heated with the test heater and the temperature of the test cell environment was controlled by a guard heater to maintain adiabatic conditions. Upon NaOH solution addition (21 equiv), heat generation quickly increased the temperature of the reaction mixture to 70 °C from 30 °C. At this temperature, the self-heating rate never fell below 0.5 °C/min. The exothermic event propagated into a runaway reaction within 20 min, with the observed peak selfheat and pressure rise rates (for the half-full test cell) exceeding 90 °C/min and 200 psi/min, respectively. After reaching 175 °C, the self-heat rate decreased and then accelerated into two additional consecutive exothermic events, possibly due to decomposition of the reaction mixture. When the temperature reached ∼285 °C, the test cell ruptured due to the suspected loss of pressure equalization resulting from a plugged test cell pressure transducer line. Details for the VSP2 test are provided in the Experimental Section. VSP2 testing results are shown in Figures 6 and 7. This test confirms that without cooling the heat of reaction from quenching TFAA could increase the temperature above the onset temperature of an exothermic event, causing a runaway reaction that eventually escalates into secondary exothermic events at higher temperatures, as suggested by the ARC testing performed with higher thermal inertia. To identify the cause of the exothermic event, several DSC tests were conducted using combinations of materials used in the process. As summarized in Table 3 and shown in Figure 8, the DSC detected an exothermic event near 56 °C on the post quench reaction mixture. After testing combinations of the reaction mixture components, it was observed that exothermic events were detected only near this temperature when acetonitrile and NaOH aqueous solution are present. It was hypothesized that hydrolysis or polymerization of acetonitrile in

runaway reaction associated with acetonitrile and aqueous sodium hydroxide solution.

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RESULTS AND DISCUSSION A pharmaceutical intermediate is formed via the cyclization reaction shown in Scheme 1. After the completion of cyclization at 55 °C using acetonitrile as solvent, the reaction mixture was cooled to ambient temperature. Aqueous sodium hydroxide was added to quench (hydrolyze and neutralize) the trifluoroacetic anhydride (TFAA) and to remove a protective group. A process safety evaluation was performed to determine if the process could be run safely at pilot scale. The heat of reaction was obtained using heat flow calorimetry in an Omnical SuperCRC (chemical reactivity calorimeter). The thermal stability of samples was measured by calorimetric methods, using instruments such as a DSC (differential scanning calorimeter), ARC (accelerating rate calorimeter), or VSP2 (Vent Sizing Package 2). A DSC was used to quickly screen thermal stabilities of many samples. An ARC has a much higher detection sensitivity, which provides a more accurate onset temperature of exothermic events for key samples from DSC screening. VSP2, with low thermal inertia, provides the best prediction of a runaway reaction scenario in a larger reactor. Thermal stability screening was performed in the DSC with results summarized in Table 1. Heats of reaction measured with Table 1. DSC Testing Results sample starting material

post cyclization reaction mixture post quench and deprotection reaction mixture product

ΔH (J/g) +84 (endo) −416 −23 −20 −403 −199 −18

temperature range of thermal event (°C) 142−170 260−324 114−171 175−203 56−209 265−350 166−253

the Omnical SuperCRC are shown in Figures 2 and 3 and Table 2. With a 27 °C ATR for the cyclization, if cooling is lost, the reaction mixture could self-heat to the MTSR of 82 °C. Since the MTSR is lower than the onset temperature of the first exothermic event and because of the low energy of the observed event, no thermal stability related safety concerns for the cyclization reaction were identified for this point of the process. Testing the reaction mixture after the quench and deprotection with sodium hydroxide included some more concerning results. Two exothermic events were detected in the DSC, including one at 56 °C and one near 265 °C, each with significant exothermicity. Since the onset temperature of the first exothermic event was near the reaction temperature, the 1502



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Figure 2. Omnical SuperCRC results of cyclization at 55 °C.

Figure 3. Omnical SuperCRC results of the TFAA quench and deprotection at ambient temperature.

Table 2. Heat of Reaction Measurement and Criticality Analysis Results

heat of reaction (kJ/mol) reaction temperature (°C) boiling point of solvent, acetonitrile (°C) ATR (°C) MTSR (°C) Tonset of highly exothermic event in reaction mix (°C) criticality index

cyclization reaction

quench and deprotection

−255 55 81 27 82 N/A

−1103 23 81 66 89 56

1

5

Figure 5. ARC test self-heating rates of the post quenching TFAA reaction mixture.

the presence of NaOH could be the source of the exothermic event. To explore the cause of the exotherm, a sample was prepared by subjecting the acetonitrile and NaOH aqueous solution in a pressure test cell to 100 °C for 2 h to analyze the composition of the exothermic reaction product. Ammonia gas was immediately identified to be present in the post-test gas space. Acetic acid was found to be present in the post-test mixture via 1H NMR analysis. Analysis by LC-MS (positive mode electrospray ionization) also confirmed the presence of acetamide in addition to acetic acid. There was no evidence of dimers or trimers of acetonitrile via LC-MS analysis. All of the LC-MS signals in the positive and negative mode ionization in the sample are accounted for by the signals observed from

Figure 4. ARC test temperature history of the post quenching TFAA reaction mixture.

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To experimentally evaluate how severe the runaway acetonitrile hydrolysis could be under adiabatic conditions, a mixture of acetonitrile, water, and sodium hydroxide with a mole ratio similar to that used in the TFAA quenching and deprotection reaction was also tested with VSP2. An exothermic event was detected at 70 °C, which propagated into a runaway reaction with peak self-heat rate and pressure rise rate exceeding 2000 °C/min and 5000 psi/min, respectively. The exothermic runaway of the acetonitrile, water, and sodium hydroxide mixture was more severe than the actual reaction mixture, which is likely due to the lack of reactants that can act as a heat sink. VSP2 testing results are shown in Figures 9 and 10. The post test mixture analyzed by LC-MS also confirmed the presence of acetamide and acetic acid (products of hydrolysis of acetonitrile), and no evidence of dimers or trimers was observed, even after exposure to higher temperature and pressure in this test. Surprisingly, in our review of existing literature, the process hazard potential of this simple combination of commonly used chemicals was not readily available. Although the process may be performed without incident if NaOH solution is added slowly and if sufficient cooling is provided, there are potentially devastating consequences of this runaway reaction upon loss of cooling. Identification of a remedy and development of an inherently safe, robust process was explored before the process could be scaled up in the pilot plant or transferred to a third party manufacturer. A study was performed to investigate if water and sodium hydroxide concentration could be used to reduce the consequences of a runaway reaction. NaOH and water equivalents were varied to observe the effect on the onset temperature. As shown in Table 4, at sodium hydroxide concentrations above 0.1 equiv, exothermic events were detected in the temperature ranges from 57 to 74 °C. After reducing the sodium hydroxide concentration to 0.025 equiv, the only exothermic event observed was in the sample with 2 equiv of water, although the detection temperature was much higher, at 157 °C. The plots of the DSC results can be found in the Supporting Information. In the cyclization reaction, approximately 20 equiv of NaOH with respect to starting material (or about 0.33 equiv with respect to acetonitrile) was used. Approximately 8 equiv of NaOH is required to quench TFAA, and the rest is needed for the deprotection reaction. The test results suggest that NaOH concentration could be used to reduce the hydrolysis rate of acetonitrile, but only at concentrations well below the level required to perform the desired chemical transformation. Since many bases, strong or weak, may be used with acetonitrile in organic synthesis, the effects of strength of bases on the initiation temperature of acetonitrile hydrolysis were briefly explored with the DSC to determine if a weaker base could prevent the runaway reaction. The DSC findings are summarized in Table 5. As shown in Figure 11, when combined with strong bases, such as potassium hydroxide and lithium hydroxide, exothermic events were detected between 60 and 72 °C, similar to those observed with sodium hydroxide. Additional testing showed that the onset temperature of the hydrolysis increased as the strength of the base decreased. In each case where an exothermic event was observed, mixtures were prepared and held at elevated temperatures within the observed exothermic event. Acetamide and acetic acid were observed in NMR analysis of each of the resulting samples.

Figure 6. VSP2 test temperature−pressure history of the fresh quenching TFAA reaction mixture.

Figure 7. VSP2 test self-heat and pressure rise rates of the fresh quenching TFAA reaction mixture.

Table 3. DSC Screening Results of the Reaction Mixture and Simulated Reaction Mixtures sample quench TFAA and deprotection reaction mixture acetonitrile/50% NaOH/pyridine acetonitrile/pyridine/TFAA pyridine/TFAA/THF/water/NaOH pyridine/TFAA/acetonitrile/NaOH/ water acetonitrile/NaOH/water/TFAA acetonitrile/NaOH/water

detection temperature of exotherm (°C) 56 43 122 123 52 58 65

acetamide, sodium acetate, and acetic acid. Thus, it was confirmed that acetonitrile was hydrolyzed in the presence of water and strong base, NaOH, to form ammonia, acetamide, and acetic acid (which then reacts with NaOH to form sodium acetate), as shown in Scheme 2. Although base-catalyzed hydrolysis of nitriles is well-known to form amides or carboxylic acids,13 the low onset temperature and amount of heat produced were unexpected. A literature search identified a patented process for removing water and HCN from acetonitrile via extraction with concentrated caustic aqueous solution and with preferred temperatures of approximately ambient which can vary up to 82.5 °C.14 Lower temperatures are preferred to minimize hydrolysis of the nitrile which can occur at elevated temperatures, although stability issues were not discussed. Diluted aqueous potassium hydroxide (1 mL of 1% solution per liter) has been used in distillation to purify acetonitrile without reported safety issues.15 1504



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Figure 8. DSC results of the quenched reaction mixture and simulated reaction mixtures.

Scheme 2. Hydrolysis of Acetonitrile

With a pKa of 9.3 or below, heat generation due to hydrolysis of acetonitrile was not observed. One exception was for the organic base DBU (pKa 13.9), in which heat generation due to hydrolysis was not observed. However, with weaker bases the deprotection reaction may not reach completion. The option of removing acetonitrile was also explored. The cyclization reaction proceeded in THF and 2-methyl THF, but it was slow and resulted in unacceptably low yields and additional impurities. To achieve a maximum yield in the cyclization reaction, we decided to conduct the cyclization in acetonitrile. After completion of the cyclization, a solvent exchange to 2-methyl THF was performed to mitigate the process safety risk during the quench of TFAA and deprotection. The reaction performed this way produced a quality product with comparable yield.

Figure 10. VSP2 test self-heat and pressure rise rates of acetonitrile/ NaOH/water.

DSC testing of the post TFAA quenching and deprotection reaction mixtures using 2-methyl THF as solvent did not detect any exothermic event until ∼260 °C. The DSC test of the cyclization reaction distillation residue during the solvent switch detected only minor exothermic events near 155 and

Figure 9. VSP2 test temperature−pressure history of acetonitrile/NaOH/water. 1505



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Table 4. DSC Results for Acetonitrile, Water, and NaOH Mixtures acetonitrile

water

NaOH

Tonset (°C)

1 2 3 4 5 6 7 8 9

1 1 1 1 1 1 1 1 1

0.5 0.5 0.5 1 1 1 2 2 2

0.025 0.1 0.3 0.025 0.1 0.3 0.025 0.1 0.3

N/D 67 74 N/D 80 57 157 71 65

Table 5. DSC Results for Acetonitrile in Water and Selected Bases and Salts basea

pKa13,16 of conjugate acid in water

detection temperature of exotherm (°C)

water equivb

base equivb

NaOH KOH LiOH K3PO4 Na2CO3 NH3 NaHCO3 KH2PO4 DBU

>14 >14 >14 12.4 10.3 9.3 6.4 6.9 13.5

65 72 60 112 137 N/D N/D N/D N/D

6.9 3.6 5.5 5.9 5.3 4.0 5.7 6.0 2.1

0.3 0.1 0.7 0.2 0.2 4.2 0.1 0.1 0.6

CONCLUSIONS

Following the cyclization reaction in acetonitrile, the quench of TFAA and deprotection with aqueous sodium hydroxide solution was found to be unsafe to scale up. In the event of a loss of cooling, the heat of reaction from the desired reaction has the thermal potential to escalate into an exothermic runaway reaction. Since the cyclization was not found to be effective in alternative solvents, it was performed in acetonitrile. A robust and safe alternative process was identified by switching the solvents from acetonitrile to 2-methyl THF to perform the quench and deprotection reaction. By eliminating a potential runaway reaction, the Stoessel criticality risk level was reduced from Class 5, with the potential to reach a runaway reaction and no inherent protection against this, to Class 1, where the process no longer has a way to reach a thermal hazard on its own. The modified process has been successfully scaled up in a pilot plant. This work shows an example where the combination of acetonitrile with a strong base could pose significant safety concerns due to a runaway reaction caused by acetonitrile hydrolysis. Even though acetonitrile hydrolysis is known to happen in the presence of water and strong base, hydrolysis reactions are often mildly exothermic. Therefore, it was unexpected that the hydrolysis reaction posed a safety risk at easily achievable temperatures in this process. The energy from the desired reaction is sufficient to self-heat the reaction mass past the onset temperature of the hydrolysis reaction and then propagate into a runaway reaction and trigger the secondary runaway reactions of the mixture. By replacing acetonitrile before the NaOH quench, the process risk due to the potential runaway reaction caused by hydrolysis of acetonitrile has been eliminated. Although they were not tested as a part of this work, similar safety concerns could exist with mixtures of acetonitrile and acids.17 The findings in this work may serve as an alert to chemists and engineers for potential safety hazards present

mole ratio entry

Article

a

In acetonitrile/water solution. bCalculated with respect to acetonitrile.

251 °C. These DSC results as well as the DSC results of the post cyclization reaction mixture are shown in Figure 12.

Figure 11. DSC results of acetonitrile and different bases and salts. 1506



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Figure 12. DSC results of process samples from the final process.

when the solvent becomes a reactant, as acetonitrile does in the presence of the strong base.

Table 6. HPLC Instrument Parameters

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HPLC gradient

EXPERIMENTAL SECTION Equipment Used. DSC anslysis was performed using a Mettler-Toledo DSC821e or DSC823e using sealed glass ampules with a capacity of approximately 50 μL. ARC analysis was performed using a Netzsch ARC 254 and titanium test cells. VSP2 testing was performed using Fauske & Associates Vent Sizing Package 2. Heat of reaction testing was performed using an Omnical SuperCRC isothermal calorimeter. Liquid chromatography mass spectrometry (LC-MS) was performed using an Agilent 1260 HPLC instrument with an Agilent 6130 single quad mass spectrometer. General Procedure for DSC Testing. Samples were first loaded into and sealed in glass ampules and ramped in the DSC furnace from 0 to 250−350 °C at 1−3 °C/min. General Procedure for Omnical Testing. Two 15 mL glass test cells were used per test, one for the sample and the other for the reference. Mixing was provided by a magnetic stir bar. General Procedure for ARC Testing. The sample was loaded into a Ti pressure bomb, which was then inserted into the calorimeter. Temperature and pressure of the test were recorded. The sample was heated in heat−wait−search steps of 10 °C, starting at 30 °C. When self-heating was detected, the calorimeter maintained the airspace around the bomb at the same temperature as the sample and tracked the exotherm to 300 °C or until a pressure of 40−70 bar was reached. General Procedure for LC-MS Testing. Samples were prepared by weighing about 55 mg of material and diluting with 1 mL of water containing 0.1% (v/v) formic acid. Water containing 0.1% (v/v) formic acid was used as the aqueous mobile phase, and acetonitrile was used as the organic mobile phase. The LC-MS conditions can be found in Tables 6 and 7. An XBridge C18 HPLC column from Waters (150 × 4.6 mm, 3.5 μm particle size) was used.

HPLC parameters flow rate: 1.0 mL/min injection volume: 3.0 μL column temperature: 30 °C UV wavelength: 210 nm UV bandwidth: 4 nm

time (min)

aqueous mobile phase (%)

organic mobile phase (%)

0.0 15.0

90 0

10 100

20.0

0

100

20.1

90

10

25.0

90

10

Table 7. Mass Spectrometer Instrument Parameters mass spectrometer parameters ionization source: electrospray drying gas temperature: 350 °C drying gas flow rate: 12 L/min capillary voltage: 3000 V nebulizer pressure: 50 psig fragmentor voltage: 70 V gain: 1 positive and negative scan mode used

General Procedure for VSP2 Testing. A closed cylindrical stainless steel test cell (∼120 mL) was placed in a 4 L containment vessel. The test cell was enclosed by a test heater, a layer of insulation, and a guard heater, which was in turn enclosed by thermal insulation. Mixing was provided by a magnetic stir bar. The sample temperature and pressure as well as the containment pressure were recorded. The VSP2 test cell was loaded into a VSP2 vessel and heated in heat−wait−search steps. When self-heating was detected, the calorimeter maintains adiabatic conditions by offsetting heat losses through the guard heater and tracks the exotherm to the temperature or pressure limits defined for the test. As test cell pressure increased, nitrogen was charged into the containment vessel to 1507



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Notes

maintain the specified test cell and containment pressure differential. Omnical Test Charges. Charges for cyclization, hydrolyzing TFAA, and deprotection during the Omnical test are shown in Table 8. The cyclization reaction was performed at 55

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, writing, reviewing, and approving of the publication. All authors are employees of AbbVie.

Table 8. Omnical Test Charges for Cyclization, Hydrolyzing TFAA, and Deprotection Using Acetonitrile as Solventa

a

material

equiv

starting material pyridine TFAA acetonitrile NaOH water

1.00 4.82 4.79 60.44 22.43 49.84

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7.64 g total.

°C. After the cyclization reaction reached completion, a new test was started at 23 °C; then, NaOH solution was added. After the reaction reached completion, 5.13 g of the reaction mixture was used to test the thermal stability in the ARC. Closed Cell VSP2 Test Charges for Hydrolyzing TFAA and Deprotection. Charges for the VSP2 test to simulate cooling failure during the initially proposed process are shown in Table 9. The reaction mixture, without 50% NaOH, was first Table 9. VSP2 Test Charges for Hydrolyzing TFAA and Deprotectiona

a

material

equiv

starting material pyridine TFAA acetonitrile NaOH water

1.00 3.32 4.18 55.28 20.91 46.46

66.32 g total.

subjected to 55 °C heating for several hours until the cyclization reaction reached completion. The reaction mixture was then cooled and loaded into the VSP2 test cell. The VSP2 test was started in adiabatic tracking mode (without heating the sample). The exothermic events were detected upon the addition of 50 wt % NaOH, which led to a runaway reaction, as shown in Figure 7.

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REFERENCES

(1) March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 2nd ed.; McGraw-Hill, Inc: New York, 1977. (2) Parris, C. L.; Christenson, R. M. N-Alkylation of Nitriles with Benzyl Alcohol, Related Alcohols, and Glycols. J. Org. Chem. 1960, 25, 331. (3) Ghaffar, T.; Parkins, A. W. The catalytic hydration of nitriles to amides using a homogeneous platinum phosphinito catalyst. J. Mol. Catal. A: Chem. 2000, 160, 249. (4) Parkins, A. W. Catalytic hydration of nitriles to amides. Platinum Met. Rev. 1996, 60, 169. (5) Chin, J. Developing artificial hydrolytic metalloenzymes by a unified mechanistic approach. Acc. Chem. Res. 1991, 24, 145. (6) West, R.; Gornowicz, G. A. Polylithium compounds. IV. Polylithiation of nitriles and the preparations of trisilylynamines. J. Am. Chem. Soc. 1971, 93, 1714. (7) Kruger, C. JOM 1967, 9, 125. (8) Smyrl, N. R.; Smithwick, R. W. J. Hydroxide-catalyzed synthesis of heterocyclic aromatic amine derivatives from nitriles. J. Heterocycl. Chem. 1982, 19 (3), 493. (9) Bengelsdorf, I. S. High Pressure−High Temperature Reactions. II. The Reactions of Aliphatic Nitriles and Amides. J. Org. Chem. 1963, 28 (5), 1369. (10) Cairns, T. L.; Larchar, A. W.; McKusick, B. C. The Trimerization of Nitriles at High Pressures. J. Am. Chem. Soc. 1952, 74 (22), 5633. (11) Baxendale, I. R.; Ley, S. V. Formation of 4-Aminopyrimidines via the Trimerization of Nitriles Using Focused Microwave Heating. J. Comb. Chem. 2005, 7 (3), 483. (12) Stoessel, F. Thermal Safety of Chemical Processes: Risk Assessment and Process Design; Wiley-VCH: Weinheim, 2008. (13) Carey, F. Organic Chemistry, 2nd ed.; McGraw-Hill, Inc., 1982. (14) Smiley, R. A. Purification of Acetonitrile by Caustic Extraction. US Patent 4287134, 1981. (15) Coetzee, J. F. Purification of acetonitrile and tests for impurities. Pure Appl. Chem. 1966, 13 (3), 427. (16) Kaupmees, K.; Trummal, A.; Leito, I. Basicities of Strong Bases in Water: A Computational Study. Croat. Chem. Acta 2014, 87, 385− 395. (17) Bretherick, L. Handbook of Reactive Chemical Hazards, 6th ed.; Butterworth-Heinemann Ltd.: Boston, MA, 1999; p 281.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.7b00158. DSC results for mixtures of acetonitrile, water, and NaOH at different ratios, reaction mixture and simulated reaction mixtures, and mixtures of acetonitrile with different bases and salts (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zhe Wang: 0000-0002-9261-6982 Steven M. Richter: 0000-0002-5135-9676 1508


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