THE SOLVENT EFFECTS ON GRIGNARD REACTION

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1 THE SOLVENT EFFECTS ON GRIGNARD REACTION Mieko Kumasaki, Takaaki Mizutani, and Yasuhiro Fujimoto National Institute of Occupational Safety and Health, 1-4-6, Umezono, Kiyose, Tokyo, , Japan; This research focuses on the effects of water in a solvent on a synthetic process of a Grignard reagent which is common in organic synthesis and triggered an accident in Japan. For the measurement, a hermetically sealed apparatus was prepared to fit a small-scaled reaction calorimeter. The experimental results revealed that the induction period appeared as the water content in the solvent increased. The function of water was considered an inhibitor of the activation of the metal surface. KEYWORDS: Grignard reaction, induction period, reaction calorimeter, water content INTRODUCTION A chemical process is designed in order to ensure a safe operation. A set of materials and the process conditions are tailored to safely run the process as well as fit the quality demand. Operators carefully control a reaction by checking a temperature monitor to prevent a runaway reaction. Nevertheless, operators are sometimes misled by the induction period. In an accident that occurred in Japan, 2005, the induction period was one of the key causes. On 12 May, 2005, the process of generating a Grignard reagent for a polymer synthesis caused a runaway reaction followed by an explosion. Fortunately, there were no fatalities; however, three workers had burns from the reaction solution. The Grignard reagent is a common chemical in organic synthesis and generally formed with magnesium and an alkyl halide in ether. In the reaction process, magnesium and the initiating reagent were mixed in ether followed by the addition of a gaseous alkyl halide while monitoring the heating and temperature. The temperature and reaction rate did not increase as expected although the reaction has been conducted more than 100 times. They added additional gaseous alkyl halide in order to increase reaction rate. After the addition, the reaction mixture exhibited a sudden temperature rise and exploded. The time period which kept the reaction rate low is considered the induction period. The Induction period is the initial time during which the chemical reaction does not appear to occur. After this period, the chemical reaction accelerates. During the induction period, a monitor shows no or only a slight signal of a reaction. Without awareness of an induction period, an operator might add excess materials to a rector aimed at starting the reaction. The addition results in a surge in the reaction rate after a short period, and a runaway reaction then occurs. Since the induction period can lead operators to misjudging the situation, the knowledge of induction period should be essential in process safety. This report focuses on the effects of the solvent on the induction period for the synthesis of Grignard reagent, especially the water content. In the experiments, Tetrahydrofuran (THF) prepared with and without further purification was used as the solvent. The reaction need to be monitored in a small-scale for safety concerns and carried out in a reactor enable to introduce gaseous alkyl halide. Furthermore, the reaction is required to provide agitation during reaction monitoring. In order to meet the requirement, an apparatus was specially prepared to fit into a small-scaled reaction calorimeter with built-in magnetic stirrer, SuperCRC. The apparatus was made from glass and designed to avoid leaking of the gas into the open atmosphere and intrusion of air. EXPERIMENTS SAMPLES THF was purchased from Kanto Chemical Co., Inc. For investigation of the solvent effects, THF was purified by refluxing with sodium metal in order to remove the usual impurities such as water, THF peroxides, and stabilizers. Prior to collection of the pure fraction, benzophenone was added to the refluxing mixture since benzophenone forms a blue coloured complex and can serve as an effective indicator to check the removal of the water and peroxides. THF including water was prepared to give about 0.5wt.% and 1.0wt.% of THF by adding to water. A CH 3 Br cylinder was obtained from Sanko Chemical Industry Co.,Ltd. Magnesium (turnings, 99.9%) was obtained from Acros Organics. APPARATUS SETTING AND THE SYNTHETIC PROCEDURE FOR GRIGNARD REAGENT The Grignard reagent was prepared in a hermetically-sealed reactor which was metal contamination proof. The reactor was designed for a small-scale reaction calorimeter, i.e., the SuperCRC. SuperCRC is a reaction calorimeter, and its features were described in a previous report (Kumasaki, Fujimoto, & Ando, 2003). The calorimeter heat sink contains two wells for the sample and reference cells. The reference cell was not used in this study. The calorimetric behavior was followed through the Peltier devices built in the heat sink. All experiments used about 50 mg of magnesium turnings and 4 ml of THF. The reaction temperature was fixed at 158C. 1

2 Pressure Gauge Valve CH3Br Cylinder Joint unit A Vacuum pump N2 gas Cylinder CH3Br Reservoir In-out tube Joint unit B Peltier devices Glass Cup Stirring bar Calorimeter heat sink Figure 1. The apparatus and pipe arrangement for the experiments The apparatus and pipe arrangement are described in Figure 1. Prior to the calorimetric data collection, the magnesium was weighed and placed in a reactor with a magnetic stirring bar. The apparatus was evacuated by a vacuum pump and filled with nitrogen. After pouring the THF, a freeze-degassing was added using liquid nitrogen. In the procedure, special attention was required since air sometimes leaked. The procedure was, however, essential to keep the reactor under reduced pressure and introduce gaseous alkyl halide smoothly. Highly pure THF was carefully transferred to avoid air intrusion. The CH 3 Br vapour was introduced from a reservoir after the baseline of SuperCRC was allowed to stabilize. Gaseous CH 3 Br had been previously transferred from the cylinder to the reservoir. WATER CONTENT The Water content was measured using an AQUACOUN- TER equipped with an AQ-2001 and AQV-2001 (Hiranuma Sangyo, Co., Ltd.). Both of them measure water content by way of the Karl Fischer titration method and the measurement ranges are from10ug to 99 mg of H 2 O. The former is coulometric and the detection range is 5 ppm to 10%. The latter is volumetric and the detection range is from 100 ppm to 100%. In the measurements, the two automatic water analyzers were switched depending on the expected water content of the THF. SEALED CELL DIFFERENTIAL SCANNING CALORIMETRY (SC-DSC) The thermal analysis with SC-DSC was utilized to check the existence of tetrahydrofuran peroxides. The peroxides is supposed to decompose exothermically in the range from C (Robertson, 1948). The measurements were carried out at the heating rate of 10K/min. The instrument was a DSC2920 from TA instruments. The Solvent THF, as sample, was heated in sealed cells made from stainless steel. RESULTS Figures 2 7 show the heat release behaviour upon the CH 3 Br to the reactor. Figure 2 shows the result with a solvent taken from a newly used THF including stabilizer. Although the THF is commercially available in an ordinary bin, the average of water content was 82.4 ppm which was quite low level against expectations. Figure 3 is a result of freshly purified THF whose water content was ppm on average. Solvents with low water content allowed an exothermic reaction to start immediately after the CH 3 Br introduction. No difference was observed between the purified THF and the THF including stabilizer. Therefore, the stabilizer in THF does not have any influence during the initial stage. Neither of solvents showed the induction period. The induction period appeared as the water content increased. Figures 4 7 show the heat flow curves of the reaction in THF with added water. At about a 0.5wt.% water content, an inflection point was found. After the inflection point, the heat flow curve surged and reached the maximum heat rate. This suggests a slight sign of an induction period. THF with about 1wt.% water exhibited two exothermic peaks (Figures 6 and 7). Magnesium did not seem to react until the reaction reached the latter exothermic process. 2

3 Figure 2. Heat flow as a function of time for the reaction in THF with stabilizer. The water content was 82.4 ppm SC-DSC measurement revealed that the change in heat release behaviour was only due to the change in water content. SC-DSC measurement did not suggest any signal indicating peroxides present in all the solvents used in this study. The Grignard reagent is recognized as a useful species to generate a carbon-carbon bond. The Griganard reagent is synthesized by the following reaction: RX þ Mg! RMgX (1) Figure 4. Heat flow as a function of time for the reaction in THF with stabilizer. The water content was wt.% R is an alkyl group, and X is a halogen atom. In general, the alkyl halide is added to THF containing magnesium. The mixture turns into a suspension. The generated Grignard reagent is utilized in the following synthesis without isolation. In the Grignard reagent, the alkyl group is negatively charged due to the low electronegativity of the magnesium. Thus, the Grignard reagent is easily deactivated by water accompanied with a heat release. RMgX þ H2O! RH þ Mg(OH)X (2) Figure 3. Heat flow as a function of time for the reaction in THF without stabilizer. The water content was ppm Figure 5. Heat flow as a function of time for the reaction in THF without stabilizer. The water content was wt.% 3

4 Figure 6. Heat flow as a function of time for the reaction in THF with stabilizer. The water content was wt.% In this experiment, the excess amount of CH3Br might cause the Wurtz-Fittig reaction as a side reaction to generate a hydrocarbon. A high temperature enhances the side reaction. RMgX þ RX! R-R þ MgX 2 (3) This study indicated that water in the solvent suppressed the heat release during the initial stage although water generally leads to decomposition of the Grignard reagent and generates heat. The Grignard reagent generation process should be developed as follows: 1. dissolution of alkyl halide into solvent, 2. removal of oxide film on magnesium surface, 3. reaction of alkyl halide with magnesium on its surface. As for step1, the calorimetric measurement revealed the dissolution was exothermic (Figure 8). This measurement was carried out in the way similar to the synthesis of the Grignard reagent. Under a decreased pressure, CH3Br was introduced into the THF without magnesium in a reactor. The step 2 to expose a fresh magnesium surface can be identified by the use of iodine. Iodine removes the oxide film on the magnesium surface and turns into iodine ion if it exists in a reactor. The removal is accompanied with the change in colour of iodine; the purple iodine radical turns into the colourless iodine ion. In other words, an iodine radical attacks on the oxide film. Step 3 is a well-known exothermic reaction. As mentioned above, the existence of water and the excess amount of alkyl halide can deactivate the Grignard reagent. How does water serve as an inhibitor of the reaction? As for step 1, water does not seem to prevent CH 3 Br from dissolution into the THF. The heat release behaviour exhibited in figure 6 and 7 have a similarity to one in Figure 8 indicating the dissolution of the CH 3 Br. Water can serve as an inhibitor of the expected reaction in step 3. The reaction caused by water, however, is also exothermic and does not exhibit an induction period. Among the three steps, the most plausible function is to prevent the smooth removal of the oxide. The process easily develops by the existence of radicals. The radical generated by CH 3 Br can be quenched or retarded by water which can result in the generation of an induction period. The question has still remained how the generation of the Grignard reagent starts even in the presence of water; Figure 7. Heat flow as a function of time for the reaction in THF without stabilizer. The water content was wt.% Figure 8. Heat flow as a function of time for the dissolution process of CH 3 Br into THF without stabilizer 4

5 the speed of the removal might exceed the inhibition of the water, or the temperature rise might allow the water to vaporize. In either case, the latter peak in Figures 6 and 7 represents that the induction period terminated and the generation of the Grignard reagent started. Figures 2 5 show the cases that the generation of the Grignard reagent occurred following to the dissolution of the CH 3 Br without interruption. proceed. In the case of a high water content, the exothermic dissolution of CH 3 Br and generation of the Grignard reagent are separate processes. That caused an induction period. The water is considered as an inhibitor to avoid exposure of the active magnesium surface. In order to control reactions concealing an induction period, awareness is the first step. Therefore, screening measures for such reactions need to be carefully devised. CONCLUSION A Chemical process should be designed as a safe process taking into consideration related past incidents, properties of materials, and the character of the reaction. They fix the recipe, the procedure, and during the operation, monitor the temperature and other parameter not to exceed the set criteria in order to maintain a stable operation. Some of the reactions, however, sometimes accelerate beyond control without awareness of an induction period. This research focused on the Grignard reagent synthesis using THF, CH 3 Br, and manganese. The effect of water in solvent was investigated. The heat flow behaviour of the reaction varied depending on the water content. THF with little water allowed the reaction to smoothly ACKNOWLEDGEMENT The authors are grateful to Mr. Keita Nagasawa at the Yokohama National University for the helpful information about THF peroxide. REFERENCE Kumasaki, M., Fujimoto, Y., Ando, T., 2003, Calorimetric behaviours of hydroxylamine and its salts caused by Fe(III), Journal of Loss Prevention in the Process Industries,16, Robertson, A., 1948, Tetrahydrofuran Hydroperoxide, NATURE, 162,153 5

The Synthesis of Triphenylmethano. will synthesize Triphenylmethanol, a white crystalline aromatic

HEM 333L rganic hemistry Laboratory Revision 2.0 The Synthesis of Triphenylmethano ol In this laboratory exercise we will synthesize Triphenylmethanol, a white crystalline aromatic compound. Triphenylmethanol