Grignard Reaction Fall 2010

Grignard Reaction Fall 2010 - GRIGNARD REACTION Preparation...

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Unformatted text preview: GRIGNARD REACTION Preparation of Triphenylmethanol (Triphenylcarbinol) from a Ketone The Grignard reaction is one of significant importance in synthetic organic chemistry. It is also one of the most temperamental synthetic organic procedures. The Grignard reagents are a special type of compounds belong— ing to the broad group of organometallic compounds. Many of these organometallic compounds are of syn- thetic importance to the organic chemist. it + Mg(OH)Br phenylmagnesium Benzophenone C bromide l (Grignard reagent) OH Triphenylmethanol The French chemist Vlctor Grignard was awarded the Nobel Prize in 1912 for his work in developing and using organomagnesium halides in organic synthesis. He discovered this class of reagents in 1898 when he found that certain alkyl or aryl halides react with magnesium metal in dry ether. These organometallic compounds are very valuable and versatile because they react easily with a wide range of molecules to synthesize an impres- sive array of products involving new C-C bonds. Some of the compounds that react readin with Grignard reagents include aldehydes (to yield 1° and 2° alcohols), ketones (2° alcohols), esters (3° alcohols or ketones), epoxides (alcohols), alkyl halides (hydrocarbons), acyl halides (ketones), nitriles (ketones), carbon dioxide (car— boxylic acids), and acids (ketones). Mg: + R—X _. Mg+[R—X]‘_. Mg+R' X'__, R‘MgHX‘ The mechanism for the formation of alcohols involves a nucleophilic attack of the Grignard reagent on the car— bon atom center of the carbonyl group. The alkoxide ion intermediate is then hydrolyzed with dilute acid to yield the desired alcohol. Organic Chemistry: Microscale Lab Techniques 0 MgX _ C I l O MgX+ OH h I H 0+ X_ + Mng C6H5 21HetI-Ieé ’ C 3 a ’ C + H20 2 I" III H5C6 / \C6H5 H5C6 / \C6H5 H5C6 H5C6 The Grignard reagent is a strong base and a strong nucleophile. As a base, it will react with all protons that are more acidic than those found on alkenes and alkanes. The high reactivity of the reagent means that it can be destroyed by a number of undesired side reactions. For example, the reagent will react easily with water. The Grignard reagent must be prepared and used under anhydrous conditions because of its reaction with water. The glassware, reactants, and solvent must be scrupu- lously dry. Besides causing unwanted sides reactions, traces of water can also strongly inhibit or even prevent the reaction that results in the formation of the reagent itself. Other possible side reactions include ones with oxygen and carbon dioxide in the air. Oxygen reacts with the Grignard reagent to form hydroperoxides. Air oxidation can also occur, resulting in ROMgX. Reaction of the Grignard reagent with CO2 results in carboxylic acids (when this is actually the desired product, crushed dry ice is added to the Grignard reagent). These side reactions can be avoided by conducting the reaction under an inert atmosphere, such as argon or nitrogen gas. Allowing the ether solvent to reflux can also be somewhat effective in shielding the reagent from components of the atmosphere. The solvent vapor will act like a blanket to exclude the air from the surface of the reaction mixture. In our experiment, there should be sufficient ether vapor above the reaction to protect the reactants from 02. The Grignard reagent can also react with any unreacted organic halide (another reagent in the Grignard reac- tion). The coupling reaction of the Grignard reagent with a second molecule of the organic halide cannot be completely prevented, but it can be minimized by avoiding the use of the more reactive organic iodides and by keeping a low concentration of the organic halide in solution. Use of an ethereal solvent is helpful for the efiicient preparation of the Grignard reagent because the basic oxy- gen atom of the ether complexes with the electropositive magnesium atom of R(Ar)—MgX to stabilize the organometallic species. However, benzene is also a good solvent for the Grignard reaction and is often used when no other solvent will allow the formation of a particular Grignard reagent that is needed. Benzene may have some stabilizing effect on the Grignard reagent as a result of its extensive cloud of p electrons. In addi- tion, benzene boils at 80°C, which allows for a significantly higher reaction temperature than ether (b.p. 34°C). Caution: When working with ether and certain other organic molecules, the chemist needs to be alert to the fact that ethyl ether, tetrahydrofuran, and many other organic materials react with oxygen in the air to form explosive hydroperoxides. Therefore, any ether that has been open for six months or longer is suspect. Such material should be tested for peroxides or disposed of and fresh material purchased. These peroxides can be destroyed by distillation of peroxide- forming materials from alkali metals or from lithium aluminum hydride. Passing the materials through an alumina column will also remove the peroxides if the contamination is not too extensive. Grignard Reaction The formation of the Grignard reagent is an exothermic process and can maintain the solvent at reflux temper— atures without any further heat being added. This can mean that solvent will be lost if more heat is added or appropriate precautions are not taken to contain the solvent in the reaction flask and control the temperature. These reactions usually need to be set up using a water condenser and well-fitted joints to contain the reflux— ing solvent. In addition, having an ice bath available to cool the reaction is often a valuable safety precaution. Therefore, use appropriate caution on the microscale. Addition of heat should not be necessary. Warming in the hand, if necessary, should be all the heat needed. Terms Nucleophile: A nucleophile is a molecule that is nucleus—seeking. It is a reagent that is rich in electrons and is attracted to an electron—deficient center. Hydrolysis: Hydrolysis involves the adding of the elements of water to a bond or cleaving a bond with water in the presence of acid or base. Peroxides: Peroxides are molecules containing the -OOH group. The peroxide group forms in susceptible chemicals (often compounds with active methylene hydrogens) due to the autoxidation of an activated hydro- gen; this process is often accelerated by exposure to light and/or air. Ethers, isopropyl compounds, aldehy— des, and allyl compounds are some examples of structures susceptible to peroxide formation. Synonyms Diethyl ether = ethyl ether = ether (similar to what is meant by "alcohol," it always means ethyl alcohol). Petroleum ether = ligroin = mixture of hydrocarbons (alkanes). Grignard reagents are extremely water—sensitive. As a result, the glassware and measuring equipment—anything that comes into contact with the Grignard reagent-must be dry. Drying ovens are a good way to prepare glass— ware for running a water—sensitive reaction. This method requires at least 1/2 hour and may require as long as overnight. Alternatively, glassware may be "flamed out" by heating it over the flame of a Bunsen burner. Heating is con— tinued until no more water vapor is seen to form on the glassware. Do not flame out the inside of glassware: water vapor from the flame will be deposited on the glassware. If magnesium is in the glassware, beware that it is flammable; the heat generated is sufficient to melt the glass! If you decide to flame out your glassware, use caution. The heavy glass bottoms of the vials must be heated with care in order to avoid stress fractures. In other words, be careful that the bottom is heated as much as the rest of the Vial. A temperature differential Will cause a fracture. The round bottom flask is not as sensitive to stress fractures and usually can be flamed dried with little danger of breaking it. You cannot heat a plastic syringe to dry it, simply buy a new syringe. It is dry and sterile as it comes from the wrapping. Organic Chemistry: Microscale Lab Techniques Compound Bromobenzene1 l 57.02 Diethyl Ether, anhydrous2 74.12 Magnesium5 24.3 Benzophenone1 Triphenylmethanol Biphenyl1 (Iodine)3 (Dibromoethane)4 MW Wt/Vol mmol 220 111 3.7 ml 54 mg 273 mg 1.491 0.708 182.21 260.34 154.21 253.81 187.87 0.992 4.930 2.180 1 crystal 2 drops 1.5590 1.3530 1.5385 1Irritant 2Extremely flammable 3Corrosive 4Toxic / cancer suspect agent 5Reactive metal/flammable Note to stockroom: Fisher ether seems to be drier than Mallinckrodt. It is necessary to change the ether for each section and check the septa often during the course of the experiment. This is important. If it is not done, 95% of the students will have the Grignard FAIL! Note: Iodine and 1,2-dibromoethane are both useful catalysts used to initiate the Grignard reac— tion. You may use either catalyst. We have found that 1,2-dibromoethane works very well as an activator in this reaction. It does not leave a residue like iodine—the by-product is volatile; and, in most cases, it cleans the magnesium as well as the iodine does. BrCH2CH2Br + Mg—> CH2=CH2+ + MgBr2 Introduction of iodine as a catalyst results in the formation of Gilman's catalyst, which is the result of interaction between iodine and magnesium in ether or benzene. Introduction of eth— ylene dibromide as the catalyst is an entrainment procedure—once the magnesium is reacting with one material, it continues to react with the other, thus forming the Grignard reagent. (This may be an exchange reaction.) Use of iodine as the catalyst may make the recrystallization of product more difficult. Whichever technique is used to catalyze the formation of the Grignard, the purpose is to keep the magnesium clean and active. Use either iodine or 1,2-dibrom0ethane, but not both! Note: It is necessary to use freshly poured anhydrous ether for all the steps of Grignard prepa— ration and reaction up to the hydrolysis step. It is not necessary to use anhydrous ether after the hydrolysis step! Anhydrous ether is expensive and should not be used except when neces— sary! Be sure that the anhydrous ether that you use is fresh for your section. If you do not do the experiment on the scheduled day, the ether you may be using may not be as free fi‘om water as it must be for the reaction to work on the scale that we are using! (A large scale reaction would allow the ether to dry itself, using the excess Grignard reagent as the drying agent.) Grignard Reaction EQUIPMENT AND REAGENTS: A 10.0—ml round bottom flask, containing the spin bar, is topped by a Claisen head. The Claisen head is fitted with a rubber septum and screw cap and a calcium chloride drying tube. Magnesium metal (54 mg), two drops of l,2—dibromoethane, and 250 pl of anhydrous diethyl ether are added to the round bottom flask. A solution of 220 pl of bromobenzene in 1 m1 of anhydrous diethyl ether is prepared in a dry, capped dram Vial. The bromobenzene—ether solu— tion is then placed in a 1.0 cc syringe, and the syringe is inserted into the rubber septum of the flask but the mixture is not yet added to the flask! 750 pl anhydrous diethyl ether is then added to the empty vial and set aside for later use. ess or desirable to Note: Polishing the magnesium in a mortar and pestle helps to remove oxide on the surface, facilitating the reaction and bettering the yield. It is NOT nec- ' d the ma esiurn to a owder—merely shine up a few of the surfaces! In addition, it may be advantageous to put the magne— sium in the flask and then flame out the flask to dry the magnesium as well as the flask. However, be careful: Direct flames on magnesium can result in a serious metal fire; keep the magnesium in the flask and heat only until no fiir— ther sign of water vapor is apparent! If you ignite the magnesium, the intense nature of the fire will melt out the bottom of the round-bottom flask. You will be responsible for the cost of the replacement! éicsifxla Chloride While stirring, 6-8 drops of the bromobenzene—ether solution in the syringe are added to the flask to initiate the formation of the Grignard reagent. Evolution of tiny bubbles on the magnesium metal's surface indicates the reaction is proceeding. When the reaction has started, the remaining bromobenzene-ether solution in the syringe is added dropwise over 3- When the bromobenzene- Note: Slow addition of the bromobenzene is important to control the formation of biphenyl. High concentrations of bromobenzene in the presence of the phenylmagnesiurnbromide will favor the coupling reaction that forms biphenyl (instead of the desired reaction with the mag- nesium to form more phenylmagnesiumbromide). Likewise, this coupling reaction is favored by increasing the temperature of the reaction mixture and by light. Note: Sometimes when the Grignard refuses to start-there seems to be no reaction on the magnesium—it may be helpful to put the reaction vial in a sonicator for a few minutes. Again this seems to help clean the magnesium and initiate the reaction. Care must be exercised in doing this since the sonicator is filled with water! 5 minutes. ether solution is added, the rinse in the Vial is then added to the flask through the sep— tum, and the resulting solution is allowed to stir for 15 minutes. The Grignard reagent is then allowed to cool to room temperature. (Formation of the Grignard reagent is an exothermic process. On this scale, heat dissi— Organic Chemistry: Microscale Lab Techniques pates quickly and may not be noticed.) The Grignard reagent solution should be brownish gray and somewhat cloudy. This reagent cannot be stored; it must be used in the next step immediately! Note: If you find it necessary to start this reaction over as a result of failure of the Grignard reagent to form, you may want to try another technique that has proved successful for Timothy Eckert* at State University College of Fredonia. Put a tiny crystal of iodine in the round bot- tom flask along with the magnesium tLu-nings. Gently flame out the flask to drive off any water and cause the iodine to sublime as evidenced by violet vapor in the flask. A solution of 273 mg of benzophenone in 0.8 ml of anhydrous diethyl ether is prepared in a dry, capped dram vial. The solution is placed in a 1.0 cc syringe, and the syringe is inserted into the septum, but the solution is not yet added. Anhydrous diethyl ether (800 pl) is then added to the empty Vial and the ether rinse set aside for later use. REACTION CONDITIONS: The benzophenone-ether solution is added carefully, with stirring, to the Grignard reagent over a period of 30 seconds at such a rate as to maintain the ether solvent at reflux. Do not heat the reaction mixture. Note that ether boils at 30°C, just barely above room temperature and that on this scale (microscale) you may not be able to detect the refluxing condition. The fact remains that the reaction is exothermic. Note: The coupling of the Grignard reagent with the benzophenone is an exothermic reaction and external heating is not required. Ether boils at 30° C at this altitude and boils off extreme- ly easily with any heating, particularly on the scale that we are using where there is only a few milliliters of ether to begin with. As the benzophenone is added, the solution changes to a red/dark pink color. If this color change does not occur, you may need to start over. Consult with your instructor or TA before starting over. After the addition of the benzophenone solution, the rinse solution from the dram vial is added in a like manner. Continue stirring. As the solution stirs and cools, the reddish-purple color fades, and a white solid usually precipitates. This precip- itate is the magnesium salt of the alcohol. If a solid does not form, the reaction may still be proceeding correctly—don't panic just yet. Stopper and store the reaction flask in a beaker (to prevent spilling) until the next laboratory period. Usually a solid will form if it is given sufficient time. If you have a solid at this point, it is not necessary to stop unless you have run out of time! ISOLATION OF PRODUCT: The magnesium alkoxide salt (the white precipitate from the reaction mixture) is hydrolyzed by the addition of 3 M HCl until the aqueous phase is acidic to pH paper. This solution must be adequately stirred to get a valid pH reading! Unreacted magnesium will also react with the acid, slowly dis- solving with the evolution of hydrogen gas. If the reaction has been left for a few days, it will be necessary to add ether in order to have two phases since ether is extremely volatile and vaporizes readily. It is NOT neces- sary to use anhydrous ether once you have started adding water! (Water is the solvent for the 3 M HCl.) Grignard Reaction The spin bar is removed and saved so it can be rinsed with ethyl ether during the extraction. The flask is shaken, the ether layer and water layer are allowed to separate, and the aqueous layer (bottom layer) is transferred to a 5 ml vial. If there is C: not a second layer at this point, more ether is added! The ether layer is saved; r it contains the product! Milky-Yellow / (Organic Ether Layer) The aqueous layer is extracted three times with 0.5 ml of ether. These ether extracts are combined with the original ether layer from the previous step. The aqueous layer is discarded after the last extraction, since the majority of Colorlessclear the product has now been removed. Make sure you are throwing away the (AqueousLayer) right layer! (This is acidic waste.) The combined ether extracts are washed with 1-2 ml of water to remove any water—soluble contaminants—acid, magnesium ions, etc. The ether solution is dried over anhydrous sodium sulfate in an Erlenmeyer flask until some of the sodium sul- fate is free-flowing. This requires a large amount of sodium sulfate because of the water that is dissolved in the ether. (Solubility of water in ether: 1.2% H20 at 20°C; azeotrope with H20 [1.3%], hp 342°C.) A TLC is run on the ether solution before the ether is evaporated. Standards are also run on the plate (these are available at the supplies table); put the standards on the plate before you develop it. The TLC is developed in methylene chloride. The TLC will give you an idea of how much biphenyl has been formed and how much product. Note: The triphenylcarbinol has the same Rf as benzophenone under the TLC conditions that we are using; only the color under UV is different. As a result, if the reaction has not occurred, you may not be able to determine this by TLC. The benzophenone can be mis- taken for product and/or mask the product spot. (The IRS of the two materials, however, are significantly different!) The ether is evaporated with a gentle stream of air and gentle warming. (Too much heat will melt the biphenyl, which will dissolve the triphenylcarbinol.) Your TLC will probably indicate significant biphenyl impurity. This by—product can be removed by extracting the solid left after the evaporation of the ether with petroleum ether, aka ligroin (30-60°C), extracting twice with 0.5 ml of pet ether each time (shake or stir well; the solid must be well broken up in order to remove the biphenyl.) The ligroin (petroleum ether) is removed by filtration or by drawing it off with a Pasteur pipet. Organic Chemistry: Microscale Lab Techniques Note: If you do not have a solid at this point, you may have biphenyl dissolved in benzophe— none or biphenyl and triphenylcarbinol dissolved in benzophenone! However, we have found that if the product is present, it will often precipitate upon the addition of the ligroin. If no solid forms, remove the petroleum ether and take an IR of the oil. Because of the characteristic peaks of the various compounds possible in the oil, it is possible to at least make a statement about whether product is present or not. You may wish to evaporate the combined ligroin extracts and determine how much biphenyl by-product was formed in your reaction. Biphenyl melts at 69-71°C; you may not have a solid at this point, but an oil. PURIFICATION: The crude triphenyhnethanol needs to be recrystallized. Isopropyl alcohol (IPA) is often suggested, but ethanol is lower boiling and thus easier to remove from the product. It has the disadvantage of reacting with the triphenylcarbinol if there is any excess acid present, particularly if the solution is boiled for an extended period of time due to the addition of too much solvent. (If you used iodine as your catalyst in this reaction, you will find that recrystallization is a bit more difficult. The iodine colors the product either brown or violet, depending on the solvent present.) CHARACTERIZATION: Weigh your product, and calculate the percent yield. Obtain an [R with the Nuj ol mull method and label the pertinent peaks. Determine the m.p. and compare this to the literature value for triph— enylcarbinol. Check the purity of your product using TLC and calculate the Rf's for the biphenyl and the triph- enylrnethanol. Identify the peaks in the NMRs accompanying this experiment. Waste Streams Generated in this Reaction: Desiccant Waste: Sodium sulfate; calcium chloride Acid Waste: the water layer following the extraction with ether. Nonhalogenated Waste: the ligroin used to extract the biphenyl; the filtrate following the recrystallization of the product alcohol. Halogenated Waste: methylene chloride used to develop TLC plates References: An Improved Preparation of a Grignard Reagent, J. Chem. Educ, 64, 1987, _2_, 79. Mayo, Dana, Ronald Pike, Samuel Butcher, Microscale Organic Laboratory, Second Edition, John Wiley & Sons, New York, 1989. Fieser, Louis and Mary Fieser, Reagents for Organic Synthesis, Volume 1, John Wiley & Sons, Inc., New York, 1967. Pasto, Daniel, Carl Johnson, Marvin Miller, Experiments and Techniques in Organic Chemistry. Prentice Hall, Englewood Cliffs, New Jersey, 1992. Pavia, D. L, Lampman, G. M., Kriz, G. S., Engel, R. G., Introduction to Organic Laboratory Techniques, Saunders College Publishing, Orlando, 1990, pp. 72. Grignard Reaction “Why” Questions—Grignard Reaction Part A: 1. What is the reaction product when benzene magnesium bromide reacts with H20? 2. How might this reaction with water be used to make a deuterated benzene? 3. What is the origin of the tiny bubbles forming on the magnesium? 4. Why is the bromobenzene added slowly rather than all at once as the Grignard reagent is formed? 5. Is it possible to determine the pH of an organic solvent? 6. How are you going to use TLC to determine the purity of your product? Do you need a reference(s)? 7. It has been reported* that if an excess of ethanol is removed by boiling the solvent away during the course of the recrystallization, some students have experienced oiling out of their product—a product that melted at 70-78°C and was identified through IR and NMR and TLC as being consistent with l-ethoxy-l,1,l- triphenylmethane! Can you explain this result? Part B: 1. On a macro scale, this Grignard reagent (benzene magnesium bromide) is considered self—drying. Why might this be so? 2. Biphenyl is soluble in petroleum ether (ligroin.) What is petroleum ether, chemically? Would biphenyl be solu- ble in hexanes if petroleum ether were not available? 3_ Why are ligroin and petroleum ether identified by boiling point? *Abhyankar, Sudhir B., and Dust, Julian M., .ZChem. Educ, 1992, l, 76. ...
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Grignard Reaction Fall 2010 - GRIGNARD REACTION Preparation...

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