Catalyzed Cross-Coupling of a Grignard Reagent with an Aryl Halide

Catalyzed Cross-Coupling of a Grignard Reagent with an Aryl HalideA carbon-carbon forming reactionObjectives:Generate a new carbon-carbon bond by the nickel-catalyzed cross-coupling of bromobenzene and isopropylmagnesium chloride (C)Prepare/characterize a coordination compound for use as catalyst for the coupling reaction (C)Determine the effect of ligand on the regiochemistry of the cross-coupling reaction (C)Analyze products of catalytic reaction by gas chromatography (T)Time Required:Four lab periods.IntroductionA variety of transition metal catalyzed reactions have beendeveloped to effect nucleophilic substitutions in aromaticsystems, 1 which occur very slowly, if at all, by direct reaction ofaryl substrate and nucleophile. Catalysts for such reactionsinclude a variety of compounds that contain Group VIII metals,with nickel and palladium being the most common. Thesereactions are ideally suited for normal synthetic applicationssince the catalysts are usually air stable materials that have a longshelf life. Nickel catalysts are particularly effective in catalyzingthe cross-coupling reaction of Grignard reagents and aryl halides,which this experiment will illustrate with the reaction of C 6 H 5 Brand (CH 3 ) 2 CHMgCl. This experiment will also illustrate theimportance of ligand on the regiochemistry of the couplingreaction.The coupling reaction is generally performed by heating thethe aryl halide, about 5 mol percent of catalyst, and excessGrignard reagent until a high conversion of aryl halide to producthas been achieved. The generally accepted mechanism for thenickel catalyzed coupling of aryl halides with Grignard reagentsis the following:L 2 NiX 2 + 2 RMgXThe conversion of L 2 NiX 2 to L 2 Ni requires some discussion.Bisphosphinenickel(II) alkyl complexes, especially those inwhich the alkyl groups contain A-hydrogens, have only limitedthermal stability, and undergo reductive elimination reactionsthat result in the formation of Ni(0) complexes, i.e.,LLNiLLL 2 Ni + C 6 H 14HNiL 2 Ni + C 3 H 8 + C 3 H 6There are two pathways for reductive elimination. The firstinvolves C-C bond formation between the two alkyl groups. Ifthere are no A-hydrogens this is the only way that reduction canoccur. The second involves A-hydrogen elimination from one ofthe alkyl substitutents (butyl in the example), which does notresult in a change in the formal oxidation state of the nickel atom,followed by reductive elimination of propane and dissociation ofpropene.The presence of A-hydrogen atoms in the Grignard reagent canresult in loss of regiochemistry in the cross-coupling reactionand/or hydrogenolysis of the aryl halide as shown in thefollowing modification of the earlier catalytic cycle.L 2 NiX 2 + 2 RMgXL 2 NiPhXL 2 NiPhXPhLNiPh LL X NiL PhXMgMgX 21Diederich, Francois. and Stang, Peter J. “Metal catalyzedcross-coupling reactions” New York : Wiley-VCH, 1998.LNiLPhPhPhPhH+LNiLHLNiLPhPhLNiLMgX 2XPhXMgThe extent to which either of these unwanted processes occurs ishighly dependent upon the nature of the ligands bound to thenickel, although not necessarily in a predictable fashion.In this experiment you will be assigned nickel complex A or1

B to prepare and characterize.Ph PhBrP ClNiNiPh 3 PBrP ClPPh 3Ph PhA BCharacterization will involve obtaining an elemental analysis fornickel. You will then use the complex that you have prepared forthe catalyzed cross-coupling of C 6 H 5 Br and (CH 3 ) 2 CHMgCl.Commercial Grignard reagent will be used for the reaction.Because of the sensitivity of the Grignard reagent to water andthe catalytically active nickel(O) species to oxygen and water itwill be necessary to use techniques designed to protect thereagents from the atmosphere.ProcedureThere are several reactions and procedures to be done for thisexperiment. Plan your work according to the following schedule.Individual procedures follow. First lab period: (1) Prepare thenickel complex assigned to you using the appropriate procedure.(2) Determine the magnetic susceptibility of your complex.Second lab period: (1) Conduct the cross-coupling reaction. (2)Do gas chromatographic analyses of standards. Third labperiod: Determine the product distribution and yield by gaschromatography.Dibromobis(triphenylphosphine)nickel(II). Add 1.4 g ofnickel bromide trihydrate to 20 mL of 1-butanol in a 50 or 125mL Erylenmeyer flask, heat it to boiling and maintain it atboiling until the nickel salt dissolves. Filter this solution ifparticulates are present. Add 2.7 g of triphenylphospine to 20mL of 1-butanol in a second Erylenmeyer flask (50 or 125 mL asavailable) and heat the mixture until the triphenylphospinedissolves and the solution boils. Add the triphenylphosphinesolution to the boiling nickel bromide solution and allow thesolution to cool in an ice bath. Collect the green product byfiltration, wash with a small amount of ether, and dry the productby pulling air over it for 15-20 min. Record the yield andproceed to the determination of magnetic susceptibility. Submitthe sample with your report.Dichlorobis(1,2-diphenylphosphino)ethanenickel(II). Place1.5 g of NiCl 2 ]6H 2 O and 15 mL of ethanol in a 50 mLErylenmeyer flask along with a magnetic stirring bar. Warm thesolution on a hot plate and stir until the nickel salt dissolves.Remove the flask from the heat and add 1.2 g of 1,2-diphenylphosphinoethane to the flask and return it to the hotplate. Precipitation of product will begin immediately. Stir thesolution and maintain it at about 60 °C for 20 min taking care.that the volume does not drop below 10 mL. Add smallquantities of ethanol as required. Remove the flask from the heatand allow the solution to cool to room temperature. Collect theproduct by suction filtration and wash it with 5 mL of ethanoland 10 mL of ether and draw air over the solid for 15-20 min todry it. Record the yield and proceed to the determination ofmagnetic susceptibility. Submit the sample with your report.Prelab: How many mL of 2.0 M isopropyl Grignard isrequired to obtain 12.5 mmol?Cross-coupling of bromobenzene and isopropylmagnesiumbromide. The cross-coupling reagent should be done using 10mmol of bromobenzene, 1.5 mol percent catalyst, and a 25%excess of Grignard reagent (12.5 mmol). Use the concentrationon the bottle of reagent to recalculate the quantity. Fit a 100 mLthree-necked flask (all glassware should be oven-dried) with 25mL pressure-equalizing dropping funnel, reflux condenser withnitrogen inlet system, and magnetic stirring bar. Flush the flaskand dropping funnel with nitrogen and then add thebromobenzene, catalyst, and 10 mL of nitrogen or argon spargedether to the flask. Use a syringe and clean 18-gauge needle towithdraw the appropriate volume of Grignard reagent and addthis to the dropping funnel. Be sure that the dropping funnelstopcock is closed. Safety: Take care not to “inject” yourselfor anyone else with the needle, and be careful not to spill theGrignard on your skin. As soon as the syringe is emptied, takeit to the hood and remove the plunger. After a few minutes, washall components with water and then with a small amount ofmethanol or acetone and return them to the oven.While stirring the mixure in the flask, slowly add the Grignardreagent to the reaction mixture. After addition is complete, heatthe mixture to gentle reflux and maintain the reflux for 2 h.Allow the reaction mixture to cool to room temperature (adjustthe nitrogen flow so that bubbler oil is not drawn into the systemduring cool down). Add 15 mL of water to the separatory funneland then to the flask to destroy any unreacted Grignard reagent.Transfer the mixture to a separatory funnel and separate theorganic layer (more ether may be added to aid in the separationif needed). Wash the aqueous layer with 15 mL of fresh etherand combine the two ether fractions. Wash the combined etherextracts twice with 15 mL portions of saturated aqueous sodiumthiosulfate and twice with 15 mL portions of water and then dryover anhydrous MgSO 4 . This solution will be used fordetermining the distribution and amounts of products. Reservethis solution until the next laboratory period for analysis of theproducts.Determination of magnetic moment the for nickel catalyst.Use the Magnetic Susceptibility Balance to determine the masssusceptibility of your complex. Use the value obtained tocalculate the magnetic moment in the same fashion as you didearlier for [Ni(en) 3 ](BF 4 ) 2 . The procedure for operation of themagnetic susceptibility balance is given in Appendix I.Gas chromatographic analysis of standards. Based upon theearlier discussion of the mechanism of the cross-couplingreaction the ether extracts should contain some combination ofbromobenzene (unreacted starting material), isopropylbenzene(desired product), propylbenzene (isomerized product,undesired) and benzene (reduction product, also undesired). Todetermine which of these products are present it will be necessaryto determine the retention times of each and compare theretention times of peaks in the sample with those of the2

standards. It is a good idea to directly compare a chromatogramof a synthetic mixture of the possible products with one for thesample, particularly if retention times of products are quitesimple. Although it is possible to determine relative amounts ofof the components in the mixture by the relative areas under thepeaks corresponding to each, a quantitative determinationrequires that a known amount of a reference material be added tothe sample, which must be contained in a known volume.Obviously the retention time of the reference material must beknown and it must different from that of any component of themixture. Mesitylene will be used as the reference material(internal standard) for this analysis. In this analysis we willassume that the response of the detector to each component is thesame per unit mass although this is definitely an assumption andresponse factors (area sample/unit mass)/(area reference/unitmass) should be determined for more exact work.You must determine retention times for each of the followingbenzene, bromobenzene, isopropylbenzene, propylbenzene andmesitylene. Identify each on the a chromatograph of thereference mixture that is supplied.Product analysis. Weigh about 5 mmol of mesitylene into a 50mL volumetric flask, then filter the ether extracts into the flaskand add enough ether to bring the volume to the mark. Obtainthe gas chromatograph of the sample, identify the components,determine the areas under the peaks, calculate the molar amountsof each component in the ether extract, and and the percent yieldof propylbenzene. Submit the chromatograms of your samplePrelab: Calculate the molar amounts of components A andB in a mixture given that their peak areas are 20 and 135,respectively, and the area of the internal standard (0.003mmol) is 62. The volume of the solution was 100 mL.along with those of the standards and the standard mixture withyour report.When preparing your report you should use your own data incalculating percent conversion to products. You should alsoconsider your own product distribution relative to the average ofthe product distributions for all people employing the samecatalyst that you have used. Finally, you should comment on theaverage product distribution obtained with your catalyst incomparison with that for the other catalyst.Use the appended Excel spread sheet to record your data andsend it as an email attachment to the lead instructor for theexperiment.3

Appendix IOperation of the Magnetic Susceptibility BalanceThe magnetic susceptibility balance operates on the Gouyprinciple as previously described except the sample remainsstationary and the magnetic moves. To see a schematic of theinternal workings of the balance see the manufacturer’s web sitehttp://www.sherwood-scientific.com/msb/shmagway.html.Be sure that the tube is clean and dry (inside and out): wipe itwith a tissue or clean with a "pipe cleaner" if it is not.The major error in this method most often arises frominhomogeneous packing. The sample should be in the form of areasonably fine and uniform powder. (Large crystals cannot bepacked homogeneously and errors may also arise from magneticaniostropy. Very fine powders, on the other hand, may packunevenly unless compacted.) Lightly crush any crystallineaggregates with a plastic spatula. Introduce a small portions ofthe solid into the weighed sample tube, and tap the bottom of thetube gently on the card beside the balance a few times to shakethe solid down. (The sample tube is fragile and expensive!!)Repeat this procedure until the depth of sample is at least 15 mm.Measure the sample length , making sure that the top of thesample is horizontal. Do not include the thickness of the glass atthe bottom of the tube.Record the mass of the tube plus sample and determine the massof the sample.Turn the balance on and let it stabilize. Place the spare tube inthe balance and once the balance zeros press the range buttononce and then the tare button to record the parameters for theblank tube in memory.Replace the empty tube with the tube containing your sample.After the balance stabilizes record the value obtained, which isthe volume susceptibility. However, by introducing the lengthand mass of the sample the instrument will calculate a masssusceptibility (the diameter of the sample column is determinedby the tube which the instrument senses).Press the “length” button and enter the sample length asdetermined above. After entering the appropriate value thereading will return to the volume susceptibility value.Press the “weight” button and enter the sample mass. Afterentering the appropriate value the reading will return to thevolume susceptibility value.Press the “Mag Sus” button to display the mass susceptibilityvalue. Press the key again to return to the volume susceptibility.Empty and repack the tube (use the same sample) and repeat theprocedure at least once more.4