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Myers Magnesium-Halogen Exchange Chem 115 Review: • Unlike many lithium-halogen exchange protocols, only one equivalent of i-PrMgX is used in typical experimental procedures. Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Ahn Vu, V. Angew. Chem., Int. Ed. Engl. 2003, 42, 4302. • THF is the most common solvent. Ethyl ether has been employed as a solvent for selective exchange of geminal dihalides to generate magnesium carbenoids. General References on the Preparation and Reactions of Grignard Reagents: Main Group Metals in Organic Synthesis, Yamamoto, H., Oshima, K., Eds.; John Wiley and • The reactivity of Grignard reagents is highly temperature dependant. Only highly reactive Sons: New York, 2004. electrophiles such as aldehydes and ketones react at significant rates below 0 °C. This allows for the preparation of organomagnesium reagents containing cyano, nitro, ester, Handbook of Grignard Reagents, Silverman, G. S., Rakita, P. E., Eds.; Marcel Dekker: and imine functional groups, provided that the rate of the exchange reaction is fast enough New York, 1996. to allow for exchange at temperatures below 0 °C. Organomagnesium Methods in Organic Synthesis, Wakefield, B. J.; Academic Press: San Diego, 1995. • The rate of magnesium-halogen exchange is accelerated by electron-withdrawing groups on the aromatic ring, and is slowed by electron-donating groups: Development and General Aspects: I MgBr RX + R'MgX' RMgX' + R'X i-PrMgBr THF, –20 °C, 30 min • Analogous to lithium-halogen exchange. The position of the equilibrium varies with the CO CH 2 3 2 3 CO2CH3 stabilities of the carbanion intermediates involved (sp >> sp >> sp ). Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Ahn Vu, V.; Knochel, P. Br Et2O MgBr + EtMgBr + EtBr Synthesis 2002, 565. 20 °C, 12 h I MgBr Prévost, C. Bull. Soc. Chim. Fr. 1931, 49, 1372. i-PrMgBr THF, 25 °C, 1 h • Although the first example was reported in 1931 (above), the preparation of Grignard reagents via metal-halogen exchange has not been widely used until recently. Knochel and OCH3 OCH3 coworkers have demonstrated the functional-group tolerance of magnesium-halogen exchange, which is now the method of choice for the preparation of highly functionalized Cali, P.; Begtrup, M. Synthesis 2002, 63. organomagnesium reagents. I MgCl • i-PrMgCl or i-PrMgBr are the most common reagents. In most cases, these reagents can be NO used interchangeably. i-PrMgBr is made by the Grignard reaction of isopropyl bromide 2 PhMgCl NO2 and magnesium turnings. It is less soluble than the chloride (solutions are ~0.8 M), and the titre must be checked more often. i-PrMgCl is commercially available as a 2.0 M solution THF, –40 °C, 30 s in THF or diethyl ether. NO2 NO2 • Solutions of i-PrMgX are titrated by the method of Paquette (Lin, H.-S.; Paquette, L. A. Synth. Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. Engl. 2002, 41, 1610. Commun. 1994, 24, 2503.) According to this procedure, a flame-dried flask is charged with menthol (a non-hygroscopic solid), 1,10-phenanthroline (indicator) and THF. The Grignard reagent is then added until a distinct violet or burgundy color persists. Jason Brubaker 1 • Aryl bromides undergo exchange more slowly than iodides, but electron-poor aryl bromides • Dibromides undergo regioselective exchange of the bromine ortho- to a chelating group. can still react at temperatures below 0 °ˇC. Note also the compatibility of the amidine group with the exchange reaction. I MgBr i-PrMgBr N(CH3)2 N(CH3)2 N(CH3)2 CHO –40 °C, 30 min N N N OH NC Br i-PrMgBr NC MgBr Bu NC Bu Br Br THF, –10 °C, 1.5 h Br Br Br Bomond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1998, 37, 1701. 68% Br MgBr Varchi, G.; Jensen, a. E.; Dohle, W.; Ricci, A.; Cahiez, G.; Knochel, P. Synlett 2001, 477. F F i-PrMgBr F F –78 °C, 30 min • Higher temperatures are required for the selective exchange with less effective chelators. F F F F F F OCH3 OCH3 OCH3 Br MgBr CO2H Br MgBr i-PrMgCl CO2 F F i-PrMgBr THF, 40 °C, 5 h –10 °C, 1 h Br Br Br F F 90% F F Nishiyama, H.; Isaka, K.; Itoh, K.; Ohno, K.; Nagase, H.; Matsumoto, K.; Yoshiwara, H. Br MgBr J. Org. Chem. 1992, 57, 407. F i-PrMgBr F 23 °C, 2 h Functional Groups Compatible with the Magnesium-Halogen Exchange: F F • Ester, benzylic chloride: Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449. CO2CH3 CO CH 2 3 CO2CH3 i-PrMgBr Cl Cl PhN C O Ortho- Directing Groups: THF, –30 °C, 1 h –10 °C → 23 °C NPh I MgBr O 75% • The presence of a chelating ortho- group facilitates exchange, increases the rate of reaction, and allows for low-temperature exchange. Delacroix, T.; Berillon, L.; Cahiez, G.; Knochel, P. J. Org. Chem. 2000, 65, 8108. Et O • Secondary alkyl tosylate: Br BrMg Br OTs OCH2OEt i-PrMgBr O OCH2OEt O O i-PrMgCl CuCN·2LiCl CH3 THF, –30 °C, 2 h CuCN 2LiCl NC NC NC THF, –20 °C, 1 h –20 → 25 °C EtO2C EtO2C I 80% CH3 83% Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Kneisel, F. F.; Monguchi, Y.; Knapp, K. M.; Zipse, H.; Knochel, P. Tetrahedron 2002, 43, Ahn Vu, V. Angew . Chem., Int. Ed. Engl. 2003, 42, 4302. 4875. Jason Brubaker 2 • Nitrile: • Unprotected anilines: OH NH CHO 2 NHMgCl NH2 OH NC I NC MgBr NC 1. PhMgCl i-PrMgBr PhCHO I I I MgCl I Bu Ph –30 °C, 5 min Bu THF, –40 °C, 30 min 2. i-PrMgCl 89% –25 °C, 10 min CN CN CN • Tertiary amide: 71% Varchi, G.; Kofink, C.; Lindsay, D. M.; Ricci, A.; Seconi, G.; Knochel, P. Chem. Commun. 2003, 396. O O Br i-PrMgBr N N • In the above example, phenyl magnesium chloride is first added because it is a strong THF, –25 °C, 30 min base and as a magnesium-halogen exchange reagent it is less reactive than i-PrMgX. I This allows for quantitative deprotonation before exchange. 81% • Heteroaromatics: Bomond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1998, 37, 1701. Conditionsa Heterocycle (°C, h) Electrophile Product Yield (%) • Amidine, note also the selective exchange of a diiodide: Br F F CO2Et N(CH ) N(CH ) –40, 0.5 F F 80 3 2 3 2 N(CH3)2 Br N N N F N F (CuCN added) F N F 1. CuCN·2LiCl I I i-PrMgBr I MgBr I O OH –20 °C, 5 min 2. CH S S 3 CH3 Br 25, 1.5 PhCHO 75 I O CO Et N N Ph CO2Et 2 CO2Et 87% Br Br Br CO2Et Varchi, G.; Jensen, A. E.; Dohle, W.; Ricci, A.; Cahiez, G.; Knochel, P. Synlett 2001, 477. O OEt OEt NN –20, 1 NN 59 NC OEt • Imine: CH3 CH3 I MgBr i-PrMgBr 1. BiCl3 O OH Bi Br Br –5, 1 PhCHO Br 73 2. SiO2 N N THF, 25 °C H 3 Bn Bn Ph N N 34% iPr iPr –30, 1 Br 80 Br O CO2Et CO2Et Murafuji, T.; Nishio, K.; Nagasue, M.; Tanabe, A.; Aono, M.; Sugihara, Y. Synthesis 2000, 1208. (CuCN added) O • Imines can be used to mask aryl aldehydes during the magnesium halogen exchange. The ai-PrMgBr (1.2 equiv), THF low yield of the reaction sequence above is likely attributable to the second step of the procedure. Abarbi, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449. Jason Brubaker 3 • Nitro arenes: • Nitro-substituted organometallic reagents are difficult to prepare through classical NO 2 NO2 NO2 methods. These electron-deficient arenes tend to undergo electron-transfer reactions, and direct oxidative addition with elemental magnesium or zinc often leads to reduction of I PhMgCl MgCl + E E the nitro group. This new procedure is the best method to date for the preparation of FG FG FG –40 °C, 5 min nitroarene organometallics. • The nitro group must be ortho to the iodide exchanged. Meta- and para-nitro substituted Nitro arene Electrophile Product Yield (%) aryl iodides give complex mixtures. NO 2 NO2 OH • PhMgCl is necessary for a successful reaction. More reactive Grignard reagents such as I i-PrMgCl give complex mixtures. PhCHO Ph 87 • For successful reactions with reactive electrophiles such as allyl bromides and acid halides, transmetallation of the organomagnesium intermediate with CuCN·2LiCl is necessary. NO2 NO OH 2 • Pd-catalyzed Negishi cross-coupling reactions are possible after transmetallation with I ZnBr : PhCHO Ph 94 2 O CO2Et 1 = P NO2 1. mesitylMgBr, –40 °C, 5 min NO 2 3 CN CN I 2. ZnBr2, –40 °C, 5 min CO Et NO2 NO OH 3. Pd(dba)2 (5 mol %) 2 2 2 = I NC 1 (10 mol %), 2 (1.5 equiv) NC –40 23 °C, 3 h PhCHO Ph 72 → 73% I CH O 3 CH3O • In the case above, mesityl magnesium bromide is used to prevent competing oxidative NO addition of the aryl iodide generated in the magnesium-iodide exchange reaction. 2 NO2 OH I cHexCHO cHex 64 Magnesium-Halogen Exchange of Vinyl Iodides: EtO C 2 EtO2C 1. i-PrMgBr, THF NO2 NO O 25 °C, 18 h 2 Ph I I 2. PhCHO PhCOBr Ph 76 OH 60% EtO C 2 EtO2C 1. i-PrMgBr, THF Ph Ph NO –70 °C, 12 h CH3O 2 NO2 OH CH3O Ph I 2. PhCHO PhCHO Ph I 81 OH O N 2 O2N 95% NO 2 Rottlander, M.; Boymond, L.; Cahiez, G.; Knochel, P.
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  • Grignard Reaction: Synthesis of Triphenylmethanol

    Grignard Reaction: Synthesis of Triphenylmethanol

    *NOTE: Grignard reactions are very moisture sensitive, so all the glassware in the reaction (excluding the work-up) should be dried in an oven with a temperature of > 100oC overnight. The following items require oven drying. They should be placed in a 150mL beaker, all labeled with a permanent marker. 1. 5mL conical vial (AKA: Distillation receiver). 2. Magnetic spin vane. 3. Claisen head. 4. Three Pasteur pipettes. 5. Two 1-dram vials (Caps EXCLUDED). 6. One 2-dram vial (Caps EXCLUDED). 7. Glass stirring rod 8. Adaptor (19/22.14/20) Grignard Reaction: Synthesis of Triphenylmethanol Pre-Lab: In the “equations” section, besides the main equations, also: 1) draw the equation for the production of the byproduct, Biphenyl. 2) what other byproduct might occur in the reaction? Why? In the “observation” section, draw data tables in the corresponding places, each with 2 columns -- one for “prediction” (by answering the following questions) and one for actual drops or observation. 1) How many drops of bromobenzene should you add? 2) How many drops of ether will you add to flask 2? 3) 100 µL is approximately how many drops? 4) What are the four signs of a chemical reaction? (Think back to Chem. 110) 5) How do the signs of a chemical reaction apply to this lab? The Grignard reaction is a useful synthetic procedure for forming new carbon- carbon bonds. This organometallic chemical reaction involves alkyl- or aryl-magnesium halides, known as Grignard 1 reagents. Grignard reagents are formed via the action of an alkyl or aryl halide on magnesium metal.