Reprinted from the Journal of the American Chemical Society, 1989, 111, 5405. Copyright @ 1989 by the American Chemical Society and reprinted by permission of the copyright owner. The Mechanism of Formation of Grignard Reagents: Trapping of Free Alkyl Radical Intermediates by Reaction with Tetramethylpiperidine-N-oxyll

Karen S. Root, Craig L. Hill, Lynette M. Lawrence, and George M. Whitesides* Contribution from the Department of Chemistry, Harvard University, Cambridge, Massachusetts 02138, and the Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139. Received November 14, 1988

Abstract: In the presence of the free radical scavenger 2,2,6,6-tetramethylpiperidine-N-oxyl(TMPO', 0.50 M), cycloheptyl bromide (RBr, 0.001 M) reacts with magnesium metal in a solution containing tert-amyl alcohol (5.0 M), lithium bromide (0.05 M), and diethyl ether at 20 OC and forms N-cycloheptoxy-2.2.6.6-tetramethylpiperidin (TMPOR) as the major product (293% yield, based on RBr). In the absence of TMPO', cycloheptane (RH) is formed in 295% yield. The dependence of the relative yields of TMPOR and RH on the initial concentration of TMPO' suggests that both products share a common precursor-free cycloheptyl radical-and that this radical has a median lifetime of ca. lo-' s. Cycloheptyl radicals appear to be intermediates on the major path to the Grignard reagent cycloheptylmagnesium bromide. TMPO' is reduced by Mg(0) to the anion of the corresponding hydroxylamine, TMPO-, at a rate that is competitive with that of the reaction between RBr and Mg(0). Although the magnesium salts of TMPO-are insoluble in diethyl ether, solutions containing TMPO-, Mg2+,and Li' remain homogeneous. For systems containing a high concentration of tert-amyl alcohol, a simple mathematical model attributes apparent zero-order kinetic behavior to the dependence of reactive surface area on the extent of reaction between alkyl halide and Mg.

The objective of this work was to confirm the existence of free Scheme I. Processes Occurring during Reaction of an Alkyl Bromide alkyl radicals as intermediates along the principal reaction pathway with Magnesium Metal in Diethyl Ether in the Presence of TMPO' between alkyl bromides and alkylmagnesium bromides during and an Alcohol R'OHa TMWR formation of Grignard reagents (Scheme I) and to estimate the wo- mpo- lifetime of these species. We used trapping with a stable free radical (TMPO*, 2,2,6,6-tetramethylpiperidine-N-oxyl) to ac- complish this objective. Radical trapping with TMPO' is normally a straightforward physical organic diagnostic test.2d In this RBr + Mg [Re] Mg RMgBr -, system of reactions, its use, was complicated by the fact that - - reaction of TMPO' with both alkyl Grignard reagents and I '\ R'OH magnesium metal were rapid. This reaction between Grignard reagent and TMPO' (re)generated, at least in part, the alkyl radical It was, therefore, necessary to destroy any Grignard reagent in situ by protonation with an added alcohol R'OH. This R-R, R-H, R (-H) paper details the experiments that defined reaction conditions "The transformations of central interest in confirming the existence permitting clear differentiation of the reaction between TMPO' of R' as an intermediate are shown with dark arrows (-); those im- and alkyl radicals R' generated from RBr from reactions between portant in dealing with the reaction of RMgBr with TMPO' use TMPO* and RMgBr. Subsequent papers will support the in- dashed arrows (-+). Competing reduction of TMPO' by magnesium is ference of radicals as intermediates in the formation of Grignard indicated with dotted arrows (-+). reagents by examinations of stereochemist# and of byproducts?.1° We have published a preliminary account of this work.I0 of the magnesium surface after c~rrosion.~A molecule of organic Current understanding of the mechanism of formation of halide in solution arrives at the surface of magnesium via a

Grignard reagents by reaction of alkyl halides and magnesium -- -- is based on studies of product^,'^-^^ and morphology (14) Barber, J. J.; Whitesides, G. M. J. Am. Chem. Soc. 1980, 102, 239-243. (15) Root, K. S.; Deutch, J.; Whitesides, G. M. J. Am. Chem. Soc. 1981, (1) This work was supported by the National Science Foundation, Grants ---.103. -5475-5479. - - - CHE-82-04143and CHE-85-08702. (16) Vogler, E. A.; Stein, R. L.; Hayes, J. M. J. Am. Chem. Soc. 1978, (2) Forrester, A. R.; Hey, J. M.; Thompson, R. H. Organic Chemistry of 100. 3163-3166. Stable Free Radicals; Academic: New York. 1968: Chaoter 5. (17) Garst, J. F.; Deutch, J. E.; Whitesides, G. M. J. Am. Chem. Soc. (3) Rozantsev, E. G. Free Nitroxyl ~adicals;plenum: '~ewYork, 1970. 1986. 108.2490-249 1. (4) Howard, J. A. Adu. Free-Radical Chem. 1972,4,49-173. (18) ~hewitz,H. W. H. J.; Blomberg, C.; Bickelhaupt, F. Tetrahedron (5) Nelson. S. F. In Free Radicals; Kochi, J. K., Ed.; Wiley: New York. Lett. 1972, 28 1-284; Tetrahedron 1973,29,719-726. 1973; Vol. 2, Chapter 21. (19) Schaart, B. J.; Bodewitz, H. W. H. J.; Blomberg, C.; Bickelhaupt, F. (6) Keana, J. F. W. Chem. Reu. 1978. 78. 37-64. J. Am. Chem. Soc. 1976, 98, 3712-3713. (7) Sholle, V. D.; Bolubev, V. A,; Rozantsev, E. G. Bull. Acad. Sci. USSR, (20) Bodewitz. H. W. H. J.: Schaart. B. J.: Van der Niet, J. D.; Blomberg, Diu. Chem. Sci. (Engl. Traml.) 1971, 200, 761-763. C.; den ~ollander,J. A,; ~ickelhau~t,F. ~eirahedron1978,34,2523-2527. (8) Root, K. S.; Hill. C. L.; Whitesides, G. M. J. Am. Chem. Soc. Sub- (21) Schaart, B. J.; Blomberg, C.; Akkerman, 0.S.; Bickelhaupt, F. Can. mitted for publication. J. Chem. 1980,58,932-937. (9) Hill, C. L.; Lawrence, L. M.; Fujiwara, Y.; Shih, Y.-S.;Izumi, A.; (22) Walborsky, H. M.; Aronoff, M. S. J. Organornet. Chem. 1973.51, Deutch, J. E.; Whitesides, G. M. Unpublished result. 31-53. (10) Preliminary account: Lawrence, L. M.; Whitesides, G. M. J. Am. (23) Walborskv. H. M. Tetrahedron 1981.37. 1625-1651 Chem. Soc. 1980. 102. 2493-2494. (24) wa1borskj.i H. M.; Banks, R. B. Bull. sic. Chim. Belg. 1980, 89, (1 1) Rogers. H. R.; Hill, C. L.; Fujiwara, Y.; Rogers. R. J. Mitchell, H. 849-868. L.; Whitesides, G. M. J. Am. Chem. Soc. 1980, 102, 217-226. (25) RCichardt, C.; Trautwein, H. Chem. Ber. 1962, 95, 1197-1205. (12) Rogers. H. R.; Deutch, J.; Whitesides, G. M. J. Am. Chem. Soc. (26) Lamb, R. C.; Ayers, P. W.: Toney, M. K.; Garst, J. F. J. Am. Chem. 1980, 102.226-231. Soc. 1966,88,4261-4262. (13) Rogers, H. R.; Rogers. R. J.; Mitchell. H. L.; Whitesides. G. M. J. (27) Kossa, W. C., Jr.; Rees. T. C.; Richey, H. G., Jr. Tetrahedron Lett. 1971. 3455-3458.

0002-7863/89/1511-5405$01.50/0O 1989 American Chemical Society