https://openriver.winona.edu/urc2018/1131/thumbnail.jp

Dorn, Rick W.

Nalli, Thomas W.

West, Joseph K.

Willcox, Eden

English

OpenRiver@Winona State University

Selectivity of Wohl-Ziegler Brominations of Cyclohexene and trans-2-HexeneRick W. Dorn, Eden Willcox, Joseph K. West and Thomas W. NalliDepartment of Chemistry, Winona State University, Winona, MinnesotaINTRODUCTION RESULTSWohl-Ziegler bromination utilizing N-bromosuccinimide (NBS) is an important reaction inorganic synthesis.1,2,3 The reaction proceeds by aradical chain mechanism (eq 1-2), in which thebromination position is determined by which hydrogenthe bromine radical abstracts (eq 1).Br ∙ + RH → HBr + R ∙ (1)R ∙ + Br2 → RBr + Br ∙ 2Unsymmetrical allylic systems should display multipleisomers according to resonance theory (Scheme 1).However, it has been reported and often claimed thatbromination of 2-heptene (1a) with NBS yields 4-bromo-2-heptene (2a) as the sole product.4,5,6,7In contrast, it is well established that allylicrearrangement occurs during NBS bromination ofterminal alkenes8,9. We reinvestigated, bothexperimentally and computationally, allylicrearrangement during NBS bromination of 2-alkenes(1a and 1b). Furthermore, selectivity was studied forthe effect of a bromine atom on radical stability insubsequent bromination steps.DISCUSSIONREFERENCES(1) Dauben, HJ.; McCoy, L. J. Chem. Soc. 1959, 81 (18), 4863 – 4873. (2) Winkler, M.; SteinbiB, M.; Meier, M. Eur. J. Lipid Sci. Technol. 2013, 116, 44 – 51. (3) Klein, D. Wiley: New Jersey, 2012.(4) Greenwood, F.; Kellert, M. J. Am. Chem. Soc. 1953, 75, 4842 – 4843. (5) Greenwood, F.; Kellert, M.; Sedlak, J. Org. Syn. 1963, 4, 108. (6) Saikia, I.; Borah, A.; Phukan, P. Chem. Rev. 2016, 116,6837 – 7042. (7) N-Bromosuccinimide. https://en.wikipedia.org/wiki/N-Bromosuccinimide (accessed Nov. 2017). (8) Kharasch, M.; Malec, R.; Yang, N. J. Org. Chem. 1957, 22, 1443 – 1444. (9)Bateman, L.; Cunneen, J.; Fabian, J.; Koch, H. J. Chem. Soc., 1950, 936 – 941. (10) Schmidt, M.; Baldrige, K.; Boatz, J.; Elbert, S.; Gordon, M.; Jensen, J.; Koseki, S.; Matsunaga, N.; Nguyen, K.;Su, S.; Windus, T.; Dupuis, M.; Montgomery, J. J. Comput. Chem. 1993, 14, 1347 – 1363. (11) Khazaei, A.; Vaghei, R.; Karkhanei, E. Syn. Comm. 2002, 32 (14), 2107 – 2113.Figure 3: Relative equilibrium geometry energies of reactant, intermediates and products from NBS bromination of trans-2-hexene (I), trans-4-bromo-2-hexene (II) and 3-bromocyclohexene (III). Wohl-Ziegler brominations of 1a and 1b both yielded a mixture of bromoalkene products(Table 1). We were able to identify the GC peaks (Figure 1) based on retention times ofindependently prepared bromohexene products (2b, 3b, 4b) and MS fragmentation patterns. Key1H NMR peaks of alpha hydrogens were also assignable (Figure 2) and relative yieldsdetermined from both methods were remarkably consistent. Our findings that the allylicrearrangement product (3a) is the major isomer clearly contradicts previous claims that NBSbromination of 2-heptene yields solely 4-bromo-2-heptene. 4,5,6,7 Moreover, our NMR resultsshow that previously reported NMR spectra of 2a are incorrect.11The relative yields of the bromoalkene products were invariant with solvent, time, initiationmethod and GC injection port temperature, indicating that the products do not equilibrate and thereaction is under kinetic control. Further reinforcing this ideal, our computations indicatedreversion of the bromoalkenes to the allylic radicals is prohibitively endergonic (ΔG = 17-19kcal/mol, Figure 3-I). The 75:25 ratio of products 2b/3b to 4b/5b is explained by formation ofthe H-4 derived radical at a rate 3 times faster than the H-1 derived radical. This would indicate atransition state for H abstraction that is ~ 1 kcal/mol more stable. This is consistent with thecomputational data, which shows a 3 kcal/mol difference in radical stability (Figure 3-I).Neglecting stereo chemistry, we found that bromination of 3-bromocyclohexene yields 3isomers (79 % 2c, 19 % 3c, 2 % 4c, Table 2). According to resonance theory, the major andminor products (2c and 3c) can come from the same radical intermediate, with the major product(2c) being more stable than the minor (3c) (Figure 3-III). However, our preliminary DFTcalculations suggest H abstraction at C4 could occur and represent another pathway (path b) tothe observed products (Scheme 2).DFT calculations relating to the bromination of 4-bromo-2-hexene indicate that the moststable radical intermediate occurs due to H abstraction at C5 (Figure 3-II) with a bromine shiftfrom C4 to C5 and the radical ending up on C4 (Scheme 3). Interestingly, the DFT minimizationpathways suggest a transition state in which the bromine has all of the radical and is hoveringover 2,4-hexadiene (Figure 4-II and 4-III). The possibility that bromine preferentially abstracts aH at C5 will be tested.Figure 1: TIC Chromatogram of Bromohexene Products (Entry 2) (IV)(II)(I)Figure 4: Radical susceptibility maps of trans-2-hexen-4-yl (I), trans-5-bromo-2-hexen-4-yl (II), trans-2,4-hexadiene + Br· (III) and 3-bromocyclohexen-6-yl (IV). Color gradient from red to blue indicates increasing radical susceptibility.Scheme 2: Resonance structures from two separate pathways (A and B) due to bromines effect on the radical stability.(III)CONCLUSION(I) (II) (III)Figure 2: 1H NMR Spectrum of Bromohexene Products (Entry 2)  Table 1: NBS Bromination of 2-heptene and 2-hexeneaGeneral. All reactions used oven dried glassware,dried solvents (4 Å molecular sieves) and were carriedout under N2. NMR spectra were obtained at 300 MHzin CDCl3.NBS Brominations. To a solution of the alkene (0.5 –2 M) was added NBS (0.67 – 1 equiv) and benzoylperoxide (BPO) (if no hv). The reaction mixture wasstirred rapidly and refluxed in front of a 275 Wsunlamp (if no BPO was used). The succinimide wasfiltered off and solvent removed in vacuo.1-Bromo-2-hexene (4b). To a chilled solution (- 8 oC)of 2-hexen-1-ol (42 mmol) in diethyl ether (0.5 M) wasadded PBr3 (17 mmol) dropwise. The solution wasstirred (r.t. 2 h) before the addition of ice, extractionwith diethyl ether, drying over Na2SO4, andconcentration in vacuo to yield 4.6 g of trans-4b (67%). 1H NMR 𝛿 5.72 (m, 2H), 3.96 (d, 2H), 2.02 (q,2H), 1.40 (sextet, 2H), 0.895 (t, 3H).4-Bromo-2-hexene/2-bromo-3-hexene (2b/3b) . 2-pentenal was treated with MeMgBr in ether (3.0 M).Neutralization (10 % HCl) followed by extraction(ether), drying (Na2SO4.), and PBr3 treatment (asabove) gave 2b/3b (1.3:1). 1H NMR 2b 𝛿 5.68 (m,2H), 4.44 (q, 1H), 2.06 (m, 2H), 1.71 (d, 3H), 0.977 (t,3H). 3b 𝛿 5.68 (m, 2H), 4.70 (quintet, 1H), 1.90 (m,2H), 1.77 (d, 3H), 1.00 (t, 3H).DFT Methods. Structures were modeled (GAMESS10)in the gas phase (B3LYP functional set). The 6-311++G** basis (C and H atoms) and the ECP-basedLANL2DZ basis (Br atoms) was applied. Vibrationalanalysis confirmed no imaginary frequencies.Wohl-Ziegler brominations of 2-alkenes (1a, 1b) do in fact display multiple isomers in accordto resonance theory. TIC chromatograms, MS fragmentation patterns and 1H NMR spectraconfirmed identification of all isomers. Previous claims stating 2a is the sole product of NBSbromination of 1a have been shown to be incorrect. The bromohexene products were determinedto be under kinetic control since equilibrium is thermodynamically prohibitive and relativeyields are invariant with solvent, time, initiation method and GC injection port temperature.DFT calculations suggest that radical susceptibility increases near a bromine atom and thusbromine helps stabilize the radical. This finding gave rise to a new possible mechanism where Habstraction occurs adjacent to Br. Further DFT calculations show Br dissociates and hovers overthe diene to induce a Br shift to a more favorable radical.EXPERIMENTALWe thank WSU Chemistry Club, WSU Student Senate, WSU Academic Affairs and the ACSLacrosse-Winona Local Sectional for the financial support to attend this conference.Scheme 1: Allylic rearrangement products due to resonance stabilization.Table 2: NBS Bromination of 3-bromocyclohexeneaScheme 3: Bromine shift to yield most stable radical intermediate when H abstraction occurs adjacent to Br.ACKNOWLEDGEMENTS1 1a CCl4 32 1b CCl4 23 1b cyclohexane 2    42    33    21    4    42    33    21    42      3      4     5Entry Reactant Solvent Time (h)  Rel. Yield (%)b    32c  44c  21    3a Reaction conditions: 0.67 equiv NBS, BPO and reflux. b cis/transIsomers were added together. Values reported are averaged from 1H NMR and GC peak integrations (± 2 %).  c 1H NMR peak integration used due to co-eluted peaks in TIC chromatogram.  Rel. Yield (%)b2      3      44 1c CCl4 11                 15                     193                              6                         9082 17    1           83 16     1            79    19     2Entry Reactant Solvent Time (min) Conversion (%)a Reaction conditions: 1 equiv NBS, reflux and hv (275 W). b cis/trans Isomers added together from GC peak integration. 

Selectivity of Wohl-Ziegler Brominations of Cyclohexene and trans-2-Hexene

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Selectivity of Wohl-Ziegler Brominations of Cyclohexene and trans-2-Hexene

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