T. M. Kosak, H. A. Conrad, A. L. Korich, R. L. Lord
FULL PAPER
at 185 °C. An initial column temperature of 80 °C was held for four
minutes and ramped at a rate of 10 °C per minute until a final
temperature of 280 °C was reached. The detector temperature was
set to 280 °C.
computational predictions indicate that demethylation of
anisole proceeds through a three-cycle mechanism that is
underpinned by previously reported and new experimental
findings. The results of this study show that sub-stoichio-
metric amounts of BBr3 can be used in place of one full
equivalent and may enable the use of BBr3 in total synthesis
when multiple moieties are susceptible to attack. However,
there are a number of lingering questions that require fur-
ther investigation. (i) Does the new mechanism for ether
cleavage extend to alkyl methyl ethers and, if so, are all
three cycles operable? (ii) Is the multi-cycle mechanism pro-
posed for aryl methyl ether cleavage general for BX3 rea-
gents (X = Br, Cl)? The reaction of BCl3 with ethers and
alcohols suggests that two- and three-cycle mechanisms are
accessible under the reported conditions.[15,16] (iii) Can a
multi-cycle extension of Sousa and Silva’s unimolecular
mechanism be viable for branched ethers? Work is ongoing
in our laboratories to answer these and related questions
about BX3 reactivity.
Representative Experimental Procedure: To a dry 5.00 mL thick
walled vial equipped with a stir bar and septum was added anisole
followed by the addition of dry dichloromethane (1 mL per 1 mL
of BBr3 solution). The vial was allowed to purge under nitrogen
for approximately 5 min, after which BBr3 was added slowly
through the septum with stirring. The reaction was left to stir over-
night before the contents were poured into ca. 1 mL of deionized
H2O. The organic layer was separated and an aliquot was analyzed
by GC using dichloromethane as the solvent.
Acknowledgments
T. M. K. acknowledges a Ott-Stiner fellowship and both T. M. K.
and H. A. C. thank the Weldon fund for financial support. A. L. K.
and R. L. L. recognize Grand Valley State University start-up
funds (GVSU-OURS, GVSU-CSCE, GVSU-CLAS) and the
National Science Foundation (NSF) (computational support
through CHE-1039925 to the Midwest Undergraduate Computa-
tional Chemistry Consortium) for financial support. Special thanks
go to Jacob Dillon and Donovan Anderson for help translating
references 15 and 16.
Computational Methods
Geometry optimizations were performed in the
Gaussian09 program (G09.D01)[17] at the B3LYP/6-31G(d)
level of theory.[18–22] The effect of implicit solvation was in-
cluded during geometry optimization using the SMD model
for dichloromethane.[23,24] Stationary points on the poten-
tial energy surface were characterized as minima or first-
order saddle points (transition states) by evaluating har-
monic frequencies at the optimized geometries.[25] From
these frequency calculations performed with a double-zeta
basis set, electronic energies [E(SCF)DZ] and Gibbs free en-
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[4] P. Gao, P. S. Portoghese, J. Org. Chem. 1996, 61, 2466.
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[6] S. Punna, S. Meunier, M. G. Finn, Org. Lett. 2004, 6, 2777.
[7] J. F. W. McOmie, M. L. Watts, D. E. West, Tetrahedron 1968,
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[8] E. H. Vickery, L. F. Pahler, E. J. Eisenbraun, J. Org. Chem.
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[9] E. Paliakov, L. Strekowski, Tetrahedron Lett. 2004, 45, 4093.
[10] C. Pasquini, A. Coniglio, M. Bassetti, Tetrahedron Lett. 2012,
53, 6191.
[11] C. Sousa, P. J. Silva, Eur. J. Org. Chem. 2013, 5195.
[12] L. Watson, O. Eisenstein, J. Chem. Educ. 2002, 79, 1269.
[13] A. L. Korich, P. M. Iovine, Dalton Trans. 2010, 39, 1423.
[14] C. D. Roy, Aust. J. Chem. 2006, 59, 657.
[15] E. Wiberg, W. Sütterlin, Z. Anorg. Allg. Chem. 1931, 202, 22.
[16] E. Wiberg, W. Sütterlin, Z. Anorg. Allg. Chem. 1931, 202, 31.
[17] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-
gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Starov-
erov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,
J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Ad-
amo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Mar-
tin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B.
Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09, re-
vision D.01, Gaussian, Inc., Wallingford, CT, USA, 2009.
ergies [G(sol)DZ
] based on standard thermodynamic
approximations were tabulated.[26] Single-point energy re-
finements with the 6-311+G(d,p) basis set, implicit sol-
vation, and Grimme’s empirical dispersion corrections
(with Becke–Johnson damping)[27,28] allowed for improved
triple-zeta electronic energies [E(SCF)TZ]. For select species,
single point energy refinements with aug-cc-pVTZ pro-
duced similar results (see Supporting Information) and the
more efficient 6-311+G(d,p) basis was therefore employed.
Approximate triple-zeta free energies were obtained by
G(sol)TZ ≈ G(sol)DZ – E(SCF)DZ + E(SCF)TZ. Visualiza-
tions were made with GaussView 5.0.9[29] and CylView.[30]
Experimental Methods
General: Anisole was purchased from Acros Organics and used
without additional purification. BBr3 was purchased from Aldrich
as a 1 m solution in CH2Cl2 and used only for two weeks after
opening to ensure purity. Dry CH2Cl2 was obtained from a Pure-
Solv solvent purification system that passes solvent over two col-
umns of neutral alumina. 1H NMR were taken on a 300 MHz
JEOL OXFORD spectrometer in CDCl3 that was stored over 4 Å
molecular sieves. Spectra were referenced to the deuterated solvent.
Gas chromatography was performed on Thermo Scientific GC-Fo-
cus Series instrument which was fitted with a Supelco MDN-5 col-
umn. The injector (Thermo Scientific AL3000) temperature was set
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