The Journal of Organic Chemistry
Article
(3) “Associated” forms (aggregates) in alkoxide-mediated metalations
have been discussed in the context of reported fractional reaction
orders. See ref 1b.
(4) Ma, Y.; Algera, R. F.; Collum, D. B. Sodium Diisopropylamide in
N,N-Dimethylethylamine: Reactivity, Selectivity, and Synthetic Utility.
J. Org. Chem. 2016, 81, 11312.
(5) Schlosser, M. Organometallics in Synthesis: A Manual, 2nd ed.;
Schlosser, M., Ed.; John Wiley & Sons: Chichester, 2002, Chapter 1.
(6) (a) For a relatively short but comprehensive bibliography of
NaDA, see ref 10. (b) For an extensive review of alkali metal amides,
see: Mulvey, R. E.; Robertson, S. D. Synthetically Important Alkali-
Metal Utility Amides: Lithium, Sodium, and Potassium Hexamethyldi-
silazides, Diisopropylamides, and Tetramethylpiperidides. Angew.
Chem., Int. Ed. 2013, 52, 11470. (c) For an interesting historical
perspective on organoalkali metal chemistry, see: Seyferth, D. Alkyl and
Aryl Derivatives of the Alkali Metals: Useful Synthetic Reagents as
Strong Bases and Potent Nucleophiles. 1. Conversion of Organic
Halides to Organoalkali-Metal Compounds. Organometallics 2009, 28,
2.
Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Gill, A.;
Nanayakkara, C.; Gonzalez, M.; Challacombe, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.;
Replogle, E. S.; Pople, J. A. Gaussian 09, revision A.02, Gaussian, Inc.:
Wallingford, CT, 2009.
(17) From Wikipedia, an isodesmic reaction is a chemical reaction in
which the type of chemical bonds broken in the reactant are the same as
the type of bonds formed in the reaction product.
́
(18) Cohen, A. J.; Mori-Sanchez, P.; Yang, W. Insights into Current
Limitations of Density Functional Theory. Science 2008, 321, 792.
(19) (a) Casado, J.; Lopez-Quintela, M. A.; Lorenzo-Barral, F. M. The
Initial Rate Method in Chemical Kinetics: Evaluation and Experimental
Illustration. J. Chem. Educ. 1986, 63, 450. (b) Initial rates (slopes) were
determined by fitting 10% of the decay to a third-order polynomial (at2
+ bt+c). The parameter b represents the rate at time zero. Initial rate =
f′(0) = b). The experimental observable (NMR intensity, IR
absorbance etc.) is converted to concentration to ensure a valid
comparison between initial rates of varying concentrations.
(20) Preparations of 1,1-1-d2 and 2,2-1-d2: Boden, N.; Bushby, R. J.;
Clark, L. D. The Synthesis of Specifically and Selectively Deuteriated
4,4′- Bis-alkoxyazoxybenzene Derivatives. J. Chem. Soc., Perkin Trans. 1
1983, 543.
(7) Transition metal catalyzed eliminations of n-alkylhalides and n-
alkyltosylates have received attention recently: Bissember, A. C.;
Levina, A.; Fu, G. C. A Mild, Palladium-Catalyzed Method for the
Dehydrohalogenation of Alkyl Bromides: Synthetic and Mechanistic
Studies. J. Am. Chem. Soc. 2012, 134, 14232.
(8) Knochel and coworkers exploited NaDA in DMEA solutions to
achieve challenging arene orthometalation-functionalization sequences
in a flow system: Wiedmann, N.; Ketels, M.; Knochel, P. Sodiation of
Arenes and Heteroarenes in Continuous Flow. Angew. Chem., Int. Ed.
2018, 57, 10748.
(21) Braida, B.; Prana, V.; Hiberty, P. C. The Physical Origin of
Saytzeff’s Rule. Angew. Chem., Int. Ed. 2009, 48, 5724.
(22) (a) Barry, J.; Bram, G.; Decodts, G.; Loupy, A.; Pigeon, P.;
Sansoulet, J. Solid−Liquid Phase-Transfer Catalysis Reactions without
Solvent; Very Mild Conditions for β-eliminations. J. Org. Chem. 1984,
49, 1138. (b) Wolkoff, P. Dehydrobromination of Secondary and
Tertiary Alkyl and Cycloalkyl Bromides with 1,8-Diazabicyclo[5.4.0]-
undec-7-ene. Synthetic Applications. J. Org. Chem. 1982, 47, 1944.
(23) (a) Jakubec, P.; Muratore, M. E.; Aillaud, I.; Thompson, A. L.;
Dixon, D. J. Design, Synthesis and Applications of New families of
Chiral Sulfonic Acids. Tetrahedron: Asymmetry 2015, 26, 251.
(b) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura,
M. Directed Ortho Borylation of Functionalized Arenes Catalyzed by a
Silica-Supported Compact Phosphine−Iridium System. J. Am. Chem.
Soc. 2009, 131, 5058.
(9) Buonora, P. T.; Lim, Y. J. The Substitution−Elimination
Mechanistic Disc Method. J. Chem. Educ. 2004, 81, No. 368.
(10) Algera, R. F.; Ma, Y.; Collum, D. B. Sodium Diisopropylamide:
Aggregation, Solvation, and Stability. J. Am. Chem. Soc. 2017, 139, 7921.
(11) (a) Algera, R. F.; Ma, Y.; Collum, D. B. Sodium
Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and
Mechanisms of Alkene Isomerizations and Diene Metalations. J. Am.
Chem. Soc. 2017, 139, 11544. (b) Algera, R. F.; Ma, Y.; Collum, D. B.
Sodium Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and
Mechanisms of Arene Metalations. J. Am. Chem. Soc. 2017, 139, 15197.
(12) (a) Collum, D. B.; McNeil, A. J.; Ramírez, A. Lithium
Diisopropylamide: Solution Kinetics and Implications for Organic
Synthesis. Angew. Chem., Int. Ed. 2007, 46, 3002. (b) Algera, R. F.;
Gupta, L.; Hoepker, A. C.; Liang, J.; Ma, Y.; Singh, K. J.; Collum, D. B.
Lithium Diisopropylamide: Non-Equilibrium Kinetics and Lessons
Learned about Rate Limitation. J. Org. Chem. 2017, 82, 4513. (c) Hsieh,
H. L.; Quirk, R. P. Anionic Polymerization: Principles and Practical
Applications; Marcel Dekker: New York, 1996. (d) Espenson, J. H.
Chemical Kinetics and Reaction Mechanisms, 2nd ed.; McGraw-Hill: New
York, 1995.
2
(24) Sodiation of sulfonate 12-d5 can be monitored by H NMR
spectroscopy at −110 °C.
(25) Bashore, C. G.; Vetelino, M. G.; Wirtz, M. C.; Brooks, P. R.;
Frost, H. N.; McDermott, R. E.; Whritenour, D. C.; Ragan, J. A.;
Rutherford, J. L.; Makowski, T. W.; Brenek, S. J.; Coe, J. W.
Enantioselective Synthesis of Nicotinic Receptor Probe 7,8-Difluoro-
1,2,3,4,5,6-hexahydro-1,5-methano-3-benzazocine. Org. Lett. 2006, 8,
5947.
(26) Substitution of an alkyl triflate by a sodium amide: Cruciani, G.;
Valeri, A.; Goracci, L.; Pellegrino, R. M.; Buonerba, F.; Baroni, M.
Flavin Monooxygenase Metabolism: Why Medicinal Chemists Should
Matter. J. Med. Chem. 2014, 57, 6183.
(13) We define the idealized rate law as that obtained by rounding the
observed reaction orders to the nearest rational order.
(14) The dielectric constants of substituted tetrahydrofurans are only
slightly lower than THF. (a) Harada, Y.; Salomon, M.; Petrucci, S.
Molecular Dynamics and Ionic Associations of Lithium Hexafluor-
oarsenate (LiAsF6) in 4-Butyrolactone Mixtures with 2-Methyltetrahy-
drofuran. J. Phys. Chem. A 1985, 89, 2006. (b) Carvajal, C.; Tolle, K. J.;
Smid, J.; Szwarc, M. Studies of Solvation Phenomena of Ions and Ion
Pairs in Dimethoxyethane and Tetrahydrofuran. J. Am. Chem. Soc.
1965, 87, 5548.
(27) For DFT computations of a lithium amide-based SN2 on a
sulfonate ester showing a Li-SO2 contact at the transition state, see:
Gupta, L.; Ramírez, A.; Collum, D. B. Reaction of Lithium
Diethylamide with an Alkyl Bromide and Alkyl Benzenesulfonate:
Origins of Alkylation, Elimination, and Sulfonation. J. Org. Chem. 2010,
75, 8392.
(28) Streitwieser, A.; Jayasree, E. G.; Hasanayn, F.; Leung, S. S.-H. A
Theoretical Study of SN2′ Reactions of Allylic Halides: Role of Ion
Pairs. J. Org. Chem. 2008, 73, 9426.
(29) Kirk, D. N.; Shaw, P. M. Elimination Reactions and
Configurations of 1-Methylcyclohexyl Derivatives, including Steroid
Analogues. J. Chem. Soc. C 1970, 182 and references cited therein.
(30) (a) Cross, B.; Whitham, G. H. Conformationally Fixed Olefins.
Part I. The Epimeric 1-Methyl-4-t-butylcyclohexanols and 1-Methyl-
ene-4-t-butylcyclohexane. J. Chem. Soc. 1960, 3892. (b) Kwart, H.;
Takeshita, T. Evaluation of the Relative Importance of Charge-Dipole
Interactions and Steric Strain Acceleration in Conformationally Mobile
Systems. J. Am. Chem. Soc. 1964, 86, 1161. (c) Baker, R.; Hudec, J.;
(15) NaDA has a half-life of 1.0 h at 25 °C in THF.10 By contrast,
NaDA in 5.0 M 2,5-dimethyltetrahydrofuran/THF decomposes with a
half-life of 2−3 h at 0 °C.
(16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.,
Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels,
A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.;
Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford,
S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
H
J. Org. Chem. XXXX, XXX, XXX−XXX