A R T I C L E S
Kolonko et al.
4.012b) in THF showed average aggregation numbers close to
tetrameric. Crystal structures of the lithium enolates of
cyclopentanone-THF,3d pinacolone-THF,3d pinacolone-
pyridine,13 and others3e,,15 also showed cubic tetramers.
The Streitwieser group has developed quantitative UV-
spectroscopy based techniques (coupled equilibria,11c singular
value decomposition11d) for assessing aggregation state of
enolates. The technique allows measurement of equilibrium
constants and identification of the principal aggregated species,
but requires systems with a usable UV absorption whose
maximum is sensitive to the aggregation state, and the presence
of two different aggregates in detectable amounts. Thus only
enolates in which either the carbonyl carbon or R-carbon bears
an aryl group have been studied. Several of the enolates (e.g.,
6-phenyl-R-tetralone,11a p-phenylisobutyrophenone11e) are mix-
tures of tetramers and monomers.11a However, when the
R-position is fully substituted or there is a conjugating R-phenyl
substituent (as in 2-benzyltetralone,11a 2-phenyl tetralone,11f or
2-biphenylylcyclohexanone11g) the enolates are predominantly
dimeric in THF, with detectable amounts of monomer. Of
interest in connection with the current study is the lithium
enolate of 1,3-diphenylacetone, which is mainly dimer in THF
solutions, with detectable amounts of monomer.11b
measurements using relaxation times, and 13C chemical shifts.
A key observation was the formation of a 3:1 mixed aggregate
with LiCl.10a Of course, the reliability of mixed aggregate
techniques for establishing homoaggregate structures depends
on the structural similarity of the components. In this regard
the use of isotopic labeling, as in the classical study of partially
13C-enriched methyllithium1b or the 6Li isotope shifts of mixed
aggregates between deuterated and undeuterated organolithium
reagents16 can provide unambiguous information, and studies
of very similar mixtures can also be productive, such as the
work confirming an aryllithium triple ion structure by the
formation of a mixed triple ion between two aryllithium
reagents.4g Definitive studies by Collum and co-workers have
recently systematized and extended the mixed aggregate ap-
proach (method of continuous variation) to the structures of
several enolates, including those of cyclopentanone, cyclohex-
anone, and indanone, all of which were found to be tetramers
in THF solution.6c
The HMPA Titration Technique. Some years ago we intro-
duced an NMR technique which employs the advantageous
NMR properties of HMPA (OdP(NMe2)3) to probe solution
structures of lithium species.4h Several other laboratories have
also reported such experiments.6e,8b,10c,17 Although there is a
significant element of “Heisenberg Uncertainty Principle” in
using a powerful cosolvent to probe structure in the absence of
the cosolvent (the probe changes the object studied), a careful
HMPA titration monitored by low-temperature (<-120 °C) 7Li,
6Li, 13C and 31P NMR spectroscopy (as well as other nuclei
when available) can often provide valuable structural insights.
The technique is usually very specific for detecting contact/
separated ion pair status (SIP/CIP) of monomers4c,e,f,i but higher
aggregates, as usually found for enolates, can also be analyzed
(e.g., MeLi tetramer4h). Less definitive results can be expected
because of the aforementioned uncertainly principle.
NMR spectroscopic determinations of solution aggregate
structure have also utilized techniques in which the symmetry
of the homoaggregates is broken by the formation of mixed
aggregates. Careful NMR studies of isobutyrophenone enolate
suggested a tetrameric structure in THF and dioxolane based
on several lines of indirect evidence, including molecular size
(6) (a) Collum, D. B. Acc. Chem. Res. 1993, 26, 227–234. Lucht, B. L.;
Collum, D. B. Acc. Chem. Res. 1999, 32, 1035–1042. (b) McNeil,
A. J.; Toombes, G. E. S.; Gruner, S. M.; Lobkovsky, E.; Collum, D. B.;
Chandramouli, S. V.; Vanasse, B. J.; Ayers, T. A. J. Am. Chem. Soc.
2004, 126, 16559–16568. (c) Liou, L. R.; McNeil, A. J.; Ramirez,
A.; Toombes, G. E. S.; Gruver, J. M.; Collum, D. B. J. Am. Chem.
Soc. 2008, 130, 4859–4868. McNeil, A. J.; Toombes, G. E. S.;
Chandramouli, S. V.; Vanasse, B. J.; Ayers, T. A.; O’Brien, M. K.;
Lobkovsky, E.; Gruner, S. M.; Marohn, J. A.; Collum, D. B. J. Am.
Chem. Soc. 2004, 126, 5938–5939. Liou, L. R.; McNeil, A. J.;
Toombes, G. E. S.; Collum, D. B. J. Am. Chem. Soc. 2008, 130,
17334–17341. (d) Gruver, J. M.; Liou, L. R.; McNeil, A. J.; Ramirez,
A.; Collum, D. B. J. Org. Chem. 2008, 73, 7743–7747. (e) Romesberg,
F. E.; Bernstein, M. P.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.;
Collum, D. B. J. Am. Chem. Soc. 1993, 115, 3475–3483. (f) Galiano-
Roth, A. S.; Collum, D. B. J. Am. Chem. Soc. 1988, 110, 3546–3554.
(7) Edlund, U.; Lejon, T.; Venkatachalam, T. K.; Buncel, E. J. Am. Chem.
Soc. 1985, 107, 6408–6409.
When LiX dimers are present, the HMPA titration usually
takes a course in which mono and bis-HMPA-solvated dimers
can be detected, followed by one or more HMPA-solvated
monomeric CIP species (e.g., LiCl4h). For some systems ion
pair separation occurs, others form significant fractions of triple
ions of the LiR2- Li+ type.4g,m In solvents less polar than THF,
HMPA-bridged dimers form.4b,f
The few tetramers that have been studied (MeLi,4h ArOLi10c
)
typically go through a series of complexes with HMPA
coordinated to the corners of the cubic structure. Lower
aggregates sometimes appear late in the titration. SIPs are not
seen. Free HMPA often appears even before one equivalent of
HMPA has been added (i.e., the HMPA-affinity of the triply
coordinated lithium is low).
(8) (a) Colquhoun, I. J.; McFarlane, H. C. E.; McFarlane, W. J. Chem.
Soc., Chem. Commun. 1982, 220–222. Hitchcock, P. B.; Lappert,
M. F.; Power, P. P.; Smith, S. J. J. Chem. Soc., Chem. Commun. 1984,
1669–1670. (b) Denmark, S. E.; Swiss, K. A. J. Am. Chem. Soc. 1993,
115, 12195–12196.
(9) Reed, D.; Stalke, D.; Wright, D. S. Angew. Chem., Int. Ed. Engl. 1991,
30, 1459–1460.
(10) (a) Jackman, L. M.; Szeverenyi, N. M. J. Am. Chem. Soc. 1977, 99,
4954–4962. (b) Jackman, L. M.; Lange, B. C. Tetrahedron 1977, 33,
2737–2769. (c) Jackman, L. M.; Chen, X. J. Am. Chem. Soc. 1992,
114, 403–411. (d) Jackman, L. M.; Lange, B. C. J. Am. Chem. Soc.
1981, 103, 4494–4499.
(11) (a) Andrew Streitwieser, A.; Kim, Y.-J.; Wang, D. Z. R. Org. Lett.
2001, 3, 2599–2601. (b) Gareyev, R.; Ciula, J. C.; Streitwieser, A. J.
Org. Chem. 1996, 61, 4589–4593. (c) Daniel Zerong Wang, D. Z.;
Streitwieser, A. J. Org. Chem. 2003, 68, 8936–8942. (d) Abbotto, A.;
Leung, S. S. W.; Streitwieser, A.; Kilway, K. V. J. Am. Chem. Soc.
1998, 120, 10807–10813. (e) Streitwieser, A.; Juaristi, E.; Kim, Y.-
J.; Pugh, J. K. Org. Lett. 2000, 2, 3739–3741. (f) Wang, D. Z.; Kim,
Y.-J.; Streitwieser, A. J. Am. Chem. Soc. 2000, 122, 10754–10760.
(g) Streitwieser, A.; Wang, D. Z. R. J. Am. Chem. Soc. 1999, 121,
6213–6219.
Addition of other coordinating cosolvents also provides
insights into solution structures, with TMEDA often favoring
dimers,6c,d whereas PMDTA and TMTAN frequently produce
monomers.4b,18
Results and Discussion
Cyclopentanone Lithium Enolate (1-Li). The lithium enolate
of cyclopentanone has been examined several times. Crystal-
lization from THF solution gave a tetrasolvated tetramer.3d
(12) (a) Arnett, E. M.; Maroldo, S. G.; Schriver, G. W.; Schilling, S. L.;
Troughton, E. B. J. Am. Chem. Soc. 1985, 107, 2091–2099. (b) Arnett,
E. M.; Moe, K. D. J. Am. Chem. Soc. 1991, 113, 7288–7293.
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