A relative organolithium stability scale derived from tin-lithium exchange equilibria. Substituent effects on the stability of α-oxy- and α-aminoorganolithium compounds

Article abstract of DOI:10.1021/ja025552r

Quantitative thermodynamic stability scales of organolithium compounds can be derived from measurements of tin-lithium exchange equilibria. A ΔG_eq scale of α-oxy- and α-aminoorganolithium compounds was established, and quantitative stabilization effects of O-alkyl, O-alkoxyalkyl, O-carbamoyl, N-carbamoyl, and O-carbonyl groups of the α-carbanion are presented. It has been found that an α-oxycarbanion is far better stabilized by a carbonyl group as the O-substituent than by an alkyl or alkoxyalkyl group, while the anion-stabilizing effects of the different O-carbonyl substituents are comparable. An N-carbamoyl group was found to have a somewhat higher stabilizing effect than its O-carbamoyl counterpart. NMR data are presented that show that benzylic N- or O-substituted carbanions have highly planarized structures where the negative charge is highly delocalized. The stability data obtained from the tin-lithium exchanges can be easily converted into "effective pK" data that are useful for predicting the acid-base behavior of this type of organolithium species.

Full text of DOI:10.1021/ja025552r

Published on Web 09/26/2002
A Relative Organolithium Stability Scale Derived from
Tin-Lithium Exchange Equilibria. Substituent Effects on the
Stability of r-Oxy- and r-Aminoorganolithium Compounds
Paula Gran˜a, M. Rita Paleo, and F. Javier Sardina*
Contribution from the Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad
de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Received January 9, 2002
Abstract: Quantitative thermodynamic stability scales of organolithium compounds can be derived from
measurements of tin-lithium exchange equilibria. A ∆Geq scale of R-oxy- and R-aminoorganolithium
compounds was established, and quantitative stabilization effects of O-alkyl, O-alkoxyalkyl, O-carbamoyl,
N-carbamoyl, and O-carbonyl groups of the R-carbanion are presented. It has been found that an
R-oxycarbanion is far better stabilized by a carbonyl group as the O-substituent than by an alkyl or alkoxyalkyl
group, while the anion-stabilizing effects of the different O-carbonyl substituents are comparable. An
N-carbamoyl group was found to have a somewhat higher stabilizing effect than its O-carbamoyl counterpart.
NMR data are presented that show that benzylic N- or O-substituted carbanions have highly planarized
structures where the negative charge is highly delocalized. The stability data obtained from the tin-lithium
exchanges can be easily converted into “effective pK” data that are useful for predicting the acid-base
behavior of this type of organolithium species.
Introduction
One potential approach to solve this problem could be the
measurement of the pK of the corresponding carbanions,3 since
the basicity of an anion is strongly correlated with its thermo-
dynamic stability, but the determination of the pK of the more
basic, highly functionalized, most synthetically useful carbanions
is still problematic, despite the fact that Streitwieser has provided
data for several types of aromatic, heteroaromatic, and benzylic
systems.4 The measurement of the equilibrium acidities of
hydrocarbon acids under synthetically significant conditions
(approximately 0.1 M ethereal solutions at low temperatures)
is very difficult because proton-transfer equilibration with bases
of known pK (the usual way to determine equilibrium acidities)3-5
take place very slowly in this environment, allowing decom-
position reactions of the involved carbanions to become
competitive.4c An additional inconvenience of the use of acidity
measurements to quantify the stability of organometallic
compounds is that ion pairing and aggregation effects have no
reflection on the pK data, since they refer only to solvent-
separated, nonaggregated species.
R-Heteroatom-substituted organometallic compounds have
gained considerable synthetic status due to their broad utility.
R-Oxy- and R-aminoorganolithium reagents, in particular, have
been the focus of much attention, especially by the groups of
Hoppe and Beak, among others, and a great deal of knowledge
has accumulated about their modes of generation, their con-
figurational stabilities, and the effect of substituents on their
ease of formation and their reactivity,1 but despite all of the
attention devoted to these systems, there remain unanswered
some fundamental questions about this type of reagents. For
instance, it was established very early that both oxygen and
nitrogen atoms considerably increase the stability of an
R-carbanion,1c,2 and yet no data on the quantitative, or even
qualitative, influence of the heteroatom substituents on their
carbanion-stabilizing effects have been reported, despite the
obvious synthetic importance of the results derived from such
a study. This situation is just an instance of a more general,
unresolved problem, that of the development of a method to
quantitatively compare the stability of structurally related,
synthetically useful, highly basic organometallics.
(3) (a) Stratakis, M.; Wang, P. G.; Streitwieser, A. J. Org. Chem. 1996, 61,
3145 and references therein. (b) Bordwell, F. G.; Drucker, G. E.; Fried, H.
E. J. Org. Chem. 1981, 46, 632 and references therein. (c) For an account
of the earlier results see: Cram, D. J. Fundamentals of Carbanion
Chemistry; Academic Press: New York, 1965.
(4) pK of polyhalogenated benzenes: (a) Reference 3a. (b) Streitwieser, A.;
Abu-Hasanyan, F.; Neuhaus, A.; Brown, F. J. Org. Chem. 1996, 61, 3151.
pK of benzylsilanes: (c) Streitwieser, A.; Xie, L.; Wang, P.; Bachrach, S.
M. J. Org. Chem. 1993, 58, 1778. pK of benzyl and fluorenyl hydrocar-
bons: (d) Streitwieser, A.; Ciula, J. C.; Krom, J. A.; Thiele, G. J. Org.
Chem. 1991, 56, 1074. (e) Kaufman, M. J.; Gronert, S.; Streitwieser, A.,
Jr. J. Am. Chem. Soc. 1988, 110, 2829 and references therein.
(5) For other important methods of measuring pK values see: (a) Jaun, B.;
Schwarz, J.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 5741 and references
therein. (b) Arnett, E. M.; Venkatasubramaniam, K. G. Tetrahedron Lett.
1981, 987.
* To whom correspondence should be addressed. E-mail: qojskd@usc.es.
(1) R-Alkoxyorganolithiums: (a) Still, W. C. J. Am. Chem. Soc. 1978, 100,
1481. (b) Still, W. C.; Sreekumar, C. J. Am. Chem. Soc. 1980, 102, 1201.
(c) Sawyer, J. S.; Kucerovy, A.; Macdonald, T. L.; McGarvey, G. J. J.
Am. Chem. Soc. 1988, 110, 842 and references therein. R-Acyloxyorga-
nolithiums: (d) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 2282 and references therein. (e) Heimbach, D. K.; Fro¨hlich, R.;
Wibbeling, B.; Hoppe, D. Synlett 2000, 950. R-Aminoorganolithiums: (f)
Pippel, D. J.; Weisenburger, G. A.; Faibish, N. C.; Beak, P. J. Am. Chem.
Soc. 2001, 123, 4919. (g) Gross, K. M. B.; Beak, P. J. Am. Chem. Soc.
2001, 123, 315 and references therein. (h) Iula, D. M.; Gawley, R. E. J.
Org. Chem. 2000, 65, 6196 and references therein.
(2) Beak, P.; Zajdel, W. J.; Reitz, D. B. Chem. ReV. 1984, 84, 471.
9
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J. AM. CHEM. SOC. 2002, 124, 12511-12514
12511

A R T I C L E S
Gran˜a et al.
A more promising alternative is based on the pioneering work
of the groups of Applequist and Dessy, who established that
halogen-Li and Hg-Mg interchange equilibria could be used
to measure the relative stabilities of simple alkyl-, alkenyl-, and
aryllithium reagents,6 although the extension of these methods
to determine the stabilities of more complex organometallics,
especially of R-heterosubstituted carbanions, is thwarted by the
instability or unavailability of the halogenated or mercuriated
precursors. A far more convenient option can be traced to the
work of Macdonald and McGarvey, who used the Sn-Li
exchange reaction (eq 1 in Figure 1) to establish a qualitatiVe
scale of the thermodynamic stabilities of several R-alkoxycar-
banions. As for the halogen-Li and Hg-Mg exchanges, the
position of the equilibrium depends on the difference of the
stabilities of the carbanions involved, the exchange favoring
the pairing of the most stable carbanion with the more
electropositive (Li or Mg) cation.1c,7 We sought to extend this
Sn-Li exchange methodology to provide quantitatiVe data on
the stabilities of R-oxy- and R-aminocarbanions, since the Sn-
containing precursors of these organometallics are readily
available and the Sn-Li exchanges can be run under conditions
where most of the synthetically useful organolithium compounds
are stable. The first key issues that we wished to address are
(1) to what extent (if any) a carbonyloxy group is more
stabilizing than an alkoxy (or alkoxyalkyl) group and (2) the
effect of the heteroatom attached to the carbanionic center (O
vs N) on the stability of the corresponding R-heterosubstituted
carbanions.
Figure 1. Organolithium compounds studied and their precursors. ∆Geq
values relative to that of 9b.
To set up the tin-lithium exchange equilibria, equimolar
amounts of stannanes 1, 3, and 5 and organolithium reagents
7b-9b (obtained from the corresponding stannanes 7a-9a and
100 mol % n-BuLi or PhLi) were mixed and kept at the
appropriate temperature for 1-24 h.9 The equilibrium concen-
trations were measured after low-temperature protonation of the
reactions and analysis of the resulting mixtures of hydrocarbons
and stannanes by NMR and/or GC.1c,10 That a true equilibrium
had been reached was established by performing the reverse
reaction in each case. The results obtained are shown in Figure
2. The ∆Geq data are reported as a single number when the
same Keq was obtained from the forward and reverse reactions,
and as an interval when different, but proximate, values were
obtained from the forward and reverse reactions. The conditions
for each particular reaction were optimized regarding carbanion
stability, the rate of the Sn-Li exchange, and minimization of
side reactions.
Fraser and co-workers have determined the “aggregate
acidities” of a number of benzylic, aromatic, and heteroaromatic
compounds by abstraction of their most acidic hydrogens with
lithiated bases of known pK under synthetically significant
conditions (in THF at low temperatures).8 Their data can be
straightforwardly converted to free energy differences between
the corresponding organolithium compounds, thus providing a
set of reference compounds which can be used to establish
quantitative relative stability scales of, in principle, any type of
carbanions.
Results and Discussion
The organolithium compounds (and their stannane precursors)
selected for this study are shown in Figure 1 along with the
reference compounds used.
The benzylic organolithiums 2, 4, and 6 were chosen since
their stabilities were estimated to be well within the limits of
the Fraser scale. The reference compounds 7-9 were chosen
post facto. The reference 0.0 kcal/mol level was arbitrarily
assigned to the most stable reference compound used.8 The ∆Geq
values shown for the reference compounds were calculated by
us from the original pK data provided by Fraser.8
The Sn-Li exchanges were usually performed at concentra-
tions of 0.08-0.1 M, but the same Keq values were obtained
when selected reactions were run at concentrations as high as
0.2 M or as low as 0.02 M, which indicates that the species
involved in the equilibria maintain the same degree of associa-
tion throughout the range of concentrations studied.
Analysis of the data shown in Figure 2 uncovered some
interesting facts regarding the data obtained in THF: (1) An
R-oxycarbanion is far better stabilized by a carbonyl group as
the O-substituent than by an alkyl or alkoxyalkyl group (∆∆Geq
is approximately 3 kcal/mol; compare entries 1 and 2 with
entries 3-5 and entry 6 with entries 7 and 8). This rather large
(6) (a) Applequist, D. E.; O’Brien, D. F. J. Am. Chem. Soc. 1963, 85, 743. (b)
Dessy, R. E.; Kitching, W.; Psarras, T.; Salinger, R.; Chen, A.; Chivers,
T. J. Am. Chem. Soc. 1966, 88, 460. (c) Salinger, R. M.; Dessy, R. E.
Tetrahedron Lett. 1963, 729.
(7) Reich et al. have used this method to establish that the equilibrium ratio of
PhLi and TolLi is 65:35, although no relative stability data were derived.
See ref 14 in Reich, H. J.; Borst, J. P.; Coplien, M. B.; Phillips, N. H. J.
Am. Chem. Soc. 1992, 114, 6577.
(8) (a) Fraser, R. R.; Bresse, M.; Mansour, T. S. J. Am. Chem. Soc. 1983, 105,
7790. (b) Fraser, R. R.; Bresse, M.; Mansour, T. S. J. Chem. Soc., Chem.
Commun. 1983, 620. (c) Fraser, R. R.; Mansour, T. S. J. Organomet. Chem.
1986, 310, C60. (d) Fraser, R. R.; Mansour, T. S.; Savard, S. J. Org. Chem.
1985, 50, 3232. (e) Fraser, R. R.; Mansour, T. S.; Savard, S. Can. J. Chem.
1985, 63, 3505.
(9) The presence of 100 mol % n-BuSnR33 or PhSnR33, which proceeds from
the generation of the initial alkyl- or aryllithium species, should not
influence the equilibrium position.
(10) This analysis allowed us to establish whether the equilibrium had been
reached and to check for signs of decomposition or other competing
reactions.
9
12512 J. AM. CHEM. SOC. VOL. 124, NO. 42, 2002

A Relative Organolithium Stability Scale
A R T I C L E S
Figure 3. 1H and 13C chemical shift data of anions 2 and 6 in THF (0.1-
0.4 M solutions). Chemical shifts are almost identical in THF and Et2O.
negatively charged carbanionic center should also experience a
greater repulsion with the two lone pairs of an attached oxygen
than with the only lone pair of a nitrogen, an effect that can
also contribute to the observed result.
We have measured the relative stabilities of selected substrates
in diethyl ether to check for solvent effects on the stabilization
of these benzylic anions by O-acyl groups (entries 9-11). The
stabilities of O-carbamoylcarbanions 2b,c and O-acylcarbanion
2f were drastically altered when the solvent was changed from
THF to ether. Thus, 2b,c,f are equally stable in THF, while
ester 2f is clearly approximately 1 kcal/mol less stable than its
carbamate counterparts in diethyl ether. It is interesting to note
that the Sn-Li exchanges of O-acylstannanes 1b,c,f occurred
much faster in ether than in the more polar THF, a trend that is
opposite to what has been reported for O-alkoxyalkylstannanes.1c
To rule out the possibility that the somewhat surprising
stability trends recorded in Figure 2 were due to differences in
the aggregation states, or to other subtle structural dissimilarities
of the implicated organolithium compounds, we proceeded to
obtain NMR spectra of carbanions 2b and 6d in THF and diethyl
Figure 2. Relative stability data of anions 2, 4, and 6. ∆Geq values in
kilocalories per mole relative to that of 9b in each solvent.
difference can provide an explanation for the observation that
R-carbamoyloxyalkyltrimethylstannanes undergo tin-lithium
exchange more cleanly than the analogous R-alkoxyalkyltrim-
ethylstannanes, presumably due to the formation of a more stable
R-oxyorganolithium species in the former case.11 (2) Ester and
carbamate substituents impart approximately the same degree
of stabilization to the R-carbanion (compare entries 3-5). This
result should provide some impetus to the design of more
synthetically useful ester activating groups for the preparation
of this type of R-heterosubstituted carbanions, since they might
be more easily removed from the final products than the
carbamate groups. (3) O-Substituted carbanions do not appear
to be sensitive to the electron-rich-ness of the aryl substituent
(compare entry 1 with entry 6, entry 3 with entry 7, and entry
4 with entry 8). (4) The stabilizing effect of a carbamate group
is slightly larger when it is attached to the carbanionic center
through its nitrogen atom rather than through the oxygen
(compare entries 3 and 4 with entries 12 and 13), a surprising
result that might imply that the carbamate group acts as an
electron-withdrawing group as a whole, regardless of the atom
which binds it to the carbon bearing the negative charge, the
electronegativity of the heteroatom directly attached to the
carbanionic center playing only a minor stabilizing role. A
6
ether at low temperature. Boche et al. have provided Li-13C
coupling data that strongly suggest that O-carbamoylalkyllithium
compounds are monomeric contact ion pairs in THF at low tem-
perature, which are the structures prevalent in the solid state as
1
well,12 but the H and 13C shift data that we have obtained for
2b and 6d (Figure 3) are strongly suggestive of highly planar-
ized, almost definitely monomeric structure, in which the neg-
ative charge is largely delocalized toward the aromatic rings.
The fact that the spectra did not undergo any noticeable modifi-
cations when the concentrations were varied in the 0.1-0.4 M
range or when the solvent was changed from THF to diethyl
ether are also suggestive that 2b and 6d are monomeric in both
solvents. The large upfield shifts of the ortho and para aromatic
hydrogen and carbon atoms and the low chemical shifts
(12) (a) Boche, G.; Bosold, F.; Lohrenz, J. C. W.; Opel, A.; Zulauf, P. Chem.
Ber. 1993, 126, 1873. (b) Boche, G.; Marsch, M.; Harbach, J.; Harms, K.;
Ledig, B.; Schubert, F.; Lohrenz, J. C. W.; Ahlbrecht, H. Chem. Ber. 1993,
126, 1887. (c) Pippel, D. J.; Weisenburger, G. A.; Wilson, S. R.; Beak, P.
Angew. Chem., Int. Ed. 1998, 37, 2522. (d) Marsch, M.; Harms, K.;
Zschage, O.; Hoppe, D.; Boche, G. Angew. Chem., Int. Ed. Engl. 1991,
30, 0, 321.
(13) (a) Vanermen, G.; Toppet, S.; Van Beylen, M.; Geerlings, P. J. Chem.
Soc., Perkin Trans. 2 1986, 699. (b) Vanermen, G.; Toppet, S.; Van Beylen,
M.; Geerlings, P. J. Chem. Soc., Perkin Trans. 2 1986, 707. (c) Fraenkel,
G.; Russell, J. G.; Chen, Y.-H. J. Am. Chem. Soc. 1973, 95, 3208. (d)
Sandel, V. R.; Freedman, H. H. J. Am. Chem. Soc. 1963, 85, 2328.
(11) Chong, J. M.; Nielsen, N. Tetrahedron Lett. 1998, 39, 9617.
9
J. AM. CHEM. SOC. VOL. 124, NO. 42, 2002 12513

A R T I C L E S
Gran˜a et al.
displayed by the benzylic hydrogens and carbons in both anions
are clearly indicative of this type of structure.13,14 Apparently,
only one species was present in solution for the case of
N-substituted anion 6d, while two species (1:1 ratio) were
detected in solutions of the O-substituted organolithium com-
pound 2b. The precise nature of the difference between these
two species could not be ascertained from our data, but it is
clear that both of them show the same degree of charge
delocalization into the phenyl ring. The appearance of hindered
rotation around the exocyclic C-C bond in two of the observed
species also lends credence to the planar, highly delocalized
structures.13c
The solvent effect on the relative stabilities of carbamoyl-
carbanions 2b,c and acylcarbanion 2f is probably originated by
differences in their aggregation behaviors. The NMR data pre-
sented above clearly suggest that the carbamate anions have
the same type of structure in both solvents, and thus no differ-
ence in their relatiVe stabilities is to be expected when the
solvent is changed from THF to Et2O. A change in their absolute
stabilities can be explained taking into account that the aggre-
gation state of the reference xanthenyllithium 9b changes with
the solvent (probably a greater proportion of contact ion pair
monomer is present in ether), as indicated by its different UV
absorptions in THF and ether (λmax(in THF) ) 475 nm, λmax(in
Et2O) ) 412 nm, -30 °C). This localization of the charge of
the xanthenyl anion 9b in Et2O should have as a consequence
its relatiVe destabilization with respect to the carbamoylcar-
banions 2b,c in this solvent (compare entries 3 and 4 with entries
9 and 10, Figure 2). The fact that acyl anion 2f is destabilized
relatiVe to the carbamoyl anions 2b,c when the solvent is
changed from THF to Et2O can likewise be explained by
solvent-induced changes in the aggregation state of 2f.
The thermodynamic data shown in Figure 2, taken together
with the structural picture derived from our NMR studies, point
to the fact that the stabilization imparted by a carbonyloxy group
in “dipole-stabilized” carbanions is at least partly derived from
an electron-withdrawing effect, and not only from the tradition-
ally accepted effect of the chelation of the Li atom bound to
the carbanionic center with the carbonyl oxygen,15 a conclusion
that should be helpful in the design of new, synthetically useful
“dipole-stabilizing” groups.
Although it must be pointed out that the Sn-Li exchange
equilibria cannot be used to derive true pK values since it is
not clear that all the involved carbanions are present as solvent-
separated ion pairs, it would be very useful, from the synthetic
point of view, to test whether the “apparent pK” values that
can be easily obtained from our data (by combining eqs 1 and
2, Figures 1 and 4) have any bearing on the acid-base behavior
of parent hydrocarbons.
By using eq 2 (Figure 4) and the “aggregate pK” data reported
by Fraser,8 a pK value of 33.2-33.4 can be derived for
carbamate 10b from our ∆∆Geq data (Figure 2), which means
that the benzylic hydrogens of 10b should be abstractable by
LDA, since a pK of 35.7 has been reported for diisopropylamine,
and that carbanion 2b should be basic enough to deprotonate
HMDS (pK ) 29.5).16 In fact, when 10b was reacted with 150
mol % LDA in THF at -78 °C and the resulting solution was
quenched with Me3SnCl, the corresponding stannyl carbamate
Figure 4. Protonation-deprotonation experiments of 10b and anions 2b,d
with secondary amines/amides.
1b was obtained in 90% yield. On the other hand, when a
solution of organolithium compound 2b, generated from 1b and
PhLi, was treated with 100 mol % HMDS prior to quenching
with Me3SnCl, no stannylation took place. As further proof that
the apparent pK values are useful to predict the acid-base
behavior of carbanions 2, 4, and 6, we tested the ability of
diisopropylamine to protonate anion 2d (apparent pK ) 37.3).
Thus, 2d was prepared by reaction of stannyl ether 1d with
100 mol % n-BuLi, and then reacted first with diisopropylamine
and then with Me3SnCl; only protonated material (10d) was
recovered from this reaction. These protonation tests were run
alongside control reactions where no amine was added before
quenching with Me3SnCl. From these control reactions the
corresponding stannylated products 1b,d were isolated in
excellent yields. It is thus apparent that the use of this Sn-Li
exchange methodology can not only provide valuable quantita-
tive information about the stabilities of closely related organo-
lithium compounds, but also supply effective pK data that can
be used to predict the acid-base behavior of these carbanions
as well. In view of this fact the following list with the effective
pK data of compounds 2, 4, and 6 in THF is provided
(compound/pK): 2a/37.3, 2d/36.9-37.0, 2b/33.2-33.5, 2c/33.2,
2f/33.3, 4a/37.2, 4b/33.4-33.5, 4c/33.3-33.4, 6d/32.1, 6e/31.5.
We believe that the methodology presented herein will have
wide application for the study of stability-structure relationships
of highly functionalized organolithium reagents, as well as for
the derivation of approximate acidity data that should be of value
in the planning of syntheses involving carbanion reagents.
Acknowledgment. Financial support from the CICYT (Spain;
Grant SAF99-0127 and a fellowship to P.G.) and the Xunta de
Galicia (Grant PGIDT00PXI20909PR) is gratefully acknowl-
edged. This paper is dedicated to Prof. Rafael Suau.
Supporting Information Available: Complete experimental
procedures and spectroscopic and analytical data (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) 1H and 13C chemical shift assignments were obtained from homonuclear
and heteronuclear two-dimensional experiments.
(15) Beak, P.; Reitz, D. B. Chem. ReV. 1978, 78, 275.
(16) Fraser, R. R.; Mansour, T. S. J. Org. Chem. 1984, 49, 3442.
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