Mechanistic studies of the lithium enolate of 4-fluoroacetophenone: Rapid-injection NMR study of enolate formation, dynamics, and aldol reactivity

Article abstract of DOI:10.1021/ja207218f

Lithium enolates are widely used nucleophiles with a complicated and only partially understood solution chemistry. Deprotonation of 4-fluoroacetophenone in THF with lithium diisopropylamide occurs through direct reaction of the amide dimer to yield a mixed enolate-amide dimer (3), then an enolate homodimer (1-Li)₂, and finally an enolate tetramer (1-Li)₄, the equilibrium structure. Aldol reactions of both the metastable dimer and the stable tetramer of the enolate were investigated. Each reacted directly with the aldehyde to give a mixed enolate-aldolate aggregate, with the dimer only about 20 times as reactive as the tetramer at -120 °C.

Full text of DOI:10.1021/ja207218f

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pubs.acs.org/JACS
Mechanistic Studies of the Lithium Enolate of 4-Fluoroacetophenone:
Rapid-Injection NMR Study of Enolate Formation, Dynamics, and Aldol
Reactivity
Kristopher J. Kolonko, Daniel J. Wherritt, and Hans J. Reich*
Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, Wisconsin 53706, United States
S Supporting Information
b
ABSTRACT: Lithium enolates are widely used nucleo-
philes with a complicated and only partially understood
solution chemistry. Deprotonation of 4-fluoroacetophe-
none in THF with lithium diisopropylamide occurs through
direct reaction of the amide dimer to yield a mixed enolate-
amide dimer (3), then an enolate homodimer (1-Li)2, and
finally an enolate tetramer (1-Li)4, the equilibrium struc-
ture. Aldol reactions of both the metastable dimer and the
stable tetramer of the enolate were investigated. Each
reacted directly with the aldehyde to give a mixed enolate-
aldolate aggregate, with the dimer only about 20 times as
reactive as the tetramer at ꢀ120 °C.
ithium enolates represent a class of powerful reagents for
L
synthesis. Much is known about their solution structures and
aggregation states,1a,2a,3,4a,b,5a,b but our understanding of the
individual reactivity and rates of interconversion of the various
homo and mixed aggregates known to be involved in their chemistry
(of interest from CurtinꢀHammett considerations) is in a more
primitive state.3,5b We address here the dynamics and chemistry
of several aggregates and mixed aggregates of the lithium enolate
of 4-fluoroacetophenone (1-Li).
Figure 1. Interaggregate exchange rates for 1-Li dimer and tetramer in
3:2 THF/ether solution. The rate constant kDT is the rate of dimeriza-
tion of (1-Li)2, kmix is the rate of tetramer heteroaggregate interchange,
measured either by DNMR line broadening of the mixtures of 1-Li and
2-Li homo- and heterotetramers or by a RI-NMR mixing experiment in
which (2-Li)4 was injected into (1-Li)4. The free energies of activation
for the aldol reactions of dimer and tetramer with benzaldehyde are
also shown.
All techniques agree that the enolates of both 4-fluoroaceto-
phenone (1-Li) and acetophenone (2-Li) form cubic tetramers
in THF solution.2a,4a,b,5a Mixing solutions of 1-Li and 2-Li6 gave
three new 19F and 13C NMR signals (1:3, 2:2, 3:1 ratio of 1-Li to
2-Li), giving a 1:3:3:1 cluster of peaks as required for a tetramer.
These species were in slow exchange on the NMR time scale
from ꢀ120 to 25 °C.7 Thus tetramers are the predominant form
over this temperature range, and they have a high barrier to
dissociation (>15.5 kcal/mol). Even with the addition of poly-
dentate ligands (N,N,N0,N0-tetramethylethylenedamine (TMEDA),
N,N,N0,N00,N00-pentamethyldiethylenetriamine (PMDTA), tri-
methyltriazacyclononane (TMTAN)) or polar solvent additives
(hexamethylphosphoric triamide (HMPA)) to solutions of (1-Li)4
in THF, no lower aggregates were detected.5a Above 25 °C, the
13C and 19F NMR signals of the homo- and heterotetramers
underwent a coalescence event.7 Simulation of the DNMR line
shapes5c,d,e assuming an exchange mechanism that involves
reversible dissociation of the tetramer provided an estimate of
the tetramer dissociation rates (Figure 1 shows the rate data).
Another estimate of the tetramer dissociation rate at lower
temperatures was provided by dynamic mixing experiments
utilizing Rapid Injection NMR (RI-NMR).5f Solutions of (2-Li)4
were injected into solutions of (1-Li)4 at several temperatures
(ꢀ56 to ꢀ18 °C), and the formation of heterotetramers was
followed.8 The initial rate of dissociation of (1-Li)4 was deter-
mined by fitting the first 5% loss of the 19F NMR signal to a first-
order decrease line at each temperature. These data fall on the
same line in an Eyring plot as did rates measured by the DNMR
experiment (Figure 1). The mechanism of these mixing reactions
was not firmly established. Bimolecular exchange through octa-
mers was ruled out, since the rate was independent of the
concentration of the enolate solutions. Exchange via rate-limiting
dissociation to dimers is questionable, because this would require
that the 2:2 heterotetramer be the first-formed exchange product.
Although this would be a subtle effect, the 2:2 actually lags behind
the 3:1 heterotetramer.7 A third mechanistic possibility is slow
dissociation todimersfollowedbyachainofexchangesviahexamers.
Attempts to find an electrophile which showed saturation kinetics
Received: August 1, 2011
Published: September 22, 2011
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2011 American Chemical Society
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Figure 3. Aggregation effects on 13C chemical shifts of several enolates
(difference between δ of the OCdC carbon of ROLi and ROSiMe3).5a
The monomers are TMTAN complexes.5h The salt-free enolate formed
by deprotonation of 1-H with the phosphazene base P4 was used as a
model for a separated ion pair (no LiꢀO contacts). Remarkably, the
points for 1-Li fall on a straight line.
they were assigned to a mixed LDA-enolate dimer 3 (δF ꢀ
118.82)11 and dimer (1-Li)2 (δF ꢀ118.76). Figure 3 shows the
very consistent aggregate 13C chemical shift effects when several
lithium enolates were compared to enol silyl ethers.5a,b The dimer
assignment was supported by an experiment where a 1:1 mixture of
1-H and 2-H was injected into a solution of LDA. The 19F NMR
spectra showed, in addition to (1-Li)2, only one additional signal
assigned to the mixed dimer aggregate (1-Li)(2-Li).4a,b A monomer
would give no new signals; higher aggregates would give more.
Having established the identity of the species involved in the
reaction, the kinetics of this system were explored. A first-order
dependence on LDA was observed when a constant concentra-
tion of 1-H (0.015 M) reacted with a range of concentrations of
LDA (0.06ꢀ0.24 M). In these experiments the ratio of mixed-
LDA-dimer to homodimer increased as the concentration of
LDA was raised, supporting the mixed dimer assignment.11 The
reaction was also first order in 1-H. Since LDA is primarily dimeric
in these solutions,4g,h the enolization must involve direct reaction of
the LDA dimer. This is reasonable, because the dissociation of LDA
dimers to monomers is much slower than the deprotonation rates.15
The concentration vs time curves of these experiments were
simulated with the COPASI program16 using the reactions
shown in Figure 2 as the kinetic model. Consistent replication
of the experimental concentrations over a range of temperatures
(ꢀ124 to ꢀ84 °C) as well as LDA dimer (0.025ꢀ0.05 M) and
ketone (0.05ꢀ0.2 M) concentrations could be achieved for the
deprotonations by LDA dimer and mixed dimer, as well as for the
much slower dimerization to form the tetramer (lines in the rate
plot of Figure 2). Thus, both the LDA dimer and the mixed dimer
3 are kinetically active.17 Direct involvement of 3 was also dem-
onstrated by the observation of primary kinetic isotope effects for
the reaction of α,α,α-trideuterio-1-H with the LDA dimer (kH/
kD = 1.7) and 3 (kH/kD = 6.3). The much larger isotope effect for
3 suggests a difference in mechanism, in spite of the near identity
of the rates. It is interesting that the mixed and homodimer have
similar reactivities. In ester deprotonations the mixed dimer
intermediates were much less reactive.4f From these simulations
the free energies of activation for the dimerization of (1-Li)2 to
(1-Li)4 were obtained and are plotted in Figure 1. With kDT
known and an upper limit on kTD established, we can calculate
that the dimer/tetramer Keq = [T]/[D]2 = kDT/kTD g 2.1 ꢁ 106
Figure 2. 19F RI-NMR spectra of the enolization of 1-H (0.085 M) by
LiNiPr2 ((LDA)2, 0.049 M) in 3:2 THF/Et2O at ꢀ125 °C. The lines are
simulations with kLDA = 2.9 ꢁ 10ꢀ4 Mꢀ1 sꢀ1, kMD = 2.2 ꢁ 10ꢀ4 Mꢀ1
s
ꢀ1, kDT = 0.013 ꢁ 10ꢀ4 Mꢀ1 sꢀ1
.
(i.e., for which dissociation of the tetramer to more reactive
dimers became rate determining) were not successful. Depend-
ing on the contributions from the hexamer, octamer, and other
processes, the dissociation to the dimer could be close to, or
substantially slower than, the measured exchange rates, i.e. kTD e
kmix (Figure 1).
With the structural identity of the thermodynamic aggregate
of 1-Li characterized and its dynamic behavior explored, at-
tempts were made to generate kinetically stable lower aggregates
of 1-Li. Previous work has shown that lithium diisopropylamide
(LDA)-mediated enolizations in ethereal solvents tend to pro-
ceed via monomeric pathways (LDA is a dimer in THF4g,h) that
should yield, at least transiently, a less associated enolate. These
studies were performed on hindered esters whose rate of de-
protonation is slow enough for careful kinetic studies.4c Very
little is known about lithium amide enolization of unhindered
ketones like 1-H.5g Isotope effects9 and Z/E ratios4e,9b based on
product studies have provided only an indirect understanding of
the role of aggregates.
The LDA mediated enolization of 1-H could be followed by
7Li or 19F RI-NMR spectroscopy (Figure 2). Deprotonation
occurred rapidly (t1/2 = 35 s) at ꢀ125 °C in 3:2 THF/Et2O. The
initial 19F NMR spectra revealed no detectable (1-Li)4, but two
new signals at δ ꢀ118.82 and ꢀ118.76, upfield from those of the
tetramer at δ ꢀ117.43, were observed (Figure 2). The first domi-
nated for several seconds, after which the second grew in at the
expense of the first and ketone. After several minutes, a signal
corresponding to (1-Li)4 was detectable, but full conversion
occurred slowly (t1/2 = 8000 s).
The 7Li, 19F, and 13C NMR shifts for the two initially formed
intermediates are consistent with enolate species of increased
charge density (lower aggregation) than (1-Li)4. Both show very
similar 13C NMR signals for the α-carbon (LiꢀOꢀC) and the
β-carbon(OꢀCdC) which are downfield and upfield, respectively,
from those of the tetramer (δC 165.8, 75.8 vs 164.4, 80.4 for
tetramer).10 Based on their NMR properties and reaction behavior,
M
ꢀ1 at ꢀ84 °C.
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observation of an intermediate 3:1 enolate/aldolate mixed
adduct supports this mechanism. Since this mixed tetramer never
accumulates to >15% of total solution concentrations it reacts
with 4 significantly faster than the homogeneous tetramer (we
estimate by a factor of 2.3 from kinetic simulations such as those
shown in Figure 4). A scheme where the 3:1 adduct dissociates
unimolecularly to lower aggregates before reacting with aldehyde
does not fit the kinetic traces. No other intermediates were detected,
so the 2:2 adduct formed next, and all subsequent intermediates,
must be even more reactive toward 4 than the 3:1 adduct, or they
rapidly dissociate to yield more reactive dimeric enolate complexes.
A small Hammett plot was constructed using the initial rates of
aldol reaction of (1-Li)4 with 3-F-, 4-F-, 4-H-, and 4-OMe-
benzaldehydes, which gave a krel of 7.7, 1.7, 1.0, and 0.02,
respectively (ꢀ120 °C), and a Hammett F value of 4.0 ( 0.8.
This follows the electrophilicity of the aldehyde rather than its
basicity and rules out mechanisms in which the aldehyde as base
catalyzes opening or deaggregation of the tetramer in the rate-
determining step, as was found for an aldehyde-RLi reaction.5i
Our success in making metastable solutions of the enolate dimer
of 1-Li allowed us to directly compare its reactivity with that of the
tetramer. The reaction of (1-Li)2 with benzaldehyde (reaction with
4 produces overlapping signals in the 19F NMR spectra) is 17 times
faster (t1/2 = 2 s, ꢀ120 °C) than that of (1-Li)4 and at the limits of
measurability with our RI apparatus.7 A single intermediate species
with two 19F NMR signals is seen (δ ꢀ106.61 and ꢀ118.93) and is
presumed to be a mixed dimer. Although a detailed kinetic study
could not be done, the reaction appeared to be first order in
aldehyde. The dimer, like the tetramer, thus reacts directly with the
aldehyde to produce a mixed enolate-aldolate species. This inter-
mediate is more reactive than the homogeneous aggregate since it
builds up to a maximum of 30% of species present. The surprisingly
small difference in reactivity of the tetramer and dimer may in part
have its origin in structural effects. Enolates differ fundamentally
from alkyl- and aryllithium reagents (where kD/kT or kM/kD ratios of
>103 are known3c,5f,i) in that the nucleophilic carbon center is not
directly encumbered by the metal upon aggregation. A similarly low
monomer/dimer reactivity ratio has been observed for lithium
enolate Claisen acylations.3d
The aggregation state of the lithium aldolates (5-Li) was not
characterized, but the spectra typically indicated several distinct
species, which were slightly different for the tetramer and dimer
reactions, and also different from the equilibrated products and
aldolate formed by deprotonation of the aldol adduct.13d
In summary, the deprotonation of 1-H with LDA at low
temperatures occurs through a dimer process to yield a mixed dimer
3, then an enolate homodimer (1-Li)2, which then dimerizes to an
enolate tetramer (1-Li)4. Both the metastable dimer and the stable
tetramer reacted directly with aldehyde in an aldol reaction under non-
CurtinꢀHammett conditions to give mixed enolate-aldolate aggre-
gates (3:1 species for the tetramer, 1:1 species for the dimer), which
were more reactive than the homoaggregate. The modestly higher
basic or nucleophilic reactivity of several mixed aggregates over the
homoaggregates reported here contrasts with a number of previous
studies which found opposite trends.4i,5f Clearly there is much we do
not understand about lithium reagent aggregate reactivities.
Figure 4. 19F RI-NMR spectra of the aldol reaction of (1-Li)4 with 4 in
3:2 THF/Et2O at ꢀ120 °C. The starred peaks identify the 3:1
enolateꢀaldolate mixed tetramer (the third 19F NMR signal would be
in the broad peak at δ ꢀ106.5 for Fc). Lines correspond to simulation of
the kinetic path involving successive reaction of (1-Li)4 (kT = 0.29 Mꢀ1
s
ꢀ1) and the 3:1 mixed aggregate (k3:1 = 0.66 Mꢀ1 sꢀ1).7
Ever since the supramolecular structure of enolates was
established, it was postulated that tetrameric structures may
directly participate in the aldol reaction.1b,c Lower aggregates
of several types of organolithium species have been shown to be
much more reactive than higher ones,3c,5f,i,j and their involve-
ment has been often detected by fractional order kinetics. The
participation of more reactive but less stable lower aggregates
depends, among other things, on the relative rate of reaction with
electrophile versus the rate of deaggregation. With clean solu-
tions of the dimer and tetramer of 1-Li available in the same
solvent, and the barrier to interconversion established, we were in
a unique position to directly address this issue. We chose the
aldol reaction with 4-fluorobenzaldehyde (4). Almost nothing is
known about the mechanism of lithium enolate aldol reactions
because the high rates limit techniques for kinetic investigations2b-e,5g,18
The reaction of (1-Li)4 with 4 was monitored by 19F RI-NMR
at ꢀ120 °C (Figure 4).2e The 19F NMR signals for the enolate
and aldehyde are well resolved from the signals of the resulting
aldolate, allowing the concentrations of all reactants and pro-
ducts to be monitored. In the first few seconds a 3:1 ratio of
product signals at δF ꢀ118.2 and ꢀ119.1 appeared, which we
have assigned to the enolate and alcoholate signals of a 3:1
enolate/aldolate mixed tetramer.19 The smaller upfield signal
was absent when benzaldehyde instead of 4 was used. The 3:1
mixed aggregate could be detected as a minor component through-
out the reaction time of about 5 min, but by 30 s two broad peaks
(δ ꢀ106.7 and ꢀ119.6), corresponding to the keto and alcoho-
late 19F signals of the aldolates, were the major product signals.
The reactions of (1-Li)4 with 4 (t1/2 = 45 s) and benzaldehyde
(t1/2 = 62 s) at ꢀ120 °C are much faster than its dissociation rate,
estimated from the data in Figure 1 to have a t1/2 g 4.2 ꢁ 1010 s,
so a mechanism involving predissociation to the dimer can be
ruled out. The aldol reaction was first order in both (1-Li)4 and 4.
The rate-limiting transition state thus consists of 1 equiv of the
tetramer and aldehyde, as suggested by Seebach and et al.1b,c The
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details, NMR
b
spectra and kinetic traces of all reactions. This material is
available free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
datum here to illustrate the remarkable consistency of the chemical shift
effect. (i) The separated ion pair of (Me3Si)3CLi is >109 times as reactive
as the triple ion (R2Liꢀ Li+) towards MeI at ꢀ131°C: Jones, A. C.;
Sanders, A. W.; Sikorski, W. H.; Jansen, K. L.; Reich, H. J. J. Am. Chem.
Soc. 2008, 130, 6060–6061. (j) The 2-lithiothiophene monomer is
>1000 times as reactive as the dimer in the lithiumꢀiodine exchange
reaction at ꢀ102 °C: Reich, H. J; Whipple, W. L. Can. J. Chem. 2005,
83, 1577–1587.
(6) Comparison of para-H and para-F analogues is ideal because the
para fluorine causes little electronic perturbation: (a) the Hammett
constants for fluorine, σpn = 0.06, σpꢀ = 0.02 (Hansch, C.; Leo, A.; Taft,
R. W. Chem. Rev. 1991, 91, 165–195). (b) pKa (DMSO) values of 1-H
and 2-H are 24.5 and 24.7, respectively (Bordwell, F. G.; Cornforth, F. J.
J. Org. Chem. 1978, 43, 1763–1768).
(7) See Supporting Information for spectra and other information.
(8) For an interesting example using the dynamics of lithium enolate
heteroaggregate formation as a mechanistic probe, see: Casey, B. M.;
Flowers, R. A., II. J. Am. Chem. Soc. 2011, 133, 11492–11495.
(9) (a) Xie, L.; Saunders, W. H. J. Am. Chem. Soc. 1991, 113,
3123–3130. (b) Held, G.; Xie, L. Microchem. J. 1997, 55, 261–269.
(10) These chemical shifts were nearly identical to the shifts of a
TMEDA-complexed dimer of 1-Li prepared as reported by Collum and
co-workers.4a,b
(11) Experiments in which a 4-fold excess of LDA was used gave a ca.
1:1 ratio of (1-Li)2 and 3, allowing spectroscopic characterization of 3.
Carbon NMR data: α-carbon δ 166.0, β-carbon δ 74.6. Mixed aggre-
gates of lithium amides and ketone or ester enolates have been
frequently detected4c,d,12,13a,b,c and have been invoked to explain
selectivity effects.1d,14
Corresponding Author
reich@chem.wisc.edu
’ ACKNOWLEDGMENT
We thank the NSF for financial support (CHE-0717954) and
funding for instrumentation (NSF CHE-9709065, CHE-9304546).
’ REFERENCES
(1) (a) Bauer, W.; Seebach, D. Helv. Chim. Acta 1984, 67,
1972–1988. (b) Amstutz, R.; Schweizer, W. B.; Seebach, D.; Dunitz,
J. D. Helv. Chim. Acta 1981, 64, 2617–2621. (c) Seebach, D.; Amstutz,
R.; Dunitz, J. D. Helv. Chim. Acta 1981, 64, 2622–2626. (d) Juaristi, E.;
Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay, T.; Simson, M.;
Seebach, D. Synthesis 1993, 1271–1290.
(2) (a) Arnett, E. M.; Moe, K. D. J. Am. Chem. Soc. 1991,
113, 7288–7293. (b) Arnett, E. M.; Fisher, F. J.; Nichols, M. A.; Ribeiro,
A. A. J. Am. Chem. Soc. 1989, 111, 748–749. (c) Arnett, E. M.; Fisher,
F. J.; Nichols, M. A.; Ribeiro, A. A. J. Am. Chem. Soc. 1990, 112, 801–808.
(d) Arnett, E. M.; Palmer, C. A. J. Am. Chem. Soc. 1990, 112, 7354–7360.
(e) A brief RI-NMR study of the aldol reaction of lithium pinacolate
(intended mainly to rule out SET mechanisms) is the only kinetic study
we are aware of: Palmer, C. A.; Ogle, C. A.; Arnett, E. M. J. Am. Chem.
Soc. 1992, 114, 5619–5625.
(3) (a) Wang, D. Z. R.; Kim, Y.-J.; Streitwieser, A. J. Am. Chem. Soc.
2000, 122, 10754–10760. (b) Kim, Y.-J.; Streitwieser, A. Org. Lett. 2002,
4, 573–575. (c) The monomer of p-phenylisobutyrophenone lithium
enolate is 2700 times as reactive as the dimer in an alkylation reaction:
Abu-Hasanayn, F.; Streitwieser, A. J. Am. Chem. Soc. 1996, 118, 8136–
8137. (d) Streitwieser, A.; Leung, S. S.-W.; Kim, Y.-J. Org. Lett. 1999,
1, 145–147.
(4) (a) Gruver, J. M.; Liou, L. R.; McNeil, A. J.; Ramirez, A.; Collum,
D. B. J. Org. Chem. 2008, 73, 7743–7747. (b) 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. (c) Sun, X. F.; Kenkre, S. L.; Remenar, J. F.;
Gilchrist, J. H.; Collum, D. B. J. Am. Chem. Soc. 1997, 119, 4765–4766.
(d) Hall, P. L.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum,
D. B. J. Am. Chem. Soc. 1991, 113, 9575. (e) Galiano-Roth, A. S.; Kim,
Y. J.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum, D. B. J. Am.
Chem. Soc. 1991, 113, 5053–5055. (f) Sun, X.; Collum, D. B. J. Am.
Chem. Soc. 2000, 122, 2459–2463. (g) Remenar, J. F.; Lucht, B. L.;
Collum, D. B. J. Am. Chem. Soc. 1997, 119, 5567–5572. (h) Ramirez, A.;
Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2006, 128, 10326–10336. (i)
Collum, D. B.; McNeil, A. J.; Ramirez, A. Angew. Chem., Int. Ed. 2007,
46, 3002–3017. (j) Remenar, J. F.; Lucht, B. L.; Kruglyak, D.; Romesberg,
F. E.; Gilchrist, J. H.; Collum, D. B. J. Org. Chem. 1997, 62, 5748–5754.
(k) Hoepker, A. C.; Gupta, L.; Ma, Y.; Faggin, M. F.; Collum, D. B. J. Am.
Chem. Soc. 2011, 133, 7135–7151.
(5) (a) Kolonko, K. J.; Biddle, M. M.; Guzei, I. A.; Reich, H. J. J. Am.
Chem. Soc. 2009, 131, 11525–11534. (b) Kolonko, K. J.; Guzei, I. A.;
Reich, H. J. J. Org. Chem. 2010, 75, 6163–6172. (c) The DNMR simula-
tions were performed with an updated version of WINDNMR (http://
www.chem.wisc.edu/areas/reich/plt/windnmr.htm). (d) Reich, H. J. J.
Chem. Educ. 1995, 72, 1086. (e) Reich, H. J. “WinDNMR Dynamic NMR
Spectra for Windows”, J. Chem. Ed. Software, Series D 1996, 3D, 17ꢀ19,
27ꢀ33, 56ꢀ66. (f) Jones, A. C.; Sanders, A. W.; Bevan, M. J.; Reich, H. J.
J. Am. Chem. Soc. 2007, 129, 3492–3493. The dimer of n-BuLi is >108
times as reactive as the tetramer in deprotonation of an acetylene, >104
in addition to an aldehyde at ꢀ130 °C. (g) Kolonko, K. J.; Reich, H. J. J.
Am. Chem. Soc. 2008, 130, 9668–9669. P4 “naked” enolates were used as
models for SIP. Reaction of 1-P4H with 4 was too fast (k > 2 sꢀ1) to
measure via RI-NMR at ꢀ127 °C. (h) The graph includes a point for the
monomeric TMTAN complex of 1-Li, prepared at ꢀ115 °C by
deprotonation of 1-H by the monomeric TMTAN complex of lithium
tetramethylpiperidide.4j We will report on this separately but include the
(12) Lecachey, B.; Duguet, N.; Oulyadi, H.; Fressignꢀe, C.; Harrison-
Marchand, A.; Yamamoto, Y.; Tomioka, K.; Maddaluno, J. Org. Lett.
2009, 11, 1907–1910.
(13) (a) Henderson, K. W.; Dorigo, A. E.; Liu, Q.-Y.; Williard, P. G.;
Schleyer, P. v. R.; Bernstein, P. R. J. Am. Chem. Soc. 1996, 118,
1339–1347. (b) Williard, P. G.; Hintze, M. J. J. Am. Chem. Soc. 1990,
112, 8602–8604. (c) Li, D.; Sun, C.; Williard, P. G. J. Am. Chem. Soc.
2008, 130, 11726–11736. (d) Williard, P. G.; Salvino, J. M. Tetrahedron
Lett. 1985, 26, 3931–3934.
(14) Pratt, L. M.; Streitwieser, A. J. Org. Chem. 2003, 68, 2830–2838.
(15) The rate of LDA dimer dissociation has been reported as kDM
=
7 ꢁ 10ꢀ7 sꢀ1 at ꢀ78 °C in THF.4k This is slower by a factor of 100 than
the deprotonation rate of 1-H by LDA at 47° lower temperature.
(16) COmplex PAthway SImulator. Hoops, S.; Sahle, S.; Gauges, R.;
Lee, C.; Pahle, J.; Simus, N.; Singhal, M.; Xu, L.; Mendes, P.; Kummer,
U. Bioinformatics 2006, 22, 3067–3074.
(17) An alternative mechanism where 3 disproportionates to (1-Li)2
and (LDA)2 rather than reacting directly with 1-H did not fit the
experimental concentrationꢀtime plots and could be ruled out by an
RINMR experiment where additional LDA was injected at ꢀ120 °C into
a solution of the enolate dimer. No change in concentration of 3 was
detected over a time period during which most of the enolate dimer was
converted to tetramer.7
(18) Even with ketones as substrates, the lithium aldol reaction is fast
at ꢀ78 °C, and aldehydes are at least 104 faster: Das, G.; Thornton, E. R.
J. Am. Chem. Soc. 1993, 115, 1302–1312.
(19) An alternative assignment of the 3:1 intermediate as an enol
ether aldehyde adduct (ArC(O-CHR-OLi)=CH2) could be ruled out on
the basis of the 19F chemical shifts: the trimethylsilyl enol ether (ArC(O-
SiMe3)=CH2, δ ꢀ114.9) and MOM enol ether (ArC(O-CH2-OMe)=CH2,
δꢀ114.4) of 4-fluoroacetophenone had chemical shifts over 4 ppm downfield
from the observed adduct at δ ꢀ119.1.
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dx.doi.org/10.1021/ja207218f |J. Am. Chem. Soc. 2011, 133, 16774–16777