A Rapid Injection NMR Study of the Reaction of Organolithium Reagents with Esters, Amides, and Ketones

Article abstract of DOI:10.1021/acs.orglett.5b00650

Unexpectedly high rates of reaction between alkyllithium reagents and amides, compared to esters and ketones, were observed by Rapid Inject NMR and competition experiments. Spectroscopic investigations with 4-fluorophenyllithium (ArLi, mixture of monomer and dimer in THF) and a benzoate ester identified two reactive intermediates, a homodimer of the tetrahedral intermediate, stable below -100°C, and a mixed dimer with ArLi. Direct formation of dimers suggested that the ArLi dimer may be the reactive aggregate rather than the usually more reactive monomer. In contrast, RINMR experiments with ketones demonstrated that the ArLi monomer was the reactive species. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b00650

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Letter
pubs.acs.org/OrgLett
A Rapid Injection NMR Study of the Reaction of Organolithium
Reagents with Esters, Amides, and Ketones
Kristin N. Plessel,† Amanda C. Jones,† Daniel J. Wherritt,† Rebecca M. Maksymowicz,† EricT. Poweleit,†
and Hans J. Reich*
Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: Unexpectedly high rates of reaction between
alkyllithium reagents and amides, compared to esters and
ketones, were observed by Rapid Inject NMR and competition
experiments. Spectroscopic investigations with 4-fluorophe-
nyllithium (ArLi, mixture of monomer and dimer in THF) and
a benzoate ester identified two reactive intermediates, a
homodimer of the tetrahedral intermediate, stable below −100
°C, and a mixed dimer with ArLi. Direct formation of dimers
suggested that the ArLi dimer may be the reactive aggregate
rather than the usually more reactive monomer. In contrast, RINMR experiments with ketones demonstrated that the ArLi
monomer was the reactive species.
he reactions of organometallic reagents with aldehydes,
Tketones, esters, and other carbonyl compounds are widely
employed C−C bond forming methods. A century of organic
chemistry lore has defined aldehydes, acid chlorides, and
anhydrides as most reactive, ketones intermediate, esters slower,
and amides and carboxylate anions the least reactive. However,
there is one important class of nucleophiles, the organolithium
reagents, for which the evidence is more anecdotal than
quantitative, since most reactions are too fast for normal kinetic
measurements, even below −78 °C. The Rapid Injection NMR
technique (RINMR)1a,b has provided an avenue for the study of
such reactions.
n-Butyllithium in THF solution is a mixture of a dimer and
tetramer.2,3 The tetramer reacts only with the most active
electrophiles such as benzaldehyde, DMF, and PhCOCl,1a but
with esters, ketones, and amides, the tetramer dissociates to
dimer faster than the reaction with the electrophile, and only the
dimer is reactive. An interesting corollary here is that these Lewis
basic electrophiles do not assist in tetramer dissociation.4 A
Figure 1. RINMR rate study of the reaction of several carbonyl
RINMR survey of the rate of reactions of n-BuLi dimer with
common electrophiles is illustrated in Figure 1. As expected,
acetone was more reactive than the ester methyl benzoate
(although only by a factor of 8.6). To our surprise, however, the
rate of reaction with the tertiary benzamide was comparable to
the reaction with the ketones, and considerably faster than that
with benzoate esters. Likewise, N,N-dimethylformamide (too
fast to measure) reacted faster than ethyl formate (half-life of 1.1
s at −130 °C).
Similar results were found when competition experiments
were performed by addition of n-BuLi into an excess of ester and
amide in THF at −78 °C (Scheme 1). We used fluorine-
substituted benzoate ester 1 and amide 2 to allow use of 19F
NMR spectroscopy for quantification. Since both 1 and 2 give a
compounds with n-BuLi dimer. The tetramer of n-BuLi (ca. 60%) is
unreactive on this time scale. The points are experimental data for
7
disappearance of (n-BuLi)2 measured from the Li NMR spectra; the
lines are first-order plots with the rate constants shown.
common ketone product, one of them was labeled with
deuterium (1-d) at the 2-position to distinguish the source.
The 19F NMR deuterium isotope shift of ca. 0.3 ppm allowed
distinction between deuterated and undeuterated ketones. In
these experiments the amide was 2.4 times as reactive as the ester
toward n-BuLi, and 3.6 times more reactive with MeLi.
Received: March 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00650
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Scheme 1. Competition Experiments
In contrast, the ester 1 was 3−4 times more reactive than 2
with the aryllithium reagents at −78 °C, and by a factor of 9 with
lithium 4-fluorophenylacetylide at 0 °C,5 still orders of
magnitude less than predicted from other nucleophilic
substitutions (e.g., the basic hydrolysis of ethyl benzoate is 645
times as fast as that of benzamide at 40 °C).6
Efforts to understand the origin of this effect in the n-BuLi
RINMR kinetic studies provided only hints of answers. The
initial rates of reaction of (n-BuLi)2 with ester 1 are first-order in
ester, and those with amide 2, at least first-order. Thus, in neither
case is conversion of (n-BuLi)2 to a more reactive species (open
dimer, monomer) rate limiting. A more detailed kinetic analysis
of these reactions was thwarted by complex and not always
reproducible kinetic behavior.
We thus directed our efforts to a study of the reactions of 4-
fluorophenyllithium7 (here referred to as ArLi). This lithium
reagent does not show the “inverted reactivity” of the
alkyllithiums, and there is the disadvantage of mostly working
under Curtin−Hammett conditions. The two aggregates present,
(ArLi)1 and (ArLi)2, interconvert rapidly on the time scale of
addition to esters and amides, with a half-life of dimer
dissociation, measured by 19F DNMR coalescence, of less than
2 s at −140 °C. However, the RINMR experiments benefitted
greatly from being able to simultaneously identify and quantify
starting materials, intermediates, and products in real time by 19F
NMR spectroscopy.
An RINMR experiment in which excess 1 was injected into
ArLi at −110 °C is shown in Figure 2. All of the ArLi was
consumed within 10 s to form a single new species, the mixed
dimer 3·ArLi.9 If only 0.5 equiv of ester was present, the reaction
stopped here. With excess ester (as in the experiment shown) the
reaction continues more slowly to cleanly form the homodimer
of the tetrahedral intermediate (3)2.14 This part of the reaction
shows an approximate first-order dependence on ester
concentration, so 3·ArLi is reacting directly, rather than via
rate-limiting dissociation to monomeric ArLi. On warming above
−100 °C the tetrahedral intermediates 3·ArLi and (3)2
decompose to ketone, which is converted to tertiary alkoxide if
any ArLi remains in solution. The half-life of (3)2 is ca. 4.7 h at
−97 °C.
Careful quench of reactions of 1 and ArLi below −100 °C gave
a nearly quantitative yield of ketone, with a ketone to tertiary
alcohol ratio greater than 200/1. This clean ketone synthesis
directly from aryllithium and ester reagents inspired investigation
of possible synthetic applications. Unfortunately, this method
requires that the addition of RLi to ester be fast below −100 °C,
which is true only in a few specific cases. With n-BuLi the dimer
reaction is fast enough, but the tetramers of both n-BuLi and
MeLi react too slowly for a synthetically viable reaction.
Disappointingly, synthetic application appears to be limited to
benzophenone formation from methyl or ethyl benzoate esters.
Figure 2. 19F RINMR experiment: injection of 1.75 equiv of ester 1 into
a solution of 75 mM 4-fluorophenyllithium.
Intermediates 3·ArLi and (3)2 appear to be the first
spectroscopically characterized anionic tetrahedral intermediates
of esters which do not bear special stabilizing features such as
cyclic structures (lactone adducts),16 strongly chelating groups,10
or very electronegative17 substituents. Amide tetrahedral
intermediates are much more stable, and several have been
characterized.15,18
A similar experiment with amide 2 was 1/160 as fast under
comparable conditions and gave a mixture of at least four
tetrahedral intermediates. Three 19F NMR peaks which might
correspond to ca. 20% of the mixed dimer between ArLi and the
tetrahedral intermediate were present during the reaction.
These experiments raise several interesting questions. First,
the competition experiment in Scheme 1 run under comparable
conditions (kester/kamide = 4.8) seems inconsistent with the
RINMR rate data (kester/kamide = 160). This relative reactivity
issue was clarified by a more careful RINMR examination of the
amide and ester reactions. Solutions of mixed dimer 3·ArLi,
stable at −110 °C, could be prepared by addition of 0.5 equiv of
ester to ArLi. This should also be the principal species present
initially in the ester−amide competition experiments. We were
then able to compare the reactivity of ester 1 and amide 2 with 3·
ArLi using separate injections of electrophile, and found ester to
be only twice as fast. The ester showed pseudo-first-order
kinetics with an excess of 3·ArLi (i.e., dissociation of the mixed
dimer is not the rate-limiting step), and the amide, more complex
behavior which we could not clarify. Thus, in the competition
experiment, during the first half of the reaction almost all of the
ArLi reacts with ester to form 3·ArLi (approximately 99% ester,
1% amide reacts). Once the free ArLi is depleted, the mixed
dimer 3·ArLi is the sole source of the nucleophile, and it reacts
only twice as fast with ester (66%) as with the amide (33%),
leading to a calculated kester/kamide of 4.9, close to the competition
experiment values of 4.8 at −110 °C and 4.3 at −78 °C.19
A second question concerns the exclusive formation of the
mixed dimer 3·ArLi from the ester, which raises the interesting
possibility that ester reacts preferentially with the dimer of ArLi.
Lower aggregates are almost invariably more reactive than higher
B
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ones.1a,d,21a Although numerous mixed aggregates have been
observed when different aggregated lithium species are
combined,2,22 these are virtually always equilibrium situations.
The very reasonable assumption that the reaction of RLi
aggregated substrates to form mixed aggregates as kinetic
products (i.e., dimer to dimer or tetramer to tetramer) has
only recently been experimentally confirmed.19
Some surprisingly small rate differences between monomer
and dimer enolates in a crossed Claisen condensation prompted
Streitwieser, Leung, and Kim21b to suggest that esters may be
unusually reactive toward dimers as a consequence of lithium
coordination to both oxygens, as in 4. Such double activation is
not available for amides or ketones. Formation of the precomplex
4 requires the less stable E conformation of the ester. A
reasonable estimate of the barrier for ester rotation (9−10 kcal/
mol23) is close to or below the barrier for the reaction of Figure 1
(10.1 kcal/mol).24
ketone, on the other hand, only trace amounts (<15%) of 6·ArLi
was formed. This is because addition of ArLi to ketone is faster
than either the cross dimerization to form 6·ArLi or the
homodimerization to form (6)2. Thus, the formation of 3·ArLi as
the sole kinetic product in the ester reaction is plausible even if
the ArLi monomer is the active reagent.
Figure 3 shows an experiment where excess 5 was injected into
a solution of ArLi at our lowest accessible temperature, −140 °C.
Several tests of the hypotheses that the ArLi dimer is involved
in the formation of 3·ArLi did not give clear answers. Addition of
PMDTA (N,N,N′,N″,N″-pentamethyl-diethylenetriamine) to
ArLi converts it to a PMDTA-complexed monomer. This
monomer is about 1/45 as reactive toward ester 1 as the THF-
solvated monomer/dimer mixture, as expected if the dimer is the
reactant. Other explanations are plausible, such as a suppression
of Lewis acid assistance by lithium by complexation to
PMDTA.1b,20c
When the ester addition was performed in a less polar solvent
(1:7 Me2O/Et2O mixture), where monomer ArLi could no
longer be detected, only a factor of 2 reduction in the addition
rate was observed, even though the monomer concentration was
reduced by at least a factor of 25. A subtle effect, but it is
consistent with reaction of the dimer.
It is not possible to perform experiments with ester 1 under
non-Curtin−Hammett conditions to specifically identify the
reactive ArLi aggregate, since the ArLi dimer-to-monomer
interconversion is several orders of magnitude faster than the
reaction with 1.7 More reactive esters were also too slow:
isopropyl 3-fluorobenzothioate (t1/2 is 15 s at −130 °C), methyl
trifluoroacetate (t1/2 ca. 25 s at −137 °C), ethyl formate (t1/2 ca.
2.5 s at −137 °C).
The higher reactivity of ketones gave some hope that an
RINMR experiment could be run under non-Curtin−Hammett
conditions. The reaction of ArLi with excess 3,4′-difluorobenzo-
phenone at −124 °C was much slower than ArLi aggregate
interconversion (t1/2 30 s). The kinetic product appears to be the
lithium alkoxide monomer, strongly suggesting that the ArLi
monomer is the reactive species. The monomer then forms a
dimer, as well as a mixed dimer (analogous to 3·ArLi) if excess
ArLi is present, which reacts much more slowly with the ketone,
the reaction being essentially complete at 4000 s.
Figure 3. 19F RINMR experiment: injection of 2.5 equiv of ketone 5
into a solution of 75 mM 4-fluorophenyllithium at −140 °C in 1:3 THF/
Me2O.
The ArLi monomer has reacted completely within 1.4 s after the
injection. However, there was still a significant concentration of
ArLi dimer present, so the ketone unambiguously reacts more
rapidly with the monomer.26 We are just slightly under the
“Curtin−Hammett limit.”
Our experiments have not answered the initial question on the
unusual reactivity effects toward amides and esters shown by
alkyllithium reagents, which must have their origin in the higher
basicity of amides vs esters toward lithium cations.27,28 Using the
RINMR technique we were able to study the reaction of 4-
fluorophenyllithium with esters, amides, and ketones, observe in
unprecedented detail the progression of tetrahedral intermedi-
ates and alkoxides formed, and obtain specific information about
the aggregation and mixed aggregation processes.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, NMR spectra, and kinetic traces of all
experiments. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: reich@chem.wisc.edu.
Present Address
3-Fluoroacetophenone (5) was more reactive. At 135 °C all of
5 has reacted after 1.6 s, and again the first formed product is a
monomeric alkoxide (6)1. If excess ArLi is present, (6)1
heterodimerizes with a half-life of ca. 8 s to form the mixed
dimer 6·ArLi25 or homodimerizes to (6)2 if ketone is in excess. If
the addition of excess ArLi to 5 was performed at the higher
temperature of the ester experiments (−110 °C), the first
observed product was the mixed dimer 6·ArLi. With excess
†Kristin N. Plessel, University of Wisconsin-Rock County, 2909
Kellogg Ave, Janesville, WI 53546. Amanda C. Jones, Depart-
ment of Chemistry, Salem Hall, Wake Forest University,
Winston-Salem, NC 27109. Daniel J. Wherritt, The Samuel
Roberts Noble Foundation, 2510 Sam Noble Pkwy, Ardmore,
OK 73401. Rebecca M. Maksymowicz, 2 Pear Tree Cottage,
Aldsworth, Cheltenham, Gloucestershire, GL54 3QZ, U.K. Eric
T. Poweleit, 229 Chemistry Building, University Park, PA 16802.
C
DOI: 10.1021/acs.orglett.5b00650
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
for bis Me2O solvate). A closely related tetrahedral intermediate
(Ph2(Me2N)COLi) crystallizes from THF as a bis-solvated dimer.15a
(15) (a) Adler, M.; Marsch, M.; Nudelman, N. S.; Boche, G. Angew.
Chem., Int. Ed. 1999, 38, 1261. (b) Adler, M.; Adler, S.; Boche, G. J. Phys.
Org. Chem. 2005, 18, 193.
(16) High yields of ketones were obtained from addition of lithium
acetylides to δ-lactones. The tetrahedral intermediates were not
detected. Chabala, J. C.; Vincent, J. E. Tetrahedron Lett. 1978, 19, 937.
(17) Bender, M. L. J. Am. Chem. Soc. 1953, 75, 5986.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSF for financial support (CHE-0717954) and
funding for instrumentation (NSF CHE-9709065, CHE-
9304546).
(18) Fraenkel, G.; Watson, D. J. Am. Chem. Soc. 1975, 97, 231.
(19) Kinetically formed mixed aggregates have been detected for the
reaction of n-BuLi with benzaldehyde,3 deprotonation of trimethylsilyl-
acetylene with (n-BuLi)2,1a deprotonation of ketone with (LiNiPr)2,1d
aldol reaction of tetrameric and dimeric lithium enolate,1d and the
conjugate addition of LiNiPr2.20a
(20) (a) Ma, Y.; Hoepker, A. C.; Gupta, L.; Faggin, M. F.; Collum, D. B.
J. Am. Chem. Soc. 2010, 132, 15610. (b) Parsons, R. L., Jr.; Fortunak, J.
M.; Dorow, R. L.; Harris, G. D.; Kauffman, G. S.; Nugent, W. A.;
Winemiller, M. D.; Briggs, T. F.; Xiang, B.; Collum, D. B. J. Am. Chem.
Soc. 2001, 123, 9135. Qu, B.; Collum, D. B. J. Org. Chem. 2006, 71, 7117.
(c) Sun, X. F.; Kenkre, S. L.; Remenar, J. F.; Gilchrist, J. H.; Collum, D.
B. J. Am. Chem. Soc. 1997, 119, 4765. Zhao, P.; Condo, A.; Keresztes, I.;
Collum, D. B. J. Am. Chem. Soc. 2004, 126, 3113.
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the Weinreb oxalamide Me(MeO)NC(O)C(O)OEt, where an
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containing solvents. In 1:3 THF/Me2O at −119 °C, KMD = [D]/[M]2 =
160 M−1. For conversion of the dimer to monomer, ΔH‡ = 6.4 kcal/mol,
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dimerization of 6 is slow. We hypothesize that any (6)1 generated could
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Li+.
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=
19.5), and for the monomer, δ 187.9 (poorly resolved 1:1:1:1 quartet).
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Li carbon shows a 1:2:3:4:3:2:1 septet at δ 180.9 (compare (ArLi)2 at δ
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showed a resonance at δ 102.7 for the acetal carbon.10 The molecular
weight of 3·ArLi in Me2O solution estimated by DOSY experi-
ments11−13 at −115 °C was 513 (calcd 464.4 for 3·ArLi ·Me2O).
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benzoate (13C signal of the acetal carbon at δ 101.9): Asakawa, K.;
Dannenberg, J. J.; Fitch, K. J.; Hall, S. S.; Kadowaki, C.; Karady, S.; Kii,
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(14) The structure assignment of (3)2 was based on its mode of
formation, its decomposition to ketone at −95 °C, and the observation
of the ketal carbon at δ 102.8 in the 13C enriched substrate.10 The dimer
aggregation state was inferred from a DOSY11−13 molecular weight
estimation in Me2O solution at −115 °C: 559 g/mol (calcd 632.5 g/mol
D
DOI: 10.1021/acs.orglett.5b00650
Org. Lett. XXXX, XXX, XXX−XXX