The two alternative rate-determining steps in benzylic lithiation reactions of esters and Carbamates

Article abstract of DOI:10.1021/acs.orglett.6b02753

Lithiation reactions of tertiary benzylic esters and carbamates have been studied. Kinetic methodology revealed that a two-step reaction pathway should be considered for these reactions, where either the lithium precomplexation and/or the proton transfer

Full text of DOI:10.1021/acs.orglett.6b02753

Letter
pubs.acs.org/OrgLett
The Two Alternative Rate-Determining Steps in Benzylic Lithiation
Reactions of Esters and Carbamates
Fernando Fernandez-Nieto,† M. Rita Paleo,† Roberto Colunga,† M. Luz Raposo,‡ Luis Garcia-Rio,*,‡
́
and F. Javier Sardina†
†Departamento de Química Organ
Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
‡Departamento de Química Física and Centro Singular de Investigacion
en Química Biolox
́
ica and Centro Singular de Investigacion
́
en Química Biolox
́
ica e Materiais Moleculares (CIQUS),
́
́
ica e Materiais Moleculares (CIQUS),
Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
S
* Supporting Information
ABSTRACT: Lithiation reactions of tertiary benzylic esters and carbamates have been studied. Kinetic methodology revealed
that a two-step reaction pathway should be considered for these reactions, where either the lithium precomplexation and/or the
proton transfer steps can be rate determining. Kinetic isotopic effects were evaluated by comparison of the lithiations of the
corresponding protio/deutero substrates, and the results obtained support the notion that lithium precomplexation is taking
place on the reaction pathway and that it is the rate-determining step in this transformation.
he mechanisms of heteroatom-directed lithiations con-
Ttinue to be the focus of theoretical and experimental
investigations due to the key role that deprotonative lithiations
play in many carbon−carbon and carbon−heteroatom bond-
forming synthetic reactions.1 These processes are commonly
hypothesized to occur via coordination of the lithium atom of
Figure 1. Compounds used in the kinetic study.
the base with a lone pair of a donor heteroatom of the directing
group of the acid, to form a prelithiation complex where the
substituents show enhanced donor ability. The main goal of the
present study was to establish which is the rate-determining
step for the deprotonation of benzyloxy systems substituted
with strong donor groups, the lithium precomplexation or the
proton transfer reaction, since neither reactivity scales based on
product yield after quenching nor competitive experiments
provide accurate information concerning the nature of the
intermediates and/or the detailed reaction mechanism.
basic center and the acidic hydrogen are located close to each
other. A large number of studies support the existence of this
type of lithium coordination to heteroatoms in ground states,2
their involvement in determining the degree of aggregation of
organolithium reagents in donor solvents being, perhaps, the
more paradigmatic example.3−5 Nevertheless, only a few studies
confirm that the prelithiation complex is on the reaction
pathway.6
Evolution of absorbance vs time for the reaction of ester 2 (5
× 10−5 M) with a large excess of n-BuLi (0.114 M) in THF/
hexane (3:1) at −80 °C gives an excellent fit to a
monoexponential increase (see Figure S1 in Supporting
Information). Figure 2 shows the dependence of the pseudo-
first-order rate constant, kobs, on [n-BuLi] in three different
solvent mixtures. Two main observations are derived from
these plots: (i) there is a nonlinear influence of [n-BuLi] on
Trapping experiments have been reported to not distinguish
between one- (direct deprotonation without prior RLi
coordination) and two-step (formation of a prelithiation
complex followed by deprotonation) processes.7 This limitation
makes advisible the use of kinetic studies to gain accurate
information about deprotonation pathways, especially when
two-step processes are suspected to be taking place.8
Our studies on the lithiation of benzyl methyl ether (1)9
(Figure 1) with n-BuLi in THF/hexane at −80 °C showed that
a precoordination step between base and acid occurs prior to
the rate-determining proton transfer reaction. We now describe
the results of a study on the lithiation of benzyl ester 2 and
carbamate 3, substrates analogous to ether 1 in which the O-
k
obs, and (ii) kobs decreases when the amount of THF in the
reaction mixture increases.
Received: September 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02753
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. (A) Dependence of the pseudo-first-order rate constant, kobs
,
on [n-BuLi] for lithiation of 2 at −80 °C in different THF/hexane
■
●
▲
mixtures: ( ) 15:85; ( ) 50:50; ( ) 75:25. (B) Pseudo-first-order
rate constants vs [n-BuLi]dimer
.
Figure 3. Time evolution of the absorbance (λ = 330 nm) for reaction
of 2-D (5.0 × 10−5 M) with n-BuLi (0.114 M), in THF/hexane
(75:25) at −80 °C. Curve shows the fitting of experimental data to a
double exponential rate equation. Note that experimental conditions
are the same as those shown in Figure S1.
Because reactivity is strongly dependent on n-BuLi
aggregation,10 the lithiation of benzyl ether 1 follows a pathway
in which n-BuLi tetramer−dimer deaggregation occurs in a fast
equilibrium step, followed by dimer complexation to the
oxygen atom of the ether, and a subsequent proton transfer as
the rate-determining step.9 When the same mechanistic scheme
is applied to the lithiation of ester 2, a rate equation is obtained,
kobs = K1k2 [dimer] (K1 and k2 being the precomplexation
equilibrium and proton transfer rate constants respectively),
which predicts a linear dependence between the observed rate
constant and [dimer] (see Figure 2, right).
behavior can, instead, be justified by the accumulation of an
intermediate along the reaction pathway. We propose that this
intermediate is a complex of n-BuLi and 2-D, where 2-D has
replaced one of the THF molecules in the coordination sphere
of the n-BuLi dimer.14
Figure 4 shows the [n-BuLi] dependence of the observed rate
fast
obs
constants of the fast, k (intermediate formation), and slow,
Slopes in the Figure 2 right-side plot, i.e. (5.37 0.1) × 10−1
M−1 s−1, (1.19 0.1) × 10−1 M−1 s−1, and (6.94 0.2) × 10−2
M−1 s−1 for solutions with 15%, 50%, and 75% THF in hexane,
respectively, indicate that the lithiation rate increases on
decreasing solvent polarity. A tentative explanation considering
proton transfer being the rate-determining step, kobs
=
K1k2[dimer], implies that the slope of kobs vs [dimer] does
not correspond to a single bimolecular rate constant, but
instead to the product of the proton transfer rate constant
multiplied by the equilibrium constant for n-BuLi dimer
precomplexation with ester 2. Because n-BuLi self-aggregation
increases on decreasing THF percentage,11 we expect a similar
effect on the equilibrium constant for n-BuLi precomplexation
with compound 2.
The observed difference, about 30 times, for lithiation of
ester 2 and ether 1 (see Figure S2 in SI) in THF/hexane
(50:50) cannot account for the larger ability of 2 to coordinate
n-BuLi and its higher acidity (at least 3 pKa units12) with
respect to ether 1.13 These results suggest a different rate-
determining step operating in both deprotonation processes.
Deuterated ester 2-D was synthesized and reacted with n-
BuLi in a mixture of THF/hexane (75:25). Unexpectedly, we
did not observe single exponential behavior, as shown in Figure
S1 for the lithiation of 2-H (see Supporting Information), but
double exponential behavior was observed instead (Figure 3).
This double exponential behavior cannot be attributed to
instability of the α-lithiated ester, as only starting material 2-D
was observed after quenching the reaction mixture with
Figure 4. Influence of [n-BuLi] for lithiation of 2 and 2-D in THF/
hexane (75:25) at −80 °C. ( ) Lithiation of 2 where a single
exponential kinetics has been observed. For 2-D, a double exponential
●
behavior has been observed with experimental values corresponding to
fast
■
▲
( ) fast exponential behavior, kobs, and ( ) slow exponential
slow
behavior, k
.
obs
slow
obs
k
(intermediate decomposition), processes calculated by
fitting the experimental absorbance vs time data with a double
exponential equation (e.g., Figure 3) for the lithiation of 2-D.
The observed rate constants for the lithiation of compound 2
are plotted for comparison purposes. The results shown in
Figure 4 agree with the reaction mechanism proposed in
Scheme 1. From Figure 4 it can be seen that the ratio between
1
deuterated methanol and checking the crude product by H
NMR spectroscopy (see Supporting Information).
Experimental behavior shown in Figure 3 cannot be
explained also as a consequence of 2-D being contaminated
with a small fraction of nondeuterated compound 2, because
the variation in absorbance detected for the first exponential is
almost half of the overall variation, which would mean that 2-D
would have to be contaminated with approximately 50% of the
protio-ester 2. This level of contamination is not supported by
the NMR spectrum of 2-D. The observed double exponential
fast
slow
both processes, k and k , is larger than 10, so they can be
obs
obs
treated independently.15 Considering that the tetramer−dimer
disaggregation is much faster than the lithiation step,16 we can
define the following rate equations for the intermediate
formation and its decomposition.
fast
obs
k
= k1[dimer] + k−1
(1)
B
DOI: 10.1021/acs.orglett.6b02753
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Organic Letters
Letter
[n-BuLi] (Figure S36 in SI). It should be noted that both k1
and the product K1k2 are 102 times larger for 3 than 2-D, due to
its higher donor ability and the isotope effect.
Scheme 1. Proposed Reaction Pathway
Lithiation of deuterated-carbamate 3-D has also been
kinetically studied with double exponential behavior being
observed. Due to the isotopic substitution, the lithiation
reaction of 3-D proceeded slower than in the case of carbamate
3 and longer time scales were required. Under the experimental
conditions the existence of two exponential processes was
confirmed, but we have been unable to obtain accurate data for
the first one corresponding to n-BuLi precomplexation. Figure
S4 also shows the rate constants observed for the slow process
in the lithiation of deuterated carbamate 3-D, allowing us to
obtain the product K1k2 = (1.9
0.1) × 10−2 M−1 s−1.
Assuming that precomplexation binding constants are mainly
unaffected by isotopic substitution, we derived a kinetic isotope
effect of kH/kD = 35, similar to that previously estimated for the
2/2-D lithiation.
K1k2[dimer]
1 + K1[dimer]
slow
k
=
obs
(2)
In summary, our results show clear evidence that lithium
precomplexation is taking place along the reaction pathway,
discarding the occurrence of one-step mechanisms with a single
transition state where complexation and proton transfer occur
simultaneously. We have also uncovered evidence that the rate-
determining step may be either the formation of the
intermediate complex or the proton transfer reaction. Most
importantly, it has been shown that kinetic methodology is
more informative than competitive or quenching experiments
to provide a reactivity scale because the existence of different
rate-determining steps along the reaction pathway are invisible
to traditional methodologies.
In proposing eq 2 we have assumed that the second step is
irreversible, because of the large pKa difference between butane
and lithiated 2. Analysis of the fast process yields k1 = (5.8
0.7) × 10−2 M−1 s−1 for the lithiation of 2-D (under the
experimental conditions it is not possible to gain an accurate
determination of the intercept, k−1). This value agrees well with
the slope previously obtained for lithiation of 2 (see Figure 2),
Slope = (6.94 0.2) × 10−2 M−1 s−1. As the precomplexation
of ester 2 with n-BuLi will be mainly unaffected by isotope
substitution, we propose that the rate-determining step in this
reaction is the formation of the precomplexed species rather
than the proton transfer process. Consequently slopes in Figure
2 can be assigned to the rate constant for the precomplexation
step, k1.
On the assumption 1 ≫ K1[dimer], a linear dependence
between the rate constant and [dimer] is expected. From
Figure 4 a value of K1k2 = (2.2 0.3) × 10−3 M−1 s−1 can be
obtained. Comparison of the rate constants for the lithiation of
2 and 2-D suggests an isotope effect of kH/kD ≥ 31. This
estimation is based on the fact that rate constants for the
proton transfer step with compound 2 should be faster than n-
BuLi precomplexation in such a way that only single
exponential behavior has been observed. This observed isotope
effect is close to those previously determined for other
lithiation reactions.17
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02753.
Full experimental details, kinetic experiments, character-
ization data, and NMR (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: luis.garcia@usc.es.
Further evidence of n-BuLi complexation as part of the
reaction pathway was obtained from the study of the lithiation
of carbamate 3, a substrate of higher donating ability than ester
2. Double exponential behavior was observed in the lithiation
reaction of carbamate 3 in THF/hexane (3:1) mixtures at −80
°C (see Figure S31 in SI). As in the previous case,
decomposition of the carbanion can be ruled out by NMR
analysis of the products after quenching (see SI). Comparison
of lithiation reactions of ester 2 and carbamate 3 shows that, on
increasing the electron donating ability of the substrate, a
change from monoexponential to double exponential behavior
is observed. The higher electron-donating ability of the
carbamate group strengthens the lithium complexation and,
therefore, increases the overall rate of the process. This is
consistent with an increase in reactivity over 500 times going
from 2 to 3, regardless of the pKa values being very close.12
Using a double exponential equation we were able to obtain the
rate constants corresponding to the fast (precomplexation, k1 =
(4.7 0.1) M−1 s−1) and slow (proton transfer reaction, K1k2 =
(0.67 0.09) M−1 s−1) processes for carbamate 3 at different
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was funded by the MINECO of Spain (CTQ2014-
55208-P) and the Xunta de Galicia (GRC 2014/029).
■
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